Optic Pathway Gliomas Secondary to Neurofibromatosis Type 1☆
Introduction
Neurofibromatosis type 1 (NF1) is a relatively common autosomal dominant genetic condition with an incidence of 1:3000 births.1 Approximately 20% of these children will have an optic pathway glioma (OPG),2, 3, 4, 5 which is a low-grade neoplasm of the visual pathway that represent 2%-5% of all childhood brain tumors.6, 7 They occur primarily in young children. OPGs are diagnosed with brain magnetic resonance imaging (MRI), frequently prompted by clinical suspicion. There is no need for biopsy of OPGs given the high risk of vision loss from the procedure8 and the pathognomonic MRI features.9, 10 The management of OPGs is challenging given the lack of evidence-based guidelines, difficult ophthalmic examination in young children, and unusual tumor behavior. The varied and unpredictable growth of OPGs has produced disagreement among specialists on how to best manage these complex cases. More recently, the research community and clinical care teams have come together, united in investigating the most effective surveillance and management of OPGs in children. An international multicenter natural history study of OPG, funded by the Children’s Tumor Foundation, is underway allowing the research community to take a monumental step toward better understanding of OPGs by analyzing clinical, imaging, biological, and treatment data from the largest cohort of children with NF1-associated OPGs.
We will review the current understanding of the molecular mechanisms of OPGs and their clinical presentation in children. A brief overview of the diagnostic evaluation and surveillance recommendations will lead to a focused discussion of the new imaging techniques and modalities that may add greater precision to monitoring these tumors. OPGs occur sporadically in children and adults without NF1 (sporadic type); however, this review focuses primarily on OPGs secondary to NF1.
Section snippets
Molecular Mechanisms
OPGs are predominantly juvenile pilocytic astrocytomas (low-grade glioma); however, fibrillary astrocytoma (grade II, World Health Organization) and other low-grade glioma variants have rarely been reported.11, 12, 13 OPGs are intrinsic to the axons of the visual pathway and can involve any of the following structures in isolation or combined with adjacent ones: optic nerve, chiasm, tracts, radiations, and hypothalamus. OPGs most commonly involve the anterior pregeniculate pathway; however,
Clinical Presentation
NF1-associated OPGs are most frequently diagnosed before 6 years of age; however, this is highly dependent on whether radiologic screening is performed (see section MRI Evaluation).2, 9 A recent large study found that all children ages 0-15 months old with normal brain and orbital MRIs did not develop symptomatic OPGs at a later age4; however, there have been cases of newly symptomatic OPGs in children with NF1 occurring later in childhood and early adolescence.9, 25, 26, 27
Most NF1-associated
Diagnostic Evaluation
Examination guidelines for children with NF1 have been developed by expert consensus.9, 35 The following provides an overview of the neuro-ophthalmic examination and the possible signs encountered.
Visual acuity is the most important factor guiding the decision to observe without treatment or initiate or change treatment in NF1-associated OPGs.9, 31, 35 Visual acuity, the clarity or sharpness of vision, is measured by using a Snellen chart that is reported as a fraction (ie, 20/20) and the
MRI Evaluation
The standard imaging for OPGs is an MRI of the brain and orbits with thin slices through the optic nerves and chiasm. Fat saturated sequences better delineate the tumors on gadolinium-enhanced images. OPGs are usually isointense on T1 and isointense to hyperintense on T2 sequences. OPGs can demonstrate enlargement of the optic nerve(s) (Fig. 1), chiasm (Fig. 2A), optic tract (Fig. 2B), and optic radiations. OPGs confined to the optic nerve usually have a tubular or fusiform appearance and can
Treatment Decisions and Outcomes
The unpredictable behavior of OPGs has resulted in much controversy of how to best manage and treat OPGs. Once discovered, OPGs can remain stable, grow, or spontaneously regress despite intervention or lack thereof. Numerous studies have assessed prognostic factors in OPGs; however, these have been mired by the lack of standardized outcome measures.37 Prior years of research driven mainly by neuro-oncologists quantified presence or absence of disease progression by changes on MRI, whereas more
New Imaging Techniques and Biomarkers for NF1-Associated OPGs
The above challenges in making evidence-based management and treatment decisions has prompted scientists to explore novel biomarkers of vision as well as improved ways to quantitatively measure NF1-associated OPGs. As a significant number of patients treated are young (ie, under 2 years old), these biomarkers must be readily obtained in children who cannot cooperate with traditional vision assessments. The goals of imaging research have been to (1) develop reliable imaging parameters to
Conclusions
The clinical assessment and management of children with NF1-associated OPGs remains challenging. A comprehensive ophthalmic examination that includes a quantitative assessment of visual acuity is the best metric to make informed treatment decisions. The relevance of MRI features and their change is still unclear, yet this is one of the most common reasons why neuro-oncologists treat NF1-associated OPGs. New MRI and OCT imaging protocols may not only elucidate the biologic behavior of these
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Supported in part by the National Eye Institute, Bethesda, MD, USA (K23-EY022673, RAA).