Using autofluorescence to detect optic nerve head drusen in children Pablo Gili, MD, PhD,a,b Patricia Flores-Rodrıguez, OD, MSc, PhD,a,c Julio Yang€ uela, MD,a d and Marıa Luisa Herreros Fernandez, MD PURPOSE
To assess the efficacy of using autofluorescence to identify optic nerve head drusen (ONHD) in children.
METHODS
We conducted a cross-sectional, descriptive study of subjects\18 years of age with possible pseudopapilledema due to ONHD. B-scan ultrasonography was considered the gold standard diagnostic technique. All participants underwent an extensive ophthalmic examination that included fundus color photography, autofluorescence analysis, and B-scan echography. ONHD were classified as visible or hidden. Autofluorescence images were analyzed by three observers who were masked to the results of B-scan ultrasonography.
RESULTS
A total of 24 children with pseudopapilledema were included. B-scan ultrasonography confirmed ONHD in 32 eyes of 18 patients (9 boys). Mean patient age was 12 years (range, 7-17 years). ONHD was bilateral in 14 patients; unilateral in 4. The majority of the drusen were hidden (26 of 32 eyes). Analysis of autofluorescence patterns identified the drusen in 94% of cases (30 of 32 eyes): visible, 100%; hidden, 92%. Interobserver agreement was high (k 5 0.91, k 5 0.96, k 5 0.89).
CONCLUSIONS
In this study cohort, autofluorescence proved a safe, fast, and reliable technique for identifying ONHD in children. ( J AAPOS 2013;17:568-571)
O
ptic nerve head drusen (ONHD) are the leading cause of pseudopapilledema. Superficial drusen are usually easily identified through ophthalmoscopic examination; hidden forms are difficult to distinguish from real papilledema.1 In children, drusen are usually hidden, which makes diagnosis difficult. They are generally asymptomatic and are discovered during routine fundus examination.2,3 Ocular ultrasonography can detect the presence of both superficial and hidden calcifications and is considered the most reliable to diagnose ONHD.4 The purpose of this study was to assess the usefulness of fundus autofluorescence imaging in the diagnosis of optic nerve head drusen in children.
Subjects and Methods This study was approved by the University Hospital Alcorcon Foundation (Spain) Ethics Committee and was conducted in accordance with the principles of the Declaration of Helsinki. Author affiliations: aOphthalmology Unit, Hospital Universitario Fundacion Alcorcon, Madrid, Spain; bHealth Sciences Faculty, Universidad Europea, Madrid, Spain; cPontificia Universidad Catolica de Valparaıso, Chile; dPaediatrics Department, Hospital Universitario Infanta Sofıa, San Sebastian de Los Reyes, Madrid, Spain Submitted April 5, 2013. Revision accepted July 20, 2013. Published online November 7, 2013. Correspondence: Pablo Gili Manzanaro, MD, PhD, Hospital Universitario Fundacion Alcorcon, Ophthalmology Unit, C/ Budapest 1, 28922 Alcorcon, Madrid, Spain (email: [email protected]). Copyright Ó 2013 by the American Association for Pediatric Ophthalmology and Strabismus. 1091-8531/$36.00 http://dx.doi.org/10.1016/j.jaapos.2013.07.012
568
This was a cross-sectional, descriptive study of all consecutive patients \18 years of age with possible pseudopapilledema due to ONHD who attended the Ophthalmology Unit from March 1, 2004, to May 1, 2011. B-scan ultrasonography was considered the gold standard technique for the diagnosis of ONHD. All participants underwent and extensive ophthalmic examination, which included color fundus photography, fundus autofluorescence imaging, and B-scan echography. Patients with ONHD but incomplete test results were excluded. Fundus images were obtained using a mydriatic fundus camera (FF450 IRplus; Zeiss, http://www.meditec.zeiss.com) with digital archiving system (Visupac 452, version 4.4.4; http://www. meditec.zeiss.com). Color photographs of the optic disk were taken with a 3CCD AVT ZK-5 high-resolution color camera (2588 1958 resolution). Fluorescein injection was not used during autofluorescence image capture. Under blue exciter filter (490 nm) and greenish-yellow barrier filter (525 nm), successive images were captured increasing flash power until the retinal vessels appeared black (Figure 1). The test was negative if whitish spots, indicating ONHD, were not yet visible on the disk area by that point. Images were analyzed by three observers with different levels of training who were masked to results of B-scan ultrasonography: an ophthalmologist (high experience), an optometrist (medium experience), and a pediatrician (low experience). In each of the images obtained with angiography filters—shown in random order and masked—the observer had to determine whether autofluorescence was positive or negative. A descriptive analysis of the study population was performed. Quantitative variables were expressed as mean and standard
Journal of AAPOS
Volume 17 Number 6 / December 2013
Gili et al
569
deviations. Interobserver agreement for qualitative variables was determined using the kappa (k) index. The ranges of kappa values were: \0.20, very low; 0.21-0.40, low; 0.41-0.60, moderate; 0.61-0.80, high; 0.81-1.00, very high.5 Statistical analysis was performed using SPSS version 15.0.1 for Windows (SPSS Inc, Chicago, IL).
Results A total of 24 pseudopapiledema patients (12 boys) were included. The mean patient age was 11.9 years (range, 5-17 years). Most patients (17) were referred by their pediatrician or primary care physician and some by the neurologist or pediatric neurologist (7 cases). Patients presented for the following reasons: routine check-up (13), decreased visual acuity (4), papilledema (4), and headaches (3). Most patients (13) underwent previous neuroradiologic study. Associated diseases included attention deficit hyperactivity disorder (2), retinitis pigmentosa (1), panhypopituitarism (1), and mild thalassemia (1). Mean visual acuity was 0.95 logMAR equivalent (range, 0.05-1). Most eyes (21) were emmetropic, with a mean spherical equivalent of 0.4 D (range, 6.3 to 16.9). B-scan ultrasonography confirmed ONHD in 32 eyes of 18 patients (9 boys), with a mean age of 12.9 years (range, 7-17 years). In 14 patients (78%) bilateral drusen were present. In 26 eyes (81%) they were hidden. Results of autofluorescence imaging were positive in 30 of 32 eyes (94%): 6 eyes (100%) were positive with visible ONHD; 24 eyes (92%), with hidden ONHD (Figure 2). Interobserver agreement in the assessment of autofluorescence was excellent: ophthalmologist versus optometrist, k 5 0.91 (95% CI, 0.79-1.03); ophthalmologist versus pediatrician, k 5 0.96 (95% CI, 0.87-1.04); and optometrist versus pediatrician, k 5 0.89 (95% CI 0.68-1.09).
Discussion
FIG 1. Sequence of fundus images showing positive autofluorescence in the visible drusen with increasing flash power (20 ): A 5 26, B 5 28, C 5 30, D 5 32.
Journal of AAPOS
Superficial or visible ONHD are easy to identify through ophthalmoscopic examination. However, they represent only between 42% and 47% of all ONHD in the general population.6,7 Their presence may also be suspected on the basis of other ophthalmoscopic characteristics, such as peripapillary elevation, lumpy bumpy borders, lack of cupping, splinterlike and peripapillary hemorrhages, vessel tortuosity, and abnormal branching.8 Different methods have been described for the diagnosis of ONHD: fluorescein angiography and autofluorescence,9,10 scanning laser ophthalmoscope,11 computed tomography,12 and, recently, optical coherence tomography.13 But since its emergence in the 1980s, ocular ultrasonography has been considered the gold standard for the diagnosis of ONHD.4 B-scan ultrasonography permits detection of hidden drusen even in uncooperative children or patients with media opacity.14 The experience and skill of the sonographer is very important in cases of
570
Gili et al
Volume 17 Number 6 / December 2013
FIG 2. Optic nerve head drusen that are hidden (A) and visible (C) on fundus photography show positive autofluorescence in both cases (B, D).
small drusen.1 Additionally, in Spain, echographers are not always available in ophthalmic units. Relying on ultrasonography in these circumstances could delay the diagnosis of pseudopapilledema or true papilledema or overburden already-busy radiology units. The presence of autofluorescence in ONHD was first described in 1967 by Sanders and Ffytche.15 It is described as the presence of papillary hyperfluorescence using angiography filters, but without colorant injection. Mustonen7 found autofluorescence to be positive in 79.69% of 192 eyes with ONHD, and Kurz-Levin and Landau14 in 47% in a retrospective study of 142 eyes. In a previous article,16 our group reported that autofluorescence showed 88% sensitivity and 100% specificity in the differential diagnosis between papilledema and ONHD in the general population. To our knowledge, results of autofluorescence analysis specifically in children with ONHD have not been previously published. In our series, 94% of eyes studied showed positive autofluorescence, despite the fact that most eyes analyzed presented hidden drusen (81%), in which lower levels of positivity have been described. These high figures are probably due to the use of digital photography equipment and the use of a standardized methodology for autofluores-
cence assessment. Digital cameras are very sensitive and permit the lighting used during the procedure to be corrected in order to assess whether there is actually positive autofluorescence, which might otherwise be considered negative (Figure 1A). Furthermore, interpretation of the test is straightforward, as shown by the excellent interobserver agreement in the present study. Although obtaining fundus photographs in uncooperative children may be challenging, we believe that autofluorescence analysis is useful in the diagnosis of ONHD in patients \18 years of age. References 1. Lam BL, Morais CG Jr, Pasol J. Drusen of the optic disc. Curr Neurol Neurosci Rep 2008;8:404-8. 2. Erkkil€a H. optic disc drusen in children. Acta Ophthalmol Suppl 1997;129:3-44. 3. Hoover DL, Robb RM, Petersen RA. Optic disc drusen in children. J Pediatr Ophthalmol Strabismus 1988;25:1991-5. 4. Atta HR. Imaging of the optic nerve with standardised echography. Eye 1988;2:358-66. 5. Altman D. Practical Statistics for Medical Research. New York: Chapman and Hall; 1991:277-300. 6. Wilkins JM, Pomeranz HD. Visual manifestations of visible and buried optic disc drusen. J Neuroophthalmol 2004;24:125-9.
Journal of AAPOS
Volume 17 Number 6 / December 2013 7. Mustonen E. Pseudopapilloedema with and without verified optic disc drusen: a clinical analisis I. Acta Ophthalmol 1983;61:1037-56. 8. Flores-Rodriguez P, Gili P, Martın-Rios MD. Ophthalmic features of optic disc drusen. Ophthalmologica 2012;228:59-66. 9. Kelley JS. Autofluorescence of drusen of the optic nerve head. Arch Ophthalmol 1974;92:263-4. 10. Mustonen E, Nieminen H. Optic disc drusen—a photographic study. I. Autofluorescence pictures and fluorescein angiography. Acta Ophthalmol (Copenh) 1982;60:849-58. 11. Haynes RJ, Manivannnan A, Walker S, Sharp PF, Forrester JV. Imaging of optic nerve head drusen with the scanning laser ophthalmoscope. Br J Ophthalmol 1997;81:654-7. 12. Bec P, Adam P, Mathis A, Alberge Y, Roulleau J, Arne JL. Optic nerve head drusen: high-resolution computed tomographic approach. Arch Ophthalmol 1984;102:680-82.
Gili et al
13. Flores-Rodrıguez P, Gili P, Martın-Rıos MD. Sensitivity and specificity of time-domain and spectral-domain optical coherence tomography in differentiating optic nerve head drusen and optic disc oedema. Ophthalmic Physiol Opt 2012;32:213-21. 14. Kurz-Levin MM, Landau K. A comparison of imaging techniques for diagnosing drusen of optic nerve head. Arch Ophthalmol 1999;117: 1045-9. 15. Sanders MD, Ffytche TJ. Fluorescein angiography in diagnosis of drusen of the disc. Trans Ophthalmol Soc UK 1967;87: 457-68. 16. Gili P, Flores-Rodrıguez P, Yang€ uela J, Ordu~ na-Azcona J, MartınRıos MD. Sensitivity and specificity of monochromatic photography of the ocular fundus in differentiating optic nerve head drusen and optic disc oedema: optic disc drusen and oedema. Graefes Arch Clin Exp Ophthalmol 2013;251:923-8.
First Person
Student 1: Do you like my new glasses? Doctor: Absolutely, they’re really cool looking. Are they helping you see better? Student 1: Yes, I can see the board now, and I’m getting all my questions correct. Student 2: Man, I need a pair of those. Contributed by Noelle Matta, CO, CRC, COT, Lancaster, Pennsylvania
Journal of AAPOS
571
To assess the efficacy of using autofluorescence to identify optic nerve head drusen (ONHD) in children.
METHODS
We conducted a cross-sectional, descriptive study of subjects\18 years of age with possible pseudopapilledema due to ONHD. B-scan ultrasonography was considered the gold standard diagnostic technique. All participants underwent an extensive ophthalmic examination that included fundus color photography, autofluorescence analysis, and B-scan echography. ONHD were classified as visible or hidden. Autofluorescence images were analyzed by three observers who were masked to the results of B-scan ultrasonography.
RESULTS
A total of 24 children with pseudopapilledema were included. B-scan ultrasonography confirmed ONHD in 32 eyes of 18 patients (9 boys). Mean patient age was 12 years (range, 7-17 years). ONHD was bilateral in 14 patients; unilateral in 4. The majority of the drusen were hidden (26 of 32 eyes). Analysis of autofluorescence patterns identified the drusen in 94% of cases (30 of 32 eyes): visible, 100%; hidden, 92%. Interobserver agreement was high (k 5 0.91, k 5 0.96, k 5 0.89).
CONCLUSIONS
In this study cohort, autofluorescence proved a safe, fast, and reliable technique for identifying ONHD in children. ( J AAPOS 2013;17:568-571)
O
ptic nerve head drusen (ONHD) are the leading cause of pseudopapilledema. Superficial drusen are usually easily identified through ophthalmoscopic examination; hidden forms are difficult to distinguish from real papilledema.1 In children, drusen are usually hidden, which makes diagnosis difficult. They are generally asymptomatic and are discovered during routine fundus examination.2,3 Ocular ultrasonography can detect the presence of both superficial and hidden calcifications and is considered the most reliable to diagnose ONHD.4 The purpose of this study was to assess the usefulness of fundus autofluorescence imaging in the diagnosis of optic nerve head drusen in children.
Subjects and Methods This study was approved by the University Hospital Alcorcon Foundation (Spain) Ethics Committee and was conducted in accordance with the principles of the Declaration of Helsinki. Author affiliations: aOphthalmology Unit, Hospital Universitario Fundacion Alcorcon, Madrid, Spain; bHealth Sciences Faculty, Universidad Europea, Madrid, Spain; cPontificia Universidad Catolica de Valparaıso, Chile; dPaediatrics Department, Hospital Universitario Infanta Sofıa, San Sebastian de Los Reyes, Madrid, Spain Submitted April 5, 2013. Revision accepted July 20, 2013. Published online November 7, 2013. Correspondence: Pablo Gili Manzanaro, MD, PhD, Hospital Universitario Fundacion Alcorcon, Ophthalmology Unit, C/ Budapest 1, 28922 Alcorcon, Madrid, Spain (email: [email protected]). Copyright Ó 2013 by the American Association for Pediatric Ophthalmology and Strabismus. 1091-8531/$36.00 http://dx.doi.org/10.1016/j.jaapos.2013.07.012
568
This was a cross-sectional, descriptive study of all consecutive patients \18 years of age with possible pseudopapilledema due to ONHD who attended the Ophthalmology Unit from March 1, 2004, to May 1, 2011. B-scan ultrasonography was considered the gold standard technique for the diagnosis of ONHD. All participants underwent and extensive ophthalmic examination, which included color fundus photography, fundus autofluorescence imaging, and B-scan echography. Patients with ONHD but incomplete test results were excluded. Fundus images were obtained using a mydriatic fundus camera (FF450 IRplus; Zeiss, http://www.meditec.zeiss.com) with digital archiving system (Visupac 452, version 4.4.4; http://www. meditec.zeiss.com). Color photographs of the optic disk were taken with a 3CCD AVT ZK-5 high-resolution color camera (2588 1958 resolution). Fluorescein injection was not used during autofluorescence image capture. Under blue exciter filter (490 nm) and greenish-yellow barrier filter (525 nm), successive images were captured increasing flash power until the retinal vessels appeared black (Figure 1). The test was negative if whitish spots, indicating ONHD, were not yet visible on the disk area by that point. Images were analyzed by three observers with different levels of training who were masked to results of B-scan ultrasonography: an ophthalmologist (high experience), an optometrist (medium experience), and a pediatrician (low experience). In each of the images obtained with angiography filters—shown in random order and masked—the observer had to determine whether autofluorescence was positive or negative. A descriptive analysis of the study population was performed. Quantitative variables were expressed as mean and standard
Journal of AAPOS
Volume 17 Number 6 / December 2013
Gili et al
569
deviations. Interobserver agreement for qualitative variables was determined using the kappa (k) index. The ranges of kappa values were: \0.20, very low; 0.21-0.40, low; 0.41-0.60, moderate; 0.61-0.80, high; 0.81-1.00, very high.5 Statistical analysis was performed using SPSS version 15.0.1 for Windows (SPSS Inc, Chicago, IL).
Results A total of 24 pseudopapiledema patients (12 boys) were included. The mean patient age was 11.9 years (range, 5-17 years). Most patients (17) were referred by their pediatrician or primary care physician and some by the neurologist or pediatric neurologist (7 cases). Patients presented for the following reasons: routine check-up (13), decreased visual acuity (4), papilledema (4), and headaches (3). Most patients (13) underwent previous neuroradiologic study. Associated diseases included attention deficit hyperactivity disorder (2), retinitis pigmentosa (1), panhypopituitarism (1), and mild thalassemia (1). Mean visual acuity was 0.95 logMAR equivalent (range, 0.05-1). Most eyes (21) were emmetropic, with a mean spherical equivalent of 0.4 D (range, 6.3 to 16.9). B-scan ultrasonography confirmed ONHD in 32 eyes of 18 patients (9 boys), with a mean age of 12.9 years (range, 7-17 years). In 14 patients (78%) bilateral drusen were present. In 26 eyes (81%) they were hidden. Results of autofluorescence imaging were positive in 30 of 32 eyes (94%): 6 eyes (100%) were positive with visible ONHD; 24 eyes (92%), with hidden ONHD (Figure 2). Interobserver agreement in the assessment of autofluorescence was excellent: ophthalmologist versus optometrist, k 5 0.91 (95% CI, 0.79-1.03); ophthalmologist versus pediatrician, k 5 0.96 (95% CI, 0.87-1.04); and optometrist versus pediatrician, k 5 0.89 (95% CI 0.68-1.09).
Discussion
FIG 1. Sequence of fundus images showing positive autofluorescence in the visible drusen with increasing flash power (20 ): A 5 26, B 5 28, C 5 30, D 5 32.
Journal of AAPOS
Superficial or visible ONHD are easy to identify through ophthalmoscopic examination. However, they represent only between 42% and 47% of all ONHD in the general population.6,7 Their presence may also be suspected on the basis of other ophthalmoscopic characteristics, such as peripapillary elevation, lumpy bumpy borders, lack of cupping, splinterlike and peripapillary hemorrhages, vessel tortuosity, and abnormal branching.8 Different methods have been described for the diagnosis of ONHD: fluorescein angiography and autofluorescence,9,10 scanning laser ophthalmoscope,11 computed tomography,12 and, recently, optical coherence tomography.13 But since its emergence in the 1980s, ocular ultrasonography has been considered the gold standard for the diagnosis of ONHD.4 B-scan ultrasonography permits detection of hidden drusen even in uncooperative children or patients with media opacity.14 The experience and skill of the sonographer is very important in cases of
570
Gili et al
Volume 17 Number 6 / December 2013
FIG 2. Optic nerve head drusen that are hidden (A) and visible (C) on fundus photography show positive autofluorescence in both cases (B, D).
small drusen.1 Additionally, in Spain, echographers are not always available in ophthalmic units. Relying on ultrasonography in these circumstances could delay the diagnosis of pseudopapilledema or true papilledema or overburden already-busy radiology units. The presence of autofluorescence in ONHD was first described in 1967 by Sanders and Ffytche.15 It is described as the presence of papillary hyperfluorescence using angiography filters, but without colorant injection. Mustonen7 found autofluorescence to be positive in 79.69% of 192 eyes with ONHD, and Kurz-Levin and Landau14 in 47% in a retrospective study of 142 eyes. In a previous article,16 our group reported that autofluorescence showed 88% sensitivity and 100% specificity in the differential diagnosis between papilledema and ONHD in the general population. To our knowledge, results of autofluorescence analysis specifically in children with ONHD have not been previously published. In our series, 94% of eyes studied showed positive autofluorescence, despite the fact that most eyes analyzed presented hidden drusen (81%), in which lower levels of positivity have been described. These high figures are probably due to the use of digital photography equipment and the use of a standardized methodology for autofluores-
cence assessment. Digital cameras are very sensitive and permit the lighting used during the procedure to be corrected in order to assess whether there is actually positive autofluorescence, which might otherwise be considered negative (Figure 1A). Furthermore, interpretation of the test is straightforward, as shown by the excellent interobserver agreement in the present study. Although obtaining fundus photographs in uncooperative children may be challenging, we believe that autofluorescence analysis is useful in the diagnosis of ONHD in patients \18 years of age. References 1. Lam BL, Morais CG Jr, Pasol J. Drusen of the optic disc. Curr Neurol Neurosci Rep 2008;8:404-8. 2. Erkkil€a H. optic disc drusen in children. Acta Ophthalmol Suppl 1997;129:3-44. 3. Hoover DL, Robb RM, Petersen RA. Optic disc drusen in children. J Pediatr Ophthalmol Strabismus 1988;25:1991-5. 4. Atta HR. Imaging of the optic nerve with standardised echography. Eye 1988;2:358-66. 5. Altman D. Practical Statistics for Medical Research. New York: Chapman and Hall; 1991:277-300. 6. Wilkins JM, Pomeranz HD. Visual manifestations of visible and buried optic disc drusen. J Neuroophthalmol 2004;24:125-9.
Journal of AAPOS
Volume 17 Number 6 / December 2013 7. Mustonen E. Pseudopapilloedema with and without verified optic disc drusen: a clinical analisis I. Acta Ophthalmol 1983;61:1037-56. 8. Flores-Rodriguez P, Gili P, Martın-Rios MD. Ophthalmic features of optic disc drusen. Ophthalmologica 2012;228:59-66. 9. Kelley JS. Autofluorescence of drusen of the optic nerve head. Arch Ophthalmol 1974;92:263-4. 10. Mustonen E, Nieminen H. Optic disc drusen—a photographic study. I. Autofluorescence pictures and fluorescein angiography. Acta Ophthalmol (Copenh) 1982;60:849-58. 11. Haynes RJ, Manivannnan A, Walker S, Sharp PF, Forrester JV. Imaging of optic nerve head drusen with the scanning laser ophthalmoscope. Br J Ophthalmol 1997;81:654-7. 12. Bec P, Adam P, Mathis A, Alberge Y, Roulleau J, Arne JL. Optic nerve head drusen: high-resolution computed tomographic approach. Arch Ophthalmol 1984;102:680-82.
Gili et al
13. Flores-Rodrıguez P, Gili P, Martın-Rıos MD. Sensitivity and specificity of time-domain and spectral-domain optical coherence tomography in differentiating optic nerve head drusen and optic disc oedema. Ophthalmic Physiol Opt 2012;32:213-21. 14. Kurz-Levin MM, Landau K. A comparison of imaging techniques for diagnosing drusen of optic nerve head. Arch Ophthalmol 1999;117: 1045-9. 15. Sanders MD, Ffytche TJ. Fluorescein angiography in diagnosis of drusen of the disc. Trans Ophthalmol Soc UK 1967;87: 457-68. 16. Gili P, Flores-Rodrıguez P, Yang€ uela J, Ordu~ na-Azcona J, MartınRıos MD. Sensitivity and specificity of monochromatic photography of the ocular fundus in differentiating optic nerve head drusen and optic disc oedema: optic disc drusen and oedema. Graefes Arch Clin Exp Ophthalmol 2013;251:923-8.
First Person
Student 1: Do you like my new glasses? Doctor: Absolutely, they’re really cool looking. Are they helping you see better? Student 1: Yes, I can see the board now, and I’m getting all my questions correct. Student 2: Man, I need a pair of those. Contributed by Noelle Matta, CO, CRC, COT, Lancaster, Pennsylvania
Journal of AAPOS
571
