To determine the relationship of high-contrast visual acuity (VA) and low-contrast letter acuity with retinal nerve fiber layer (RNFL) thickness in children with optic pathway gliomas.
Cross-sectional convenience sample, with prospective data collection, from a tertiary care children’s hospital of patients with optic pathway gliomas associated with neurofibromatosis type 1, sporadic optic pathway gliomas, and neurofibromatosis type 1 without optic pathway gliomas.
Patients underwent best-corrected VA testing using surrounded H, O, T, V optotypes and low-contrast letter acuity (5%, 2.5%, and 1.25% low-contrast Sloan letter charts). Mean RNFL thickness (micrometers) was measured by a Stratus optical coherence tomography device (Carl Zeiss Meditec) using the fast RNFL thickness protocol. Eyes were classified as having abnormal vision if they had high-contrast VA of more than 0.1 logarithm of the minimal angle of resolution units or visual field loss. The association of subject age, glioma location, and RNFL thickness with both VA and low-contrast letter acuity scores was evaluated by 1-way analysis of variance and linear regression, using the generalized estimating equation approach to account for within-patient intereye correlations.
Eighty-nine eyes of patients with optic pathway gliomas were included, and 41 were classified as having abnormal VA or visual field loss. Reduced RNFL thickness was associated significantly with higher logarithm of the minimal angle of resolution scores for both VA ( P < .001) and all low-contrast letter acuity charts ( P < .001) when accounting for age and glioma location.
Eyes of most children with optic pathway gliomas and decreased RNFL thickness had abnormal VA or visual field loss.
Low-grade gliomas (World Health Organization grade 1 juvenile pilocytic astrocytomas and grade 2 diffuse fibrillary astrocytomas) are the most common central nervous system tumor in children. When low-grade gliomas involve structures of the afferent visual pathway (ie, optic nerve, optic chiasm, optic tract, or optic radiations), they are referred to commonly as optic pathway gliomas. Optic pathway gliomas develop in nearly 20% of children with neurofibromatosis type 1 (NF1), and up to one half of these tumors can cause vision loss. Optic pathway gliomas in children without NF1 are termed sporadic gliomas and are believed to be clinically more aggressive than NF1 associated optic pathway gliomas.
Standard measures of high-contrast visual acuity (VA)—highly dependent on the child’s cooperation—typically are used to screen and monitor vision outcomes in children with optic pathway gliomas. Vision loss from NF1 associated optic pathway gliomas occurs at a median age of 4.9 years, and infrequently occurs after 8 years of age. VA and or visual field (VF) loss resulting from optic pathway gliomas can occur despite improvement, stability, or progression of radiographic findings. As soon as vision loss has occurred, it can remain stable, can improve, or can continue to worsen, regardless of radiographic changes or therapeutic intervention. Because not all optic pathway gliomas cause vision loss, treatment for an optic pathway glioma usually is initiated only after vision loss has been detected, in the hopes of preventing further vision loss, or after significant radiographic progression with associated symptoms. The management of a child with an optic pathway glioma is more challenging in the absence of knowing the child’s VA. Therefore, a reliable quantitative ophthalmologic tool that does not rely on patient cooperation is needed to evaluate optic pathway integrity in children with an optic pathway glioma, particularly in those who are unable to cooperate with VA and VF examinations.
The retinal nerve fiber layer (RNFL), the most proximal region of the afferent visual pathway, has been examined as a structural marker of visual integrity in patients with compressive optic neuropathy resulting from sellar masses and demyelinating optic neuropathy from multiple sclerosis. RNFL thickness, as measured by optical coherence tomography (OCT), is correlated closely with low-contrast letter acuity in patients with multiple sclerosis. Studies of optic neuritis show RNFL thinning over time by OCT, yet eyes of patients with multiple sclerosis and no history of optic neuritis also have RNFL thinning. To the best of our knowledge, no studies have examined whether RNFL thickness could serve as a structural marker of vision loss in children with optic pathway gliomas. The primary aim of this study was to determine the relation of VA and low-contrast letter acuity with RNFL thickness, as measured by OCT, in children with optic pathway gliomas.
A cross-sectional convenience sample with prospective data collection identified candidate subjects between 6 and 21 years of age during their routine clinical visits to the neuro-ophthalmology or neuro-oncology clinics at Children’s Hospital of Philadelphia from July 2009 through January 2010. Children between 6 and 17 years of age required parental or guardian informed consent and, when appropriate, child assent before study enrollment. Participants 18 to 21 years of age provided their own consent. Children in the NF1-associated optic pathway gliomas group were required to have both a diagnosis of NF1 based on established National Institutes of Health criteria and magnetic resonance imaging (MRI) results of the brain demonstrating the presence of optic pathway gliomas. Children in the sporadic optic pathway glioma group required documented MRI findings characteristic of low-grade optic pathway gliomas or diagnostic biopsy results. For purposes of descriptive comparison and a secondary analysis, children with a diagnosis of NF1 but without optic pathway gliomas also were enrolled. Patients were excluded if they had a history of ophthalmologic or neurologic disease, other than optic pathway gliomas, that could have affected their VA or their optic nerve function (eg, amblyopia, cataracts, glaucoma, retinopathy of prematurity, or elevated intracranial pressure requiring ventriculoperitoneal shunting). Healthy control subjects with no significant history of ophthalmologic or neurologic disease were recruited. Institutional review board approval of the protocol and an informed consent form were obtained before study initiation.
Using a standardized form, demographic and clinical data were collected from each patient’s clinical chart including: presence of NF1, history of optic pathway gliomas treatment (ie, chemotherapy or radiation), and VF testing results. Findings for the most recent MRI were abstracted from the formal reading and were classified as follows: no evidence of optic pathway glioma (tortuous optic nerves allowed), optic pathway glioma involving only the optic nerve, and optic pathway glioma involving the optic chiasm and posterior structures, including the hypothalamus.
Best-corrected VA was determined using the electronic visual acuity (EVA) system for pediatric patients. The subject was seated 3 m from the computer monitor in a windowless room. The examination chair was elevated to a level where the subject’s eyes were parallel to the center of the computer monitor. Each eye was tested separately, beginning with the right eye. First, the need for refraction was assessed. Optotypes equivalent to 20/16 were displayed. Children not able to read the 20/16 line accurately were refracted with trial lenses according to a standard protocol. If a refraction had been performed within the past 6 months, this was the subject’s starting refraction. High-contrast VA was tested according to the Amblyopia Treatment Study VA testing protocol with the EVA monitor placed at 3 m. The EVA computer monitor was calibrated for appropriate luminance before each testing session. Single-letter (H, O, T, or V) crowded optotypes were presented in 4 phases: screening, phase 1 (first threshold determination), reinforcement, and phase 2 (second threshold determination). Final VA was the smallest logarithm of the minimal angle of resolution (logMAR) level passed in phase 1 or phase 2.
Low-contrast letter acuity testing of each eye was performed in the same windowless examination room with the lights turned off using a retroilluminated cabinet. Sloan low-contrast letter acuity charts at 5%, 2.5%, and 1.25% contrast level (Precision Vision, LaSalle, Illinois, USA) were presented sequentially at 2 m. Low-contrast letter acuity score (logMAR) for each eye was determined to be the lowest line for which the subject was able to identify correctly at least 3 of the 5 letters.
Definition of Clinical Outcomes
High-contrast VA testing was used to classify eyes as having normal VA (logMAR, ≤ 0.1; 20/25 or better) or abnormal VA (logMAR, > 0.1). VF loss, determined by one coinvestigator (G.T.L.), was defined as any noncentral scotoma (ie, quadrantanopia, hemianopia, VF constriction, arcuate defect, or altitudinal defect) that was detected reliably with automated perimetry or confrontation testing. Our younger subjects, especially those with NF1, are not able to complete automated perimetry reliably; therefore, the VF results were not quantified, but rather categorized as either present or absent. Type of vision loss was classified into categories: normal VA and normal VF results, abnormal VA and normal VF results, normal VA and abnormal VF results, and abnormal VA and abnormal VF results. Patients with unilateral glioma of the optic nerve contributed that eye as an optic pathway glioma eye, whereas their fellow eye was classified as not having an optic pathway glioma. Both eyes were classified as having optic pathway glioma when the optic pathway glioma was present in the optic chiasm, posterior structures, or both.
Optical Coherence Tomography Imaging
RNFL thickness (in micrometers) of each eye was measured using the fast RNFL thickness protocol with a Stratus OCT (Carl Zeiss Meditec, Dublin, California, USA). Scan quality was optimized before imaging each eye by adjusting the polarization. Scanning commenced when the 3.4-mm diameter circle was centered over the optic nerve head as the subject fixated on an external or internal fixation light. Scans with a signal strength of less than 6 were discarded. Three scans were averaged to produce anatomic quadrant and average RNFL thickness in micrometers. If the pupil diameter was not sufficient to obtain OCT images successfully, mydriatic eye drops (1% tropicamide and 2.5% phenylephrine hydrochloride) were used.
Demographic and clinical characteristics were summarized by standard descriptive summaries (eg, means and standard deviations for continuous variables such as age and percentages for categorical variables such as gender). RNFL thickness was categorized into quartiles from the optic pathway glioma patients resulting from the nonlinear association between RNFL thickness and the measures of vision. RNFL measurements from healthy controls and NF1 patients without an optic pathway glioma were not used to calculate the quartiles and were presented for descriptive comparison.
A one-way analysis of variance was used to determine if high-contrast VA (logMAR) and low-contrast letter acuity (logMAR) were associated with RNFL thickness quartiles in patients with optic pathway gliomas. The generalized estimating equation approach to variance estimation was used to account for the correlation between eyes of patients and to provide a robust estimator to accommodate for unequal variance in vision measures among RNFL thickness groups. Similarly, the generalized estimating equation approach also was used in multiple regression analyses to examine the influence of RNFL thickness quartiles, patient age, and tumor location on both high-contrast VA and low-contrast letter acuity in patients with optic pathway gliomas.
Because we were not aware of any previously published studies of RNFL thickness in children with optic pathway gliomas, sample size was calculated using RNFL data from studies of optic neuritis in multiple sclerosis. RNFL thickness differs by roughly 20% between patients with optic neuritis (80 ± 20 μm) and healthy controls (103 ± 12 μm). Setting the α value to 0.01 (based on multiple comparisons) to achieve a power of 0.9 necessitates recruitment of a total of 32 eyes (16 eyes with vision loss and 16 eyes without vision loss). The multivariate model contained 4 variables, and thus required a minimum of 80 study eyes (20 eyes per variable) to achieve sufficient precision.
Sixty-two patients (124 study eyes) were enrolled and attempted to complete the study procedures. OCT imaging was unsuccessful for both eyes in 3 patients and for 1 eye in 7 patients because of patient cooperation, immobile eye, or facial plexiform fibroma impeding the OCT. During the study, one patient originally diagnosed to have NF1 was found to have an as-yet unidentified genetic mutation, and this child’s data were not included in the analysis. Therefore, 58 patients contributed 109 eyes to the study. Forty-eight patients (89 study eyes) had optic pathway gliomas (both eyes, n = 41; one eye, n = 7) and were included in the primary analysis. Fourteen NF1 subjects without an optic pathway glioma (20 study eyes; mean age, 11.3 years; 65% female [9/14]) and 14 healthy controls (28 study eyes; mean age, 11.5 years; 65% female [9/14]) were enrolled. Table 1 lists the demographic and MRI findings for the NF1-associated optic pathway gliomas and sporadic optic pathway glioma patients.
|Characteristics||Study Eyes (N = 89)|
|Range||6.4 to 20.8|
|Female sex, no. (%)||40 (45)|
|Race, no. (%)|
|Multiple races||6 (6.7)|
|Ethnicity, no. (%)|
|Diagnosis, no. (%)|
|NF1 with optic pathway glioma||61 (68.5)|
|Sporadic optic pathway glioma||28 (31.5)|
|Location of optic pathway glioma, no. (%)|
|Optic nerve only||20 (22.5)|
|Optic chiasm and posterior||69 (77.5)|
|Category of vision loss, no. (%)|
|Normal VA/normal VF||48 (53.9)|
|Abnormal VA/normal VF||12 (13.5)|
|Normal VA/abnormal VF||12 (13.5)|
|Abnormal VA/abnormal VF||17 (19.1)|
|Treatment for optic pathway glioma, a no. (%)||70 (78.7)|
|Age at onset b||3.6|
Of those with NF1-associated optic pathway gliomas and sporadic optic pathway gliomas, 48 study eyes were found to have normal high-contrast VA and normal VF results, 12 had decreased VA (> 0.1 logMAR) with normal VF results, 12 had normal VA but an abnormal VF results, and 17 had both abnormal VA and abnormal VF results ( Table 1 ). Table 2 lists the high-contrast VA, low-contrast letter acuity, and RNFL thickness measures for those with normal VA and VF results compared with those with abnormal VA, abnormal VF results, or both, and healthy controls.
|Optic Pathway Glioma Patients||Healthy Control (n = 28)|
|Normal Vision a (n = 48)||Abnormal Vision b (n = 41)|
|High contrast c||–0.0/0.0||0.6/0.3||–0.1/–0.1|
|Visual acuity||(–0.1) to (0.1)||(–0.1) to (1.5)||(–0.1) to (0)|
|Low contrast c||0.3/0.3||0.8/0.7||0.2/0.2|
|Letter acuity (5.0%)||(0.1) to (0.5)||(0.1) to (1.1)||(0.0) to (0.4)|
|Low contrast c||0.4/0.4||0.9/0.9||0.3/0.3|
|Letter acuity (2.5%)||(0.2) to (0.6)||(0.3) to (1.1)||(0.1) to (0.4)|
|Low contrast c||0.6/0.6||1.0/1.1||0.5/0.5|
|Letter acuity (1.25%)||(0.4) to (1.0)||(0.1) to (1.1)||(0.3) to (0.8)|
|Mean RNFL d||101/101||60/56||113/110|
|Micrometers||(45) to (159)||(32) to (120)||(85) to (155)|
Average RNFL thickness in micrometers was divided into quartiles based on the 89 study eyes from patients with optic pathway gliomas: the top 25% (mean, 121.4 μm; standard deviation [SD], 14.3 μm), 51% to 75% (mean, 93.5 μm; SD, 6.1 μm), 26% to 50% (mean, 67.5 μm; SD, 7.5 μm), and 0% to 25% (mean, 44.7μm; SD, 6.8μm). One-way analysis of variance of RNFL quartiles demonstrated significant between-group differences in mean values for high-contrast VA ( F = 27.45; P < .001), 5% low-contrast letter acuity ( F = 36.45; P < .001), 2.5% low-contrast letter acuity ( F = 36.28; P < .001), and 1.25% low-contrast letter acuity ( F = 25.53; P < .001).
Table 3 lists the unadjusted and adjusted multiple regression analysis of the effect of RNFL quartile, age, and optic pathway glioma location on high-contrast VA in optic pathway glioma patients. In unadjusted and adjusted analysis, the bottom 2 RNFL quartiles were associated with worse VA scores. Figure 1 is a scatterplot of VA and average RNFL thickness. Higher RNFL thickness (approximately > 80 μm) was associated with uniformly normal or near normal VA, whereas lower RNFL thickness was associated with worse VA scores, but with wide variability in VA at particular RNFL thickness values.
|Variable||Unadjusted Coefficient||Adjusted Coefficient||95% Confidence Interval||P Value a|
|76% to 100%||Reference||Reference||Reference||Reference|
|51% to 75%||0.034||0.034||–0.06 to 0.13||.489|
|26% to 50%||0.192 b||0.240||0.05 to 0.43||.014|
|0% to 25%||0.857 c||0.882||0.64 to 1.13||< .001|
|Age||–0.012||–0.014||–0.03 to 0.01||.242|
|Optic pathway glioma location|
|Optic chiasm and posterior||0.104||0.044||–0.17 to 0.09||.504|