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Visual Loss in Orbitofacial Neurofibromatosis Type 1
Visual Loss in Orbitofacial Neurofibromatosis Type 1 Darren T. Oystreck, MMedSci, OC(C),1,4 Jose Morales, MD,2 Imtiaz Chaudhry, MD, PhD,2 Ibrahim A. Alorainy, MD,3 Sahar M. Elkhamary, MD,2 Taha M. U. Pasha, MBBS,1 Thomas M. Bosley, MD1 Purpose: On occasion, neurofibromas in neurofibromatosis type 1 may be present on the lid, brow, or face of an infant or child, a circumstance commonly referred to as “orbitofacial neurofibromatosis” (OFNF). The present study evaluates the causes and extent of visual loss in a group of patients with OFNF. Design: Case series. Participants: Fifty-five patients with OFNF. Methods: Retrospective medical record review and reexamination of selected patients from one institution. Main Outcome Measures: Visual acuity and identification of underlying cause of reduced vision. Results: Fifty patients with unilateral OFNF (23 male, 27 female, aged 4 – 48 years at last visit) and 5 patients with bilateral OFNF (2 male, 3 female, aged 15– 43 years) had adequate information available to assess afferent visual functioning. Nine patients (4 male, 5 female, aged 4 –28 years) had optic pathway glioma (OPG) in addition to OFNF. Patients were followed as long as 27 years (mean 8.4 years). Thirty-nine patients (71% of total) had visual acuity of ⱕ20/60 on the side of OFNF involvement (or the side of worse OFNF involvement in patients with bilateral disease). One or more causes of amblyopia were present in 29 of these patients, 19 patients had organic disease of the eye (e.g., glaucoma or retinal detachment) or the afferent system (e.g., OPG), and 12 patients had correctable refractive errors. Conclusions: Visual loss in this OFNF cohort was common, typically profound, and usually multifactorial. Some causes of visual loss (including congenital glaucoma with buphthalmos and retinal detachment, disconjugate gaze due in part to distorted skull development causing strabismic amblyopia, and OPG) were difficult to treat adequately and tended to cause progressive, profound visual loss. Therefore, careful observation should be made during the period of visual immaturity for possible causes of amblyopia that might be treatable, such as refractive changes, occlusion of the visual axis, or congenital glaucoma. As affected individuals get older, physicians must be vigilant for the progression of optic nerve disease due to glaucoma or OPG and to the possibility that vision might be improved by refraction. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. Ophthalmology 2012;119:2168 –2173 © 2012 by the American Academy of Ophthalmology.
Neurofibromatosis type 1 (NF1; von Recklinghausen disease; Online Mendelian Inheritance in Man 162200) is a fairly frequent (1 in 3000 live births) autosomal dominant, neurocutaneous disorder that has considerable clinical variability, the potential for multisystem involvement,1 and the possibility of malignant transformation.2 Neurofibromas can also cause devastating functional and cosmetic effects. In orbitofacial neurofibromatosis (OFNF) type 1, which occurs in 1% to 22% of patients with NF1, neurofibromas may result in progressive, disfiguring tumors of the orbit and face.3,4 Orbitofacial neurofibromatosis has been recognized as a unique variant of NF1 for many years.5–7 From earliest reports, neurofibromas involving the face in infancy and early childhood have been recognized as virtually a separate syndrome because of the aggressiveness of these infiltrating tumors.8 For reasons not currently understood, these tumors almost always occur over only 1 side of the face, typically favoring the upper eyelid, brow, and temporal region, although bilateral OFNF has been reported.9 –11 Tumors in the
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orbitofacial region generally have a higher growth rate than neurofibromas elsewhere in the body; aggressiveness is most striking in early childhood and tends to improve somewhat as the individual ages.8,10,12 Substantial attention has been given to the natural history and treatment of optic pathway gliomas (OPGs),13–16 but the visual consequences of OFNF have not received as much attention. Globe enlargement affecting refraction occurs frequently on the affected side of patients with OFNF;17 some of these patients develop glaucoma, but others do not.9,11 Both neuroimaging9,18,19 and clinical reports20 have documented that neurofibromas are commonly present in the orbit and cavernous sinus and are frequently contiguous to globes that are abnormally large and to bony changes in the skull and orbit.21 This suggests the possibility of optic nerve compression by neurofibroma or dysplastic bone within the orbital structure, but the visual implications of these observations have not been carefully evaluated. This study evaluates the frequency, severity, and cause of visual loss in a large group of patients with OFNF. ISSN 0161-6420/12/$–see front matter http://dx.doi.org/10.1016/j.ophtha.2012.04.032
Oystreck et al 䡠 Vision in OFNF
Materials and Methods Medical records were reviewed of all patients fulfilling National Institutes of Health criteria for NF122,23 who were examined between 1982 and 2011 at the King Khaled Eye Specialist Hospital, a major national ophthalmology referral site in Saudi Arabia. Orbitofacial neurofibromatosis was diagnosed by the presence of tumor mass involving the lid, brow, or temporal region at birth or shortly thereafter. Most patients had multiple examinations over a decade or more in different subspecialty clinics. Most also had 1 or more orbital or facial surgeries, providing a histologic diagnosis of neurofibroma, usually plexiform in type. Information was collected regarding age at onset of symptoms, age at presentation to the hospital, age at time of any ophthalmologic surgery, predominant signs and symptoms, presence of lid or facial neurofibroma, globe size (by refraction, ultrasound, or neuroimaging), laterality of OFNF, laterality of OPG if present, and initial and final Snellen visual acuity. For statistical analysis, Snellen visual acuity was converted to the logarithm of the minimum angle of resolution (logMAR) equivalent. The diagnosis of amblyopia was made in patients with documented uncorrected anisometropia (⬎1.5 diopters [D] hyperopia, 2.5 D myopia, or 2 D astigmatism), manifest strabismus, or blockage of the visual axis by ptosis or media opacification at or before the age of 6 years and optotype acuity reduced by ⱖ2 lines compared with the contralateral eye in patients with unilateral OFNF or to ⱕ20/60 in patients with bilateral disease.24 Glaucoma was defined by the presence of intraocular pressure consistently elevated to ⬎23 mmHg with evidence of glaucomatous optic nerve damage. All patients had computed tomography or magnetic resonance imaging (typically 3 Tesla) or both. Patients were excluded if afferent visual functioning could not be adequately assessed from chart information and the patient could not be recalled for a prospective reexamination. Institutional review board/ethics committee approval was obtained for both the retrospective and prospective components of this study, and examined patients signed informed consent. This study adhered to the tenants of the Declaration of Helsinki.
Results We reviewed the medical records of 84 patients with probable or definite OFNF who were followed during a 28-year period between 1983 and 2011. Fifty-five patients (25 male and 30 female) had OFNF and adequate information to assess afferent visual functioning, 50 with unilateral involvement (Fig 1) and 5 with bilateral involvement. One patient had a prosthesis ipsilateral to OFNF at presentation with limited data from elsewhere document-
ing orbital and sphenoid dysplasia and tumor in the orbit and cavernous sinus before enucleation. Three-fourths of these patients had comitant or noncomitant strabismus present at the most recent examination, although no individual had significant restriction of ocular motility. General neurologic examinations were nonfocal in all. Data regarding presumed causes of visual impairment in these patients are detailed in Table 1. Visual acuity of ⱕ20/60 on the affected side was documented in 39 patients (71% of all patients with OFNF), with the mean visual acuity of these patients being 20/400. Amblyopia was common in this group (29/39 patients), precipitated by uncorrected refractive asymmetry due to globe enlargement ipsilateral to OFNF; visual deprivation due to complete or almost complete lid closure caused by lid or brow neurofibromas (Fig 2); or strabismus related to a combination of large globe, sphenoid and orbital dysplasia, and orbital and cavernous sinus tumor (Fig 3). Organic causes of visual loss were documented in 26 of 39 patients and included glaucoma, OPG (Fig 4), optic atrophy for unclear reasons, or retinal detachment. Only 3 patients had scarring of the cornea or tumor invasion of the anterior globe. Some patients had axial myopia (associated with a large globe ipsilateral to OFNF) that could be partially corrected by refraction. Multiple potential causes of visual loss almost always interacted in each individual patient. For this reason, mean visual acuities of patients were typically poor, even when one particular cause of visual loss was isolated and analyzed (Table 1). Most patients with various subtypes of amblyopia had visual acuities ranging from 20/60 (the upper boundary for inclusion in Table 1) to no light perception. One exception was strabismic amblyopia, where the best recorded visual acuity was 20/120, possibly because strabismus in the visually immature age group typically occurred in patients with severe OFNF, usually including globe enlargement and sphenoid dysplasia. Mean visual acuity was worst in patients with congenital glaucoma or OPG. Eleven patients had no light perception in the affected eye, most commonly because of advancing glaucoma. Causes of visual impairment varied somewhat with the degree of visual loss (Table 2). The most frequent factor disturbing vision in patients with visual acuity ⬎20/60 was refractive error, although these patients often had various types of amblyopia as well. Patients with moderately reduced vision (20/60 –20/200) were almost all amblyopic and less commonly had refractive and organic abnormalities. Patients with the most profound visual loss (visual acuity ⬍20/200) had a higher frequency of organic abnormalities, including glaucoma (13 patients), OPG (5 patients), and retinal detachment (3 patients) in addition to refractive changes. Amblyopia was again common in this group, whereas correctable refrac-
Figure 1. Unilateral orbitofacial neurofibromatosis (OFNF). Images of 3 different patients showing varying severity of unilateral left OFNF. A, Isolated left upper lid involvement with infiltration of neurofibroma resulting in the characteristic S-shaped lid. B, More extensive tumor infiltration involving left lid, brow, and temple and causing occlusion of the visual axis. C, Severe neurofibroma infiltration of the entire left hemiface. This patient had 2 previous tumor debulking procedures involving the left lid and face.
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Ophthalmology Volume 119, Number 10, October 2012 Table 1. Causes and Degree of Visual Impairment Cause
No.
VA Mean
VA Range
Patients with Snellen VA of ⱕ20/60 on affected side(s) Amblyopia Refractive Deprivation Strabismic Organic Glaucoma OPG Optic atrophy, unspecified Retinal detachment Correctable refractive error Compound myopic astigmatism Myopia Mixed astigmatism
39 29 21 18 12 26 13 7 8 4 12 8 4 1
20/400 20/400 20/300 20/250 20/400 20/800 HM 20/400 20/600 HM 20/300 20/300
20/60 to NLP 20/60 to NLP 20/60 to NLP 20/60 to NLP 20/120 to NLP 20/60 to NLP 20/800 to NLP 20/60 to NLP 20/50 to NLP 20/150 to NLP 20/60 to NLP 20/80 to NLP
HM ⫽ hand motions; NLP ⫽ no light perception; OPG ⫽ optic pathway glioma; VA ⫽ visual acuity. This includes patients with both unilateral and bilateral orbitofacial neurofibromatosis (OFNF). Subcategories are indented. Almost all patients had multiple causes of poor vision (e.g., multiple causes of amblyopia, amblyopia and organic abnormalities, or glaucoma and OPG).
tive error played a smaller role. No patient had definitive evidence of visual loss due to optic nerve compression either by neurofibroma within the orbit or by abnormal bone resulting from sphenoid or orbital dysplasia. On follow-up of all patients with unilateral OFNF, 10 patients (20%) had improved visual acuity (typically due to refraction), whereas 30 patients (60%) had no change and 10 patients (20%) had a decrease in vision. A comparison of logMAR visual acuities of patients with (mean 0.90, standard deviation 0.69) and without (mean 1.0, standard deviation 0.65) orbital neurofibroma revealed no statistical difference between these patient groups (P ⫽ 0.62). Likewise, a comparison of patients with (mean 1.1, standard deviation 0.66) and without (mean 0.8, standard deviation 0.65) sphenoid dysplasia also revealed no statistical difference in logMAR visual acuities (P ⫽ 0.20). Because of the potential confounding effect of multiple causes of reduced visual acuity, the presence of orbital neurofibroma or sphenoid dysplasia was compared independently with the presence of optic atrophy. The presence of optic atrophy due to all causes (glaucoma, OPG, and unexplained) was not correlated with orbital neurofibroma (r ⫽ ⫺0.13, P ⫽ 0.36) or sphenoid dysplasia (r ⫽ ⫺0.19, P ⫽ 0.89). The presence of optic atrophy unexplained by glaucoma or OPG was not correlated with sphenoid dysplasia (r ⫽ ⫺0.57, P ⫽ 0.68) but was minimally correlated with the presence orbital neurofibroma (r ⫽ ⫺0.28, P ⫽
0.04). However, this correlation lost significance after Bonferroni correction for multiple statistical tests. A comparison of logMAR visual acuities of the 9 patients with OPG (mean 1.14, standard deviation 0.67) with the 46 patients without OPG (mean 0.97, standard deviation 0.70) revealed no statistical difference between these patient groups (P ⫽ 0.50). Seven patients with OPG had visual acuity ⬍20/60 ipsilateral to OFNF involvement, and 1 patient had good vision ipsilateral to OFNF but was blind contralaterally because of OPG. No patient in this cohort had optic disc edema documented in the setting of OPG.16 All 5 patients with bilateral OFNF had visual loss ipsilateral to the worst facial tumor involvement (total blindness in 3) and contralaterally in 2 patients (due to glaucoma and retinal detachment). One of these patients had disfiguring bilateral OFNF, bilateral OPG, bilateral congenital glaucoma, and eventually bilateral retinal detachments causing bilateral total blindness.
Discussion This study reviewed 55 patients with OFNF type 1, of whom 50 had unilateral OFNF and 5 had bilateral disease. The
Figure 2. Progressive unilateral orbitofacial neurofibromatosis (OFNF) resulting in deprivational amblyopia. A, Patient at age 18 months with an S-shaped lid secondary to infiltration by neurofibroma. Lid position was normal medially, and he readily adopted a left face turn to maintain a clear visual axis. B, Same patient at age 24 months with progressive tumor infiltration now completely blocking the visual axis in all gazes. His previous anomalous head posture was abandoned. He developed amblyopia in the left eye and a sensory esotropia.
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Figure 3. Unilateral orbital and cavernous sinus tumor associated with orbital and sphenoid bony dysplasia. Axial computed tomography scan (A) and axial T2-weighted magnetic resonance image (B) showing right globe enlargement, tumor in the right orbit and cavernous sinus, and sphenoid and orbital dysplasia. This young child with congenital glaucoma and occlusion of the visual axis by lid neurofibroma was unable to fixate with the right eye.
genetic diagnosis was not in question because of the specificity of National Institutes of Health criteria,22,23 the unique characteristics of the OFNF presentation,8 and the availability of histologic confirmation of facial neurofibroma in almost all of these patients. Visual impairment was more common than expected, with more than three-fourths of patients with unilateral OFNF having visual acuity of ⱕ20/60 and all patients with bilateral disease having reduced vision. Decreased visual acuity was most commonly multifactorial with amblyopia being common and organic abnormalities affecting two-thirds. All types of amblyopia taken together were the most frequent cause of reduced visual acuity, with refractive amblyopia occurring in approximately three-fourths of all patients whose vision was reduced to ⱕ20/60 (Table 1). Because young patients with OFNF commonly have rapidly progressive disease of the upper eyelid and brow (Figs 1 and
2),10 this patient group was at risk for occlusion of the visual axis. Others have suggested that an attempt be made to delay surgery in young children because of rapid progression,12 but delay may not be advisable if the patient is at risk for deprivational amblyopia. Approximately half of patients with reduced vision had globe enlargement at an early age ipsilateral to OFNF causing refractive amblyopia that was sometimes not recognized or treated by physicians who were understandably concentrating on the cosmetic aspects of the disease. Buphthalmos was associated with congenital glaucoma at times,11 but globe enlargement occurred in other patients independently of glaucoma, presumably as the result of a secondary effect of contiguous orbital neurofibromas.9,11,17 Globe enlargement was progressive at an early age in some patients,9,11 and some developed severe globe enlargement associated with posterior staphylomas and myopic macular
Figure 4. Optic pathway glioma in orbitofacial neurofibromatosis (OFNF). Images of a patient with left OFNF, bilateral optic nerve, and chiasmal glioma, and visual acuities of 20/25 on the right and 20/60 on the left. Axial T2-weighted (A), coronal T1-weighted (B), and sagittal T1-weighted (C) nonenhanced magnetic resonance images showing an OPG involving the prechiasmatic part of both optic nerves and the optic chiasm. The glioma fills most of the suprasellar cistern and is larger on the right side. The patient has extensive OFNF involving the left lid, brow, temple, and orbit (A).
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Ophthalmology Volume 119, Number 10, October 2012 Table 2. Causes of Visual Reduction in Patients with Orbitofacial Neurofibromatosis Snellen VA
Total
Amblyopic
Organic
Refractive
⬎20/60 20/60–20/200 ⬍20/200 Total patients
16 16 23 55
10 14 15 39
4 8 18 30
12 6 6 24
VA ⫽ visual acuity. Patients with unilateral and bilateral orbitofacial neurofibromatosis (OFNF) were included in Table 2 with vision tabulated on the worst affected side. The sum of patients with “amblyopic,” “organic,” and “refractive” causes of visual disturbance (last row) is ⬎55 (the total number of patients) because many patients had ⬎1 cause of visual loss.
changes that likely affected vision independently. Anisometropia was frequently dealt with as a less severe problem than disfiguring facial tumors, and even when recognized, was difficult to treat because the facial tumors of OFNF made glasses difficult to wear. Nevertheless, adequate optical correction worn regularly might have ameliorated amblyopia in at least the 7 patients who had refractive amblyopia as the most prominent cause of poor vision. Biannual ophthalmologic examinations with refractions are appropriate for children aged less than 5 years, with annual examinations thereafter. Strabismus was not particularly common during visual immaturity in this patient population. The visual effects of globe displacement associated with globe enlargement and sphenoid and orbital dysplasia were exacerbated by visual loss due to other mechanisms (e.g., refractive amblyopia) that impeded the fusion reflex. Nevertheless, visual acuity in 1 of these patients was improved into the normal range after ocular motility surgery, demonstrating the possible value of early surgical intervention. Organic causes of visual loss also were common. Congenital glaucoma in the setting of OFNF was difficult to manage, and the visual outcome was commonly poor because of progressive optic nerve disease, progressive globe enlargement, and retinal detachment associated with severe myopia.11 Most patients who eventually had an enucleation or evisceration had this surgery performed in part because of a blind, painful eye resulting from glaucoma. Visual loss associated with unilateral or bilateral OPG was sometimes minimal but often severe.16,25 Nevertheless, these patients with OPG had visual acuities on the side affected by OFNF (or the worst affected side in patients with bilateral disease) that were statistically indistinguishable from patients without OPGs, an observation that highlights the severity of visual loss in OFNF even in the absence of OPGs. Progressive visual loss in the setting of OPG may be due to some other mechanism instead of, or in addition to, the OPG, complicating management decisions. Correctable refractive errors were present in 12 of the 16 patients with mild visual loss ipsilateral to OFNF and in smaller fractions of patients with more severe visual loss. In general, only a relatively small component of an individual’s visual loss could be corrected by refraction, given that these patients almost always had other causes of visual
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disturbance as well. More important, additional attention by neurologists and ophthalmologists to refractive abnormalities early in life might have resulted in considerably improved vision in those patients with substantial refractive amblyopia. More than half of these patients with OFNF had orbital neurofibromas (23 patients) or sphenoid dysplasia (28 patients), or both. In these patients, orbital neurofibroma or dysplastic bone was often contiguous with the orbital optic nerve, raising the possibility that intraorbital optic nerve compression might be a cause of optic nerve disease. However, a comparison of patients with and without orbital neurofibromas and sphenoid dysplasia revealed no statistical difference in the visual acuities of these patient groups, although the situation is complex and optic nerve compression may be a mechanism in some patients. Nine patients had optic atrophy that was not obviously explained by the presence of glaucoma or OPG, but only 4 of these patients had orbital neurofibromas or sphenoid dysplasia obvious on neuroimaging. These observations suggest that caution is appropriate when considering orbital or skull surgery in an attempt to improve vision by decompressing the optic nerve. Optic pathway gliomas occur in 15% to 20% of patients with NF125–27 and can be expected to cause visual loss to some degree in half or more of affected patients.16 In this series, 9 of the 55 patients (16%) had OPGs, only 1 of whom had vision ⬎20/60 on the affected side; this patient was completely blind in the contralateral eye as the result of OPG. Despite this relatively poor visual record, visual acuity on the side of OFNF in patients with OPGs was statistically indistinguishable from other patients with OFNF without OPGs. Therefore, patients with OPG cannot be recognized in a population with OFNF by visual loss alone, and current quality neuroimaging is crucial for the diagnosis.16,28 In conclusion, current literature on OFNF appropriately stresses facial manifestations, sphenoid and orbital dysplasia, proptosis, and OPG.1 However, multifactorial loss of vision in the current cohort was more frequent and severe than anticipated and was often associated with amblyopia and refractive errors that could have been partially corrected with additional attention to afferent visual functioning in early childhood. Some causes of visual loss (including congenital glaucoma with buphthalmos and retinal detachment, disconjugate gaze due in part to distorted skull development causing strabismic amblyopia, and OPG) were difficult to treat adequately and tended to cause progressive, profound visual loss. These patients were all referred to a national eye center, and many were followed for years because of complex, progressive disease. This patient cohort may, therefore, represent somewhat worse OFNF than would be found in a local or regional facility. Nevertheless, these data highlight the need for careful follow-up of patients with OFNF with attention to visual acuity and potential causes of amblyopia. Patient compliance is crucial at an early age regarding correctable factors such as wearing the appropriate refraction and using glaucoma medications. Surgical intervention early in life, particularly ptosis and brow repair, may be necessary for visual and cosmetic reasons.
Oystreck et al 䡠 Vision in OFNF
References 1. Brodsky MC. Neuro-Ophthalmologic Manifestations of Systemic and Intracranial Disease. In: Pediatric Neuro-ophthalmology. 2nd ed. New York: Springer; 2010:503–9. 2. Wong WW, Hirose T, Scheithauer BW, et al. Malignant peripheral nerve sheath tumor: analysis of treatment outcome. Int J Radiat Oncol Biol Phys 1998;42:351– 60. 3. North K. Introduction. In: Davis P, ed. Neurofibromatosis Type 1 in Childhood. London: Mac Keith Press; 1997:5–15. 4. Erb MH, Uzcategui N, See RF, Burnstine MA. Orbitotemporal neurofibromatosis: classification and treatment. Orbit 2007; 26:223– 8. 5. Davis WB, Edgerton MT, Hoffmeister SF. Neurofibromatosis of the head and neck. Plast Reconstr Surg (1946) 1954;14:186 –99. 6. Griffith BH, McKinney P, Monroe CW, Howell A. Von Recklinghausen’s disease in children. Plast Reconstr Surg 1972;49: 647–53. 7. Grabb WC, Dingman RO, Oneal RM, Dempsey PD. Facial hamartomas in children: Neurofibroma, lymphangioma, and hemangioma. Plast Reconstr Surg 1980;66:509 –27. 8. Jackson IT, Carbonnel A, Potparic Z, Shaw K. Orbitotemporal neurofibromatosis: classification and treatment. Plast Reconstr Surg 1993;92:1–11. 9. Jacquemin C, Bosley TM, Svedberg H. Orbit deformities in craniofacial neurofibromatosis type 1. AJNR Am J Neuroradiol 2003;24:1678 – 82. 10. Lee V, Ragge NK, Collin JR. Orbitotemporal neurofibromatosis: clinical features and surgical management. Ophthalmology 2004; 111:382– 8. 11. Morales J, Chaudhry IA, Bosley TM. Glaucoma and globe enlargement associated with neurofibromatosis type 1. Ophthalmology 2009;116:1725–30. 12. Lee V, Ragge NK, Collin JR. The surgical management of childhood orbito-temporal neurofibromatosis. Br J Plast Surg 2003;56:380 –7. 13. Simmons I, Gogi D. Screening children with NF1 for optic pathway glioma–Yes. Eye (Lond) 2010;24:1429 –31. 14. Pilling RF, Taylor RH. Screening children with NF1 for optic pathway glioma–No. Eye (Lond) 2010;25:1432– 4. 15. Liu GT, Brodsky MC, Phillips PC, et al. Optic radiation involvement in optic pathway gliomas in neurofibromatosis. Am J Ophthalmol 2004;137:407–14.
16. Balcer LJ, Liu GT, Heller G, et al. Visual loss in children with neurofibromatosis type 1 and optic pathway gliomas: relation to tumor location by magnetic resonance imaging. Am J Ophthalmol 2001;131:442–5. 17. Hoyt CS, Billson FA. Buphthalmos in neurofibromatosis: is it an expression of regional giantism? J Pediatr Ophthalmol 1977;14:228 –34. 18. Jacquemin C, Bosley TM, Liu D, et al. Reassessment of sphenoid dysplasia associated with neurofibromatosis type 1. AJNR Am J Neuroradiol 2002;23:644 – 8. 19. Zimmerman RA, Bilaniuk LT, Metzger RA, et al. Computed tomography of orbitalfacial neurofibromatosis. Radiology 1983;146:113– 6. 20. Macfarlane R, Levin AV, Weksberg R, et al. Absence of the greater sphenoid wing in neurofibromatosis type 1: congenital or acquired: case report. Neurosurgery 1995;37:129 –33. 21. Grenier N, Guibert-Tranier F, Nicolau A, Caille JM. Contribution of computerized tomography to the study of sphenoorbital dysplasia in neurofibromatosis [in English, French]. J Neuroradiol 1984;11:201–11. 22. Neurofibromatosis: Conference Statement. National Institutes of Health Consensus Development Conference. Arch Neurol 1988;45:575– 8. 23. Gutmann DH, Aylsworth A, Carey JC, et al. The diagnostic evaluation and multidisciplinary management of neurofibromatosis 1 and neurofibromatosis 2. JAMA 1997;278:51–7. 24. American Academy of Ophthalmology Pediatric Ophthalmology/ Strabismus Panel. Preferred Practice Guidelines. Amblyopia. San Francisco, CA: American Academy of Ophthalmology; 2007. Available at: http://one.aao.org/CE/PracticeGuidelines/ PPP.aspx. Accessed April 17, 2012. 25. Listernick R, Charrow J, Gutmann DH. Intracranial gliomas in neurofibromatosis type 1. Am J Med Genet 1999;89:38 – 44. 26. Lewis RA, Gerson LP, Axelson KA, et al. von Recklinghausen neurofibromatosis. II. Incidence of optic gliomata. Ophthalmology 1984;91:929 –35. 27. Listernick R, Louis DN, Packer RJ, Gutmann DH. Optic pathway gliomas in children with neurofibromatosis 1: consensus statement from the NF1 Optic Pathway Glioma Task Force. Ann Neurol 1997;41:143–9. 28. Dutton JJ. Gliomas of the anterior visual pathway. Surv Ophthalmol 1994;38:427–52.
Footnotes and Financial Disclosures Originally received: November 11, 2011. Final revision: February 27, 2012. Accepted: April 30, 2012. Available online: June 17, 2012.
Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. Manuscript no. 2011-1629.
1
Department of Ophthalmology, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
2
King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia.
3
Department of Radiology, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
4
Supported in part by the King Abdulaziz City for Science and Technology (Project AT-29-31).
Division of Ophthalmology, Faculty of Health Sciences, University of Stellenbosch, Tygerberg, South Africa.
Correspondence: Darren T. Oystreck, MMedSci, OC(C), King Abdulaziz University Hospital, PO Box 245, Riyadh 11411, Saudi Arabia. E-mail: darrenoystreck@ ymail.com.
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Neurofibromatosis type 1 (NF1; von Recklinghausen disease; Online Mendelian Inheritance in Man 162200) is a fairly frequent (1 in 3000 live births) autosomal dominant, neurocutaneous disorder that has considerable clinical variability, the potential for multisystem involvement,1 and the possibility of malignant transformation.2 Neurofibromas can also cause devastating functional and cosmetic effects. In orbitofacial neurofibromatosis (OFNF) type 1, which occurs in 1% to 22% of patients with NF1, neurofibromas may result in progressive, disfiguring tumors of the orbit and face.3,4 Orbitofacial neurofibromatosis has been recognized as a unique variant of NF1 for many years.5–7 From earliest reports, neurofibromas involving the face in infancy and early childhood have been recognized as virtually a separate syndrome because of the aggressiveness of these infiltrating tumors.8 For reasons not currently understood, these tumors almost always occur over only 1 side of the face, typically favoring the upper eyelid, brow, and temporal region, although bilateral OFNF has been reported.9 –11 Tumors in the
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orbitofacial region generally have a higher growth rate than neurofibromas elsewhere in the body; aggressiveness is most striking in early childhood and tends to improve somewhat as the individual ages.8,10,12 Substantial attention has been given to the natural history and treatment of optic pathway gliomas (OPGs),13–16 but the visual consequences of OFNF have not received as much attention. Globe enlargement affecting refraction occurs frequently on the affected side of patients with OFNF;17 some of these patients develop glaucoma, but others do not.9,11 Both neuroimaging9,18,19 and clinical reports20 have documented that neurofibromas are commonly present in the orbit and cavernous sinus and are frequently contiguous to globes that are abnormally large and to bony changes in the skull and orbit.21 This suggests the possibility of optic nerve compression by neurofibroma or dysplastic bone within the orbital structure, but the visual implications of these observations have not been carefully evaluated. This study evaluates the frequency, severity, and cause of visual loss in a large group of patients with OFNF. ISSN 0161-6420/12/$–see front matter http://dx.doi.org/10.1016/j.ophtha.2012.04.032
Oystreck et al 䡠 Vision in OFNF
Materials and Methods Medical records were reviewed of all patients fulfilling National Institutes of Health criteria for NF122,23 who were examined between 1982 and 2011 at the King Khaled Eye Specialist Hospital, a major national ophthalmology referral site in Saudi Arabia. Orbitofacial neurofibromatosis was diagnosed by the presence of tumor mass involving the lid, brow, or temporal region at birth or shortly thereafter. Most patients had multiple examinations over a decade or more in different subspecialty clinics. Most also had 1 or more orbital or facial surgeries, providing a histologic diagnosis of neurofibroma, usually plexiform in type. Information was collected regarding age at onset of symptoms, age at presentation to the hospital, age at time of any ophthalmologic surgery, predominant signs and symptoms, presence of lid or facial neurofibroma, globe size (by refraction, ultrasound, or neuroimaging), laterality of OFNF, laterality of OPG if present, and initial and final Snellen visual acuity. For statistical analysis, Snellen visual acuity was converted to the logarithm of the minimum angle of resolution (logMAR) equivalent. The diagnosis of amblyopia was made in patients with documented uncorrected anisometropia (⬎1.5 diopters [D] hyperopia, 2.5 D myopia, or 2 D astigmatism), manifest strabismus, or blockage of the visual axis by ptosis or media opacification at or before the age of 6 years and optotype acuity reduced by ⱖ2 lines compared with the contralateral eye in patients with unilateral OFNF or to ⱕ20/60 in patients with bilateral disease.24 Glaucoma was defined by the presence of intraocular pressure consistently elevated to ⬎23 mmHg with evidence of glaucomatous optic nerve damage. All patients had computed tomography or magnetic resonance imaging (typically 3 Tesla) or both. Patients were excluded if afferent visual functioning could not be adequately assessed from chart information and the patient could not be recalled for a prospective reexamination. Institutional review board/ethics committee approval was obtained for both the retrospective and prospective components of this study, and examined patients signed informed consent. This study adhered to the tenants of the Declaration of Helsinki.
Results We reviewed the medical records of 84 patients with probable or definite OFNF who were followed during a 28-year period between 1983 and 2011. Fifty-five patients (25 male and 30 female) had OFNF and adequate information to assess afferent visual functioning, 50 with unilateral involvement (Fig 1) and 5 with bilateral involvement. One patient had a prosthesis ipsilateral to OFNF at presentation with limited data from elsewhere document-
ing orbital and sphenoid dysplasia and tumor in the orbit and cavernous sinus before enucleation. Three-fourths of these patients had comitant or noncomitant strabismus present at the most recent examination, although no individual had significant restriction of ocular motility. General neurologic examinations were nonfocal in all. Data regarding presumed causes of visual impairment in these patients are detailed in Table 1. Visual acuity of ⱕ20/60 on the affected side was documented in 39 patients (71% of all patients with OFNF), with the mean visual acuity of these patients being 20/400. Amblyopia was common in this group (29/39 patients), precipitated by uncorrected refractive asymmetry due to globe enlargement ipsilateral to OFNF; visual deprivation due to complete or almost complete lid closure caused by lid or brow neurofibromas (Fig 2); or strabismus related to a combination of large globe, sphenoid and orbital dysplasia, and orbital and cavernous sinus tumor (Fig 3). Organic causes of visual loss were documented in 26 of 39 patients and included glaucoma, OPG (Fig 4), optic atrophy for unclear reasons, or retinal detachment. Only 3 patients had scarring of the cornea or tumor invasion of the anterior globe. Some patients had axial myopia (associated with a large globe ipsilateral to OFNF) that could be partially corrected by refraction. Multiple potential causes of visual loss almost always interacted in each individual patient. For this reason, mean visual acuities of patients were typically poor, even when one particular cause of visual loss was isolated and analyzed (Table 1). Most patients with various subtypes of amblyopia had visual acuities ranging from 20/60 (the upper boundary for inclusion in Table 1) to no light perception. One exception was strabismic amblyopia, where the best recorded visual acuity was 20/120, possibly because strabismus in the visually immature age group typically occurred in patients with severe OFNF, usually including globe enlargement and sphenoid dysplasia. Mean visual acuity was worst in patients with congenital glaucoma or OPG. Eleven patients had no light perception in the affected eye, most commonly because of advancing glaucoma. Causes of visual impairment varied somewhat with the degree of visual loss (Table 2). The most frequent factor disturbing vision in patients with visual acuity ⬎20/60 was refractive error, although these patients often had various types of amblyopia as well. Patients with moderately reduced vision (20/60 –20/200) were almost all amblyopic and less commonly had refractive and organic abnormalities. Patients with the most profound visual loss (visual acuity ⬍20/200) had a higher frequency of organic abnormalities, including glaucoma (13 patients), OPG (5 patients), and retinal detachment (3 patients) in addition to refractive changes. Amblyopia was again common in this group, whereas correctable refrac-
Figure 1. Unilateral orbitofacial neurofibromatosis (OFNF). Images of 3 different patients showing varying severity of unilateral left OFNF. A, Isolated left upper lid involvement with infiltration of neurofibroma resulting in the characteristic S-shaped lid. B, More extensive tumor infiltration involving left lid, brow, and temple and causing occlusion of the visual axis. C, Severe neurofibroma infiltration of the entire left hemiface. This patient had 2 previous tumor debulking procedures involving the left lid and face.
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Ophthalmology Volume 119, Number 10, October 2012 Table 1. Causes and Degree of Visual Impairment Cause
No.
VA Mean
VA Range
Patients with Snellen VA of ⱕ20/60 on affected side(s) Amblyopia Refractive Deprivation Strabismic Organic Glaucoma OPG Optic atrophy, unspecified Retinal detachment Correctable refractive error Compound myopic astigmatism Myopia Mixed astigmatism
39 29 21 18 12 26 13 7 8 4 12 8 4 1
20/400 20/400 20/300 20/250 20/400 20/800 HM 20/400 20/600 HM 20/300 20/300
20/60 to NLP 20/60 to NLP 20/60 to NLP 20/60 to NLP 20/120 to NLP 20/60 to NLP 20/800 to NLP 20/60 to NLP 20/50 to NLP 20/150 to NLP 20/60 to NLP 20/80 to NLP
HM ⫽ hand motions; NLP ⫽ no light perception; OPG ⫽ optic pathway glioma; VA ⫽ visual acuity. This includes patients with both unilateral and bilateral orbitofacial neurofibromatosis (OFNF). Subcategories are indented. Almost all patients had multiple causes of poor vision (e.g., multiple causes of amblyopia, amblyopia and organic abnormalities, or glaucoma and OPG).
tive error played a smaller role. No patient had definitive evidence of visual loss due to optic nerve compression either by neurofibroma within the orbit or by abnormal bone resulting from sphenoid or orbital dysplasia. On follow-up of all patients with unilateral OFNF, 10 patients (20%) had improved visual acuity (typically due to refraction), whereas 30 patients (60%) had no change and 10 patients (20%) had a decrease in vision. A comparison of logMAR visual acuities of patients with (mean 0.90, standard deviation 0.69) and without (mean 1.0, standard deviation 0.65) orbital neurofibroma revealed no statistical difference between these patient groups (P ⫽ 0.62). Likewise, a comparison of patients with (mean 1.1, standard deviation 0.66) and without (mean 0.8, standard deviation 0.65) sphenoid dysplasia also revealed no statistical difference in logMAR visual acuities (P ⫽ 0.20). Because of the potential confounding effect of multiple causes of reduced visual acuity, the presence of orbital neurofibroma or sphenoid dysplasia was compared independently with the presence of optic atrophy. The presence of optic atrophy due to all causes (glaucoma, OPG, and unexplained) was not correlated with orbital neurofibroma (r ⫽ ⫺0.13, P ⫽ 0.36) or sphenoid dysplasia (r ⫽ ⫺0.19, P ⫽ 0.89). The presence of optic atrophy unexplained by glaucoma or OPG was not correlated with sphenoid dysplasia (r ⫽ ⫺0.57, P ⫽ 0.68) but was minimally correlated with the presence orbital neurofibroma (r ⫽ ⫺0.28, P ⫽
0.04). However, this correlation lost significance after Bonferroni correction for multiple statistical tests. A comparison of logMAR visual acuities of the 9 patients with OPG (mean 1.14, standard deviation 0.67) with the 46 patients without OPG (mean 0.97, standard deviation 0.70) revealed no statistical difference between these patient groups (P ⫽ 0.50). Seven patients with OPG had visual acuity ⬍20/60 ipsilateral to OFNF involvement, and 1 patient had good vision ipsilateral to OFNF but was blind contralaterally because of OPG. No patient in this cohort had optic disc edema documented in the setting of OPG.16 All 5 patients with bilateral OFNF had visual loss ipsilateral to the worst facial tumor involvement (total blindness in 3) and contralaterally in 2 patients (due to glaucoma and retinal detachment). One of these patients had disfiguring bilateral OFNF, bilateral OPG, bilateral congenital glaucoma, and eventually bilateral retinal detachments causing bilateral total blindness.
Discussion This study reviewed 55 patients with OFNF type 1, of whom 50 had unilateral OFNF and 5 had bilateral disease. The
Figure 2. Progressive unilateral orbitofacial neurofibromatosis (OFNF) resulting in deprivational amblyopia. A, Patient at age 18 months with an S-shaped lid secondary to infiltration by neurofibroma. Lid position was normal medially, and he readily adopted a left face turn to maintain a clear visual axis. B, Same patient at age 24 months with progressive tumor infiltration now completely blocking the visual axis in all gazes. His previous anomalous head posture was abandoned. He developed amblyopia in the left eye and a sensory esotropia.
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Figure 3. Unilateral orbital and cavernous sinus tumor associated with orbital and sphenoid bony dysplasia. Axial computed tomography scan (A) and axial T2-weighted magnetic resonance image (B) showing right globe enlargement, tumor in the right orbit and cavernous sinus, and sphenoid and orbital dysplasia. This young child with congenital glaucoma and occlusion of the visual axis by lid neurofibroma was unable to fixate with the right eye.
genetic diagnosis was not in question because of the specificity of National Institutes of Health criteria,22,23 the unique characteristics of the OFNF presentation,8 and the availability of histologic confirmation of facial neurofibroma in almost all of these patients. Visual impairment was more common than expected, with more than three-fourths of patients with unilateral OFNF having visual acuity of ⱕ20/60 and all patients with bilateral disease having reduced vision. Decreased visual acuity was most commonly multifactorial with amblyopia being common and organic abnormalities affecting two-thirds. All types of amblyopia taken together were the most frequent cause of reduced visual acuity, with refractive amblyopia occurring in approximately three-fourths of all patients whose vision was reduced to ⱕ20/60 (Table 1). Because young patients with OFNF commonly have rapidly progressive disease of the upper eyelid and brow (Figs 1 and
2),10 this patient group was at risk for occlusion of the visual axis. Others have suggested that an attempt be made to delay surgery in young children because of rapid progression,12 but delay may not be advisable if the patient is at risk for deprivational amblyopia. Approximately half of patients with reduced vision had globe enlargement at an early age ipsilateral to OFNF causing refractive amblyopia that was sometimes not recognized or treated by physicians who were understandably concentrating on the cosmetic aspects of the disease. Buphthalmos was associated with congenital glaucoma at times,11 but globe enlargement occurred in other patients independently of glaucoma, presumably as the result of a secondary effect of contiguous orbital neurofibromas.9,11,17 Globe enlargement was progressive at an early age in some patients,9,11 and some developed severe globe enlargement associated with posterior staphylomas and myopic macular
Figure 4. Optic pathway glioma in orbitofacial neurofibromatosis (OFNF). Images of a patient with left OFNF, bilateral optic nerve, and chiasmal glioma, and visual acuities of 20/25 on the right and 20/60 on the left. Axial T2-weighted (A), coronal T1-weighted (B), and sagittal T1-weighted (C) nonenhanced magnetic resonance images showing an OPG involving the prechiasmatic part of both optic nerves and the optic chiasm. The glioma fills most of the suprasellar cistern and is larger on the right side. The patient has extensive OFNF involving the left lid, brow, temple, and orbit (A).
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Ophthalmology Volume 119, Number 10, October 2012 Table 2. Causes of Visual Reduction in Patients with Orbitofacial Neurofibromatosis Snellen VA
Total
Amblyopic
Organic
Refractive
⬎20/60 20/60–20/200 ⬍20/200 Total patients
16 16 23 55
10 14 15 39
4 8 18 30
12 6 6 24
VA ⫽ visual acuity. Patients with unilateral and bilateral orbitofacial neurofibromatosis (OFNF) were included in Table 2 with vision tabulated on the worst affected side. The sum of patients with “amblyopic,” “organic,” and “refractive” causes of visual disturbance (last row) is ⬎55 (the total number of patients) because many patients had ⬎1 cause of visual loss.
changes that likely affected vision independently. Anisometropia was frequently dealt with as a less severe problem than disfiguring facial tumors, and even when recognized, was difficult to treat because the facial tumors of OFNF made glasses difficult to wear. Nevertheless, adequate optical correction worn regularly might have ameliorated amblyopia in at least the 7 patients who had refractive amblyopia as the most prominent cause of poor vision. Biannual ophthalmologic examinations with refractions are appropriate for children aged less than 5 years, with annual examinations thereafter. Strabismus was not particularly common during visual immaturity in this patient population. The visual effects of globe displacement associated with globe enlargement and sphenoid and orbital dysplasia were exacerbated by visual loss due to other mechanisms (e.g., refractive amblyopia) that impeded the fusion reflex. Nevertheless, visual acuity in 1 of these patients was improved into the normal range after ocular motility surgery, demonstrating the possible value of early surgical intervention. Organic causes of visual loss also were common. Congenital glaucoma in the setting of OFNF was difficult to manage, and the visual outcome was commonly poor because of progressive optic nerve disease, progressive globe enlargement, and retinal detachment associated with severe myopia.11 Most patients who eventually had an enucleation or evisceration had this surgery performed in part because of a blind, painful eye resulting from glaucoma. Visual loss associated with unilateral or bilateral OPG was sometimes minimal but often severe.16,25 Nevertheless, these patients with OPG had visual acuities on the side affected by OFNF (or the worst affected side in patients with bilateral disease) that were statistically indistinguishable from patients without OPGs, an observation that highlights the severity of visual loss in OFNF even in the absence of OPGs. Progressive visual loss in the setting of OPG may be due to some other mechanism instead of, or in addition to, the OPG, complicating management decisions. Correctable refractive errors were present in 12 of the 16 patients with mild visual loss ipsilateral to OFNF and in smaller fractions of patients with more severe visual loss. In general, only a relatively small component of an individual’s visual loss could be corrected by refraction, given that these patients almost always had other causes of visual
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disturbance as well. More important, additional attention by neurologists and ophthalmologists to refractive abnormalities early in life might have resulted in considerably improved vision in those patients with substantial refractive amblyopia. More than half of these patients with OFNF had orbital neurofibromas (23 patients) or sphenoid dysplasia (28 patients), or both. In these patients, orbital neurofibroma or dysplastic bone was often contiguous with the orbital optic nerve, raising the possibility that intraorbital optic nerve compression might be a cause of optic nerve disease. However, a comparison of patients with and without orbital neurofibromas and sphenoid dysplasia revealed no statistical difference in the visual acuities of these patient groups, although the situation is complex and optic nerve compression may be a mechanism in some patients. Nine patients had optic atrophy that was not obviously explained by the presence of glaucoma or OPG, but only 4 of these patients had orbital neurofibromas or sphenoid dysplasia obvious on neuroimaging. These observations suggest that caution is appropriate when considering orbital or skull surgery in an attempt to improve vision by decompressing the optic nerve. Optic pathway gliomas occur in 15% to 20% of patients with NF125–27 and can be expected to cause visual loss to some degree in half or more of affected patients.16 In this series, 9 of the 55 patients (16%) had OPGs, only 1 of whom had vision ⬎20/60 on the affected side; this patient was completely blind in the contralateral eye as the result of OPG. Despite this relatively poor visual record, visual acuity on the side of OFNF in patients with OPGs was statistically indistinguishable from other patients with OFNF without OPGs. Therefore, patients with OPG cannot be recognized in a population with OFNF by visual loss alone, and current quality neuroimaging is crucial for the diagnosis.16,28 In conclusion, current literature on OFNF appropriately stresses facial manifestations, sphenoid and orbital dysplasia, proptosis, and OPG.1 However, multifactorial loss of vision in the current cohort was more frequent and severe than anticipated and was often associated with amblyopia and refractive errors that could have been partially corrected with additional attention to afferent visual functioning in early childhood. Some causes of visual loss (including congenital glaucoma with buphthalmos and retinal detachment, disconjugate gaze due in part to distorted skull development causing strabismic amblyopia, and OPG) were difficult to treat adequately and tended to cause progressive, profound visual loss. These patients were all referred to a national eye center, and many were followed for years because of complex, progressive disease. This patient cohort may, therefore, represent somewhat worse OFNF than would be found in a local or regional facility. Nevertheless, these data highlight the need for careful follow-up of patients with OFNF with attention to visual acuity and potential causes of amblyopia. Patient compliance is crucial at an early age regarding correctable factors such as wearing the appropriate refraction and using glaucoma medications. Surgical intervention early in life, particularly ptosis and brow repair, may be necessary for visual and cosmetic reasons.
Oystreck et al 䡠 Vision in OFNF
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16. Balcer LJ, Liu GT, Heller G, et al. Visual loss in children with neurofibromatosis type 1 and optic pathway gliomas: relation to tumor location by magnetic resonance imaging. Am J Ophthalmol 2001;131:442–5. 17. Hoyt CS, Billson FA. Buphthalmos in neurofibromatosis: is it an expression of regional giantism? J Pediatr Ophthalmol 1977;14:228 –34. 18. Jacquemin C, Bosley TM, Liu D, et al. Reassessment of sphenoid dysplasia associated with neurofibromatosis type 1. AJNR Am J Neuroradiol 2002;23:644 – 8. 19. Zimmerman RA, Bilaniuk LT, Metzger RA, et al. Computed tomography of orbitalfacial neurofibromatosis. Radiology 1983;146:113– 6. 20. Macfarlane R, Levin AV, Weksberg R, et al. Absence of the greater sphenoid wing in neurofibromatosis type 1: congenital or acquired: case report. Neurosurgery 1995;37:129 –33. 21. Grenier N, Guibert-Tranier F, Nicolau A, Caille JM. Contribution of computerized tomography to the study of sphenoorbital dysplasia in neurofibromatosis [in English, French]. J Neuroradiol 1984;11:201–11. 22. Neurofibromatosis: Conference Statement. National Institutes of Health Consensus Development Conference. Arch Neurol 1988;45:575– 8. 23. Gutmann DH, Aylsworth A, Carey JC, et al. The diagnostic evaluation and multidisciplinary management of neurofibromatosis 1 and neurofibromatosis 2. JAMA 1997;278:51–7. 24. American Academy of Ophthalmology Pediatric Ophthalmology/ Strabismus Panel. Preferred Practice Guidelines. Amblyopia. San Francisco, CA: American Academy of Ophthalmology; 2007. Available at: http://one.aao.org/CE/PracticeGuidelines/ PPP.aspx. Accessed April 17, 2012. 25. Listernick R, Charrow J, Gutmann DH. Intracranial gliomas in neurofibromatosis type 1. Am J Med Genet 1999;89:38 – 44. 26. Lewis RA, Gerson LP, Axelson KA, et al. von Recklinghausen neurofibromatosis. II. Incidence of optic gliomata. Ophthalmology 1984;91:929 –35. 27. Listernick R, Louis DN, Packer RJ, Gutmann DH. Optic pathway gliomas in children with neurofibromatosis 1: consensus statement from the NF1 Optic Pathway Glioma Task Force. Ann Neurol 1997;41:143–9. 28. Dutton JJ. Gliomas of the anterior visual pathway. Surv Ophthalmol 1994;38:427–52.
Footnotes and Financial Disclosures Originally received: November 11, 2011. Final revision: February 27, 2012. Accepted: April 30, 2012. Available online: June 17, 2012.
Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. Manuscript no. 2011-1629.
1
Department of Ophthalmology, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
2
King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia.
3
Department of Radiology, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
4
Supported in part by the King Abdulaziz City for Science and Technology (Project AT-29-31).
Division of Ophthalmology, Faculty of Health Sciences, University of Stellenbosch, Tygerberg, South Africa.
Correspondence: Darren T. Oystreck, MMedSci, OC(C), King Abdulaziz University Hospital, PO Box 245, Riyadh 11411, Saudi Arabia. E-mail: darrenoystreck@ ymail.com.
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