Definition and Epidemiology

Approximately 10% of all OPGs are confined to the optic nerve ( Fig. 17.1 ). Isolated optic nerve gliomas do not infiltrate the eye, but due to increasing size may compress the posterior globe. Isolated OPGs of the optic chiasm account for about one third of the cases, and OPGs of both the optic nerve and optic chiasm account for another one third of the cases. Involvement of the optic chiasm and posterior structures (e.g., optic tracts and thalamus) account for one fourth of cases.

Juvenile pilocytic astrocytomas (World Health Organization grade 1) are the most common central nervous system tumors in children1 and comprise the overwhelming majority of OPGs.2 A smaller portion of OPGs are diffuse fibrillary astrocytomas (grade 2) or other astrocytoma subtypes.3,4 Because isolated optic nerve gliomas or optic chiasm OPGs are intrinsic to the structures of the visual pathway or are located near critical structures (e.g., the circle of Willis), biopsy is often deferred to avoid functional deficits or complications from this diagnostic procedure. Thus, the exact tumor grade is not confirmed in a large number of cases.

More than half of the OPG cases occur in children with neurofibromatosis type 1 (NF-1), a common neurocutaneous genetic condition with an incidence of 1:3,500 births.5 Nearly 20% of children with NF-1 will develop OPGs, of which up to 50% can be symptomatic and cause vision loss.6,7 Sporadic OPGs, typically used to describe OPGs in children without NF-1, are believed to be more aggressive with poorer clinical outcomes.8,9

Clinical Presentation

Optic/visual pathway gliomas confined to the optic nerve are discovered when the patient is noticed to have proptosis ( Fig. 17.2 ) or decreased ocular motility, or they complain of visual loss. Pure optic nerve gliomas occur more frequently in children with NF-1, so this population is observed more closely for the development of proptosis.8,10 In children with NF-1, symptomatic orbital gliomas are detected at a mean of 26 months of age and they almost always develop proptosis11 ( Table 17.1 ).

The clinical presentation of OPGs involving the optic chiasm ( Figs. 17.3 and 17.4 ), hypothalamus, optic tracts ( Fig. 17.5 ), or optic radiations is heterogenous. In preverbal children, clinical signs and symptoms such as horizontal pendular nystagmus, papilledema, strabismus (misalignment of the eyes), vision loss, and optic nerve pallor lead to the discovery of OPGs. If a chiasmal OPG obstructs the third ventricle, patients may complain of headache secondary to hydrocephalus.

Symptoms and treatment of OPGs in children with NF-1 typically occur before the age of 6 years.6,7,12 Although rare, newly symptomatic OPGs in children with NF-1 have been reported after age 8 years,12 occasionally in the setting of previously normal neuroimaging.13,14 Most sporadic OPGs also present before 8 years of age,9,15 but have been reported to present in the second decade ( Table 17.2 ).

Natural History

The natural history of sporadic and NF-1–associated OPG is unpredictable. Most case series in children with NF-1 report that the OPG becomes symptomatic in one third to one half of all cases.13,16 Sporadic OPGs, reported to be more aggressive,8,9 are discovered only after they become symptomatic, thereby limiting the ability to determine their true prevalence and natural history. Spontaneous radiographic regression in size and enhancement characteristics have been reported in both NF-1–associated and sporadic OPGs.17–21 However, improvement in the radiographic findings does not guarantee improvement in visual function.19

Diagnostic and Imaging Features

High-resolution magnetic resonance imaging (MRI) of the brain and orbits with and without contrast is recommended for all children suspected of and monitored for OPGs. T1-weighted images are typically isointense, whereas T2-weighted images can be a mixture of isointense and hyperintense signal. Enhancement with gadolinium is frequently present and may occur throughout or along the border of the OPG. Involvement of the optic tracts and radiations may demonstrate more diffuse enhancement rather than a focal, well-circumscribed pattern ( Table 17.3 ). Cystic rather than solid features are reported more frequently in sporadic OPGs. Children with NF-1 are frequently found to have tortuous optic nerves with dilated optic nerve sheaths that do not enhance and should not be classified as an OPG.22 Despite good criteria between normal nerves and tortuous nerves, classifying between tortuous nerves and OPG has not been well described. Unfortunately, tumor progression and vision-related clinical outcomes cannot be predicted by imaging findings at baseline or throughout treatment.9,23,24 Specifically, OPG enhancement can resolve or tumor size remain stable or regress, yet visual acuity and visual fields may decline.24

Pathology of Optic Pathway Gliomas

An overwhelming majority of OPGs are juvenile-pilocytic-astroctyomas, with the remainder being diffuse-fibrillary-astroctyomas or other low-grade glioma variants.3,4 When these lesion are biopsied, often only small fragments of tumor are available for study, making it difficult to confirm that the tumor is a pilocytic glioma rather than another low-grade variant. The pilomyxoid variant of pilocytic astrocytoma has been reported primarily in younger children and may have a greater tendency to disseminate the nervous system early in the course of illness.25,26 The fibrillary variant of the chiasmatic low-grade glioma may act somewhat more aggressively and is somewhat more common in children without neurofibromatosis. High-grade gliomas of the visual pathway are rare, occurring predominantly in adults.27 Although histological and immunohistochemical studies of visual pathway gliomas may demonstrate few mitoses and a low mitotic index, prompting some to suggest visual pathway gliomas are instead hamartomas, these lesions can demonstrate radiographic progression and cause significant neurologic and visual impairment.28

Molecular Aspects

Advances in molecular genetics and understanding of the RAS/RAF/MEK/MAPK pathway have provided much needed insight regarding low-grade gliomas including visual pathway tumors. The protein product of the NF gene neurofibromin regulates RAS signaling by conversion of active guanosine triphosphate (GTP)-bound RAS to inactive guanosine diphosphate (GDP)-bound RAS. The loss of neurofibromin function, as is seen in NF-1, activates the RAS/MAPK pathway and allows for tumor proliferation and tumorigenesis.29,30 Upregulation of the mammalian target of rapamycin (mTOR) via the RAS pathway also occurs after inactivation of the NF-1 gene and decreases apoptosis and promotes tumorigenesis. The biological underpinnings of non–NF-1 chiasmatic gliomas has recently been better clarified. The majority of pilocytic astrocytomas are due to mutation of BRAF, a part of the RAS/RAF/MEK/MAPK pathway. This is usually due to a fusion gene incorporating elements of the KIAA-1549 gene. This activating gene mutation, at the 7_q34 gene locus, results in amplification of the kinase domain of BRAF and secondary activation of the MAPK pathway.31–33 Thus, the same pathway is activated in NF and non–NF-related tumors through different mechanisms. Less commonly, BRAF can be activated in sporadic tumors by point mutations of BRAF, point mutations or duplications of RAF1, and point mutations of KRAS.

Management Strategies

The management of pediatric OPG requires a multidisciplinary team with expertise in pediatric neuro-oncology, neuroophthalmology, and neurosurgery. Significant radiographic progression and concern about declining visual function are the main factors determining the need for medical or surgical treatment. Recent guidelines for clinical monitoring of OPG in children with NF-1 can also be modified to care for those with sporadic OPG.12 Children with NF-1 should have a complete ophthalmologic exam every year until 8 years of age, and then every 2 years thereafter. NF-1 children younger than 8 years of age with suspected ophthalmologic abnormalities or that have an OPG should have an ophthalmologic exam every 6 months until age 8. If an OPG becomes symptomatic (e.g., vision loss) or treatment with chemotherapy is initiated, eye examinations should be performed every 3 months for the first year.

The neuro-ophthalmologic exam should always include a quantitative assessment of visual acuity, testing each eye separately. In preverbal or developmentally delayed children, Teller grating acuity provides a quantitative, highly reproducible measure of visual acuity that can be performed in children as young as 6 months of age.34 Testing of color vision, visual fields, pupils, ocular motility, and alignment, and visualization of the optic nerve should be performed at every examination. The visual field examination should be attempted in all children, regardless of their age, by an ophthalmologist or neuro-ophthalmologist experienced in caring for young children. Although computerized automated perimetry testing is ideal, most children under 8 to 10 years of age cannot reliably perform the automated visual field test. Arc perimetry and Goldman visual field testing are labor intensive, but can be reliable quantitative measures of visual fields in infants and toddlers.35–37

Visual evoked potentials (VEPs) have been a proposed screening and visual outcome measure in children with OPG,38–41 but are not recommended due to poor diagnostic sensitivity, especially with chiasm and postchiasm OPG.12,42 Optical coherence tomography (OCT) provides a high-resolution structural measure of the retinal nerve fiber layer—the most proximal portion of the visual pathway. Measurements of the retinal nerve fiber layer have shown a strong relationship with visual acuity and visual field defects in children with OPG.43 Before retinal nerve fiber layer thickness can be considered a surrogate marker of visual integrity, longitudinal studies are needed.

Operative Treatment

The surgical approach to OPG has become more conservative over the last decade. OPG confined to the intraorbital optic nerve should not be resected unless significant cosmetic disfigurement or corneal exposure is present. Intraorbital OPGs rarely, if ever, spread or grow (posteriorly) back into the optic chiasm; thus, no therapeutic benefit results from surgery. Because OPGs are typically intrinsic to the axons of the visual pathway, even biopsy presents a risk for a functional deficit, and biopsy may be more seriously considered if ipsilateral visual loss is already significant.

If surgery is undertaken for tumors isolated to the optic nerve, then globe-sparing procedures should be performed whenever possible. These tumors can be approached in different ways. One common approach is extradurally via unilateral frontal craniotomy and orbitotomy. An ipsilateral fronto-orbital approach, with orbitozygomatic osteotomy allowing for extradural exposure of the nerve is preferred and gives excellent exposure. The nerve is divided proximally and distally, allowing globe-sparing resection. If there is radiographic tumor extending intracranially, then intradural exposure is necessary. The optic canal is unroofed, the anterior clinoid process may be removed, and the dura opened to allow visualization of the nerve and chiasm. If the tumor extends to the chiasm, surgery is often purposefully incomplete, so as not to risk damage to the nasal fibers from the contralateral eye.

Radical partial resections or debulking of chiasmatic tumors is infrequently undertaken and is usually restricted to tumors that have failed other means of therapy or are causing significant neurologic impairment or hydrocephalus due to tumor size or cystic elements. Such diffuse visual pathway tumors often infiltrate and compress surrounding neural structures, such as the hypothalamus and thalamus. More globular, cystic tumors, typically pilocystic and soft, are more amenable to surgical decompression. The goals of surgical debulking include diagnosis and decompression in specific circumstances. A variety of different surgical approaches can be utilized for visual pathway tumor resection including subfrontal, pterional/transsylvian, transcortical, subtemporal, and interhemispheric transcallosal, or through a combination of exposures. Optimally, the approach should take into consideration the functional visual status of the patient. Attempts should be made to avoid injuring pathways from the contralateral eye in attempts to preserve visual field. Given the infiltrative nature of these lesions, and the tremendous size of some, it may be impossible, even with real-time intraoperative ultrasound, computed tomography (CT), or MRI, to know whether lesional tissue is also functional tissue. After extensive surgical resections, even in cases where specific areas of the visual pathway were avoided and postoperative imaging reveals a resection isolated only to the tumor, there can be significant loss of vision secondary to edema or manipulation of the visual pathway, and injury to the hypothalamus or diencephalon. That is, even modest resections of large tumors may be associated with severe neurologic sequelae including difficulties in arousal, motor difficulties, and even, in rare cases, vegetative states.44

More commonly, when surgery is undertaken for patients with visual pathway gliomas, the goals of surgery are predominantly to make a tissue diagnosis to guide further treatment. This is primarily done in children without NF-1. In these cases, biopsies can also be performed by a variety of different approaches, dependent on the size and location of the tumor and the preoperative visual and neurologic function of the child. Even after minimal resection, visual loss may occur unilaterally or contralaterally to the area of surgical resection.

A variety of new techniques are available that may aid in increasing the safety of surgery for these deep-seated, infiltrating lesions. Diffusion-weighted imaging (DWI) and associated tractography may facilitate a better understanding of the visual pathway prior to the initiation of surgery. Intraoperative adjuncts such as endoscopy, image guidance, and real-time imaging with MRI, CT, and ultrasound may alone or in combination enable safer, more focused, and less invasive surgery. Although complete resection of these infiltrative lesions may seem at times feasible, the resultant neurologic, ophthalmologic, and endocrinologic devastation should keep the surgeon′s intention focused on diagnosis and relief of symptoms.