Letters
Figure 2. Intraoperative View of the Operative Field
Additional Contributions: We thank the patient for granting permission to publish this information. 1. Pollock J, Hassan A, Smith M. Periocular necrotising soft tissue infections: three cases of mistaken identity. Eye (Lond). 2015;29(1):151. 2. Lazzeri D, Agostini T. Eyelid and periorbital necrotizing fasciitis as an early devastating complication of blepharoplasty. Plast Reconstr Surg. 2010;126(3): 1112-1113. 3. Gelaw Y, Abateneh A. Periocular necrotizing fasciitis following retrobulbar injection. Clin Ophthalmol. 2014;8:289-292. 4. Marchino T, Vela JI, Bassaganyas F, Sánchez S, Buil JA. Acute-onset endophthalmitis caused by Alloiococcus otitidis following a dexamethasone intravitreal implant. Case Rep Ophthalmol. 2013;4(1):37-41. 5. Arıkan Yorgun M, Mutlu M, Toklu Y, Cakmak HB, Cağıl N. Suspected bacterial endophthalmitis following sustained-release dexamethasone intravitreal implant: a case report. Korean J Ophthalmol. 2014;28(3):275-277.
Conjunctival necrosis and purulent discharge were observed at the site of the initial intravitreal injection.
common trigger for PNF is penetrative surgical trauma. Although this has occurred with other types of procedures, it may never have been seen with this specific implant. Several factors concurred to create the necessary conditions for infection in this case: a patient older than 50 years with diabetes had streptococcal pharyngitis and was receiving mycophenolate mofetil, and the dexamethasone intravitreal implant injection acted as a triggering incident. It is highly improbable that the infection had any other cause, although it is impossible to rule out another source of infection coincidental to the dexamethasone intravitreal implant injection. Prior to the injection, conjunctival disinfection with 5% povidone iodine was performed. The pathogen, S pyogenes, a group A β-hemolytic streptococcus, was probably carried postoperatively by the patient’s hands, a tissue, or saliva from the pharynx to the conjunctival opening. The surprising absence of endophthalmitis could be due to transfer of the organism while the sclera was closed. The loss of vision can be attributed to infectious or mechanical neuropathy. Shocklike syndrome, skin necrosis, skin anesthesia, hyperacute pain onset, and rapid deterioration suggested the possibility of PNF. Early detection of these signs and symptoms is critical as the reported mortality and blindness rates for PNF are 8.5% and 13.8%, respectively.6 This case highlights the need to have detailed patient history and to be aware of proximal infections before routine dexamethasone intravitreal implant injections. Jeremy Danan, MD Antoine Heitz, MD Tristan Bourcier, MD, PhD Author Affiliations: Department of Ophthalmology, Strasbourg University Hospital, Fédération de Médecine Translationnelle de Strasbourg, University of Strasbourg, Strasbourg, France. Corresponding Author: Jeremy Danan, MD, Department of Ophthalmology, Nouvel Hôpital Civil, Strasbourg University Hospital, BP426, 67091 Strasbourg, France ([email protected]). Published Online: November 5, 2015. doi:10.1001/jamaophthalmol.2015.4351. Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. jamaophthalmology.com
6. Amrith S, Hosdurga Pai V, Ling WW. Periorbital necrotizing fasciitis: a review. Acta Ophthalmol. 2013;91(7):596-603.
Retinal Arterial Tortuosity in Moyamoya Disease Moyamoya disease is a cerebrovascular disorder of unknown etiology that is characterized by bilateral progressive stenosis of the distal internal carotid artery and proximal anterior and middle cerebral arteries, which may result in transient ischemic attacks or strokes.1 Although it is not primarily an eye disorder, multiple ocular conditions including morning glory optic disc anomaly, chorioretinal coloboma, anterior ischemic optic neuropathy, ocular ischemic syndrome, and retinal vascular occlusions among others have been associated with the disease. We report a case of moyamoya disease in a young woman with unique retinal arterial vascular changes. Report of Case | A woman in her early 30s with migraine disorder presented with headaches associated with blurred vision. There was no family history of vascular or ophthalmic disease. Snellen visual acuity was 20/20 OU. Ophthalmoscopy revealed marked bilateral retinal arteriolar tortuosity extending from the disc to the periphery (Figure 1). Magnetic resonance angiography of the brain and neck demonstrated bilateral narrowing of the M1 segment of the middle cerebral arteries with collateralization and tortuosity of the branch vessels. Vascular tortuosity of the left anterior inferior cerebellar and left posterior cerebral arteries was noted. No flow was identified within the intracranial right vertebral artery (Figure 2B). Magnetic resonance imaging of the brain demonstrated foci of T2/fluid-attenuated inversion recovery hyperintensity within the centrum semiovale and corona radiata (Figure 2A) consistent with chronic ischemic microangiopathic abnormalities related to proximal intracranial arterial stenosis. Based on these features, a diagnosis of moyamoya disease was made. There was neither stigmata of neurofibromatosis on clinical examination nor any radiographic finding consistent with this diagnosis on review by neuroradiology. Fundus photographs demonstrated diffuse retinal arterial tortuosity with normal retinal veins bilaterally (Figure 1A and B). Ultra-widefield fluorescein angiography revealed normal arterial and venous filling without evidence of peripheral nonperfusion (Figure 1C and D). Spectral-domain optical coherence tomography revealed focal elevations of the retinal surface consistent with the corkscrew configuration of the (Reprinted) JAMA Ophthalmology January 2016 Volume 134, Number 1
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Letters
Figure 1. Multimodal Retinal Imaging A Fundus photograph, right eye
B
C
Fluorescein angiography, right eye
D Fluorescein angiography, left eye
E
SD-OCT, right eye
F
Angioflow OCT Outer retina
Choroid capillary
Superficial
Deep
Outer retina
Choroid capillary
En face OCT
Deep
En face OCT
Superficial
112
SD-OCT, left eye
H Angioflow and en face OCT, left eye
Angioflow OCT
G Angioflow and en face OCT, right eye
Fundus photograph, left eye
A and B, Fundus photographs demonstrate abnormal retinal arteries. C and D, Fluorescein angiography shows normal vascular filling. E and F, Spectral-domain optical coherence tomography (SD-OCT) reveals focal elevations at the
vitreoretinal interface consistent with corkscrew vessels. G and H, Angioflow optical coherence tomography (OCT) and en face OCT (8 × 8 mm) confirm the multilevel twisting of retinal arteries.
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Figure 2. Magnetic Resonance Imaging and Angiography A T2-weighted magnetic resonance imaging
B
Magnetic resonance angiography
A
A, Axial T2-weighted magnetic resonance imaging reveals hyperintensity (arrowheads) consistent with chronic ischemia. A indicates anterior; P, posterior. B, Magnetic resonance angiography demonstrates stenosis of the right internal carotid artery (white arrowhead) and no flow in the right vertebral artery (black arrowhead).
P cm
abnormal retinal arteries (Figure 1E and F), a finding that was also evident on en face optical coherence tomography (Figure 1G and H). On the optical coherence tomographic angiography deep capillary plexus segmentation slab, certain corkscrew vessels appeared more prominent, suggesting localization to this deeper plane (Figure 1G and H). The patient has been followed up for 12 months with regular examinations, without progressive changes in appearance of the retinal vasculature. Discussion | This is the first case report, to our knowledge, of retinal arterial tortuosity associated with moyamoya syndrome. Moyamoya syndrome is a rare idiopathic cerebrovascular disorder that can be associated with neurofibromatosis type 1 (NF1), characterized by progressive bilateral stenosis or occlusion of the distal internal carotid arteries.2 Patients may have transient ischemic attacks, seizures secondary to carotid insufficiency, and intracerebral hemorrhage.2,3 Associated ocular complications include corneal neovascularization, morning glory disc anomaly, and ophthalmic artery ischemic syndrome.4,5 Retinal vascular ischemia may be associated, and there have been reports of central retinal artery occlusion.6 Chorioretinal atrophy resulting from choroidal vascular insufficiency and anterior ischemic optic neuropathy has also been described.4,5,7 Analysis of the vascular abnormalities in our patient revealed multifocal hairpin loops or corkscrew abnormalities diffusely distributed throughout the retinal arterial circulation, distinguishing this presentation from the characteristic arterial tortuosity seen in familial retinal arterial tortuosity syndrome.8 The abnormalities also appeared distinct from those described in IRVAN syndrome (idiopathic retinal vasculitis aneurysms and neuroretinitis) in which the lesions are usually located at bifurcations, clustered around the disc, and associated with other findings including papillitis. jamaophthalmology.com
Corkscrew retinal vessels have been noted in a prior case of NF1, but confined to retinal veins.7 The pathogenesis of NF1 vasculopathy has been linked to abnormal function of neurofibromin, the protein product of NF1 in vascular smooth muscle and endothelial cells, which may lead to abnormal proliferation of vascular smooth muscle.8 Studies have demonstrated that neurofibromin-deficient mice express higher levels of proangiogenic factors, exhibiting greater neovascularization in the retina and cornea in response to hypoxia than wild-type counterparts.8 These findings suggest that ischemia of the carotid vascular complex resulting from the abnormal moyamoya vasculature, and consequent increased proangiogenic drive, may be an underlying mechanism for the retinal vascular tortuosity in moyamoya syndrome. Diana Katsman, MD, PhD Michael A. Klufas, MD David Sarraf, MD SriniVas Sadda, MD Author Affiliations: Retina Division, Stein Eye Institute, University of California, Los Angeles (Katsman, Klufas); Retinal Disorders and Ophthalmic Genetics Division, Stein Eye Institute, University of California, Los Angeles (Sarraf); Doheny Eye Institute, University of California, Los Angeles (Sadda). Corresponding Author: Michael A. Klufas, MD, Retina Division, Stein Eye Institute, University of California, Los Angeles, 100 Stein Plaza, Los Angeles, CA 90095 ([email protected]). Published Online: November 25, 2015. doi:10.1001/jamaophthalmol.2015.4645. Author Contributions: Drs Katsman and Klufas contributed equally as first authors. Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Sarraf reported receiving grants from Genentech and Regeneron and nonfinancial support from Optovue. Dr Sadda reported receiving grants and personal fees from Optos and Carl Zeiss Meditec. No other disclosures were reported. (Reprinted) JAMA Ophthalmology January 2016 Volume 134, Number 1
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113
Letters
Funding/Support: Dr Klufas is supported for vitreoretinal surgery fellowship training as a John and Theiline McCone Fellow at Stein Eye Institute, University of California, Los Angeles. Role of the Funder/Sponsor: The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. 1. Kronenburg A, Braun KP, van der Zwan A, Klijn CJ. Recent advances in moyamoya disease: pathophysiology and treatment. Curr Neurol Neurosci Rep. 2014;14(1):423. 2. Scott RM, Smith ER. Moyamoya disease and moyamoya syndrome. N Engl J Med. 2009;360(12):1226-1237. 3. Williams M, Adas A, Sharma N, Gibson M. Moyamoya disease presenting to the ophthalmology clinic. Can J Ophthalmol. 2006;41(5):633-634. 4. Taşkintuna I, Oz O, Teke MY, Koçak H, Firat E. Morning glory syndrome: association with moyamoya disease, midline cranial defects, central nervous system anomalies, and persistent hyaloid artery remnant. Retina. 2003;23(3): 400-402. 5. Witmer MT, Levy R, Yohay K, Kiss S. Ophthalmic artery ischemic syndrome associated with neurofibromatosis and moyamoya syndrome. JAMA Ophthalmol. 2013;131(4):538-539. 6. Kumar MA, Ganesh BA. CRAO in moyamoya disease. J Clin Diagn Res. 2013;7 (3):545-547. 7. Wu M, Wallace MR, Muir D. Nf1 haploinsufficiency augments angiogenesis. Oncogene. 2006;25(16):2297-2303. 8. Seo JH, Kim I, Yu HG. A case of carotid aneurysm in familial retinal arterial tortuosity. Korean J Ophthalmol. 2009;23(1):57-58.
COMMENT & RESPONSE
Incidence of Orbital Recurrence After Enucleation or Ophthalmic Artery Chemosurgery for Advanced Intraocular Retinoblastoma To the Editor Our team read with interest the article by Yannuzzi et al 1 about enucleation vs ophthalmic artery chemosurgery (OAC) as primary treatment for advancedstage retinoblastoma. This is an important article reviewing the outcome of patients who received OAC. We wonder whether their conclusions should have greater caution regarding the confidence in them, given the relatively small number of cases evaluated (resulting in relatively high uncertainty regarding the precise outcomes) and the risk of selection bias of cases that were evaluated. To test for selection bias only iris neovascularization and International Classification of Retinoblastoma group were considered, but intraocular pressure was not. Were these the only criteria used to decide on treatment? Were both treatment regimens equally distributed over time, or was there a gradual shift from one to the other? The authors concluded that only OAC remained as an independent predictor of orbital recurrence, although the statistical analysis of this conclusion suggests minimal confidence in OAC as an independent predictor from their Cox regression analysis of orbital recurrence–free survival. Isn’t it difficult to have such confidence in this claim with only 6 events? The authors did not specifically state the time between initial diagnosis and start of treatment, but the differences between the mean age at diagnosis and that at OAC and enucleation were 1.4 and 2.0 months, respectively. Perhaps treatment delay also contributed to the difference between the 2 treatment modalities and might have added to the fact that the group of primary enucleations showed so many recurrences? 114
Eleven patients (17.5%) in the enucleation group had a higher-risk feature (postlaminar optic nerve invasion), but not all received adjuvant intravenous chemotherapy (9.5%). On the other hand, some patients in the OAC group also received intravenous chemotherapy (6.5%) or radiotherapy (1.3%). Heterogeneity regarding systemic treatment between both treatment groups might be an important confounder. Nowadays, many centers perform pre-enucleation magnetic resonance imaging, which in our opinion greatly adds to pretreatment stage prediction of the affected eye(s) and justifies a safe, conservative treatment approach in which no histopathologic analysis will become available.2,3 Was pretreatment magnetic resonance imaging performed in all patients? We also believe that OAC will play an increasingly important role in the future and that with increasing experience OAC will keep showing better results. We believe the results from Yannuzzi and colleagues should be interpreted with care, and we encourage the authors and others to work on studies with larger cohorts, preferably well-designed prospective (multicenter) trials. Marcus C. de Jong, MD, MSc Arjenne Kors, MD Pim de Graaf, MD, PhD Author Affiliations: Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, the Netherlands (de Jong, de Graaf); Department of Pediatric Oncology, VU University Medical Center, Amsterdam, the Netherlands (Kors). Corresponding Author: Marcus C. de Jong, MD, MSc, Department of Radiology and Nuclear Medicine, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam, the Netherlands ([email protected]). Published Online: November 19, 2015. doi:10.1001/jamaophthalmol.2015.4578. Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. Funding/Support: Dr De Jong was supported by a grant from the ODAS Foundation. Role of the Funder/Sponsor: The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. 1. Yannuzzi NA, Francis JH, Marr BP, et al. Enucleation vs ophthalmic artery chemosurgery for advanced intraocular retinoblastoma: a retrospective analysis. JAMA Ophthalmol. 2015;133(9):1062-1066. 2. de Jong MC, de Graaf P, Noij DP, et al; European Retinoblastoma Imaging Collaboration (ERIC). Diagnostic performance of magnetic resonance imaging and computed tomography for advanced retinoblastoma: a systematic review and meta-analysis. Ophthalmology. 2014;121(5):1109-1118. 3. de Jong MC, de Graaf P, Brisse HJ, et al; European Retinoblastoma Imaging Collaboration (ERIC). The potential of 3T high-resolution magnetic resonance imaging for diagnosis, staging, and follow-up of retinoblastoma. Surv Ophthalmol. 2015;60(4):346-355.
In Reply We thank De Jong and colleagues for their interest in our article and for their continued contributions to the field. We too recognize that new observations must always be viewed with caution. While the numbers may seem small (140 eyes), they represent the largest published series, to our knowledge, with follow-up ranging from 6 to 104 months. Our re-
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Figure 2. Intraoperative View of the Operative Field
Additional Contributions: We thank the patient for granting permission to publish this information. 1. Pollock J, Hassan A, Smith M. Periocular necrotising soft tissue infections: three cases of mistaken identity. Eye (Lond). 2015;29(1):151. 2. Lazzeri D, Agostini T. Eyelid and periorbital necrotizing fasciitis as an early devastating complication of blepharoplasty. Plast Reconstr Surg. 2010;126(3): 1112-1113. 3. Gelaw Y, Abateneh A. Periocular necrotizing fasciitis following retrobulbar injection. Clin Ophthalmol. 2014;8:289-292. 4. Marchino T, Vela JI, Bassaganyas F, Sánchez S, Buil JA. Acute-onset endophthalmitis caused by Alloiococcus otitidis following a dexamethasone intravitreal implant. Case Rep Ophthalmol. 2013;4(1):37-41. 5. Arıkan Yorgun M, Mutlu M, Toklu Y, Cakmak HB, Cağıl N. Suspected bacterial endophthalmitis following sustained-release dexamethasone intravitreal implant: a case report. Korean J Ophthalmol. 2014;28(3):275-277.
Conjunctival necrosis and purulent discharge were observed at the site of the initial intravitreal injection.
common trigger for PNF is penetrative surgical trauma. Although this has occurred with other types of procedures, it may never have been seen with this specific implant. Several factors concurred to create the necessary conditions for infection in this case: a patient older than 50 years with diabetes had streptococcal pharyngitis and was receiving mycophenolate mofetil, and the dexamethasone intravitreal implant injection acted as a triggering incident. It is highly improbable that the infection had any other cause, although it is impossible to rule out another source of infection coincidental to the dexamethasone intravitreal implant injection. Prior to the injection, conjunctival disinfection with 5% povidone iodine was performed. The pathogen, S pyogenes, a group A β-hemolytic streptococcus, was probably carried postoperatively by the patient’s hands, a tissue, or saliva from the pharynx to the conjunctival opening. The surprising absence of endophthalmitis could be due to transfer of the organism while the sclera was closed. The loss of vision can be attributed to infectious or mechanical neuropathy. Shocklike syndrome, skin necrosis, skin anesthesia, hyperacute pain onset, and rapid deterioration suggested the possibility of PNF. Early detection of these signs and symptoms is critical as the reported mortality and blindness rates for PNF are 8.5% and 13.8%, respectively.6 This case highlights the need to have detailed patient history and to be aware of proximal infections before routine dexamethasone intravitreal implant injections. Jeremy Danan, MD Antoine Heitz, MD Tristan Bourcier, MD, PhD Author Affiliations: Department of Ophthalmology, Strasbourg University Hospital, Fédération de Médecine Translationnelle de Strasbourg, University of Strasbourg, Strasbourg, France. Corresponding Author: Jeremy Danan, MD, Department of Ophthalmology, Nouvel Hôpital Civil, Strasbourg University Hospital, BP426, 67091 Strasbourg, France ([email protected]). Published Online: November 5, 2015. doi:10.1001/jamaophthalmol.2015.4351. Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. jamaophthalmology.com
6. Amrith S, Hosdurga Pai V, Ling WW. Periorbital necrotizing fasciitis: a review. Acta Ophthalmol. 2013;91(7):596-603.
Retinal Arterial Tortuosity in Moyamoya Disease Moyamoya disease is a cerebrovascular disorder of unknown etiology that is characterized by bilateral progressive stenosis of the distal internal carotid artery and proximal anterior and middle cerebral arteries, which may result in transient ischemic attacks or strokes.1 Although it is not primarily an eye disorder, multiple ocular conditions including morning glory optic disc anomaly, chorioretinal coloboma, anterior ischemic optic neuropathy, ocular ischemic syndrome, and retinal vascular occlusions among others have been associated with the disease. We report a case of moyamoya disease in a young woman with unique retinal arterial vascular changes. Report of Case | A woman in her early 30s with migraine disorder presented with headaches associated with blurred vision. There was no family history of vascular or ophthalmic disease. Snellen visual acuity was 20/20 OU. Ophthalmoscopy revealed marked bilateral retinal arteriolar tortuosity extending from the disc to the periphery (Figure 1). Magnetic resonance angiography of the brain and neck demonstrated bilateral narrowing of the M1 segment of the middle cerebral arteries with collateralization and tortuosity of the branch vessels. Vascular tortuosity of the left anterior inferior cerebellar and left posterior cerebral arteries was noted. No flow was identified within the intracranial right vertebral artery (Figure 2B). Magnetic resonance imaging of the brain demonstrated foci of T2/fluid-attenuated inversion recovery hyperintensity within the centrum semiovale and corona radiata (Figure 2A) consistent with chronic ischemic microangiopathic abnormalities related to proximal intracranial arterial stenosis. Based on these features, a diagnosis of moyamoya disease was made. There was neither stigmata of neurofibromatosis on clinical examination nor any radiographic finding consistent with this diagnosis on review by neuroradiology. Fundus photographs demonstrated diffuse retinal arterial tortuosity with normal retinal veins bilaterally (Figure 1A and B). Ultra-widefield fluorescein angiography revealed normal arterial and venous filling without evidence of peripheral nonperfusion (Figure 1C and D). Spectral-domain optical coherence tomography revealed focal elevations of the retinal surface consistent with the corkscrew configuration of the (Reprinted) JAMA Ophthalmology January 2016 Volume 134, Number 1
Copyright 2016 American Medical Association. All rights reserved.
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111
Letters
Figure 1. Multimodal Retinal Imaging A Fundus photograph, right eye
B
C
Fluorescein angiography, right eye
D Fluorescein angiography, left eye
E
SD-OCT, right eye
F
Angioflow OCT Outer retina
Choroid capillary
Superficial
Deep
Outer retina
Choroid capillary
En face OCT
Deep
En face OCT
Superficial
112
SD-OCT, left eye
H Angioflow and en face OCT, left eye
Angioflow OCT
G Angioflow and en face OCT, right eye
Fundus photograph, left eye
A and B, Fundus photographs demonstrate abnormal retinal arteries. C and D, Fluorescein angiography shows normal vascular filling. E and F, Spectral-domain optical coherence tomography (SD-OCT) reveals focal elevations at the
vitreoretinal interface consistent with corkscrew vessels. G and H, Angioflow optical coherence tomography (OCT) and en face OCT (8 × 8 mm) confirm the multilevel twisting of retinal arteries.
JAMA Ophthalmology January 2016 Volume 134, Number 1 (Reprinted)
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Letters
Figure 2. Magnetic Resonance Imaging and Angiography A T2-weighted magnetic resonance imaging
B
Magnetic resonance angiography
A
A, Axial T2-weighted magnetic resonance imaging reveals hyperintensity (arrowheads) consistent with chronic ischemia. A indicates anterior; P, posterior. B, Magnetic resonance angiography demonstrates stenosis of the right internal carotid artery (white arrowhead) and no flow in the right vertebral artery (black arrowhead).
P cm
abnormal retinal arteries (Figure 1E and F), a finding that was also evident on en face optical coherence tomography (Figure 1G and H). On the optical coherence tomographic angiography deep capillary plexus segmentation slab, certain corkscrew vessels appeared more prominent, suggesting localization to this deeper plane (Figure 1G and H). The patient has been followed up for 12 months with regular examinations, without progressive changes in appearance of the retinal vasculature. Discussion | This is the first case report, to our knowledge, of retinal arterial tortuosity associated with moyamoya syndrome. Moyamoya syndrome is a rare idiopathic cerebrovascular disorder that can be associated with neurofibromatosis type 1 (NF1), characterized by progressive bilateral stenosis or occlusion of the distal internal carotid arteries.2 Patients may have transient ischemic attacks, seizures secondary to carotid insufficiency, and intracerebral hemorrhage.2,3 Associated ocular complications include corneal neovascularization, morning glory disc anomaly, and ophthalmic artery ischemic syndrome.4,5 Retinal vascular ischemia may be associated, and there have been reports of central retinal artery occlusion.6 Chorioretinal atrophy resulting from choroidal vascular insufficiency and anterior ischemic optic neuropathy has also been described.4,5,7 Analysis of the vascular abnormalities in our patient revealed multifocal hairpin loops or corkscrew abnormalities diffusely distributed throughout the retinal arterial circulation, distinguishing this presentation from the characteristic arterial tortuosity seen in familial retinal arterial tortuosity syndrome.8 The abnormalities also appeared distinct from those described in IRVAN syndrome (idiopathic retinal vasculitis aneurysms and neuroretinitis) in which the lesions are usually located at bifurcations, clustered around the disc, and associated with other findings including papillitis. jamaophthalmology.com
Corkscrew retinal vessels have been noted in a prior case of NF1, but confined to retinal veins.7 The pathogenesis of NF1 vasculopathy has been linked to abnormal function of neurofibromin, the protein product of NF1 in vascular smooth muscle and endothelial cells, which may lead to abnormal proliferation of vascular smooth muscle.8 Studies have demonstrated that neurofibromin-deficient mice express higher levels of proangiogenic factors, exhibiting greater neovascularization in the retina and cornea in response to hypoxia than wild-type counterparts.8 These findings suggest that ischemia of the carotid vascular complex resulting from the abnormal moyamoya vasculature, and consequent increased proangiogenic drive, may be an underlying mechanism for the retinal vascular tortuosity in moyamoya syndrome. Diana Katsman, MD, PhD Michael A. Klufas, MD David Sarraf, MD SriniVas Sadda, MD Author Affiliations: Retina Division, Stein Eye Institute, University of California, Los Angeles (Katsman, Klufas); Retinal Disorders and Ophthalmic Genetics Division, Stein Eye Institute, University of California, Los Angeles (Sarraf); Doheny Eye Institute, University of California, Los Angeles (Sadda). Corresponding Author: Michael A. Klufas, MD, Retina Division, Stein Eye Institute, University of California, Los Angeles, 100 Stein Plaza, Los Angeles, CA 90095 ([email protected]). Published Online: November 25, 2015. doi:10.1001/jamaophthalmol.2015.4645. Author Contributions: Drs Katsman and Klufas contributed equally as first authors. Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Sarraf reported receiving grants from Genentech and Regeneron and nonfinancial support from Optovue. Dr Sadda reported receiving grants and personal fees from Optos and Carl Zeiss Meditec. No other disclosures were reported. (Reprinted) JAMA Ophthalmology January 2016 Volume 134, Number 1
Copyright 2016 American Medical Association. All rights reserved.
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113
Letters
Funding/Support: Dr Klufas is supported for vitreoretinal surgery fellowship training as a John and Theiline McCone Fellow at Stein Eye Institute, University of California, Los Angeles. Role of the Funder/Sponsor: The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. 1. Kronenburg A, Braun KP, van der Zwan A, Klijn CJ. Recent advances in moyamoya disease: pathophysiology and treatment. Curr Neurol Neurosci Rep. 2014;14(1):423. 2. Scott RM, Smith ER. Moyamoya disease and moyamoya syndrome. N Engl J Med. 2009;360(12):1226-1237. 3. Williams M, Adas A, Sharma N, Gibson M. Moyamoya disease presenting to the ophthalmology clinic. Can J Ophthalmol. 2006;41(5):633-634. 4. Taşkintuna I, Oz O, Teke MY, Koçak H, Firat E. Morning glory syndrome: association with moyamoya disease, midline cranial defects, central nervous system anomalies, and persistent hyaloid artery remnant. Retina. 2003;23(3): 400-402. 5. Witmer MT, Levy R, Yohay K, Kiss S. Ophthalmic artery ischemic syndrome associated with neurofibromatosis and moyamoya syndrome. JAMA Ophthalmol. 2013;131(4):538-539. 6. Kumar MA, Ganesh BA. CRAO in moyamoya disease. J Clin Diagn Res. 2013;7 (3):545-547. 7. Wu M, Wallace MR, Muir D. Nf1 haploinsufficiency augments angiogenesis. Oncogene. 2006;25(16):2297-2303. 8. Seo JH, Kim I, Yu HG. A case of carotid aneurysm in familial retinal arterial tortuosity. Korean J Ophthalmol. 2009;23(1):57-58.
COMMENT & RESPONSE
Incidence of Orbital Recurrence After Enucleation or Ophthalmic Artery Chemosurgery for Advanced Intraocular Retinoblastoma To the Editor Our team read with interest the article by Yannuzzi et al 1 about enucleation vs ophthalmic artery chemosurgery (OAC) as primary treatment for advancedstage retinoblastoma. This is an important article reviewing the outcome of patients who received OAC. We wonder whether their conclusions should have greater caution regarding the confidence in them, given the relatively small number of cases evaluated (resulting in relatively high uncertainty regarding the precise outcomes) and the risk of selection bias of cases that were evaluated. To test for selection bias only iris neovascularization and International Classification of Retinoblastoma group were considered, but intraocular pressure was not. Were these the only criteria used to decide on treatment? Were both treatment regimens equally distributed over time, or was there a gradual shift from one to the other? The authors concluded that only OAC remained as an independent predictor of orbital recurrence, although the statistical analysis of this conclusion suggests minimal confidence in OAC as an independent predictor from their Cox regression analysis of orbital recurrence–free survival. Isn’t it difficult to have such confidence in this claim with only 6 events? The authors did not specifically state the time between initial diagnosis and start of treatment, but the differences between the mean age at diagnosis and that at OAC and enucleation were 1.4 and 2.0 months, respectively. Perhaps treatment delay also contributed to the difference between the 2 treatment modalities and might have added to the fact that the group of primary enucleations showed so many recurrences? 114
Eleven patients (17.5%) in the enucleation group had a higher-risk feature (postlaminar optic nerve invasion), but not all received adjuvant intravenous chemotherapy (9.5%). On the other hand, some patients in the OAC group also received intravenous chemotherapy (6.5%) or radiotherapy (1.3%). Heterogeneity regarding systemic treatment between both treatment groups might be an important confounder. Nowadays, many centers perform pre-enucleation magnetic resonance imaging, which in our opinion greatly adds to pretreatment stage prediction of the affected eye(s) and justifies a safe, conservative treatment approach in which no histopathologic analysis will become available.2,3 Was pretreatment magnetic resonance imaging performed in all patients? We also believe that OAC will play an increasingly important role in the future and that with increasing experience OAC will keep showing better results. We believe the results from Yannuzzi and colleagues should be interpreted with care, and we encourage the authors and others to work on studies with larger cohorts, preferably well-designed prospective (multicenter) trials. Marcus C. de Jong, MD, MSc Arjenne Kors, MD Pim de Graaf, MD, PhD Author Affiliations: Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, the Netherlands (de Jong, de Graaf); Department of Pediatric Oncology, VU University Medical Center, Amsterdam, the Netherlands (Kors). Corresponding Author: Marcus C. de Jong, MD, MSc, Department of Radiology and Nuclear Medicine, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam, the Netherlands ([email protected]). Published Online: November 19, 2015. doi:10.1001/jamaophthalmol.2015.4578. Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. Funding/Support: Dr De Jong was supported by a grant from the ODAS Foundation. Role of the Funder/Sponsor: The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. 1. Yannuzzi NA, Francis JH, Marr BP, et al. Enucleation vs ophthalmic artery chemosurgery for advanced intraocular retinoblastoma: a retrospective analysis. JAMA Ophthalmol. 2015;133(9):1062-1066. 2. de Jong MC, de Graaf P, Noij DP, et al; European Retinoblastoma Imaging Collaboration (ERIC). Diagnostic performance of magnetic resonance imaging and computed tomography for advanced retinoblastoma: a systematic review and meta-analysis. Ophthalmology. 2014;121(5):1109-1118. 3. de Jong MC, de Graaf P, Brisse HJ, et al; European Retinoblastoma Imaging Collaboration (ERIC). The potential of 3T high-resolution magnetic resonance imaging for diagnosis, staging, and follow-up of retinoblastoma. Surv Ophthalmol. 2015;60(4):346-355.
In Reply We thank De Jong and colleagues for their interest in our article and for their continued contributions to the field. We too recognize that new observations must always be viewed with caution. While the numbers may seem small (140 eyes), they represent the largest published series, to our knowledge, with follow-up ranging from 6 to 104 months. Our re-
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