Neurofibromatosis type 1 (NF-1) is a multi-system dominantly inherited disorder with an estimated worldwide incidence of 1:3,500.1 However, approximately half of NF-1 cases occur due to new mutations.2 Patients with NF-1 are predisposed to develop benign intracranial neoplasms, including optic pathway gliomas, which occur in 15% to 25% of patients and typically develop between the ages of 3 and 5 years.3 Although many optic pathway gliomas remain benign and never progress or become symptomatic, previous studies indicate that some may cause ophthalmologic disturbances, including vision loss, proptosis, optic atrophy, and strabismus.4–8 However, no previous studies have analyzed the rate of strabismus in patients with NF-1 with normal neuroimaging or calculated the increased risk of strabismus development specifically when optic pathway glioma is present. Consequently, the purpose of this study was to evaluate the prevalence of strabismus in NF-1 by comparing children with normal neuroimaging to those with optic pathway glioma.
Patients and Methods
In a review of all children with NF-1 examined between 2000 and 2016 at the Gilbert Israeli Neurofibromatosis Center, a national tertiary referral center for patients with neurofibromatosis, we retrospectively collected data based on the diagnostic criteria as established by the National Institutes of Health.9 Only children who had brain magnetic resonance imaging as part of their evaluation were included in the analysis, and presence of strabismus was used as the primary outcome measure. Strabismus rates were compared between children with NF-1 with normal neuroimaging and those with an optic pathway glioma involving the optic nerves and/or chiasm. The study was approved by the institutional review board and was performed in accordance with its rules and regulations.
Data including age, sex, visual acuity, presence or absence of strabismus, and neuroimaging findings were collected based on a review of patients' initial and most recent follow-up eye examinations. When strabismus was present, additional information was recorded, including type (sensory versus non-sensory), direction (esotropia, exotropia, or vertical deviation), and whether or not surgical correction was performed. Strabismus type was labeled non-sensory if the patient's visual acuity was better than 20/100 and the optic disc appeared normal in both eyes. Conversely, strabismus type was labeled sensory if the patient's visual acuity was worse than 20/100 in either eye in addition to optic disc atrophy.
Statistical analysis was conducted using Graph-Pad Prism software (version 7; GraphPad Software Inc., San Diego, CA). The association between the presence of optic pathway glioma and strabismus was analyzed using an odds ratio. The risk of strabismus development in children with optic pathway glioma was calculated using relative risk. Spearman's correlation coefficient was also calculated between the presence of strabismus and visual acuity of the worse-seeing eye converted into the logarithm of minimum angle of resolution (logMAR). Fisher's exact test was used to compare strabismus rates and types according to the presence of optic pathway glioma. All statistical tests performed were two-tailed, and statistical significance was defined as a P value of less than .05.
A total of 236 children with NF-1 were seen at our clinic during the study period. Of these, 38 children who did not have brain magnetic resonance imaging were excluded from analysis. Of the remaining 198, 109 (55%) were male, 121 (61%) had normal neuroimaging, and 77 (39%) had an optic pathway glioma. Thirty-eight (49%) optic pathway gliomas affected one optic nerve, 9 (12%) affected both optic nerves, 11 (14%) affected the chiasm alone, and 19 (25%) affected both optic nerves and the chiasm. Sixty-four (83%) optic pathway gliomas were found prior to the child's initial eye examination at our clinic, and an additional 13 (17%) optic pathway gliomas were identified during follow-up appointments. The mean age at presentation was 6.3 ± 4.7 years (range: 9 months to 17 years) and was significantly lower in children with optic pathway glioma (5.3 ± 0.5 years) than in children who had normal neuroimaging (6.8 ± 0.4 years; P = .02, unpaired t test). Mean follow-up after presentation was 4.8 ± 3.1 years (range: 2 months to 16 years).
Strabismus was found during the initial ophthalmological examination in 21 (11%) children, including 7 (6%) with normal neuroimaging and 14 (18%) with an optic pathway glioma. Of these 14 optic pathway gliomas, 13 (93%) were already known at the time of the first eye examination and 1 (7%) was found later when imaging was performed. During the most recent follow-up examination, 29 (15%) children had strabismus. The prevalence of strabismus was significantly higher among children with optic pathway glioma (21 of 77 [27%]) than among children with NF-1 and normal neuroim-aging (8 of 121 [7%], P < .001, Fisher's exact test; Figure 1). Fifteen (8%) children had exodeviations, 11 (6%) had esodeviations, and 3 (2%) had vertical deviations. The direction of ocular misalignment in children with NF-1 with optic pathway glioma was not significantly different from that observed in children without optic pathway glioma (P = .197, Fisher's exact test). Overall, sensory strabismus was the most common type of strabismus identified in children with optic pathway glioma, during both initial presentation (8 of 14 [57%]) and most recent examination (12 of 21 [57%]). In contrast, children with NF-1 with normal neuroimaging all had non-sensory strabismus (P = .003, Fisher's exact test).
Prevalence of strabismus in children with neurofibromatosis type 1 (NF-1) with and without optic pathway glioma (OPG).
A strong association between optic pathway glioma and strabismus is demonstrated by an odds ratio of 5.29 (95% confidence interval: 2.17 to 12.1; P < .001). Children with NF-1 with optic pathway glioma have a 4.13 times higher risk of developing strabismus than children with NF-1 without optic pathway glioma (95% confidence interval: 1.97 to 8.73; P = .001). In children with optic pathway glioma, Spearman's correlation coefficient between visual acuity in the worse-seeing eye and presence of strabismus was statistically significant (r = 0.335, P = .003). Only 5 (17%) children with NF-1 with strabismus (3 with optic pathway glioma) underwent surgery to correct their ocular misalignment, including 2 esodeviations, 2 vertical deviations, and 1 exodeviation.
In this study, we found that children with NF-1 with optic pathway glioma are approximately four times more likely to develop strabismus (often sensory) than children with NF-1 without this tumor.
Several studies reported that strabismus is a possible outcome of optic pathway glioma in patients with NF-1; however, the frequency of strabismus in these studies varies widely, primarily because of differences in rates of symptomatic optic pathway glioma.4,5,7,8,10 For example, Parness-Yossifon et al.7 reviewed 76 pediatric patients with NF-1 with optic pathway glioma involving the optic nerve and/or chiasm and reported that 22 (29%) had strabismus when last examined. Conversely, in reviewing 12 children with NF-1 with orbital optic pathway glioma, Zeid et al.8 found strabismus in 6 (50%). King et al.10 reported strabismus in 6 of 51 (12%) children with NF-1 with symptomatic optic pathway glioma. Furthermore, Kaufman and Doroftei5 reported that 2 of 3 (66%) pediatric patients with NF-1 with optic pathway glioma and unilateral vision loss had ipsilateral exotropia. Finally, Castanheira-Dinis et al.4 reviewed the visual outcome of 75 patients with NF-1 and reported that 2 had strabismus secondary to optic pathway glioma and reduced visual acuity. Similarly, our study identified a strong association between optic pathway glioma and strabismus development. However, analysis of strabismus rates according to neuroimaging findings indicated that the presence of optic pathway glioma increases the chances of strabismus by 4.13 fold. Similar to other reports, most strabismus cases analyzed in this study were sensory at both initial presentation and the last follow-up examination.5,7,11,12
There is an ongoing debate among clinicians concerning whether routine neuroimaging should be performed in all children with NF-1, even when asymptomatic. Proponents of routine neuroimaging base their approach on three facts: (1) one-third of pediatric patients with NF-1 have optic pathway glioma, (2) children with optic pathway glioma frequently do not complain of vision loss, especially when it is unilaterally reduced, and (3) early detection of optic pathway glioma and intervention in symptomatic cases may improve visual acuity.13,14 However, other physicians counter that asymptomatic optic pathway glioma detection does not alter patient clinical outcomes, because normal magnetic resonance imaging results do not exclude the possibility of later optic pathway glioma development. Furthermore, opposing physicians posit that detection of asymptomatic optic pathway glioma causes increased anxiety among patients and their caregivers, requiring additional costs and sedation for continued neuroimaging to monitor changes.15,16
In 1997, the National Institutes of Health published guidelines for screening, monitoring, and treating optic pathway gliomas in patients with NF-1,17 recommending that a complete ophthalmological examination be performed at diagnosis followed by an annual examination until the patient reaches 7 years of age. Subsequent examinations can occur after longer intervals. The guidelines only recommend neuroimaging when optic pathway glioma is clinically suspected. Ophthalmological signs suggestive of symptomatic optic pathway glioma include proptosis, reduced visual acuity, nystagmus, disturbed color vision, visual field defect, abnormal pupillary response, and optic disc edema or atrophy. Our study provides support for the increased prevalence of strabismus in children with optic pathway glioma and the need for neuroimaging in children with NF-1 when ocular misalignment is present. In our study, most children who developed strabismus already had a known optic pathway glioma, but some developed strabismus prior to optic pathway glioma diagnosis. Although previous studies indicated that exotropia is the most common type of ocular misalignment in children with NF-1 with optic pathway glioma,5,7 our results suggest that the direction of ocular mis-alignment is not a reliable predictor of the presence of optic pathway glioma.
Prior studies also reported that only a minority of children with NF-1 with strabismus undergo corrective surgery, even if the angle of ocular deviation is large.7 Similarly, only 17% of patients analyzed in this study had strabismus surgery. Reluctance to undergo corrective strabismus surgery among children with NF-1 may stem from the fact that the surgery typically can only alleviate the cosmetic ocular mis-alignment without a significant change in vision and the achieved outcome may be temporary.18
This study's results should be interpreted within the context of its limitations. Because data were collected retrospectively based on chart reviews, it is subject to variability depending on the accuracy and completeness of records. Furthermore, because all children with NF-1 included were examined in a tertiary referral medical center, they may not accurately represent the entire pediatric population of patients with NF-1.
Optic pathway glioma in children with NF-1 is associated with an increased risk of strabismus, especially sensory strabismus. Although exotropia is the most common ocular misalignment associated with optic pathway glioma, the direction of strabismus cannot be used as an accurate predictor for the presence of optic pathway glioma. Many children with NF-1 with strabismus do not undergo corrective surgery.
- Abdolrahimzadeh B, Piraino DC, Albanese G, Cruciani F, Rahimi S. Neurofibromatosis: an update of ophthalmic characteristics and applications of optical coherence tomography. Clin Ophthalmol. 2016;10:851–860.
- Jett K, Friedman JM. Clinical and genetic aspects of neurofibromatosis 1. Genet Med. 2010;12:1–11. doi:10.1097/GIM.0b013e3181bf15e3 [CrossRef]
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- Listernick R, Ferner RE, Liu GT, Gutmann DH. Optic pathway gliomas in neurofibromatosis-1: controversies and recommendations. Ann Neurol. 2007;61:189–198. doi:10.1002/ana.21107 [CrossRef]
- Parness-Yossifon R, Listernick R, Charrow J, Barto H, Zeid JL. Strabismus in patients with neurofibromatosis type 1-associated optic pathway glioma. J AAPOS. 2015;19:422–425. doi:10.1016/j.jaapos.2015.06.003 [CrossRef]
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- King A, Listernick R, Charrow J, Piersall L, Gutmann DH. Optic pathway gliomas in neurofibromatosis type 1: the effect of presenting symptoms on outcome. Am J Med Genet A. 2003;122A:95–99. doi:10.1002/ajmg.a.20211 [CrossRef]
- Ganesh S, Gupta A, Sharma M, Bhuttan S. A case of neurofibromatosis 1 presenting with optic pathway glioma with an early onset and an aggressive course. Indian J Ophthalmol. 2008;56:161–162. doi:10.4103/0301-4738.39128 [CrossRef]
- Listernick R, Darling C, Greenwald M, Strauss L, Charrow J. Optic pathway tumors in children: the effect of neurofibromatosis type 1 on clinical manifestations and natural history. J Pediatr. 1995;127:718–722. doi:10.1016/S0022-3476(95)70159-1 [CrossRef]
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- Pilling RF, Lloyd IC, Huson S. Utility of optic pathway glioma screening in young children with neurofibromatosis type I: questions generated by a clinical audit. Eye (Lond). 2010;24:1603–1605. doi:10.1038/eye.2010.99 [CrossRef]
- 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;41:143–149. doi:10.1002/ana.410410204 [CrossRef]
- Dotan G, Nelson LB, Mezad-Koursh D, Stolovitch C, Cohen Y, Morad Y. Surgical outcome of strabismus surgery in patients with unilateral vision loss and horizontal strabismus. J Pediatr Ophthalmol Strabismus. 2014;51:294–298. doi:10.3928/01913913-20140709-02 [CrossRef]