Ocular motility abnormalities in orbitofacial neurofibromatosis type 1 Darren T. Oystreck, MMedSci,a,d Ibrahim A. Alorainy, MD,b Jose Morales, MD,c Imtiaz A. Chaudhry, MD, PhD, FACS,c,e Sahar M. Elkhamary, MD,c and Thomas M. Bosley, MDa PURPOSE
To evaluate the causes of ocular motility disturbances in a group of patients with orbitofacial neurofibromatosis (OFNF) with neurofibromas on the lid, brow, face, or in the orbit from infancy or early childhood.
METHODS
The medical records of patients with OFNF from one institution were retrospectively reviewed; selected patients were reexamined.
RESULTS
A total of 45 patients with unilateral OFNF and 4 with bilateral OFNF were included. Of these, 14 had no strabismus and relatively good vision, with no ductional abnormalities on either side despite large globes, sphenoid dysplasia, and neurofibromas in the orbit and/or cavernous sinus in many. The 8 patients with comitant strabismus also had no ductional abnormalities with a similar constellation of anatomic abnormalities, but these patients all had poor vision in at least one eye. The 27 patients with incomitant strabismus all had downward displacement of the globe and limited ductions.
CONCLUSIONS
The pathologic anatomic changes associated with OFNF do not always cause ocular motility abnormalities: strabismus generally was not present when ocular motility was full and visual acuity was good. Comitant strabismus occurred in the setting of full ocular motility with reduced vision in at least one eye. Incomitant strabismus was always accompanied by reduced vision and a ductional abnormality in one or both eyes due to anatomic abnormalities of the orbit and skull. ( J AAPOS 2014;18:338-343)
N
eurofibromatosis type 1 (NF1; von Recklinghausen disease; OMIM 162200) is a fairly frequent (1 in 3000 live births), autosomal dominant, neurocutaneous disorder with considerable clinical variability.1 In orbitofacial NF1 (OFNF), neurofibromas (NFs) cause progressive, often disfiguring tumors of the lid, brow, temple, face, and orbit.2,3 Orbitofacial neurofibromatosis has long been recognized as a unique variant of NF1.4-7 The earliest reports recognized neurofibromas involving the face or orbit during infancy and early childhood as virtually a separate syndrome because of the aggressiveness of these infiltrating tumors.2,8 Tumors in the orbitofacial region generally have a much higher growth rate than neurofibromas elsewhere in the body and often result in recurrence that requires debulking surgery for cosmetic and functional
Author affiliations: aOphthalmology and bRadiology, College of Medicine, King Saud University, Riyadh, Saudi Arabia; cThe King Khaled Eye Specialist Hospital, Riyadh; dThe Division of Ophthalmology, Faculty of Health Sciences, University of Stellenbosch, Tygerberg, South Africa; eHouston Oculoplastics Associates, Houston, Texas This project was supported by the King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia [Project AT-30-20]. Submitted September 15, 2013. Revision accepted February 18, 2014. Correspondence: Mr. Darren T. Oystreck, MMedSci, King Abdulaziz University Hospital, PO Box 245, Riyadh 11411, Saudi Arabia (email:
[email protected]). Copyright Ó 2014 by the American Association for Pediatric Ophthalmology and Strabismus. 1091-8531/$36.00 http://dx.doi.org/10.1016/j.jaapos.2014.02.018
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reasons.9 Tumor growth rate tends to improve somewhat as the individual ages8,10,11; however, processes affecting afferent12 and efferent visual functioning are set in motion during the visually immature period of childhood. Apart from the disfiguring characteristics of tumors of OFNF, certain pathological processes related to the disease may be important factors contributing to ocular motility abnormalities. Facial NFs occurring early in life are commonly associated with sphenoid dysplasia, a prominent skull feature with radiologic characteristics that include defects in the greater sphenoid wing and enlargement of the middle cranial fossa.13,14 The orbit is often affected by these changes, with bone erosion associated with contiguous tumor and decalcification and distortion of the orbital walls.15 The globe may be enlarged in NF1, sometimes due to congenital glaucoma but often even in the absence of glaucoma,16 resulting in refractive changes. Current neuroimaging has dramatically improved the ability to resolve subtle soft-tissue and bone changes due to NF infiltration of orbital nerves, sclera, choroid, extraocular muscles, optic nerve sheath, and cavernous sinus.17 Both neuroimaging15,18 and clinical reports19,20 have now shown that NFs are frequently present near orbital and skull changes,21 implying that many of these developmental abnormalities are caused indirectly by contiguous tumor. Decreased visual acuity,12 a large and displaced globe, skull and orbital deformity, and tumor within the orbit and cavernous sinus are potential causes of
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Volume 18 Number 4 / August 2014 ocular motility disturbance. Nevertheless, little is known about how these factors interact to cause abnormalities of ocular motility. The purpose of this study was to evaluate the causes of ocular motility disturbances in a group of patients with OFNF with neurofibromas on the lid, brow, face or in the orbit from infancy or early childhood.
Subjects and Methods The medical records of all patients fulfilling National Institutes of Health criteria for NF122,23 who were examined between 1982 and 2012 at the King Khaled Eye Specialist Hospital (KKESH), the major national ophthalmology referral site, were retrospectively reviewed. OFNF was diagnosed by the presence of NF tumor mass involving the lid, brow, or temporal region at birth or shortly thereafter.8 Patients generally had multiple examinations in different subspecialty clinics, often over 10 or more years. Most also had one or more orbital or facial surgeries, and a histological diagnosis of plexiform NF was obtained in each surgical case. Information was collected from medical records regarding presence of OFNF, age at onset of symptoms, globe size (by refraction, ultrasound, and/or neuroimaging), laterality of OFNF and/or optic pathway glioma, initial and final Snellen visual acuity, ocular motility and alignment, and the results of any neuroimaging studies. 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 having documented uncorrected anisometropia (.1.5 D hyperopia, 2.5 D myopia, and/or 2 D astigmatism), manifest strabismus, and/or blockage of the visual axis by ptosis or media opacification at or before the age 6 years and optotype acuity reduced by $2 lines as compared to the contralateral eye in patients with unilateral OFNF or to #20/60 in patients with bilateral disease in the absence of overt organic disease.24 Patients were recalled for reexamination if ocular motility information could not be adequately assessed from the medical record. Ocular motility was often difficult to quantify by casual observation because of associated abnormalities of the lid and of the position of the globe within the orbit, making careful assessment and quantitative measurements necessary. An ocular motility disturbance was determined by assessing the extent of excursion (ductional movement) of each eye in all gaze directions with the head in straight-ahead position. An observed ductional deficit was confirmed by identifying a manifest strabismus with the cover-uncover test in that field of gaze and by measuring a change in the size of an already present strabismus as compared to straight ahead position with the prism-cover test.25 Strabismus was diagnosed by the presence of ocular misalignment in at least one position of gaze and was quantified with the prism-cover test. Strabismus was considered comitant if the angle of misalignment was within 5D in gaze right, left, up, and down and incomitant if .5D.26 Downward displacement of the globe (hypoglobus) was diagnosed when the pupil of the affected eye was $2 mm lower than the pupil of the other eye.27 Glaucoma
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Table1. Demographics of patient population Number of patients (N 5 49) Sex (M/F) Mean age, years (range)b Involved side Right Left Bilateral Visual acuity, mean (range)c Large globe Sphenoid dysplasia Orbital NF Cavernous sinus NF Total infiltrating NFd Optic pathway glioma
Percentagea
24/25 22.3 (4-48)
49/51
19 26 4 20/200 (20/20 to NLP) 38 31 25 15 27 9
39 53 8 78 63 51 31 55 18
NF, neurofibroma. a Percentage of total. b Age at last examination. c Based on affected side of unilaterally affected patients and on most affected side of patients with bilateral disease. d Total patients with NF in orbit and/or cavernous sinus on neuroimaging. was defined by the presence of consistently elevated intraocular pressure (.23 mm Hg) with evidence of glaucomatous optic nerve damage. Most patients underwent imaging, either computed tomography (CT) or 3-Tesla magnetic resonance imaging (MRI) or both. This study adhered to the tenets of the Declaration of Helsinki. KKESH Institutional Review Board/Ethics Committee approval was obtained for both the retrospective and prospective components of this study, and signed informed consent was obtained from all examined patients.
Results A total of 84 patients who were followed between 1982 and 2012 were included. Table 1 provides the demographic characteristics of the 49 patients who had OFNF with adequate ocular motility information and neuroimaging for interpretation, 45 of whom had unilateral OFNF and 4 had bilateral involvement. Of the 49 patients, 38 had a large globe ipsilateral to OFNF (defined by the presence of severe axial myopia documented by clinical examination, A-scan, and/or neuroimaging), which commonly affects visual functioning12 and may restrict ocular motility when severe, in combination with other factors (Figure 1A-E). Despite frequent developmental abnormalities involving the orbit and skull, no patient had a striking ocular motility limitation or diplopia except for one patient who developed diplopia due to a superior oblique palsy that occurred after surgical decompression of orbital neurofibromas (Figure 1F-J). General neurologic examinations were normal; in particular, no patient complained of facial numbness ipsilateral to OFNF. Ocular Motility and Strabismus Assessment Table 2 details anatomic abnormalities in these patients that might be relevant to limitation of ocular motility
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FIG 1. Patients with buphthalmos and postoperative superior oblique palsy. Eyes positioned in primary gaze (A, F), right gaze (B, G), left gaze (C, H), upgaze (D, I), and downgaze (E, J). A-E, Patient with buphthalmos on the right due to congenital glaucoma showing moderately restricted ocular motility in all directions. F-J, patient with acquired right superior oblique palsy after decompression of orbital neurofibroma showing right hypertropia in primary gaze (F) worse on left gaze (H). Table 2. Association of anatomic abnormalities by presence and type of strabismus in orbitofacial NF1a Anatomy b
Large globe, no. (%) Sphenoid dysplasia, no. (%) Optic pathway glioma, no. (%) Orbital NF, no. (%) Cavernous sinus NF, no. (%) Total infiltrating NF,c no. (%)
Total
No strabismus (n 5 14)
Comitant strabismus (n 5 8)
Incomitant strabismus (n 5 27)
38 31 9 25 15 27
9 (64) 5 (36) 2 (14) 4 (29) 3 (21) 4 (29)
6 (75) 6 (75) 1 (13) 3 (38) 3 (38) 4 (50)
23 (85) 20 (74) 6 (22) 18 (67) 9 (33) 19 (70)
NF, neurofibroma; NF1, neurofibromatosis type 1; NLP, no light perception. a Percentage of patients in each strabismus category. b Ten patients had ipsilateral glaucoma; the remaining 28 patients had a large globe without glaucoma. c Total patients with NF in orbit and/or cavernous sinus.
and occurrence of strabismus in OFNF, including ipsilateral large globe, sphenoid dysplasia, orbital and cavernous sinus NF, and ipsilateral or bilateral optic pathway glioma. The most common anatomic abnormality in the 14 patients without strabismus was a large globe ipsilateral to OFNF, but 5 also had sphenoid dysplasia and 4 had orbital and/or cavernous sinus NFs (Figure 2). The 8 patients with comitant strabismus more commonly had sphenoid dysplasia and infiltrating neurofibromas in the orbit and cavernous sinus than patients without strabismus, although this was not always the case (see Figure 3). The 27 patients with incomitant strabismus had infiltrating neurofibromas in the orbit more commonly than patients with comitant strabismus or with no strabismus. All of these patients had minor ductional abnormalities and displacement of the globe within the orbit (Figure 4). Table 3 compares visual acuity to type of strabismus in these patients. Patients without strabismus had a mean visual acuity on the affected side of .20/50; none had a visual acuity in either eye of \20/150. Patients with comitant strabismus had mean visual acuity of 20/100 on the side with OFNF; 1 had light perception vision in the contralateral eye due to an optic pathway glioma. The 27 patients with incomitant strabismus had worse visual acuity than patients in the other groups (mean, 20/400), and all had downward displacement of the affected globe and/or ductional abnormalities as well. Anatomic Abnormalities Radiologic changes typical of sphenoid dysplasia were evident in 31 patients (Figures 2 and 4). Of these, 11 had
either no strabismus or comitant strabismus, even though 7 of this number had downward displacement of the affected globe with or without proptosis. The rest had some ductional limitation causing incomitant strabismus, and all but 3 of these had either downward displacement of the affected globe or proptosis or both. Medical record and photographic data in many patients documented a clinical course over a period of years. The visual system can adapt to gradual globe displacement if vision remains good by maintaining a robust fusional response that inhibits the onset of strabismus in some individuals (see e-Supplement 1, available at jaapos.org). Nine patients had pulsatile exophthalmos associated with sphenoid dysplasia, of whom 1 had oscillopsia (Video 1, available at jaapos.org). All patients with pulsatile exophthalmos had strabismus (incomitant in 8) and downward displacement of the globe. Of the 27 patients with tumor infiltrating the orbit or cavernous sinus, 9 had full ductions (Figures 2 and 3) and the remaining 18 patients had relatively minor ductional defects (Figures 4 and e-Supplement 1), possibly due to either mass effect or direct effect on orbital muscles. In the 9 patients with optic pathway glioma, unilateral or bilateral optic pathway glioma coexisted with unilateral (7 patients) or bilateral (2 patients) OFNF. Three had full ocular motility with no obvious proptosis, of whom 2 had no strabismus (each with good vision in both eyes) and one had comitant strabismus (visual acuity 20/800 in one eye). The other 6 patients all had mildly restricted ocular motility. They represented a spectrum of strabismus types (none in 2, comitant in 1, and incomitant in 6), ductional limitations (full motility in 4), and globe displacement
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FIG 2. Patient with no strabismus. Full ocular motility in all directions: primary gaze (A), right gaze (B), left gaze (C), upgaze (D), and downgaze (E) showing. Axial (F), reformatted coronal (G), and reformatted sagittal (H) computed tomogaphy images showing extensive right orbitofacial neurofibroma involving the soft tissues of the temporal fossa (open arrow on F and G) as well as the eyelid (arrows on H), including the medial and lateral canthi (arrows on F). The axial image (F) clearly depicts dysplasia of the greater wing of sphenoid bone on the right side that is seen as thinning and abnormal shape of the bone in addition to enlargement of the superior orbital fissure (double long arrows) compared to the normal fissure (single long arrow) on the left side. The lateral wall of the right orbit is small, irregular, and dysplastic as well. The coronal image (G) shows enlargement of the bony orbit on the right side with involvement of the extraocular muscles.
FIG 3. Patient with vertically comitant strabismus. A-E, External photos of a patient with downward and forward displacement of the right globe showing 30D exotropia and 12D right hypotropia (A), largely unchanged in right gaze (B) and left gaze (C); exotropia was somewhat increased in upgaze (D) and downgaze (E), but right hypotropia was unchanged. F, Axial T2-weighted magnetic resonance (MR) image at the level of the orbits showing extensive right plexiform neurofibroma involving the extraocular muscles, retro-orbital fat, and eyelid, with medial displacement of the optic nerve (arrow). A component of the neurofibroma is seen in the right cavernous sinus (open arrow). There is no sphenoid bone dysplasia. G, Unenhanced coronal T1-weighted MR image showing enlargement of the right orbit due to plexiform neurofibroma involving the extraocular muscles and orbital fat as well as the right temporal fossa. H, Enhanced coronal T1-weighted MR image at the level of the cavernous sinuses clearly depicting a right cavernous mass (open arrow).
(none in 3, downward displacement of the globe in 6, and proptosis in 2).
Discussion This study details ocular motility information on 49 patients with OFNF, of whom 45 had unilateral involvement and 4 had bilateral disease. There is no indication of an increased OFNF frequency in an Arab population; however, KKESH has been the major tertiary eye facility in the region during the 30 years of this study. This may account for the large number of patients, with a selection bias for more advanced cases and a referral pattern that differs from that of OFNF studies emerging from neurofibromatosis clinics1 or the National Neurofibromatosis Foundation International Database.28 OFNF affects facial appearance14 and can also disturb growth patterns of the developing skull,18,19 orbit,15,17 and
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globe,16,29 which in turn affect afferent12 and efferent visual functioning. Sphenoid and orbital dysplasia are prominent skull and facial features that are always ipsilateral to OFNF and that include enlargement of the middle cranial fossa and defects in the greater sphenoid wing and lateral orbital wall. In addition, globe enlargement occurs on the affected side of patients with OFNF under certain circumstances. For obvious reasons, management of certain features of OFNF, such as glaucoma16 and disfiguring facial tumors, tends to fall to ophthalmologists9 and other surgeons. However, neuro-ophthalmologists and neurologists are frequently involved in assessing ocular motility, neuroanatomic changes involving the skull and orbit, pulsatile exophthalmos, and optic pathway gliomas in these patients. Table 2 confirms that most patients in this group had a number of associated abnormalities that might affect ocular motility. Globe size causes a refractive change and potentially a decrease in visual acuity with loss of fusion,16 and a
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FIG 4. Patient with incomitant strabismus. A-E, External photographs. In primary gaze (A) there was 30D of exotropia and 4D of left hypotropia, with downward displacement of the globe. Despite having mild limitation of left eye in adduction (B), abduction (C), elevation (D), and depression (E), prism and cover test measurements met criteria for an incomitant strabismus pattern. F, Axial T2-weighted MR image at the level of the orbits showing remarkable dysplasia of the left greater wing of the sphenoid bone resulting in herniation of brain and meninges into the orbit, anterior displacement of the left globe, and mass effect on the extraocular muscles and optic nerve (open arrow). G, Enhanced axial T1-weighted MR image showing plexiform neurofibroma involving the lateral aspect of the left orbit and eye lid (open arrow) with no cavernous sinus mass. H, Coronal T1weighted MR image showing left greater sphenoid wing dysplasia compared to the normal right side (open arrow).
Table 3. Association of visual acuity by presence and type of strabismus in orbitofacial NF1 Visual acuity, no. (%)a
Total N 5 49
No strabismus (n 5 14)
Comitant strabismus (n 5 8)
Incomitant strabismus (n 5 27)
Better than 20/60, no. (%) 20/60 to 20/200, no. (%) Worse than 20/200, no. (%)
18 13 18
9 (64) 5 (36) 0
2 (25) 4 (50) 2 (25)
7 (26)b 4 (15)c 16 (59)d
NF1, neurofibromatosis type 1; OFNF, orbitofacial neurofibromatosis; OPG, optic pathway glioma. a Visual acuity on the affected side of patients with unilateral OFNF or on the most affected side of patients with bilateral disease. Percentage figures represent percent of patients in that category having that level of visual acuity. b Six had excellent vision bilaterally; 1 had NLP contralateral to facial OFNF due to an OPG. c All patients had a large globe ipsilateral to OFNF; 3 also had sphenoid dysplasia and orbital tumor. d All patients had a large globe (14 patients), sphenoid dysplasia (12), OPG (4), orbital neurofibroma (9), and/or cavernous sinus neurofibroma (6).
very enlarged globe may also restrict ocular ductions. Sphenoid and orbital dysplasia progressively distort the skull and orbit15,18 causing downward displacement of the globe that, when severe, may impede ductions. Orbital and cavernous sinus tumor infiltration is a possible alternative explanation for strabismus.11,19 However, orbital tumor in isolation was never the cause of significant proptosis, and ocular motility restriction was never striking in patients with NF infiltration of the orbit or cavernous sinus. Optic pathway gliomas sometimes decrease visual acuity and affect ocular motility because of globe displacement due to orbital mass effect.30-33 In general, each factor was more common in patients with incomitant strabismus than in patients with comitant strabismus or no strabismus at all. However, these problems appeared at different ages, in different combinations, and with differing degrees of progression and severity in individual patients. Although identifying one factor or combination of factors as more responsible for strabismus was difficult, globe displacement (usually downward and forward) was present in 30 of the 35 patients with strabismus, most commonly associated with a large globe or sphenoid and orbital dysplasia. No one in this group had a severe restriction of ocular motility despite disfiguring distortion of orbital and sphenoid anatomy and obvious downward displacement of the globe in most. No patient had diplopia except for
1 individual who had an acquired right superior oblique palsy after debulking of orbital tumor in adulthood. None had a complete abduction defect or a presentation compatible with partial or complete third cranial nerve palsy. Likewise, no patient with cavernous sinus neurofibroma had facial numbness or exposure keratopathy not explained by proptosis or lid abnormalities, implying that clinically significant compression of the trigeminal nerve within the cavernous sinus was uncommon. NFs are soft and malleable so that they likely mold themselves around orbital and cavernous sinus structures. Therefore, ocular motor nerve compression due to NFs did not seem to be a significant factor in ocular motility limitation, just as it was not a significant factor in visual loss in OFNF.12 The only other efferent symptom in this group was oscillopsia in 1 patient due to pulsatile exophthalmos. This relative paucity of ocular motility symptoms was most commonly due to development of suppression or amblyopia in early severe disease but at times was testimony to the ability of the fusional system to adapt to changes in globe positioning that are sometimes dramatic and progressive into adult life. Patients with OFNF frequently have reduced visual acuity due to amblyopia and anatomic causes such as glaucoma, retinal detachment, and optic pathway glioma,12 and decreased vision clearly played a role in the development
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Volume 18 Number 4 / August 2014 of strabismus by removing part of the substrate necessary to maintain fusion. No patient without strabismus had visual acuity of \20/200 in either eye, whereas almost 60% of patients with strabismus (26/35 patients) had visual acuity of \20/200 in at least one eye. Table 3 confirms that worse vision was associated with an increasing incidence of comitant and incomitant strabismus. Current literature on OFNF appropriately stresses the disfiguring facial manifestations, proptosis, sphenoid and orbital dysplasia, and optic pathway glioma.34 However, strabismus was more frequent and severe than anticipated in the current cohort and resulted from the interplay of reduced vision with anatomic factors disturbing globe size, position, and movement. Orbital tumor almost never seemed to be the sole cause of strabismus in the absence of other factors, and therefore orbital neurofibroma decompression was unlikely to improve ocular motility. Hypoglobus was always accompanied by sphenoid dysplasia on neuroimaging, but proptosis could imply an orbital optic pathway glioma, sphenoid dysplasia, orbital neurofibroma, or a large globe, alone or in combination. Unfortunately, many factors affecting ocular motility in OFNF, including globe enlargement, sphenoid and orbital dysplasia, and NF infiltration of the orbit and cavernous sinus, are currently difficult to treat. Reduced vision, on the other hand, is potentially amenable to treatment of amblyopia and other causes of visual loss,12 which in turn might benefit both ocular motility and visual acuity as these patients age.
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