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Retinal Area and Optic Disc Rim Area in Amblyopic, Fellow, and Normal Hyperopic Eyes: A Hypothesis for Decreased Acuity in Amblyopia
Retinal Area and Optic Disc Rim Area in Amblyopic, Fellow, and Normal Hyperopic Eyes: A Hypothesis for Decreased Acuity in Amblyopia Philip Lempert, MD Purpose: Defects in visual functions in amblyopic eyes may have a neuroretinal explanation. The retinal area to optic disc rim area ratios of hyperopic normal, amblyopic, and fellow eyes were evaluated. Design: Case-controlled study. Participants: A total of 293 patients with amblyopia and bilateral hyperopia and 77 non-amblyopic bilaterally hyperopic patients without strabismus. Methods: Disc areas were measured using magnification correction formulas developed by Bengtsson and Krakau. Axial lengths were determined by ultrasound biometry or laser interferometry with a Zeiss AOL Master (Carl Zeiss Co., Oberkochen, Germany). The visual area of the retina was calculated using axial length measurements. Main Outcome Measures: Optic disc rim areas, corrected for magnification, retinal areas, and a derived ratio, retinal area/disc rim area (RetA/DRimA). Results: The RetA/DRimA for the amblyopic eyes was significantly greater than that of the fellow and normal eyes, indicating that amblyopic eyes have larger retinal receptor areas than fellow or normal eyes. The RetA/ DRimA of the fellow eyes was smaller than for the amblyopic but larger than that of the normal eyes. These differences were due to smaller optic disc rim areas in the amblyopic and fellow eyes. Conclusions: Amblyopic and their fellow eyes, when compared with normal eyes, have reduced innervations of comparable retinal areas. These differences can be attributed to a paucity of nerve fibers, as indicated by the smaller neuroretinal rim areas. Financial Disclosure(s): The authors have no proprietary or commercial interest in any materials discussed in this article. Ophthalmology 2008;115:2259 –2261 © 2008 by the American Academy of Ophthalmology.
Vision impairments in amblyopia are characterized by spatial deficits that, since the animal research by Wiesel and Hubel,1 have been attributed to anatomic anomalies or defective processing in the visual cortex. Nonetheless, caveats such as one raised by Moseley,2 “. . . it should be borne in mind that much of the animal literature relates to amblyopia arising from stimulus deprivation a condition whose pathophysiology may differ substantially from that of the target conditions,” indicate that questions persist as to the contribution of neuroretinal causes for the impaired vision.3–5 In addition, Horton and Stryker6 and Horton and Hocking7 used cytochrome oxidase histochemistry to examine the ocular dominance columns in 2 patients with amblyopia: 1 with anisometropia and 1 with strabismus, respectively. They found no anatomic differences between the layers of the lateral geniculate bodies and concluded that naturally occurring amblyopia in humans has a different basis than amblyopia produced in animals by early severe form deprivation. Quigley et al8 determined that the number of optic nerve fibers is directly correlated to disc area. Aberrations in the size of the optic discs in amblyopic eyes have been reported.9,10 © 2008 by the American Academy of Ophthalmology Published by Elsevier Inc.
Optic nerve hypoplasia is recognized to be “an important cause of childhood visual disability”11 and perhaps the most common optic disc anomaly encountered in clinical practice.12 Patients with unrecognized optic nerve hypoplasia may be unnecessarily treated for amblyopia.13 Magnification-corrected imaging is necessary for recognizing optic nerve hypoplasia because differences in axial length and refractive error, as occur in anisometropia, can alter the apparent size of the optic disc. “It is important to understand these differences so that inaccurate conclusions are not drawn and inappropriate therapy will not be instituted . . . .”14 The purpose of this retrospective study was to measure the retinal receptor areas of amblyopic, fellow, and normal eyes. Quantitative data obtained from routine examinations of both eyes of hyperopic patients with amblyopia and right eyes of non-amblyopic hyperopic patients were compared.
Materials and Methods All of the amblyopic and normal patients in this report were seen in the author’s private practice between October 1994 and NovemISSN 0161-6420/08/$–see front matter doi:10.1016/j.ophtha.2008.07.016
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Ophthalmology Volume 115, Number 12, December 2008 Table 1. Ocular Measurements in the 3 Groups of Eyes Normal Eye
Fellow Eye
Amblyopic
Spherical equivalent, 2.57 ⫾ 2.02 2.47 ⫾ 1.97 3.89 ⫾ 1.94 diopters Range of refractive 0.25 to 8.00 0.25 to 13.75 0.375 to 11.00 errors, diopters Axial length mm 22.25 ⫾ 1.15 22.28 ⫾ 1.05 21.73 ⫾ 1.04 781 ⫾ 81 781 ⫾ 73 743 ⫾ 71 Retinal area mm2 Optic disc area mm2 2.32 ⫾ 0.85 2.05 ⫾ 0.66 1.73 ⫾ 0.6 Optic disc rim area mm2 2.1 ⫾ 0.68 1.9 ⫾ 0.62 1.61 ⫾ 0.54 Retinal area/optic disc 406 ⫾ 127 452 ⫾ 150 508 ⫾ 160 rim area No. of subjects 77 293 293 The values represent the means and standard deviations for the various groups. The values in “retinal area/optic disc rim area” represent the mean square millimeters of retina served per square millimeter of optic nerve.
ber 2007. They were invited to have retinal photography and axial length measurements performed. There were no fees for any of these additional tests, and patients were not paid for their participation. The inclusion criteria for the amblyopic subjects were best corrected Snellen visual acuity of 20/40 or less, 2 or more lines difference between the amblyopic and fellow eye, at least ⫹0.25 diopters of hyperopia in each eye, and absence of gross ocular defects. Patients with glaucoma or a history of optic nerve disorders were excluded. Axial length measurements were performed with a Sonomed 4000 ultrasound biometer or a Zeiss IOL Master laser interferometer (Carl Zeiss Co., Oberkochen, Germany) on both eyes of all subjects. Photographs were taken with a Topcon fundus camera (Topcon Medical Systems, Inc, Paramus, NJ). Disc and cup measurements were carried out on 35-mm slides or digitized images. Magnification factor of the eye/camera combination and the absolute size of the optic nerve calculations were performed by using formulas developed by Bengtsson and Krakau.15,16 These formulas use axial length, as the most important factor, and refractive error. The cup area was subtracted from the disc area to obtain the neuroretinal rim area. Calculations of magnification factors and disc rim size, and analysis of the data were conducted within Lotus Approach versions 3.0 to 9.617 and Lotus 1-2-3 (Lotus Development Corporation, Cambridge, MA). Axial length was used to calculate the area of a sphere, and this was divided in half to estimate the functional retinal area. This value was divided by the neuroretinal rim area to acquire a value for the retinal area to optic disc rim area ratio (RetA/DRimA).
Results The amblyopic group included the eyes of 293 patients, of whom 127 had amblyopic right eyes and 166 had amblyopic left eyes. There were 82 patients with anisometropia exceeding 1.5 diopters, 88 with strabismus and 47 with both anisometropia and strabismus. The ocular measurements in the 3 groups of eyes are summarized in Table 1. The retinal areas of the amblyopic and fellow eyes, listed in Table 1, differed substantially (paired t test, 9.78 ⫻ 10⫺11). There was a significant difference between the RetA/DRimA of the amblyopic and fellow eyes (paired t test 1.27 ⫻ 10⫺5). The RetA/DRimA of the amblyopic and normal eyes was also significantly different (unpaired t test 5.0 ⫻ 10⫺7), whereas the differ-
2260
ence between the fellow and normal eyes was smaller (unpaired t test 1.67 ⫻ 10⫺2) but still significant. The RetA/DRimA was greatest for the amblyopic eyes despite their retinal area being smaller than either the fellow or normal eyes. This reflects the reduced size of the optic disc and neuroretinal rim areas in the amblyopic eyes.
Discussion Visual acuity is dependent on the neural connectivity of retinal cells. Summation of signals from relatively larger areas implies that spatial discrimination, and subsequently visual acuity and other functions,8 would be reduced. Optic nerve hypoplasia is a nonprogressive congenital anomaly caused by prenatal insults.18 These could affect the number of axons initially formed, whereas factors later in pregnancy could accelerate apoptosis resulting in a diminution of optic nerve axons.19 The central observation of this study is that amblyopic and their fellow eyes have reduced optic disc rim areas, which leads directly to expanded retinal receptor areas. This reduction in the retinal resolution of both eyes is consistent with reports of visual field20 and other deficits in the amblyopic and fellow non-amblyopic eyes.21 Leguire et al22 warned that “In future studies of amblyopia, whether in children or in adults, caution is advised in assuming that the non-amblyopic eye is normal because acuity is normal.” The demonstration of decreased optic disc rim areas and increased neuroretinal receptor areas in amblyopic and fellow eyes, compared with a normal population, suggests that there is a peripheral cause for vision defects that are usually attributed to amblyopia. This finding should be a stimulus for prospective quantitative studies of ocular anatomy in presumed amblyopia.
References 1. Wiesel TN, Hubel DH. Single-cell responses in striate cortex of kittens deprived of vision in one eye. J Neurophysiol 1963;26:1003–17. 2. Moseley MJ. Preschool vision screening: a recent report calls for a halt. Br J Ophthalmol 1998;82:722–3. 3. Simons K. Stereoscopic neurotropy and the origins of amblyopia and strabismus. In: Simons K, ed. Early Visual Development: Normal and Abnormal. New York: Oxford University Press; 1993:409-53. 4. Hess RF, Baker CL Jr, Verhoeve JN, et al. The pattern evoked electroretinogram: its variability in normals and its relationship to amblyopia. Invest Ophthalmol Vis Sci 1985;26: 1610 –23. 5. Hess RF. Amblyopia: site unseen. Clin Exp Optom 2001;84: 321–36. 6. Horton JC, Stryker MP. Amblyopia induced by anisometropia without shrinkage of ocular dominance columns in human striate cortex. Proc Natl Acad Sci U S A 1993;90:5494 – 8. 7. Horton JC, Hocking DR. Pattern of ocular dominance columns in human striate cortex in strabismic amblyopia. Visual Neurosci 1996;13:787–95. 8. Quigley HA, Coleman AL, Dorman-Pease ME. Larger optic nerve heads have more nerve fibers in normal monkey eyes. Arch Ophthalmol 1991;109:1441–3.
Philip Lempert 䡠 Retinal Area/Optic Disc Rim Area Ratio in Amblyopia 9. Lempert P. Optic nerve hypoplasia and small eyes in presumed amblyopia. J AAPOS 2000;4:258 – 66. 10. Duranoglu Y. Optic nerve head topographic analysis and retinal nerve fiber layer thickness in strabismic and anisometropic amblyopia. Ann Ophthalmol (Skokie) 2007;39: 291–5. 11. Oster SF, Sretavan DW. Connecting the eye to the brain: the molecular basis of ganglion cell axon guidance. Br J Ophthalmol 2003;87:639 – 45. 12. Brodsky MC, Baker RS, Hamed LM. Congenital optic disc anomalies. In: Pediatric Neuro-ophthalmology. New York: Springer; 1996:43. 13. Yang LL, Lambert SR. Reappraisal of occlusion therapy for severe structural abnormalities of the optic disc and macula. J Pediatr Ophthalmol Strabismus 1995;32:37– 41. 14. Repka MX, Uozato H, Guyton DL. Depth distortion during slitlamp biomicroscopy of the fundus. Ophthalmology 1986; 93(suppl):47–51. 15. Bengtsson B, Krakau CET. Some essential optical features of the Zeiss fundus camera. Acta Ophthalmol (Copenh) 1977; 55:123–31.
16. Bengtsson B, Krakau CE. Correction of optic disc measurements on fundus photographs. Graefes Arch Clin Exp Ophthalmol 1992;230:24 – 8. 17. Lempert P. Objective assessment of the optic disc features with personal computers. In: Schuman JS, ed. Imaging in Glaucoma. Thorofare, NJ: Slack Inc; 1996:35– 43. 18. Strömland K. Ocular involvement in the fetal alcohol syndrome. Surv Ophthalmol 1987;31:277– 84. 19. Provis JM, van Driel D, Billson FA, Russell P. Human fetal optic nerve: overproduction and elimination of retinal axons during development. J Comp Neurol 1985;238:92–100. 20. Johnson DA. Relative scotomata in the “normal” eye of functionally amblyopic patients: a scanning laser ophthalmoscope (SOL) microperimetric study. Binocul Vis Strabismus Q 2007;22:17– 48. 21. Chatzistefanou KI, Theodossiadis GP, Damanakis AG, et al. Contrast sensitivity in amblyopia: the fellow eye of untreated and successfully treated amblyopes. J AAPOS 2005;9:468 –74. 22. Leguire LE, Rogers GL, Bremer DL. Amblyopia: the normal eye is not normal. J Pediatr Ophthalmol Strabismus 1990;27:32– 8.
Footnotes and Financial Disclosures Originally received: December 29, 2007. Final revision: June 17, 2008. Accepted: July 30, 2008. Available online: September 18, 2008.
Financial Disclosure(s): The authors have no proprietary or commercial interest in any materials discussed in this article. Manuscript no. 2008-6.
Visiting Scientist, Department of Neurobiology and Behavior, Cornell University, Ithaca, New York. Presented at: the American Academy of Ophthalmology Annual Meeting, November 2007, New Orleans, Louisiana.
Correspondence: Philip Lempert, MD, 100 Uptown Road, Ithaca, NY 14850. E-mail: [email protected].
2261
Vision impairments in amblyopia are characterized by spatial deficits that, since the animal research by Wiesel and Hubel,1 have been attributed to anatomic anomalies or defective processing in the visual cortex. Nonetheless, caveats such as one raised by Moseley,2 “. . . it should be borne in mind that much of the animal literature relates to amblyopia arising from stimulus deprivation a condition whose pathophysiology may differ substantially from that of the target conditions,” indicate that questions persist as to the contribution of neuroretinal causes for the impaired vision.3–5 In addition, Horton and Stryker6 and Horton and Hocking7 used cytochrome oxidase histochemistry to examine the ocular dominance columns in 2 patients with amblyopia: 1 with anisometropia and 1 with strabismus, respectively. They found no anatomic differences between the layers of the lateral geniculate bodies and concluded that naturally occurring amblyopia in humans has a different basis than amblyopia produced in animals by early severe form deprivation. Quigley et al8 determined that the number of optic nerve fibers is directly correlated to disc area. Aberrations in the size of the optic discs in amblyopic eyes have been reported.9,10 © 2008 by the American Academy of Ophthalmology Published by Elsevier Inc.
Optic nerve hypoplasia is recognized to be “an important cause of childhood visual disability”11 and perhaps the most common optic disc anomaly encountered in clinical practice.12 Patients with unrecognized optic nerve hypoplasia may be unnecessarily treated for amblyopia.13 Magnification-corrected imaging is necessary for recognizing optic nerve hypoplasia because differences in axial length and refractive error, as occur in anisometropia, can alter the apparent size of the optic disc. “It is important to understand these differences so that inaccurate conclusions are not drawn and inappropriate therapy will not be instituted . . . .”14 The purpose of this retrospective study was to measure the retinal receptor areas of amblyopic, fellow, and normal eyes. Quantitative data obtained from routine examinations of both eyes of hyperopic patients with amblyopia and right eyes of non-amblyopic hyperopic patients were compared.
Materials and Methods All of the amblyopic and normal patients in this report were seen in the author’s private practice between October 1994 and NovemISSN 0161-6420/08/$–see front matter doi:10.1016/j.ophtha.2008.07.016
2259
Ophthalmology Volume 115, Number 12, December 2008 Table 1. Ocular Measurements in the 3 Groups of Eyes Normal Eye
Fellow Eye
Amblyopic
Spherical equivalent, 2.57 ⫾ 2.02 2.47 ⫾ 1.97 3.89 ⫾ 1.94 diopters Range of refractive 0.25 to 8.00 0.25 to 13.75 0.375 to 11.00 errors, diopters Axial length mm 22.25 ⫾ 1.15 22.28 ⫾ 1.05 21.73 ⫾ 1.04 781 ⫾ 81 781 ⫾ 73 743 ⫾ 71 Retinal area mm2 Optic disc area mm2 2.32 ⫾ 0.85 2.05 ⫾ 0.66 1.73 ⫾ 0.6 Optic disc rim area mm2 2.1 ⫾ 0.68 1.9 ⫾ 0.62 1.61 ⫾ 0.54 Retinal area/optic disc 406 ⫾ 127 452 ⫾ 150 508 ⫾ 160 rim area No. of subjects 77 293 293 The values represent the means and standard deviations for the various groups. The values in “retinal area/optic disc rim area” represent the mean square millimeters of retina served per square millimeter of optic nerve.
ber 2007. They were invited to have retinal photography and axial length measurements performed. There were no fees for any of these additional tests, and patients were not paid for their participation. The inclusion criteria for the amblyopic subjects were best corrected Snellen visual acuity of 20/40 or less, 2 or more lines difference between the amblyopic and fellow eye, at least ⫹0.25 diopters of hyperopia in each eye, and absence of gross ocular defects. Patients with glaucoma or a history of optic nerve disorders were excluded. Axial length measurements were performed with a Sonomed 4000 ultrasound biometer or a Zeiss IOL Master laser interferometer (Carl Zeiss Co., Oberkochen, Germany) on both eyes of all subjects. Photographs were taken with a Topcon fundus camera (Topcon Medical Systems, Inc, Paramus, NJ). Disc and cup measurements were carried out on 35-mm slides or digitized images. Magnification factor of the eye/camera combination and the absolute size of the optic nerve calculations were performed by using formulas developed by Bengtsson and Krakau.15,16 These formulas use axial length, as the most important factor, and refractive error. The cup area was subtracted from the disc area to obtain the neuroretinal rim area. Calculations of magnification factors and disc rim size, and analysis of the data were conducted within Lotus Approach versions 3.0 to 9.617 and Lotus 1-2-3 (Lotus Development Corporation, Cambridge, MA). Axial length was used to calculate the area of a sphere, and this was divided in half to estimate the functional retinal area. This value was divided by the neuroretinal rim area to acquire a value for the retinal area to optic disc rim area ratio (RetA/DRimA).
Results The amblyopic group included the eyes of 293 patients, of whom 127 had amblyopic right eyes and 166 had amblyopic left eyes. There were 82 patients with anisometropia exceeding 1.5 diopters, 88 with strabismus and 47 with both anisometropia and strabismus. The ocular measurements in the 3 groups of eyes are summarized in Table 1. The retinal areas of the amblyopic and fellow eyes, listed in Table 1, differed substantially (paired t test, 9.78 ⫻ 10⫺11). There was a significant difference between the RetA/DRimA of the amblyopic and fellow eyes (paired t test 1.27 ⫻ 10⫺5). The RetA/DRimA of the amblyopic and normal eyes was also significantly different (unpaired t test 5.0 ⫻ 10⫺7), whereas the differ-
2260
ence between the fellow and normal eyes was smaller (unpaired t test 1.67 ⫻ 10⫺2) but still significant. The RetA/DRimA was greatest for the amblyopic eyes despite their retinal area being smaller than either the fellow or normal eyes. This reflects the reduced size of the optic disc and neuroretinal rim areas in the amblyopic eyes.
Discussion Visual acuity is dependent on the neural connectivity of retinal cells. Summation of signals from relatively larger areas implies that spatial discrimination, and subsequently visual acuity and other functions,8 would be reduced. Optic nerve hypoplasia is a nonprogressive congenital anomaly caused by prenatal insults.18 These could affect the number of axons initially formed, whereas factors later in pregnancy could accelerate apoptosis resulting in a diminution of optic nerve axons.19 The central observation of this study is that amblyopic and their fellow eyes have reduced optic disc rim areas, which leads directly to expanded retinal receptor areas. This reduction in the retinal resolution of both eyes is consistent with reports of visual field20 and other deficits in the amblyopic and fellow non-amblyopic eyes.21 Leguire et al22 warned that “In future studies of amblyopia, whether in children or in adults, caution is advised in assuming that the non-amblyopic eye is normal because acuity is normal.” The demonstration of decreased optic disc rim areas and increased neuroretinal receptor areas in amblyopic and fellow eyes, compared with a normal population, suggests that there is a peripheral cause for vision defects that are usually attributed to amblyopia. This finding should be a stimulus for prospective quantitative studies of ocular anatomy in presumed amblyopia.
References 1. Wiesel TN, Hubel DH. Single-cell responses in striate cortex of kittens deprived of vision in one eye. J Neurophysiol 1963;26:1003–17. 2. Moseley MJ. Preschool vision screening: a recent report calls for a halt. Br J Ophthalmol 1998;82:722–3. 3. Simons K. Stereoscopic neurotropy and the origins of amblyopia and strabismus. In: Simons K, ed. Early Visual Development: Normal and Abnormal. New York: Oxford University Press; 1993:409-53. 4. Hess RF, Baker CL Jr, Verhoeve JN, et al. The pattern evoked electroretinogram: its variability in normals and its relationship to amblyopia. Invest Ophthalmol Vis Sci 1985;26: 1610 –23. 5. Hess RF. Amblyopia: site unseen. Clin Exp Optom 2001;84: 321–36. 6. Horton JC, Stryker MP. Amblyopia induced by anisometropia without shrinkage of ocular dominance columns in human striate cortex. Proc Natl Acad Sci U S A 1993;90:5494 – 8. 7. Horton JC, Hocking DR. Pattern of ocular dominance columns in human striate cortex in strabismic amblyopia. Visual Neurosci 1996;13:787–95. 8. Quigley HA, Coleman AL, Dorman-Pease ME. Larger optic nerve heads have more nerve fibers in normal monkey eyes. Arch Ophthalmol 1991;109:1441–3.
Philip Lempert 䡠 Retinal Area/Optic Disc Rim Area Ratio in Amblyopia 9. Lempert P. Optic nerve hypoplasia and small eyes in presumed amblyopia. J AAPOS 2000;4:258 – 66. 10. Duranoglu Y. Optic nerve head topographic analysis and retinal nerve fiber layer thickness in strabismic and anisometropic amblyopia. Ann Ophthalmol (Skokie) 2007;39: 291–5. 11. Oster SF, Sretavan DW. Connecting the eye to the brain: the molecular basis of ganglion cell axon guidance. Br J Ophthalmol 2003;87:639 – 45. 12. Brodsky MC, Baker RS, Hamed LM. Congenital optic disc anomalies. In: Pediatric Neuro-ophthalmology. New York: Springer; 1996:43. 13. Yang LL, Lambert SR. Reappraisal of occlusion therapy for severe structural abnormalities of the optic disc and macula. J Pediatr Ophthalmol Strabismus 1995;32:37– 41. 14. Repka MX, Uozato H, Guyton DL. Depth distortion during slitlamp biomicroscopy of the fundus. Ophthalmology 1986; 93(suppl):47–51. 15. Bengtsson B, Krakau CET. Some essential optical features of the Zeiss fundus camera. Acta Ophthalmol (Copenh) 1977; 55:123–31.
16. Bengtsson B, Krakau CE. Correction of optic disc measurements on fundus photographs. Graefes Arch Clin Exp Ophthalmol 1992;230:24 – 8. 17. Lempert P. Objective assessment of the optic disc features with personal computers. In: Schuman JS, ed. Imaging in Glaucoma. Thorofare, NJ: Slack Inc; 1996:35– 43. 18. Strömland K. Ocular involvement in the fetal alcohol syndrome. Surv Ophthalmol 1987;31:277– 84. 19. Provis JM, van Driel D, Billson FA, Russell P. Human fetal optic nerve: overproduction and elimination of retinal axons during development. J Comp Neurol 1985;238:92–100. 20. Johnson DA. Relative scotomata in the “normal” eye of functionally amblyopic patients: a scanning laser ophthalmoscope (SOL) microperimetric study. Binocul Vis Strabismus Q 2007;22:17– 48. 21. Chatzistefanou KI, Theodossiadis GP, Damanakis AG, et al. Contrast sensitivity in amblyopia: the fellow eye of untreated and successfully treated amblyopes. J AAPOS 2005;9:468 –74. 22. Leguire LE, Rogers GL, Bremer DL. Amblyopia: the normal eye is not normal. J Pediatr Ophthalmol Strabismus 1990;27:32– 8.
Footnotes and Financial Disclosures Originally received: December 29, 2007. Final revision: June 17, 2008. Accepted: July 30, 2008. Available online: September 18, 2008.
Financial Disclosure(s): The authors have no proprietary or commercial interest in any materials discussed in this article. Manuscript no. 2008-6.
Visiting Scientist, Department of Neurobiology and Behavior, Cornell University, Ithaca, New York. Presented at: the American Academy of Ophthalmology Annual Meeting, November 2007, New Orleans, Louisiana.
Correspondence: Philip Lempert, MD, 100 Uptown Road, Ithaca, NY 14850. E-mail: [email protected].
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