Radiographic Biomarkers and Functional Outcomes of Vision in Optic Pathway Gliomas

Peter de Blank, M.D., MSCE

Case Western Reserve University

Grant Program:

David Mahoney Neuroimaging Program

Funded in:

September 2013, for 3 years

Funding Amount:


Lay Summary

Imaging-derived biomarkers may help physicians preserve vision in children with optic glioma

This first phase of a planned two-phase study will determine whether it is feasible to use two imaging techniques in very young children with optic glioma. If feasible, the investigators propose a second phase to determine if the combined imaging can identify which of the children are at high risk of losing their sight in the future, so that chemotherapy can be initiated early to improve their visual outcomes.

Optic gliomas are low grade tumors that occur in early childhood. Rarely fatal, these tumors do cause permanent and uncorrectable vision loss in about 50 percent of the children. Detecting which children are at risk so that treatment could be started early is impeded by two problems. First, clinicians have a hard time detecting early visual loss because the young children tire quickly and often become uncooperative. Second, there are currently no reliable indicators of future visual acuity problems so physicians delay using chemotherapy until a child’s eyesight actually declines to avoid exposing unaffected children to the risks of this harsh treatment. If there were a “biomarker” in the brain that identified the children likely to lose vision in the future, physicians could initiate early prevention and treatment strategies to preserve vision.

Identifying a biomarker through imaging may be feasible. Visual acuity decreases due to evolving damage to the visual pathway axons (the communication cables that link the eyes to regions of the brain that process sight). The researchers have found that “optical coherence tomography” (OCT) detects cell loss in the retinal nerve fiber layer of the eye that is located in the front part of the visual pathway. This cell loss is correlated with visual loss in children with optical gliomas. OCT cannot, however, assess damage in the optic pathway in the back of the brain, where initial damage may have the capacity to predict future vision loss. Diffusion tensor imaging (DTI) might be able to assess axonal damage. DTI is non-invasive, relatively fast (about four minutes), and does not require the child’s attention.

The investigators hypothesize that DTI detection of early axonal damage will serve as a biomarker for future vision loss. They also hypothesize that combining OCT and DTI may further improve the ability to predict which children will develop vision loss so that treatment can be initiated at the earliest stage. Working with collaborators at the Children’s Hospital of Philadelphia, the investigators initially will assess the feasibility of using both OCT and DTI in a small number of children 12 years or younger to detect biomarkers. Thereafter, a recommendation for phase II may be brought to the Board for consideration. In that phase, investigators would use the combined imaging in a total of 68 children and follow the children’s vision for a year to see if the imaging results accurately identify the children who begin to lose visual acuity. If the biomarkers correlate with vision deficits, the study will help validate the predictive capacity of this combined imaging.

Significance: Reliable predictions of pediatric optic glioma patients who are at risk for developing tumor-induced vision loss would enable physicians to initiate chemotherapy early to maximize each child’s visual outcome. Additionally, the biomarker could be used in future clinical trials to assess the effectiveness of potential new prevention and therapeutic strategies.


Radiographic Biomarkers and Functional Outcomes of Vision in Optic Pathway Gliomas

Development of non-invasive biomarkers of functional outcomes in pediatric brain tumors offers the prospect of early identification, allowing for subsequent preemptive intervention in subclinical disease to improve clinical outcomes. This is particularly evident in optic pathway gliomas (OPGs), where the traditional endpoint of progression-free survival does not correlate with the functional outcome of vision. Although preserving vision is the primary objective in treating OPGs, visual deficits measured by ophthalmologic examination can be difficult to measure accurately due to young age, fatigue or lack of cooperation, and challenging to compare longitudinally due to the variety of measurements (visual acuity, visual field defects) and testing methods (preferential looking tests, recognition acuity). A reliable, quantifiable surrogate measure of vision would help identify subjects with early vision loss who may benefit from early intervention, stratify risk of subsequent vision loss to identify individuals who require therapy, and provide an accessible longitudinal measure of vision for future clinical trials.
In this proposal, we hypothesize that diffusion tensor imaging (DTI) of the optic pathway will serve as a non-invasive imaging biomarker of visual acuity in children with OPGs. By measuring the diffusion of water preferentially along and not across hydrophobic myelin, DTI can identify specific pathways, quantify white matter microstructure, and assess tract integrity. Fractional anisotropy (FA) assesses the uniformity of the direction of diffusion and is sensitive to damage within white matter tracts. We will study white matter tract microstructure and integrity in the optic radiations to investigate the correlation between tract damage and functional outcomes. In the first phase of this study, we will conduct a multi-institutional study of DTI and concurrent ophthalmology evaluations among children with OPGs to validate FA of the optic pathways as a non-invasive biomarker of best-corrected visual acuity. In the second phase of the project, we will prospectively gather longitudinal DTI and ophthalmology evaluations in this cohort to assess whether FA corresponds with changes in visual acuity or predicts future visual acuity changes. We will also investigate a combined biomarker of DTI of the optic radiations and optical coherence tomography (OCT) of the retinal nerve fiber layer to assess microstructural damage and neuronal loss in both the pre-synaptic (OCT) and post-synaptic (DTI) portions of the visual pathway and their association with visual acuity loss.
Through the proposed studies we will investigate the connection between structural damage and functional outcomes in pediatric brain tumors. We will validate and describe a vitally needed biomarker of visual acuity that may be superior to traditional vision assessments in the identification of subclinical visual acuity loss, the measurement of visual deficits and the prediction of future risk of visual acuity loss. This proposal will characterize DTI for future use in clinical trials and investigate a unique combined biomarker to evaluate damage both anterior and posterior portions of the visual pathway.

Investigator Biographies

Peter de Blank, M.D., MSCE

Peter de Blank, MD, MA, MSCE is a graduate of the University of California, San Francisco School of Medicine. He completed a Masters of Arts in English and American Literature at Stanford University, and a Masters of Science in Clinical Epidemiology and Biostatistics at the University of Pennsylvania. He underwent residency in Pediatrics, and fellowships in Pediatric Hematology & Oncology and Pediatric Neuro-Oncology at the Children’s Hospital of Philadelphia. In 2012, Dr. de Blank joined the faculty at Case Western Reserve University as a physician-scientist. He is a practicing Pediatric Neuro-Oncologist and Director of Cancer Survivorship in Pediatric Hematology & Oncology at Rainbow Babies & Children’s Hospital. His research focuses on the development of early radiographic biomarkers of functional complications of brain tumors and brain tumor therapy. Functional, non-invasive biomarkers of important clinical outcomes such as Diffusion Tensor Imaging may improve clinical outcomes, guide early intervention efforts and direct support for children with brain tumors.