To evaluate longitudinal changes in circumpapillary retinal nerve fiber layer (RNFL) thickness, as measured by spectral-domain optical coherence tomography (SD OCT), in children with optic pathway gliomas.
Longitudinal cohort study.
Global and quadrant-specific circumpapillary RNFL thickness measures were acquired using either a hand-held SD OCT during sedation or a table-top SD OCT in children old enough to cooperate. Vision loss was defined as either a 0.2 logMAR decline in visual acuity or progression of visual field. Percent change in circumpapillary RNFL thickness in eyes experiencing vision loss was compared to eyes with stable vision.
Fifty-five eyes completed 250 study visits. Ten eyes (18%) from 7 patients experienced a new episode of vision loss during the study and 45 eyes (82%) from 39 patients demonstrated stable vision across study visits. Percent decline of RNFL thickness between the baseline visit and first event of vision loss event was greatest in the superior (−14%) and inferior (−10%) quadrants as well as global average (−13%). Using a threshold of ≥10% decline in RNFL, the positive and negative predictive value for vision loss when 2 or more anatomic sectors were affected was 100% and 94%, respectively.
Children experiencing vision loss from their optic pathway gliomas frequently demonstrate a ≥10% decline of RNFL thickness in 1 or more anatomic sectors. Global average and the inferior quadrant demonstrated the best positive and negative predictive values. Circumpapillary RNFL is a surrogate marker of vision and could be helpful in making treatment decisions for children with optic pathway gliomas.
Spectral-domain optical coherence tomography (SD OCT) measures of circumpapillary retinal nerve fiber layer (RNFL) thickness are used to diagnose and monitor a variety of genetic and acquired optic neuropathies. Understanding the relationship between functional decline (ie, visual acuity or visual field loss) and structure changes (ie, circumpapillary RNFL thickness) is essential to incorporating SD OCT measures into patient management decisions. While glaucoma studies have provided the most insight about the structure-function relationship, disease-specific mechanisms undoubtedly impact this correlation. For example, most glaucoma patients experiencing visual field (VF) loss demonstrate relatively small changes in longitudinal measures of circumpapillary RNFL thickness (eg, approximately 2 μm per year), although acute or undertreated glaucoma can produce more profound declines. On the other hand, patients with Leber hereditary optic neuropathy demonstrate a more rapid decline in retinal axons and vision.
Children with optic pathway gliomas, low-grade gliomas of the anterior visual pathway, require frequent ophthalmologic monitoring, as they can experience visual acuity (VA) and/or VF loss, typically progressing over a period of months to years. Despite treatment with chemotherapy and stability of tumor size, vision loss can occur multiple times throughout childhood. While quantitative VA testing is the recommended metric to monitor tumor progression and treatment response and guide management decisions in these young children, a surrogate marker of vision is desperately needed, since most have difficulty cooperating and accurately completing quantitative VA and VF testing. Previous cross-sectional studies have demonstrated that the amount of circumpapillary RNFL loss is closely related to the magnitude of vision loss, and can readily discriminate between children with and without vision loss from their optic pathway gliomas. In order to determine if circumpapillary RNFL thickness can serve as a surrogate marker of vision in young children with optic pathway gliomas, obtaining SD OCT measures before and after episodes of vision loss is necessary.
The purpose of this study was to examine longitudinal changes in circumpapillary RNFL thickness measures acquired before, during, and after experiencing vision loss from an optic pathway glioma.
Children with optic pathway gliomas receiving their clinical care at Children’s National Medical Center, who were participating in a longitudinal study of SD OCT between January 1, 2012 and December 31, 2014, were eligible for study enrollment. Written informed consent from the parent/guardian and written assent from the child, when applicable, was obtained before study enrollment. The study adhered to the tenets of the Declaration of Helsinki and was approved by the Children’s National Medical Center Institutional Review Board. All data collected were HIPAA compliant.
Diagnosis of an optic pathway glioma was established either by biopsy demonstrating pathologic features consistent with a World Health Organization (WHO) grade I or II low-grade astrocytoma, or by radiographic features for those tumors isolated to the optic nerve. In children with neurofibromatosis type 1, optic pathway gliomas were diagnosed using established National Institutes of Health (NIH) criteria. Patients meeting all of the following inclusion criteria were enrolled: (1) a minimum of 3 separate SD OCT imaging sessions that acquired technically acceptable circumpapillary RNFL measures; (2) successful quantitative VA testing at each study visit; and (3) no ophthalmologic or neurologic conditions, other than the optic pathway glioma, that could potentially damage their visual pathway and affect circumpapillary RNFL thickness measures (eg, hydrocephalus, glaucoma). Patients experiencing vision loss within 3 months prior to study entry were excluded. Portions of data from previously reported studies were included if the additional study visits, meeting the above eligibility criteria, were obtained.
A complete ophthalmologic examination was performed at each study visit. Best-corrected VA using quantitative testing methods (ie, Teller grating acuity or standard recognition acuity methods) were chosen based on the child’s cognitive ability to perform the task using established protocols. VA loss was defined as a decline of 0.2 logarithm of the minimal angle of resolution (logMAR) or more compared to the baseline visit. Patients did not change VA testing formats during the study. Patient age and cooperation determined VF testing method and included testing by confrontation, automated perimetry using standard Humphrey 24-2 strategy (Carl Zeiss Meditec, Dublin, California), or Goldmann kinetic perimetry. Using confrontation methods, only new VF defects determined to be reproducible were considered new events of VF loss. Progressive VF loss using Humphrey 24-2 was defined as 3 or more contiguous points reaching significance ( P < .05). Humphrey VF were included if false-positive errors, false-negative errors, and fixation losses were less than 20%. Goldmann kinetic perimetry was tested using a minimum of V-4-E and I-4-E isopters. Extent of the VF along 12 vectors was confirmed by retesting the response. Goldmann kinetic perimetry VF loss was defined as any constriction greater than 10 degrees across a minimum of 3 contiguous 15-degree vectors using the V-4-E or I-4-E isopter. Either VA or VF loss could be considered an event of vision loss, as both are indications for treatment. If VA and VF occurred at same study visit, this was considered to be 1 event of vision loss.
A standardized form was used to collect the following clinical characteristics: age, sex, race, ethnicity, diagnosis of neurofibromatosis type 1, and location of optic pathway glioma on magnetic resonance imaging. Classification of optic pathway gliomas location were defined as (1) optic nerve only; (2) optic chiasm with or without optic nerve involvement; or (3) optic tracts with or without involvement of the optic nerves or chiasm. Patients with unilateral optic nerve gliomas could only contribute 1 study eye for the analysis, as this was the only eye at risk for vision loss. Patients with abnormal vision at study entry could contribute 2 eyes to the analysis, as they previously demonstrated the greatest intervisit variability. Patients with normal vision who did not experience any events of vision loss could only contribute 1 study eye, chosen by a random number generator, as previous research from our laboratory has established intervisit variability for circumpapillary RNFL thickness measures.
Spectral-Domain Optical Coherence Tomography Image Acquisition and Analysis
Circumpapillary RNFL thickness measures were acquired using either a hand-held SD OCT (Bioptigen, Research Triangle Park, North Carolina, USA) during sedation or a table-top SD OCT (Spectralis; Heidelberg Engineering GmbH, Heidelberg, Germany) in children old enough to cooperate. As stated in the inclusion criteria, at least 1 SD OCT scan had to be acquired before the patient experienced a new episode of vision loss. All study visits were completed on the same SD OCT device. Hand-held SD OCT was acquired according to previously published protocols. After receiving mydriatric eye drops, hand-held SD OCT imaging was performed approximately 1 hour later while the child was sedated for his or her clinically indicated magnetic resonance imaging to monitor the child’s optic pathway glioma. Hand-held SD OCT acquired a 6 × 6 × 2 mm volume scan centered over the optic nerve comprised of either 300 A-scans across 300 B-scans (2.5 second acquisition time) or 1000 A-scans across 100 B-scans (2.8 second acquisition time) for all study visits. Alterations to the working distance of hand-held SD OCT probes were made according to previously published recommendations and adjusted according to the child’s axial length and image quality. Scans with a quality index below 20 were excluded from analysis. Hand-held OCT volumes were de-identified and analyzed by the same investigator (C.-L.C.) using custom software with an established algorithm. If the software could not automatically detect the optic disc margin, it was drawn manually. Then a 3.45 mm circle was placed over the geometric center of the optic nerve head and sampled along 1024 equally spaced A-scans. The 1024 A-scans were equally divided into 4 anatomic quadrants (superior, nasal, inferior, temporal) to measure the circumpapillary RNFL thickness.
In children old enough to cooperate, circumpapillary RNFL measures were acquired with the Spectralis SD OCT (Heidelberg Engineering GmbH) using the “Nsite Analytics” (version 184.108.40.206) and “TruTrack” eye tracking. The eye tracking feature allows the operator to “freeze” the infrared image and accurately center the 3.5 mm circle over the optic nerve head. The highest image quality scan from the baseline visit was chosen as the reference scan, and all future acquisitions were acquired at the same location using the eye tracking feature. All scans were acquired in high-speed mode (768 A-scans) with an automatic real-time (ART) setting of 16. Scans with a signal strength <20 db were discarded. Circumpapillary RNFL thickness measures from the 4 anatomic quadrants (superior, nasal, inferior, temporal) and global average were recorded. All scans were reviewed for segmentation errors and image artifacts by the same investigator (C.T.-H.).
Demographic and clinical characteristics were summarized by standard descriptive statistics (eg, means and standard deviations for continuous variables such as age and percentages for categorical variables such as sex). To account for differences between patient-specific circumpapillary RNFL values at study entry, SD OCT devices, and SD OCT segmentation algorithms, change in circumpapillary RNFL thickness was calculated as a percent change from baseline. A change of ≥10% was chosen a priori, based on previously published intra- and intervisit reproducibility data. Wilcoxon rank-sum was used to compare baseline and final study visit thickness measures between those with stable vision and those who experienced vision loss during the study. Kaplan-Meier curve and Cox proportional hazards models were used to assess the impact of SD OCT measures and clinical characteristics on events of new vision loss. Data were analyzed using commercially available software (STATA, version 13; StataCorp, College Station, Texas, USA).
Fifty-five eyes from 46 patients met inclusion criteria and completed 250 study visits. Ten eyes (18%) from 7 patients experienced 18 distinct episodes of new vision loss during the study and 45 eyes (82%) from 39 patients demonstrated stable vision across a median of 4 study visits ( Table 1 ). Patients were similar in age and most demographic features. A majority of those patients experiencing new vision loss had sporadic optic pathway gliomas, whereas a majority of patients with stable vision had optic pathway gliomas secondary to neurofibromatosis type 1. Ninety percent of patients experiencing new vision loss compared to 38% with stable vision were actively receiving treatment with chemotherapy and/or biologic agents (ie, bevacizumab, MEK inhibitor) during portions of the study. Three patients were excluded from the study because they could not cooperate with quantitative VA testing and another was excluded owing to development of hydrocephalus that required treatment. None of the patients experienced a significant change (ie, ±0.50 spherical equivalents) in their refractive error during the study.
|New Vision Loss (N = 10)||Stable Vision (N = 45)|
|Age, y (mean/median) |
|Female sex, n (%)||5 (50)||30 (67)|
|Race, n (%)|
|White/Caucasian||9 (90)||34 (76)|
|Black/African American||1 (10)||6 (13)|
|Ethnicity, n (%)|
|Non-Hispanic||10 (100)||42 (93)|
|Hispanic||0 (0)||3 (7)|
|Diagnosis, n (%)|
|NF1 – optic pathway glioma||2 (20)||29 (64)|
|Sporadic – optic pathway glioma||8 (80)||16 (36)|
|Treatment of optic pathway glioma, n (%)|
|Never||1 (10)||18 (40)|
|During study||9 (90)||17 (38)|
|Past||0 (0)||10 (22)|
|Total visits, n (mean/median) |
|67 (6.2/5) |
|183 (4.0/4) |
|Duration of enrollment, mo (mean/median) |
|Abnormal vision prior to study entry, n (%)||5 (50)||13 (29)|
|Vision loss events during study a||–|
|Time to event, mo (mean/median) |
|Visual acuity, n (%)||7 (39)||–|
|Visual field, n (%)||8 (44)||–|
|Both visual acuity/field, n (%)||3 (17)||–|
New-onset vision loss during the study was manifested as VA loss only (39%), VF loss only (44%), or both VA and VF loss (17%). Circumpapillary RNFL thickness at the first study visit was generally lower in the new vision loss group as compared to those eyes with stable vision ( Table 2 ), but only reached statistical significance in the temporal quadrant ( P < .05) and global average ( P < .05). Those patients with abnormal vision experienced their vision loss, on average, 26 months (range, 4–48 months) prior to study entry. Given the known differences between SD OCT devices, the analysis was repeated on subjects imaged with the same device. Subjects who experienced vision loss imaged with the hand-held SD OCT demonstrated a thinner RNFL at the first study visit than those without vision loss in the superior and temporal quadrants ( P < .05 and P < .01, respectively). There was no difference in RNFL thickness at the first study visit between groups in those imaged with the table-top SD OCT (Spectralis).
|New Vision Loss (N = 10)||Stable Vision (N = 45)|
|First Visit||Last Visit||First Visit||Last Visit|
|Global||84.7 ± 21.0 a||66.5 ± 18.3 b||104.7 ± 30.5||103.3 ± 29.5|
|Superior||109.7 ± 34.0||86.1 ± 31.7 b||131.3 ± 35.5||131.7 ± 34.3|
|Nasal||65.4 ± 19.9||52.4 ± 18.8 b||81.4 ± 27.6||78.9 ± 26.5|
|Inferior||115.4 ± 25.4||89.1 ± 25.5 b||127.4 ± 37.6||125.1 ± 36.6|
|Temporal||49.4 ± 19.0 a||38.5 ± 16.9 b||76.6 ± 30.1||74.8 ± 28.8|
The circumpapillary RNFL thickness at the last study visit was significantly lower in the new vision loss group ( P < .01 for all locations, except for inferior P < .05). This finding was confirmed using either SD OCT device. Since some eyes had reduced circumpapillary RNFL thickness at study entry, the percent change in circumpapillary RNFL from study entry was calculated and those who experienced vision loss demonstrated approximately 20% decline, whereas those eyes with stable vision did not demonstrate much change ( Table 3 ).
|New Vision Loss (N = 10)||Stable Vision (N = 45)|
|Global||−21 ± 9||−1 ± 3|
|Superior||−21 ± 11||0 ± 4|
|Nasal||−19 ± 14||−1 ± 6|
|Inferior||−23 ± 12||−1 ± 4|
|Temporal||−20 ± 19||−1 ± 6|
Using a threshold of ≥10% decline in circumpapillary RNFL, the number of study visits exceeding this threshold across anatomic location was highest for those eyes experiencing new vision loss ( Table 4 ). Eyes with stable vision during the study did demonstrate visits with a ≥10% decline in circumpapillary RNFL, although most were isolated and occurred in patients with and without abnormal vision prior to study entry. To determine if the decline in quadrant or global average circumpapillary RNFL was consistent, the number of subjects experiencing ≥10% decline on 2 consecutive visits was also calculated ( Table 4 ). In the vision loss group, the 2 consecutive visits with circumpapillary RNFL decline had to occur at the time of vision loss. Three patients not experiencing vision loss had 2 or more consecutive visits with circumpapillary RNFL decline in the superior quadrant. One of these patients had an unusually high baseline measure; therefore all subsequent measures were ≥10% lower, but none of the visits after the baseline visit varied by more than 4%. Another patient with stable vision demonstrated ≥10% decline in the superior quadrant at 2 consecutive visits, although visits following this decline returned to normal in the setting of clinical stability, suggesting that unidentified segmentation or acquisition factors resulted in increased variability. A third eye with stable vision that demonstrated a decline in superior circumpapillary RNFL experienced VF loss in the contralateral eye from a chiasmal optic pathway glioma, suggesting the decline was indeed real but was not enough to manifest as vision loss.
|New Vision Loss (N = 67) c||Stable Vision (N = 183) c|
|Visits With ≥10% Decline||2 Consecutive Visits ≥10% Decline a , b||Visits With ≥10% Decline||2 Consecutive Visits ≥10% Decline a|
|Global||35 (42)||6 (60)||1 (1)||0 (0)|
|Superior||33 (49)||6 (60)||8 (4)||3 (7)|
|Nasal||36 (54)||6 (60)||20 (11)||1 (2)|
|Inferior||30 (45)||5 (50)||5 (3)||0 (0)|
|Temporal||26 (39)||4 (40)||14 (8)||2 (4)|
b Occurring at time of vision loss.