Neurofibromatosis Type 2-Related Eye Disease Correlated With Genetic Severity Type

Objective: Neurofibromatosis type 2 (NF2) is an uncommon but well-recognized disorder characterized by multiple schwannomas and meningiomas. Adults typically present with hearing loss and balance disturbance, and children with ocular, dermatological, and neurological signs. Clinical diagnosis is confirmed by neuroimaging and genetic testing. Although ophthalmic features are present in patients with NF2, there are no reports correlating genetic severity subtypes with ophthalmic involvement. Methods: We retrospectively reviewed longitudinal ophthalmological data of 83 patients with NF2, with known genetic severity subtype, to determine visual function over time. We created a scoring system (Oxford NF2 Ophthalmic Score [ONOS]) to quantify visually debilitating pathology. Results: The prevalence of optic atrophy, combined hamartomas, cataract, and epiretinal membranes significantly increased with genetic severity. Median age of survival to visual acuity worse than 1.0 logarithm of minimum angle of resolution in one eye significantly decreased with genetic severity and was 38 years in the genetically severe group, 49 years in moderate classics, 64 years in mild classics, and 84 years in the tissue mosaics. In the genetically severe, the visually damaging pathologies were largely untreatable. The ONOS correlated with genetic severity longitudinally and cross-sectionally. Conclusions: Mutations associated with severe systemic disease result in greater visual morbidity at an earlier age. Those with tissue mosaicism are unlikely to have visually debilitating pathology secondary to NF2. Potentially treatable sources of damage to vision, however, affect all groups and must be identified early and treated effectively to retain useful vision throughout life.

Original Contribution Neurofibromatosis Type 2-Related Eye Disease Correlated With Genetic Severity Type Sally L. Painter, MA, MB, BChir, FRCOphth, Zuzana Sipkova, BM, BS, FRCOphth, Beatrice Emmanouil, PhD, Dorothy Halliday, PhD, MBBS, FRCP, Allyson Parry, MB, ChB, DPhil, FRCP, John S. Elston, MD, FRCOphth Objective: Neurofibromatosis type 2 (NF2) is an uncommon but well-recognized disorder characterized by multiple schwannomas and meningiomas. Adults typically present with hearing loss and balance disturbance, and children with ocular, dermatological, and neurological signs. Clinical diagnosis is confirmed by neuroimaging and genetic testing. Although ophthalmic features are present in patients with NF2, there are no reports correlating genetic severity subtypes with ophthalmic involvement. Methods: We retrospectively reviewed longitudinal ophthalmological data of 83 patients with NF2, with known genetic severity subtype, to determine visual function over time. We created a scoring system (Oxford NF2 Ophthalmic Score [ONOS]) to quantify visually debilitating pathology. Results: The prevalence of optic atrophy, combined hamartomas, cataract, and epiretinal membranes significantly increased with genetic severity. Median age of survival to visual acuity worse than 1.0 logarithm of minimum angle of resolution in one eye significantly decreased with genetic severity and was 38 years in the genetically severe group, 49 years in moderate classics, 64 years in mild classics, and 84 years in the tissue mosaics. In the genetically severe, the visually damaging pathologies were largely untreatable. The ONOS correlated with genetic severity longitudinally and cross-sectionally. Conclusions: Mutations associated with severe systemic disease result in greater visual morbidity at an earlier age. Those with tissue mosaicism are unlikely to have visually debilitating pathology secondary to NF2. Potentially treatable sources of damage to vision, however, affect all groups and must be identified early and treated effectively to retain useful vision throughout life. Journal of Neuro-Ophthalmology 2019;39:44-49 doi: 10.1097/WNO.0000000000000675 © 2018 by North American Neuro-Ophthalmology Society Oxford Eye Hospital (SLP, ZS, JSE), John Radcliffe Hospital, Headley Way, Headington Oxford, United Kingdom; Department of Neurology (BE, AP), John Radcliffe Hospital; and Oxford Centre for Genomic Medicine (DH), Nuffield Orthopaedic Hospital, Oxford, United Kingdom. The authors report no conflicts of interest. Address correspondence to Sally L. Painter, MA, MB, BChir, FRCOphth, Oxford Eye Hospital, John Radcliffe Hospital, Headley Way, Headington, Oxford OX3 9DU, United Kingdom; E-mail: [e-mail] 44 N eurofibromatosis type 2 (NF2) is an inherited tumor suppressor disease characterized principally by the development of tumors of the central and peripheral nervous system. Bilateral vestibular schwannomas are the hallmark of the condition and cranial, spinal, and peripheral nerve schwannomas also develop. Intracranial and spinal meningioma, often multiple, and ependymoma are other characteristic tumors. The NF2 gene is on chromosome 22q11.2. A range of pathogenic mutations have been identified, and it is known that overall disease severity is strongly associated with the type and extent of mutation (1,2). Truncating mutations are associated with the most severe phenotype, earlier presentation, and severe morbidity (3,4). Quality of life evaluations in individuals with NF2 of all severities identify hearing loss and balance disturbance, the complications of facial palsy and the impact of the condition on employment as major causes of morbidity (5,6). Impaired vision is a particular handicap in those with substantial hearing loss. Ophthalmological features of NF2 have been well described (7). These features have begun to be correlated with genetic severity (8). The extent to which vision is affected and the practical issues that follow are not well recognized. In childhood, visual development may be compromised by congenital anomalies of the optic disc, retinal hamartomas, and juvenile cataracts (9-11). Refractive error, amblyopia with compromise of binocular visual development, is common (12,13). NF2-related optic nerve sheath meningioma may develop in childhood or adolescence and usually progresses to blindness in the involved eye (14). In adulthood, optic nerve function may be damaged by extrinsic tumorous compression or raised intracranial pressure (ICP) (7,15). Vision also may be impaired by corneal opacity secondary to the combination of neurotrophic and neuroparalytic keratitis. Diplopia may be due to a third-nerve schwannoma or cavernous sinus meningioma (7,16); Painter et al: J Neuro-Ophthalmol 2019; 39: 44-49 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution nystagmus also may be present. All these pathologies summate to reduce visual function. The aims of our study were to: 1. Identify the ophthalmological conditions responsible for reduced visual function in patients with NF2, measure their effect on specific measurable parameters of vision, and generate an ophthalmic pathology score (Oxford NF2 Ophthalmic Score [ONOS]); 2. Correlate the ONOS with the individuals' genotype as defined by the UK NF2 genetic severity score to determine genotype-phenotype correlations (8). METHODS Patients Clinical data were reviewed retrospectively from patients attending a national NF2 service provided at the Oxford University Hospitals NHS Foundation Trust, under the care of the multidisciplinary team. All patients had a confirmed diagnosis of NF2 with a mutation present on blood testing, or identical mutations found in 2 or more tissue samples, or they met the updated Manchester modified criteria for a clinical diagnosis of NF2 (17). Data were collected on age, sex, and classified according to genotype, based on a validated NF2 genetic severity score as 1. tissue mosaic, 2A. mild classic, 2B. moderate classic, and 3. severe (17). All patients with NF2 had a full ophthalmological examination on initial evaluation and were re-examined annually at a minimum. Any individual whose visual function was compromised was reviewed according to standard clinical protocols or when seen for other NF2-related issues. The examination protocol included ophthalmic history; bestcorrected visual acuity (logarithm of minimum angle of resolution [logMAR]) in each eye and binocularly; ocular motility and dilated fundoscopy; assessment of facial nerve function (including House-Brackmann score) and corneal sensation; and where indicated visual field testing, visual electrophysiology, optical coherence tomography, and neuroimaging. C. Persistent corneal damage secondary to facial palsy and corneal anesthesia. The highest possible score for an individual was 10. A higher ONOS indicated the presence of more visiondamaging pathology. An individual's score would increase if new pathology developed. Statistical Analyses All statistical analyses were conducted using SPSS 23. Summary statistics were reported, and the statistical significance of inferences was set to 5%. To account for multiple comparisons, Bonferroni-corrected P values were reported. Genetic severity was treated as an ordinal variable, and Spearman correlations were used to assess relationships between variables after visual confirmation of monotonic relationships of pairs of variables using scatterplots. Trends in proportions of eyes affected by ophthalmic pathologies with genetic severity were investigated using Mantel- Haenszel linear-by-linear x2 tests of association. Differences in the distributions of demographic variables between genetic severity groups were investigated using Kruskal- Wallis H tests. Changes in ONOS from baseline were investigated using Wilcoxon signed-rank test. Survival distributions for different genetic severity groups and median ages were compared by generating actuarial tables and using life table algorithms, and trends in survival times were investigated using Mantel-Cox tests (18,19). RESULTS Demographics Eighty-three patients fulfilled the Manchester criteria for a clinical diagnosis of NF2 and were included in the study. The genotype distribution was representative of the NF2 population as a whole (Table 2), and patients were unselected except by geographical locality. Patients with more severe genotype were diagnosed younger (P , 0.001). There were no differences between genetic severity groups in terms of sex or in the distributions of years of follow-up. Oxford NF2 Ophthalmic Score Ophthalmological Assessments Ophthalmological findings were categorized as follows (Table 1): Reduced Visual Acuity Our initial examinations of the effect of genetic severity on visual acuity revealed that the percentage of patients with visual impairment in one eye (LogMAR .0.3) at both diagnosis and latest assessment were significantly higher for severe patients (42% and 50%, respectively) and decreased to 15% and 12% for tissue mosaics (Table 3). Of the 83 patients in our study, 8 patients (with tissue mosaicism and normal vision) had only a single examination. All other patients had a minimum of two examinations. We found a statistically significant trend (x2 = 17.10, P , 0.001) with a marked reduction in the age of loss of A. Ocular or visual developmental anomalies: • optic nerve dysplasia • congenital combined hamartoma involving central retina or optic nerve B. Visual deficits acquired secondary to neurological complications of NF2: • ocular motor deficits due to third, fourth, or sixth nerve palsy • optic atrophy Painter et al: J Neuro-Ophthalmol 2019; 39: 44-49 45 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 1. Oxford NF2 Ophthalmic Score Pathology Optic nerve/macula hamartoma Facial nerve palsy/corneal scarring (House-Brackmann score $5) Visual acuity less than or equal to 6/12 (0.3 LogMAR) Optic atrophy Third/fourth/sixth nerve palsy Total for each eye Right Eye Left Eye /1 /1 /1 /1 /1 /1 /1 /1 /5 /1 /1 /5 severity both at diagnosis (rs(81) = 0.45, P , 0.001) and at last assessment (rs(81) = 0.42, P , 0.001) (Table 5). Overall, the ONOS score captured the progression of visual function impairment in patients with NF2 as there was a statistically significant increase of ONOS from baseline to latest assessment (P , 0.001). There was a statistically significant weak positive correlation (rs(75) = 0.24, P = 0.04) of ONOS annual rate of increase with genetic severity indicating that the more severe patients seemed to acquire visually significant pathologies at a faster rate compared with milder-genotype patients. LogMAR, logarithm of minimum angle of resolution; NF2, neurofibromatosis type 2. DISCUSSION vision in one eye (LogMAR $1) with increased genetic severity. Patients who reached this endpoint had visual loss due to optic atrophy (various causes, n = 3), corneal damage secondary to facial nerve palsy (n = 1), or combined hamartoma involving the macula (n = 4). The median age of survival to loss of vision in one eye was 84 years for tissue mosaic patients, whereas 50% of severe patients lost eyesight in one eye by the age of 38 years (Table 4). Although the median survival ages were overall significantly different across genetic severity groups (P , 0.001), pairwise comparisons revealed that there were no statistically significant differences when comparing the median ages of mild classics (64 years) to moderate classics (49 years). Ophthalmic Pathologies The percentages of eyes affected by different ophthalmic pathologies were separated across different genetic severity groups (Fig. 1). We found that NF2 genetic severity was associated with increasing prevalence of combined hamartoma, epiretinal membranes (ERMs), and optic atrophy. To avoid confounding NF2-related lens changes with those due to advancing age, we selected patients with juvenile posterior lens opacities of plaque-like morphology and found an increased proportion of eyes that were affected by cataract with increasing NF2 genetic severity. Oxford NF2 Ophthalmic Score Using a combination of visual acuity and visually significant ophthalmic pathologies, the ONOS reflects the overall impact of NF2 on visual function. As expected, the ONOS score was moderately positively correlated with genetic Pathologies Affecting Vision Ocular The most common ocular pathologies identified were combined hamartoma (n = 11), ERM (n = 12), and cataract (n = 32) (Fig. 1). Combined hamartoma increase in size over time causing worsening vision; complications include retinal traction and ERM. There is no effective treatment (19,20). Juvenile cataracts, with a characteristic posterior cortical location and plaque or shield morphology, were identified in 32 individuals but none were deemed visually significant and none required surgery. Facial Nerve Palsy Loss of facial nerve function (n = 33) occurs either directly due to vestibular or facial nerve schwannoma or secondary to surgical treatment. Contemporary treatment modalities may reduce the incidence of this complication. An unrecovered facial palsy is particularly likely to result in corneal damage and opacity if the cornea is anesthetic (neurotrophic keratopathy). Surgical management may be required, including lower eyelid tightening/shortening, tarsorrhaphy, or upper eyelid gold or platinum weight. Pathologies Causing Optic Atrophy Optic atrophy was seen in 17/83 patients, with the highest prevalence in the severe group. Atrophy was due to tumors of the optic nerve, or as a result of increased ICP. Optic nerve sheath meningioma was diagnosed in 3 children at ages 8, 9, and 16 years (2 genetically severe and one moderate). One adult had bilateral meningiomas diagnosed TABLE 2. NF2 genetic severity Number of patients Male:female Average age at diagnosis (yr) (range) Average years of follow-up (range) Tissue Mosaic (1) Mild Classic (2A) Moderate Classic (2B) Severe (3) 34 12:22 48.7 (22-80) 15.1 (1-30) 19 12:7 26.3 (6-60) 6.0 (1-16) 18 10:8 18.8 (1-44) 5.72 (1-16) 12 6:6 12.5 (1-29) 9.83 (2-20) NF2, neurofibromatosis type 2. 46 Painter et al: J Neuro-Ophthalmol 2019; 39: 44-49 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 3. NF2 genetic severity Visual Acuity Worse Than 0.3 LogMAR: Tissue Mosaic (1), N = 34 In one eye at presentation* In one eye at most recent assessment* Bilaterally at presentation Bilaterally at most recent assessment 5 4 0 0 14.7% 11.8% 0.0% 0.0% Mild Classic (2A), N = 19 6 6 0 2 Moderate Classic (2B), N = 18 31.6% 31.6% 0.0% 10.5% 8 7 1 2 Severe (3), N = 12 44.4% 38.9% 5.6% 11.1% 5 6 1 2 41.7% 50.0% 8.3% 16.7% *Statistically significant association. LogMAR, logarithm of minimum angle of resolution; NF2, neurofibromatosis type 2. at age 63 years (mosaic). The cases aged 8 and 16 years were not treated, and all vision in the affected eye was progressively lost over 2 and 4 years, respectively. Fractionated radiotherapy could be considered for these patients; this carries a 10%-15% risk of radiation retinopathy, and in patients carrying a tumor suppressor gene, the possibility of second tumors (22). Compression of the anterior visual pathways by a parasellar meningioma is a potential cause of progressive optic nerve dysfunction and atrophy. Such tumors were identified in 2 individuals; one, with an anterior clinoid meningioma, did not lose vision while the other, with pre-existing optic atrophy secondary to a period of raised ICP, sustained damage to the optic tract resulting in a homonymous visual field defect and poor vision. Both had severe genetic mutations. Optic atrophy developing secondary to chronic papilledema occurred in all groups, apart from those with mosaicism. The chronic papilledema was usually due to multiple intracranial meningiomas. This is a difficult neurosurgical management problem as total tumor load removal is not possible. Other therapeutic measure to be considered included medication, CSF diversion procedures, and optic nerve sheath fenestration (14). Ocular Motor Cranial Nerve Palsies Partial bilateral third nerve palsies of infantile onset were evident in one patient with severe mutation. A persistent third nerve palsy developed in another child in the first decade of life, and a relapsing third nerve palsy with recovery on 2 occasions but persistently on the third occasion was the presenting feature in another child. All these children had severe mutations. Neuroimaging showed a third nerve schwannoma in the last case, and the same pathology was assumed to be responsible in the other 2 patients. Although cavernous sinus meningioma was identified in some cases, combinations of ocular motor palsies did not always develop. One patient had unilateral partial fourth nerve palsy. Double vision due to an ocular motor palsy, either isolated or in combination, was difficult to treat, compounded, in NF2, by progression of the eye movement deficit over time. Prism correction may be helpful. A patient with a stable, fourth nerve palsy had binocular function restored by surgery. Painter et al: J Neuro-Ophthalmol 2019; 39: 44-49 Most other affected individuals were either able to ignore or suppress double vision or patched 1 eye. Nystagmus Although gaze-evoked nystagmus frequently was observed in our patient cohort, there were no individuals whose vision was judged to be compromised by fixation instability alone. This may, in part, be due to the relative symmetry of the underlying pathology (bilateral vestibular schwanommas) and the relatively slow progression over time allowing time for compensatory mechanisms to reduce symptoms. Visual Field Changes The most frequent cause of visual field deficits sufficient to preclude driving (failure to meet the Driver and Vehicle Licensing Agency binocular Estermann criteria) was optic atrophy. In one patient, an occipital meningioma caused homonymous visual field loss. More often, another NF2related issue, such as epilepsy or physical incapacity, precluded driving or working, or both. Visual Acuity Over Time With the exception of 8 individuals with tissue mosaicism and normal vision at presentation, the vision of each eye of each patient was recorded at least once per year. The severe mutation group included children with a parent with NF2 in whom screening began at young age. In addition, new mutations with a severe genotype typically were evaluated in the first or second decade. This group had worse vision at a younger age, usually due to a combination of ocular pathologies-optic nerve dysplasia TABLE 4. NF2 genetic severity Tissue Mild Moderate Mosaic Classic Classic Severe (1) (2A) (2B) (3) Median age of LogMAR .1 in one eye (yr)* 84 64 49 38 *Statistically significant association. LogMAR, logarithm of minimum angle of resolution; NF2, neurofibromatosis type 2. 47 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 1. Neurofibromatosis type 2 (NF2)-related ophthalmic pathology by genetic severity group. Asterisk (*) denotes a statistically significant trend in the proportion of eyes affected by that pathology with NF2 genetic severity. (one case age 2 years), and combined hamartoma (2 cases ages 4 and 8 years). These patients were likely to have refractive errors, amblyopia, and fail to develop binocular vision. In addition, they were the group most likely to lose further vision over time, principally due to optic nerve meningioma, progression of combined hamartoma, or corneal scarring (Table 4). Visual acuity also declined substantially over time in moderate genotype patients because of either optic nerve damage secondary to intracranial tumors or raised ICP or corneal opacity. The adverse outcome for vision in these individuals was, therefore, potentially preventable. In mild genotypes, good vision is preserved into the seventh decade of life, whereas mosaicism individuals retained age appropriate visual function (Table 4). Oxford NF2 Ophthalmic Score The ONOS provided an easily calculated number that gave an indication of overall visual function. Stability of the score indicated that visual function remained unchanged. Identifi- cation of an individual whose score was increasing signified a potentially treatable cause for the change. The ONOS can be used as an element of on-going quality of life assessment in patient with NF2. Reduced visual function has a disproportionate impact on individuals whose activities are already compromised by hearing loss, balance, and coordination problems (5). As well as early identification of treatable conditions, ONOS alerts the medical team to the importance of appropriate counseling and referral for those patients with established visual deficits. This may include certification of visual impairment and involvement of the visual impairment teacher for children in school. In conclusion, the genotype of an individual with NF2 correlated with the level of visual function at diagnosis and the likelihood of deterioration over time. For those with severe genotype, the pathologies that progressed and further reduced vision over time currently were difficult to treat. These individuals required consistent monitoring to identify and treat potential complications, particularly raised ICP and neurotrophic keratopathy. TABLE 5. NF2 genetic severity ONOS at diagnosis (mean ± SD)* ONOS at most recent appointment (mean ± SD)* Tissue Mosaic (1) Mild Classic (2A) Moderate Classic (2B) Severe (3) 0.09 ± 0.29 0.38 ± 0.78 0.26 ± 0.56 0.37 ± 0.68 0.61 ± 1.02 1.50 ± 1.69 1.17 ± 1.11 2.33 ± 2.35 *Statistically significant association. NF2, neurofibromatosis type 2; ONOS, Oxford NF2 Ophthalmic Score; SD, standard deviation. 48 Painter et al: J Neuro-Ophthalmol 2019; 39: 44-49 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution Moderate NF2 is associated with reduced vision over time due principally to the potentially treatable complications of raised ICP and facial palsy. In the mild genotype patients, over one-quarter of cases will develop a facial palsy and nearly 20% optic atrophy. Long-term visual prognosis is, however, good. Individuals with mosaicism have a good long-term visual prognosis, and interventions to protect vision are rarely needed in this group. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: S. L. Painter, Z. Sipkova, D. Halliday, B. Emmanouil, A. Parry, and J. S. Elston; b. Acquisition of data: S. L. Painter, and Z. Sipkova; c. Analysis and interpretation of data: S. L. Painter, Z. Sipkova; D. Halliday, B. Emmanouil, A. Parry, and J. S. Elston. Category 2: a. Drafting the manuscript: S. L. Painter, Z. Sipokva, B. Emmanouil, D. Halliday, A. Parry, and J. S. Elston; b. Revising it for intellectual content: D. Halliday, A. Parry, and J. S. Elston. Category 3: a. Final approval of the completed manuscript: S. L. Painter, Z. Sipkova; D. Halliday, B. Emmanouil, A. Parry, and J. S. Elston. 8. 9. 10. 11. 12. 13. 14. 15. REFERENCES 1. Baser ME, Kuramoto L, Joe H, Friedman JM, Wallace AJ, Gillespie JE, Ramsden RT, Evans DG. Genotype-phenotype correlations for nervous system tumors in neurofibromatosis 2: a population-based study. Am J Hum Genet. 2004;75:231-239. 2. Kluwe L, Bayer S, Baser ME, Hazim W, Haase W, Funsterer C, Mautner VF. Identification of NF2 germ-line mutations and comparison with neurofibromatosis 2 phenotypes. Hum Genet. 1996;98:534-538. 3. Selvanathan SK, Shenton A, Ferner R, Wallace AJ, Huson SM, Ramsden RT, Evans DG. Further genotype-phenotype correlations in neurofibromatosis 2. Clin Genet. 2010;77:163-170. 4. Evans DG. Neurofibromatosis type 2 (NF2): a clinical and molecular review. Orphanet J Rare Dis. 2009;4:16. 5. Cosetti MK, Golfinos JG, Roland JT Jr. Quality of life (QoL) assessment in patients with neurofibromatosis type 2 (NF2). Otolaryngol Head Neck Surg. 2015;153:599-605. 6. Neary WJ, Hillier VF, Flute T, Stephens SD, Ramsden RT, Evans DG. The relationship between patients' perception of the effects of neurofibromatosis type 2 and the domains of the Short Form-36. Clin Otolaryngol. 2010;35:291-299. 7. Bosch MM, Boltshauser E, Harpes P, Landau K. Ophthalmologic findings and long-term course in patients with Painter et al: J Neuro-Ophthalmol 2019; 39: 44-49 16. 17. 18. 19. 20. 21. 22. neurofibromatosis type 2. Am J Ophthalmol. 2006;141:1068- 1077. Halliday D, Emmanouil B, Pretorious P, MacKeith S, Painter S, Tomkins H, Evans DG, Parry A. Genetic severity score predicts clinical phenotype in NF2. J Med Genet Published Online First. Doi: 10.1136/jmedgenet-2017-104519. Ruggieri M, Iannetti P, Polizzi A, La Mantia I, Spalice A, Giliberto O, Platania N, Gabriele AL, Albanese V, Pavone L. Earliest clinical manifestations and natural history of neurofibromatosis type 2 (NF2) in childhood: a study of 24 patients. Neuropediatrics. 2005;36:21-34. Evans DG, Huson SM, Donnai D, Neary W, Blair V, Newton V, Harris R. A clinical study of type 2 neurofibromatosis. Q J Med. 1992;84:603-618. MacCollin M, Mautner VF. The diagnosis and management of neurofibromatosis 2 in childhood. Semin Pediatr Neurol. 1998;5:243-252. Akinc A, Acaroglu G, Guven A, Degerliyurt A. Refractive errors in neurofibromatosis type 1 and type 2. Br J Ophthalmol. 2007;91:746-748. Nunes F, MacCollin M. Neurofibromatosis 2 in the pediatric population. J Child Neurol. 2003;18:718-724. Bosch MM, Wichmann WW, Boltshauser E, Landau K. Optic nerve sheath meningiomas in patients with neurofibromatosis type 2. Arch Ophthalmol. 2006;124:379-385. Thomas DA, Trobe JD, Cornblath WT. Visual loss secondary to increased intracranial pressure in neurofibromatosis type 2. Arch Ophthalmol. 1999;117:1650-1653. Barrett VJ, Tan MH, Elston JS. Recurrent third nerve palsy as the presenting feature of neurofibromatosis 2. J Neuroophthalmol. 2012;32:329-331. Smith MJ, Bowes NL, Bulman M, Gokhale C, Wallace AK, King AT, Lloyd SK, Rutherford SA, Hammerbeck-Ward CL, Freeman SR, Evans DG. Revisiting neurofibromatosis type 2 diagnostic criteria to exclude LZTR1-related schwannomatosis. Neurology. 2017;88:87-92. Gehan EA. Statistical methods for survival time studies. In: Staquet MJ, ed. Cancer Therapy: Prognostic Factors and Criteria. New York, NY: Raven Press, 1975:7-36. Lee E, Desu M. A computer program for comparing k samples with right censored data. Computer Programs Biomed. 1972;2:315-321. McLaughlin ME, Pepin SM, Maccollin M, Choopong P, Lessell S. Ocular pathologic findings of neurofibromatosis type 2. Arch Ophthalmol. 2007;125:389-394. Han DP, Chin M, Simons KB, Albert DM. Surgical removal of an atypical macular epiretinal membrane in neurofibromatosis type 2: clinicopathologic correlation and visual outcome. Arch Ophthalmol. 2012;130:1337-1339. Lesser RL, Knisely JP, Wang SL, Yu JB, Kupersmith MJ. Longterm response to fractionated radiotherapy of presumed optic nerve sheath meningioma. Br J Ophthalmol. 2010;94:559-563. 49 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.