Optic Gliomas: Past, Present, and Future

Jacobson Lecture Daniel M. Jacobson, MD Daniel M. Jacobson, MD, completed neurology training at the University of Pittsburgh and neuro-ophthalmology fellowship at the University of Iowa. He joined the staff of the Marshfield Clinic in Marshfield, Wisconsin, in the Departments of Neurosciences and Ophthalmology in 1987 with a faculty appointment at the University of Wisconsin. During a 16-year period at the Marshfield Clinic, Dr. Jacobson cared for thousands of patients and authored more than 50 scientific manuscripts in the field of neuro-ophthalmology. He was honored with numerous teaching and research awards and recognized for his ability to apply basic science principles to the investigation of the most pressing clinical issues. The Marshfield Clinic Foundation has established a memorial fund in his name. In recognition of the profound impact Dr. Jacobson had on the field of neuro-ophthalmology, the North American Neuro-Ophthalmology Society has established a lecture to be presented each year at the NANOS meeting. Optic Gliomas: Past, Present, and Future Neil R. Miller, MD Journal of Neuro-Ophthalmology 2016;36:460-473 doi: 10.1097/WNO.0000000000000439 © 2016 by North American Neuro-Ophthalmology Society some system of clinical staging that considers both the location of the tumor and visual function may be helpful in patient management (3-5). OPTIC NERVE GLIOMAS T he term "optic glioma" refers to glial tumors that involve the anterior visual pathway-optic nerves, optic chiasm, and optic tracts. These tumors are composed primarily of pilocytic astrocytes (1). The presenting symptoms and signs, management, and prognosis may vary, depending on whether the tumor is confined to one optic nerve or involves the optic chiasm (2). Many investigators do not consider this concept important, choosing to consider all these tumors as a single clinical entity and calling them all "optic gliomas" or "gliomas of the anterior visual pathway." In this article, however, I will use the term "optic nerve glioma" (ONG) to describe tumors that appear to involve only 1 optic nerve and the term "optic chiasmal glioma" (OCG) to describe tumors that involve the optic chiasm, whether or not they also involve 1 or both optic nerves, the optic tracts and/or the hypothalamus. These 2 types of tumors will be reviewed here as separate clinical entities, in agreement with the idea that The Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, Maryland. The author reports no conflicts of interest. Address correspondence to Neil R. Miller, MD, The Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Woods 458, 600 North Wolfe Street, Baltimore, MD 21287; E-mail: [e-mail] 460 Demographics ONGs comprise approximately 1% of all intracranial tumors (6). They usually are unilateral and occur more frequently in females than in males (6,7). Approximately 75% of patients with ONGs become symptomatic in the first decade of life, and 90% become symptomatic during the first 2 decades of life (8). In one series of 33 patients with histologically verified ONGs, the age range was 2-46 years, with a median age of 6.5 years and a mean age of 10.9 years (9). Nevertheless, even elderly patients can develop these lesions (10). Clinical Manifestations The manifestations of ONGs can be separated into anterior presentations or posterior presentations or as an asymptomatic mass. The anterior presentation consists of unilateral decreased acuity and color vision associated with a variable visual field defect, an ipsilateral relative afferent pupillary defect, moderate-to-severe proptosis that may be axial but that often is associated with hypoglobus, strabismus, and optic disc swelling (Fig. 1) that may or may not be associated with Paton lines, retinochoroidal striae, or even a central retinal vein occlusion (CRVO) that may result in rubeosis iridis and neovascular glaucoma (11,12). The Miller: J Neuro-Ophthalmol 2016; 36: 460-473 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Jacobson Lecture with optic nerve or chiasmal gliomas ranges from 10% to 70% in large series, probably reflecting the differing degrees of thoroughness with which investigators examined their patients for the stigmata of NF1, different institutional biases, and patterns of referral. Conversely, the prevalence of ONGs in patients with NF1 ranges from 7.8% based on clinical findings (20) to 31% based on magnetic resonance imaging (MRI) (21). Interestingly, it has been suggested that macrocephaly may be an intrinsic marker for an ONG in children with NF1 (22). Diagnosis The diagnosis of an ONG usually can be made with confidence by either computed tomography (CT) or MRI (23,24). The appearance typically is that of a fusiform enlargement of the optic nerve with a clear-cut margin produced by the intact dural sheath (Fig. 2A). Kinking and buckling of the optic nerve as well as low-density areas within the nerve (presumably corresponding to cysts) also are characteristic neuroimaging features of ONGs, especially in patients with NF1 (23,24) (Fig. 2B). MRI typically shows these lesions to be hypointense to isointense on FIG. 1. External (A) and funduscopic (B) appearance in an 8-year-old girl with a right optic nerve glioma. A. The right eye is proptotic and displaced downward. B. The right optic disc is swollen, and there are faint retinal striae present. posterior presentation consists of evidence of a unilateral optic neuropathy associated with a normal-appearing or pale ipsilateral optic disc. Neither orbital nor ocular pain is typically present. Rare patients with ONGs experience acute loss of vision, usually associated with development or worsening of proptosis, from hemorrhage into the tumor (13). Anterior segment ischemia, presumably from compromise of the arterial blood supply to the eye, has been described (14) but is extremely rare because the slow (if any) growth of the lesion allows for collateral blood flow to develop. Not all ONGs are symptomatic. Some are compatible with clinically normal visual function (15). I have examined many children and young adults in whom neuroimaging studies obtained for other reasons (usually because of cutaneous evidence of neurofibromatosis Type 1 [NF1]) suggested an ONG but in whom there was no clinical evidence of either an orbital mass or visual dysfunction. In some of these patients, visual evoked potentials (VEPs) are abnormal (16), and optical coherence tomography (OCT) reveals thinning of the peripapillary retinal nerve fiber layer (PRNFL), retinal ganglion cell/inner plexiform layer (RGC/IPL), or both (17,18). A relationship between ONGs and NF1 is well established (19). The reported incidence of NF1 among patients Miller: J Neuro-Ophthalmol 2016; 36: 460-473 FIG. 2. Postcontrast axial T1 magnetic resonance imaging with fat suppression. A. Appearance of a left optic nerve glioma shows fusiform enlargement in a child without neurofibromatosis Type 1 (NF1). B. In a child with NF1, the right optic nerve glioma is kinked and has the "pseudocerebrospinal fluid" sign. 461 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Jacobson Lecture T1-weighted images and mildly to strongly hyperintense on T2-weighted and fluid-attenuated inversion recovery (FLAIR) images. Most but not all enhance after intravenous administration of paramagnetic contrast material or, in the case of CT, iodinated contrast material. Some patients with ONGs have an enlarged optic canal on the side of the lesion (8,9,25). The enlargement can be identified by both CT and MRI (Fig. 3). Before CT and MRI were available, it was impossible to diagnose ONGs with certainty without biopsy and, indeed, there are a number of other lesions that may mimic ONGs, including primary optic nerve sheath meningiomas and infiltrative processes such as sarcoid and lymphoma. However, biopsy of a presumed ONG may not only cause loss of vision from damage to the optic nerve in such patients (26) but also result in an erroneous diagnosis of optic nerve sheath meningioma if only a superficial portion of the optic nerve with arachnoid hyperplasia (see below) is biopsied (27). At present, MRI usually allows the diagnosis of ONG with such reasonable confidence that biopsy of the FIG. 3. Axial computed tomography (A) and T1 magnetic resonance imaging (B) of patients with optic nerve gliomas that extend intracranially with enlargement of the ipsilateral optic canals (arrows). 462 optic nerve is rarely, if ever, warranted. MRI also can show extension of the tumor and tumor-associated changes beyond the optic nerve into the chiasm, findings that may not be apparent on CT (Fig. 4); however, it has been shown pathologically that even when MRI shows no apparent involvement of the chiasm by a unilateral ONG, tumor cells are often present in the chiasm (28). Pathology The macroscopic appearance of an ONG is characteristic. It appears as a fusiform expansion that may extend the entire length of the nerve or occur along any portion of it. The tumor usually remains within the confines of the dural sheath of the optic nerve as long as it stays within the confines of the orbit or optic canal. Once it extends intracranially, however, it may remain primarily intraneural or develop a sizable exophytic component that in rare cases compresses the opposite optic nerve, optic chiasm, or both. When an ONG is examined in crosssection, the nerve is expanded by the growth, and portions of the nerve may appear gelatinous. Areas may be present where the tumor has broken through the pia and filled the subarachnoid or subdural space, particularly in patients with NF1 (see below). Immunohistochemical stains for glial fibrillary acidic protein, Type 1 astrocyte marker (HNK-1), Type 2 astrocyte precursor marker (AZB5), S100, vimentin, myelin basic protein, laminin, keratin, cytokeratin, epithelial membrane antigen, and neuron-specific enolase indicate that ONGs arise from Type 1 astrocytes (29). In addition, their molecular genetic makeup commonly is identical with that of low-grade astrocytomas elsewhere in the central nervous system (see below). Thus, the most accurate term to describe them is "pilocytic astrocytoma," and those individuals who persist in labeling these lesions as "hamartomas" (30) simply do not appreciate these findings (31,32). ONGs usually have a benign histologic appearance. Some of the tumors contain degenerating axons called Rosenthal fibers, and most have microcystoid spaces containing acid mucopolysaccharide. Enlargement of these tumors is usually slow if at all; however, tumors that have a significant Ki-67 index are more likely to enlarge than those without them (33,34). In addition, some tumors grow rapidly, usually from an increase in mucopolysaccharide content or hemorrhage (13,35). Many optic nerves that contain gliomas develop a reactive leptomeningeal hyperplasia (36,37). In some cases, the hyperplasia extends beyond the limits of the tumor (37). Biopsy of this material may lead to the erroneous diagnosis of meningioma (37,38). Some ONGs invade and infiltrate the leptomeninges (perineural gliomatosis) (39,40). It has been observed that patients without NF1 have tumors that generally remain within the confines of the neural tissue, whereas tumors in patients with NF1 may rupture through the pia surrounding Miller: J Neuro-Ophthalmol 2016; 36: 460-473 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Jacobson Lecture FIG. 4. Postcontrast axial (A) and noncontrast coronal (B) T1 magnetic resonance imaging shows that although the tumor is located intracranially, it does not involve the optic chiasm, at least by imaging criteria. In another patient, postcontrast axial (C) and coronal (D) scans reveal tumor involvement of the intracranial optic nerve (white arrow) and left side of the chiasm (black arrow). the optic nerve and proliferate within the subarachnoid space (41) (Fig. 5A, B). This phenomenon may be observed on MRI in patients with NF1 as the "pseudo-cerebrospinal fluid [CSF]" sign (Fig. 2B), in which the enlarged nerve looks as if it is surrounded by CSF when, in fact, the surrounding material is tumor, not fluid (23,39,42). Natural History Most ONGs grow slowly in a self-limited fashion causing little or no progressive visual loss, with little or no tendency for malignant transformation; hence, the belief by some authors that they are hamartomas (30,43) (in fact, malignant transformation has been reported in some chiasmal gliomas-see below). Rare patients, however, experience rapid visual loss associated with an increase in the size of the tumor as well as the development of enhancement on MRI after intravenous administration of gadolinium or a similar substance. Studies have indicated that the patients most likely to have a benign prognosis are those who present with mild proptosis and optic disc pallor, whereas patients who are likely to experience symptomatic growth are those with moderate-to-severe proptosis and optic disc swelling. No randomized controlled study has been performed to determine if this supposition is correct, and important exceptions exist, including instances of spontaneous improvement (44,45) and instances where the absence of severe proptosis and optic disc swelling did not necessarily indicate a benign prognosis (46). In addition, some gliomas that appear confined to the optic nerve may have Miller: J Neuro-Ophthalmol 2016; 36: 460-473 the capacity to damage the optic chiasm and adjacent structures if left untreated. In one study, 2 of 7 patients without NF1 and 5 of 7 patients with NF1 without initial chiasmal involvement progressed to chiasmal involvement during follow-up, most within 12 months (47). Differences in tumor behavior also were observed in a cooperative national clinical trial in which 106 patients with unilateral gliomas apparently confined to the orbital portion of the optic nerve were followed clinically and with neuroimaging studies (48). Local progression was observed in 7 of 35 patients (20%) followed without treatment. In addition, there is some evidence that females with NF1 are more likely than males to experience visual loss over time (49,50). Management In view of the usual lack of clinical or imaging progression of ONGs, most patients with presumed ONGs, whether or not the patients have NF1, can be followed clinically and with neuroimaging without the need for intervention. The most important parameter to follow is visual acuity (51). In children in whom acuity cannot be assessed because of age or lack of cooperation, OCT to determine the thickness of the PRNFL and RGC/IPL may be an acceptable alternative (17,18,52); however, if this or any other technique (e.g., VEPs) is used to determine progression, a plan needs to be in place as to how much of a change in VEP amplitude and/ or latency or of PRNFL and/or RGC/IPL thickness is required to affect management. In addition, it is critical 463 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Jacobson Lecture excellent color vision when tested with Hardy-Rand-Rittler or Ishihara color plates, whereas patients with visual loss from optic nerve dysfunction typically have poor color perception, often worse than acuity would suggest. For patients who require intervention, there are surgical, radiotherapeutic, and chemotherapeutic options (53). Surgery generally is reserved for patients who have cosmetically unacceptable proptosis associated with severe visual loss and generally involves resection or debulking of the affected optic nerve (54,55) (Fig. 6); however, in some cases, the optic nerve sheath can be opened to release trapped CSF or loose tumor (56,57). It is important to spare the orbital sensory nerves during these procedures as failure to do so can result in a neurotrophic keratopathy leading to corneal perforation and the need for enucleation. Although some authors recommend resection of ONGs to prevent extension to the chiasm, this approach is rarely indicated and, in any event, as noted above, tumor cells are often present beyond the apparent limits suggested by MRI (28). Radiotherapy is appropriate for some patients with ONGs and can be used as adjunctive or as an alternative to surgery (46,58). It usually is reserved for patients above 5 years of age and, ideally, for patients after puberty. The authors of 2 early studies claimed that radiation treatment produced shrinkage of both the intraorbital and intracranial portions of ONGs, with subsequent reduction of proptosis, improvement in vision, and reduction in optic disc swelling (59), and arrest of progressive visual loss or improvement of vision (60). FIG. 5. Histological appearance of an optic nerve glioma. A. Cross-section shows marked enlargement of the nerve (ON) with extension of the tumor beyond its confines into the subarachnoid/subdural space (SAS/SDS) (hematoxylin and eosin, ·10). B. Higher power view of the nerve (ON) and SAS/SDS shows tumor both within the nerve and outside it. Note Rosenthal fibers (arrows) in both the nerve and the SAS/SDS, indicating that the material in the SAS/SDS is tumor tissue (i.e., perineural gliomatosis) rather than "arachnoid hyperplasia" (hematoxylin and eosin, ·100). to distinguish loss of vision due to amblyopia from loss of vision due to optic nerve dysfunction. In my experience, assessment of color vision is extremely helpful as even patients with moderate amblyopia (better than 20/200) have 464 FIG. 6. Contrast-enhanced axial T1 magnetic resonance images illustrate the effects of resection of an extensive right optic nerve glioma. A. Before surgery, the patient has a large, partially cystic optic nerve tumor causing marked proptosis. B. After surgery, there is no significant proptosis. The patient was blind in the eye at the time of surgery. Miller: J Neuro-Ophthalmol 2016; 36: 460-473 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Jacobson Lecture However, in a more recent study, when compared with surgery or observation alone, radiation of ONGs did not seem to improve the overall course (2). In addition, children who undergo radiation therapy have an increased risk of behavior problems, endocrinologic disturbances, vascular changes (e.g., moyamoya-like), and postradiation malignancies. Most radiation therapy is performed by a stereotactic fractionated technique using photons; there are no long-term data on the use of proton beam therapy for ONGs. Chemotherapy is sometimes used to treat ONGs associated with progressive visual loss. It may be particularly useful in children below 5 years of age. A number of chemotherapeutic agents have been recommended, including vincristine, carboplatin, vinblastine, and temozolomide. Although none of these agents is consistently effective, impressive results have been seen in some cases (61). In addition to chemotherapy, topical nerve growth factor (NGF) may be associated with improvement in vision in patients with known or presumed ONGs. Falsini et al treated 5 children with ONGs and severe optic disc pallor with a 10-day course of topical murine NGF (62). After treatment, all 5 showed an increase in VEP amplitudes that persisted for 90 days. The amplitudes declined by 180 days but remained above baseline. During this period, MRI showed no change in tumor size. Summary Optic chiasmal gliomas are most often Grade 1 (pilocytic) astrocytomas, not hamartomas. Most remain stable throughout life and do not cause progressive visual loss; however, some tumors do increase in size and cause visual loss, in which case, it is appropriate to consider radiation therapy, chemotherapy, or a combination of these approaches. In addition, surgery to debulk the lesion can be useful in patients with cosmetically unacceptable proptosis and profound visual loss, and optic nerve sheath fenestration may result in visual improvement in patients in whom the tumor appears to have trapped CSF anteriorly, causing visual loss from compression rather than infiltration of the nerve. OPTIC CHIASMAL GLIOMAS Demographics Gliomas that involve the optic chiasm are more common than gliomas confined to one optic nerve (63), but they still represent less than 10% of all intracranial tumors in adults and children. Females and males appear equally affected. The age range of patients with OCGs is somewhat broader than that of patients with gliomas confined to the optic nerve (63). Some patients are diagnosed shortly after birth, whereas others present with symptoms in the 6th-8th decades of life (64,65). Nevertheless, as is true for patients with Miller: J Neuro-Ophthalmol 2016; 36: 460-473 ONGs, most patients with OCGs are diagnosed within the first 2 decades of life (63,66). Although most OCGs are sporadic, they occur with increased frequency in patients with NF1 and in monozygotic twins (63,67,68). Clinical Manifestations Most patients with OCGs present with bilateral visual loss (2,63). The visual loss is usually slow and insidious or found during a routine examination. The severity of visual loss in patients with OCGs most often is similar in the 2 eyes but occasionally it is highly asymmetric. When the loss of vision is associated with normal-appearing or minimally pale optic discs, it initially may be ascribed to amblyopia or thought to be nonorganic (69). Occasionally, there is a precipitous visual loss in 1 or both eyes usually caused by acute hemorrhage within the tumor or "chiasmal apoplexy" (70,71). As is the case with patients who have ONGs, patients with OCGs and clinically normal visual function usually have abnormal VEPs (72). In patients with OCGs in whom visual fields can be tested, bitemporal visual field defects are common; however, any type of field defect may be present because the tumor also may involve 1 or both optic nerves, the optic tracts, or a combination of these structures (66,67,73). Optic disc pallor is usually present when a patient with an OCG is first evaluated. Some patients have normalappearing optic discs, but OCT in such patients usually shows reduction in the thickness of the PRNFL, RGC/IPL, or both (17,18). Proptosis occasionally occurs in patients with OCGs that involve not only the optic chiasm but also the orbital portion of 1 or both optic nerves, but in my experience, the proptosis is invariably mild. Patients with OCGs also may present with or develop strabismus (64,69). The strabismus is usually a consequence of asymmetric or unilateral visual loss, but it rarely may result from damage to the ocular motor nerves directly from the tumor or indirectly from increased intracranial pressure (ICP) (69). In addition, asymmetric or monocular nystagmus similar to or identical with spasmus nutans may develop in patients with OCGs (74-76). It, thus, is prudent to perform both a comprehensive clinical examination and neuroimaging in infants and children with monocular or asymmetric nystagmus. If the nystagmus has a vertical component, and especially if there is see-saw nystagmus, neuroimaging is mandatory. In addition to visual symptoms and signs, patients with gliomas that involve the optic chiasm may present with symptoms and signs of hypothalamic dysfunction- including precocious puberty and the diencephalic syndrome, increased ICP, or a combination of these (77-79). As with ONGs, OCGs may be associated with NF1 and may be asymptomatic when detected during routine neuroimaging studies of such patients (24). The percentage of patients with OCGs who also have NF1 varies 465 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Jacobson Lecture widely among authors but is approximately 30% (6,63), whereas approximately 18% of patients with NF1 have an OCG (24). Diagnosis An OCG should be considered in any patient, particularly a child, who presents with unexplained visual loss, monocular or asymmetric nystagmus, optic disc pallor, or hypothalamic symptoms. Once such a lesion is suspected, appropriate neuroimaging studies should be performed to document its presence, appearance, and extent. MRI is by far the most sensitive method of detecting an OCG, particularly when performed using high-resolution techniques and an intravenous paramagnetic contrast agent (24). In most cases, MRI can determine not only if a lesion is present but also if it is intrinsic or extrinsic with respect to the anterior visual system (Fig. 7). MRI typically shows gliomas to be hypointense to isointense on T1-weighted images and mildly to strongly hyperintense on T2weighted images (24,53,63,66,80). As in the case of ONGs, OCGs almost always show enhancement after intravenous contrast material. Pathology The macroscopic appearance of OCGs varies depending on whether or not there is a significant exophytic component. Many lesions simply enlarge the chiasm and the intracranial portions of the optic nerves, leaving their macroarchitecture relatively intact. In other cases, however, the tumor has an exophytic component that disrupts the macroarchitecture of the chiasm, such that both the gross appearance of the lesion and its appearance on neuroimaging is that of a poorly defined suprasellar mass that replaces the chiasm (Fig. 7B). When such an exophytic component is present, it may be impossible to determine the nature of the lesion, thus requiring a biopsy (see below). The histopathological features of such tumors, however, are virtually identical with those of ONGs; i.e., they are those of a pilocytic astrocytoma (1). Natural History Once the diagnosis of an OCG is made, by either neuroimaging or biopsy (see below), a decision must be made as to whether the patient should be followed clinically and with neuroimaging without intervention or treated with radiotherapy, chemotherapy, or both. To make an informed decision, the physician must know the natural history of the lesion. This is particularly difficult, primarily because there may be 2 types of gliomas that involve the chiasm, an anterior type that originates within the anterior visual system and may or may not infiltrate the hypothalamus and adjacent structures, and a posterior type that actually is FIG. 7. Extrinsic vs intrinsic optic chiasmal gliomas. Postcontrast axial (A) and sagittal (B) T1 magnetic resonance imaging of a primarily extrinsic tumor. Noncontrast axial (C) and coronal (D) scans demonstrate an intrinsic chiasmal glioma. 466 Miller: J Neuro-Ophthalmol 2016; 36: 460-473 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Jacobson Lecture hypothalamic in origin and secondarily invades the optic chiasm (64). Nevertheless, there is some information regarding the natural history of OCGs. In 1969, Hoyt and Baghdassarian (81) described 18 patients, 9 of whom had untreated gliomas involving only the optic chiasm and optic nerves and 9 who also had involvement of the hypothalamus. In these patients, the diagnosis was made by either neuroimaging or biopsy. During a follow-up period that ranged from 3 to more than 20 years, they recorded deterioration in 8 of 36 eyes (22%). Of the remaining 28 eyes, visual acuity was stable in 24 and improved spontaneously in 4. An update on the fate of the 18 patients originally reported by Hoyt and Baghdassarian, with a median period of follow-up of 20 years, showed that 16 had died, 5 from their glioma and 11 from other causes, primarily because of the development of new intracranial or extracranial tumors (82). Of the 5 patients who had died of their glioma, 4 had already died by 1969. Thus, 1 patient had died of the effects of the OCG between 1969 and 1986. The mortality rates in patients with and without NF1 were similar, although patients with NF1 tended to die of malignant tumors, whereas patients without NF1 had died of a variety of other causes. Other authors have reported patients with untreated OCGs who were visually and neurologically stable over an extended follow-up period (2,36,63,64,66,73). Some of these and other patients even improved spontaneously, both clinically and with respect to neuroimaging (45,83-86). Despite numerous reports of long-term stability or improvement in visual and systemic health in patients with untreated OCGs, it is clear that a substantial proportion of these patients subsequently develop visual and neurologic deficits and that some die because of the effects of their tumor (63,66,73,87). In addition, in rare patients, malignant transformation of a previously benign lesion may develop (88,89), and in other patients, metastases may occur, particularly in patients with a ventricular shunt (90-92). Although some authors have found no clinical features that appear to predict the visual, neurologic, or systemic prognosis in patients with OCGs (93), others have found that young age and hypothalamic involvement as evidenced by clinical, laboratory, imaging, or a combination of these modalities are associated with a worse prognosis in patients both with and without NF1 (5,77,87). Management As is the case with ONGs, patients with known or presumed OCGs should be followed clinically and with neuroimaging. Visual acuity is the key parameter to follow (51,53); however, in patients in whom acuity cannot be assessed, OCT of the PRNFL, RGC/IPL, or both may be appropriate as may assessment of VEPs (17,18,52). Again, however, before performing these tests, one must decide how much of a change is required Miller: J Neuro-Ophthalmol 2016; 36: 460-473 to affect management, particularly given both the morbidity and mortality associated with the available treatment options. As with ONGs, interventions for progressive OCGs include surgery, radiation therapy, chemotherapy, or a combination of these modalities. In most patients with a suprasellar mass confirmed by neuroimaging studies, a craniotomy with attempted removal of the mass usually is appropriate; however, OCGs are an exception. Although some of these lesions have a large exophytic component that may be excised or ultrasonically aspirated (69,87,94), resulting in subsequent improvement in vision, most are primarily or wholly intrinsic tumors that cannot be resected completely without sacrificing all vision and permanently damaging the hypothalamus and other surrounding structures. Thus, the only consideration in most cases is whether or not a biopsy of the lesion needs to be performed. In my opinion, there is little need for a tissue diagnosis when neuroimaging studies performed in the appropriate clinical setting (e.g., a child with pale optic discs) clearly define an intrinsic lesion involving the optic chiasm with preservation of the gross outline of this structure. Such patients rarely have any evidence of hypothalamic dysfunction, but even when they do, the only real issue is whether or not any other therapy (i.e., radiotherapy or chemotherapy) is indicated (see below). However, when it is unclear by neuroimaging if a suprasellar mass is compressing or infiltrating the chiasm (i.e., if the mass is intrinsic or extrinsic), or if an intrinsic lesion is present in an unusual clinical setting (e.g., an adult with diabetes insipidus), I and others would not hesitate to recommend biopsy of the lesion (73,87). The morbidity and mortality of such a procedure, regardless of the technique (e.g., stereotactic, endoscopic, or transcranial) is acceptably low and usually not associated with any substantial loss of visual function. Because of the potentially grim prognosis for some patients with OCGs, some authors have recommended radiotherapy or stereotactic radiosurgery in the management of selected patients without evidence of NF1 and in whom there is progressive disease by clinical evaluation or imaging (95,96). Although we have also found radiation beneficial by both clinical examination and imaging in such patients (Fig. 8), one must be aware of the side effects of radiation, including mental retardation, psychiatric problems, growth retardation (with or without other pituitary and hypothalamic abnormalities), damage to cerebral tissue from direct parenchymal destruction as well as from vasculopathy, and development of other intracranial tumors. In view of the potentially significant side effects from radiotherapy, even in older children and adults, attention has shifted toward chemotherapy for OCGs, particularly for prepubertal children. Indeed, chemotherapy has become accepted as a well-tolerated and safe way to treat 467 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Jacobson Lecture statistically significant improvement in all parameters in subjects receiving NGF. Visual field worsening occurred only in subjects who had received placebo. Summary OCGs present a somewhat different clinical challenge from ONGs. First, when they are globular, a biopsy may be required to confirm the diagnosis. Second, these lesions are not amenable to surgical resection, although debulking of any extrinsic portion may be beneficial. Third, unlike ONGs that generally cause only visual dysfunction, OCGs may present with or subsequently cause not only visual dysfunction but also hypothalamic dysfunction and neurological deficits. However, these lesions, like ONGs, often are very slow-growing, low-grade pilocytic astrocytomas associated with stable vision, and some even regress spontaneously, resulting in improved vision. Thus, as long as they have no hypothalamic or other neurologic manifestations, children with OCGs can be followed both clinically and with neuroimaging without intervention. Should visual function worsen chemotherapy and radiation therapy have both been used, alone and in combination, with reasonable success, and the potential for benefit with topical NGF is particularly encouraging. WHERE DO WE GO FROM HERE? MOLECULAR GENETICS OF OPTIC PATHWAY GLIOMAS FIG. 8. Postcontrast axial computed tomography in a 6year-old girl with a biopsy-proven optic chiasmal glioma before (A) and after (B) conventional fractionated radiation therapy. Note almost complete regression of the tumor after radiation. OCGs that appear to progress, particularly in children below 5 years of age and patients with NF1. As in the case of ONGs, drugs including vincristine, actinomycin D, carboplatin, temozolomide, and bevacizumab, alone or in combination, have all been used with varying degrees of success (5,49,97-99) (Fig. 9). In addition to chemotherapeutic agents, topical NGF has been found to be of benefit in patients with OCGs. Falsini et al (100) performed a randomized, doublemasked, Phase II clinical trial in 17 patients with OCGs who had stable visual function and imaging. Patients were treated with either a 10-day course of 0.5 mg of murine NGF (n = 10) or placebo (n = 8). All were evaluated at baseline and at 15, 30, 90, and 180 days. The evaluation included assessment of visual acuity and visual field as well as VEP amplitudes, OCT of the PRNFL, and MRI. These investigators noted no adverse effects from treatment and 468 It seems clear that the future treatment and perhaps prevention of the development of optic pathway gliomas (OPGs) will depend on attention to 2 major factors. First, we need a more scientific approach to the natural history of these lesions and their response to various forms of treatment using prospective, randomized, masked clinical trials. Examples include the multicenter, NF1-related OPG natural history study that is being sponsored by the Children's Tumor Foundation and the Gilbert Family Neurofibromatosis Institute (study coordinators: Michael Fisher and Rob Avery) and the treatment trial at the Hospital for Sick Children in Toronto that will compare the effects of vinblastine and bevacizumab vs vinblastine alone in previously untreated children with OPGs. Second, we need to assess in more detail the molecular genetic makeup of optic nerve and chiasmal gliomas (101), with respect to patients both with and without NF1. Normal persons have 2 copies of the NF1 gene. This gene, located on chromosome 17q11.2, produces neurofibromin, a protein that is expressed in the cytoplasm of neurons, oligodendrocytes, Schwann cells, and astrocytes and that plays a central role in regulating the Ras-dependent intracellular signaling pathways. Patients with NF1 have a mutated or nonfunctional copy of the gene in all cells in the body. In such persons, NF1-associated tumors develop only when the remaining NF1 gene undergoes somatic mutation, Miller: J Neuro-Ophthalmol 2016; 36: 460-473 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Jacobson Lecture FIG. 9. Contrast-enhanced T1 sagittal (A) and coronal (B) magnetic resonance images of a 4-year-old girl with an optic chiasmal glioma (A and B) who, because of progressive visual loss, received chemotherapy consisting of a combination of thioguanine, procarbazine, lomustine, and vincristine. After treatment, marked reduction in the size of the glioma (C and D). The patient experienced visual improvement as well. resulting in complete loss of neurofibromin function. This results in Ras hyperactivation, leading to increased cellular proliferation through MAP kinase (102). In addition, neurofibromin regulates cyclic adenosine monophosphate (cAMP), high levels of which inhibit tumor growth. Loss of neurofibromin results in low levels of cAMP, resulting in the loss of this inhibition (103). Thus, it is no surprise that mice genetically engineered to lack neurofibromin in both Schwann cells and glial precursors develop both plexiform neurofibromas and OPGs (104,105). Indeed, it is now clear that the germline NF1 mutation is a major determinant of the development of OPGs (106). It is possible, therefore, that gene therapy could be used to restore neurofibromin function in patients with a mutated NF1 gene, thus preventing the development and growth of OPGs. Over 60% of OPGs in patients without NF1 have a tandem duplication at the BRAF locus that produces a fusion gene between KIAA1549 (an uncharacterized gene) Miller: J Neuro-Ophthalmol 2016; 36: 460-473 and BRAF (101,107-109). The BRAF gene normally produces a protein that is part of the Ras/MAP kinase pathway. Increased BRAF in astrocytes causes activation of MEK and ERK proteins downstream, leading to the development of pilocytic astrocytomas. It is possible that patients with NF1unrelated OPGs who require treatment therefore could be treated with MEK inhibitors such as trametinib and selumetinib. In the final analysis, I believe that the continued assessment of the molecular genetics of OPGs, whether confined to one optic nerve or involving more of the anterior visual sensory pathway, combined with natural history studies and properly performed treatment trials, not only will lay to rest the controversies regarding the nature of these lesions (i.e., tumors vs hamartomas) but also will provide evidence-based data that will guide the management of patients who harbor them and may even lead to a method (e.g., gene therapy) to prevent their development and growth. 469 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Jacobson Lecture MALIGNANT OPTIC PATHWAY GLIOMAS Although most gliomas that involve the anterior visual pathways have a benign histologic appearance and a relatively benign prognosis (see above), malignant astrocytomas occasionally involve the anterior visual system, producing a clinical course characterized by rapidly progressive visual loss, neurologic deficits, and death (110-113). Unlike low-grade gliomas of the anterior visual system that occur in children, malignant gliomas almost always occur in adults. Some reports suggested that these tumors occur primarily in men, but in other series, men and women are affected with equal frequency. The specific pattern of visual loss that occurs in patients with malignant gliomas of the anterior visual pathways seems to depend on the site of origin of the tumor. Tumors that originate in the proximal portion of one of the optic nerves produce a syndrome characterized by initial monocular blurring of vision and retrobulbar pain simulating optic neuritis. The fundus of the affected eye may initially appear normal, but many patients rapidly develop evidence of occlusive vascular disease involving the optic disc, including venous stasis and edema. There may be extensive hemorrhage in the posterior pole; the appearance of the fundus, thus, may resemble the ischemic form of CRVO or a combined CRVO and central retinal artery occlusion (114), although in such cases, the patient's visual acuity usually is much worse than the funduscopic picture would suggest. Neovascular glaucoma develops in some cases. This does not remain a monocular disease, however. Within 5-6 weeks, both eyes become affected, and the patient soon becomes completely blind. Hypothalamic dysfunction, hemiparesis, and other neurologic deficits may develop in the latter stages of the disease, and despite treatment, death usually occurs in less than 1 year (113). Malignant optic gliomas that originate closer to, or within, the optic chiasm produce a similar syndrome of progressive visual loss, neurologic symptoms, and death; however, the visual loss in these patients almost always is bilateral and simultaneous (or nearly so) and is associated with normalappearing or pale optic discs (110-114). The neuroimaging appearance of a malignant glioma of the anterior visual system is nonspecific. In some cases, the optic nerves, chiasm, and tracts appear diffusely thickened. MRI after intravenous injection of a paramagnetic contrast agent may show marked enhancement of one or both optic nerves, the optic chiasm, and one or both optic tracts (Fig. 10A), with inhomogeneity and cystic-appearing areas, whereas in other cases, there is a large mass in the suprasellar cistern (112,115,116). The pathologic features of a malignant optic glioma are characteristic. The vascular and partially necrotic tumor occupies most of the optic nerves, optic chiasm, and optic tracts. Intracranially, the tumor eventually infiltrates the hypothalamus and adjacent parts of the brain; in the orbit, it usually infiltrates the meninges of the nerve and the surrounding soft tissue. The histopathology of this tumor is 470 FIG. 10. Magnetic resonance imaging and histopathological appearances of a malignant optic pathway glioma. The patient presented with sudden complete loss of vision in the right eye associated with a funduscopic picture consistent with a central retinal vein occlusion. A. Contrastenhanced axial T1 image shows a markedly enhancing lesion involving the right optic nerve. B. Optic nerve biopsy is highly cellular. The cells are pleomorphic, have nuclear hyperchromicity, and show scattered mitoses. Numerous microcysts also are present (hematoxylin and eosin, ·500). completely different from that of the typical ONG; it is characterized by extreme cellular pleomorphism, nuclear hyperchromatism, and scattered mitoses (112) (Fig. 10B). There often are numerous areas of vascular endothelial proliferation, necrosis, and hemorrhage, similar to those seen in anaplastic gliomas and glioblastoma multiforme, and their molecular genetic makeup is more consistent with these lesions than with pilocytic astrocytomas (115). Malignant gliomas that involve the anterior visual system are difficult to treat, and death is the result in most cases, although rare cases of long-term patient survival have been reported after a combination of chemotherapy and radiation therapy (116). It is to be hoped that, as in the case of benign OPGs, more information regarding the molecular genetic makeup of malignant OPGs will lead to more targeted and successful treatment. Miller: J Neuro-Ophthalmol 2016; 36: 460-473 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Jacobson Lecture SUMMARY Our understanding of the clinical presentation, natural history, and responses to therapy of OPGs, both ONGs and OCGs, is steadily increasing. At the same time, the molecular biology and genetics of these tumors are becoming increasingly clear in both NF1 and non-NF1 patients. It is to be hoped that an understanding of these issues hopefully will lead to molecular therapies (?gene therapy, ?nanoparticles) to prevent or treat these lesions. REFERENCES 1. Brat DJ. Astrocytic tumors. In: Love S, Perry A, Ironside J, Budka H, eds. Greenfield's Neuropathology. 9th edition. Vol 2. Boca Raton, FL: CRC Press, 2015. 2. Tow SL, Chandela S, Miller NR, Avellino AM. Long-term outcome in children with gliomas of the anterior visual pathway. Pediat Neurol. 2003;28:262-270. 3. Balcer LJ, Liu GT, Heller G, Bilaniuk L, Volpe NJ, Galetta SL, Molloy PT, Phillips PC, Janss AJ, Vaughn S, Maguire MG. Visual loss in children with neurofibromatosis type 1 and optic pathway gliomas relation to tumor location by magnetic resonance imaging. Am J Ophthalmol. 2001;131:442-445. 4. Laithier V, Grill J, Le Deley MC, Ruchoux MM, Couanet D, Doz F, Pichon F, Rubie H, Frappaz D, Vannier JP, Babin-Boilletot A, Sariban E, Chastagner P, Zerah M, Raquin MA, Hartmann O, Kalifa C; for the French Society of Pediatric Oncology. Progression-free survival in children with optic pathway tumor: dependence on age and the quality of the response to chemotherapy-results of the First French Prospective Study for the French Society of Pediatric Oncology. J Clin Oncol. 2003;21:4572-4578. 5. Dodgshun AJ, Elder JE, Hansford JR, Sullivan MJ. Long-term visual outcome after chemotherapy for optic pathway glioma in children: site and age are strongly predictive. Cancer. 2015;121:4190-4196. 6. Dutton JJ. Gliomas of the anterior visual pathway. Surv Ophthalmol. 1994;38:427-452. 7. Nair AG, Pathak RS, Iyer VR, Gandhi RA. Optic nerve glioma: an update. Int Ophthalmol. 2014;34:999-1005. 8. Chutorian AM, Schwartz JF, Evans RA, Carter S. Optic gliomas in children. Neurology. 1964;14:83-95. 9. Rush JA, Younge BR, Campbell RJ, MacCarty CS. Optic glioma: long-term follow-up of 85 histopathologically verified cases. Ophthalmology. 1982;89:1213-1219. 10. Dua S, Sharma K, Juneja R, Kalakoti P, Kamble M, Subramanian P. Unusual presentation of unilateral intraorbital optic nerve pilocytic astrocytoma of the juvenile type in a geriatric patient. J Clin Neurosci. 2016;25:143-144. 11. Buchanan TA, Hoyt WF. Optic nerve glioma and neovascular glaucoma: report of a case. Br J Ophthalmol. 1982;66:96-98. 12. Kozak I, Elkhamary SM, Bosley TM. Central retinal vein occlusion in a childhood optic nerve tumour. Neuroophthalmol. 2016;40:35-39. 13. Sharma A, Mohan K, Saini JS. Haemorrhagic changes in pilocytic astrocytoma of the optic nerve. Orbit. 1990;9:29-33. 14. Donaldson DD. Atlas of External Diseases of the Eye, Anterior Chamber, Iris, and Ciliary Body. St Louis, MO: CV Mosby, 1973:238. 15. Campagna M, Opocher E, Viscardi E, Calderone M, Severino SM, Cermakova I, Perilongo G. Optic pathway glioma: longterm visual outcome in children without neurofibromatosis type-1. Pediatr Blood Cancer. 2010;55:1083-1088. 16. Kelly JP, Weiss AH. Detection of tumor progression in optic pathway glioma with and without neurofibromatosis type 1. Neuro Oncol. 2013;15:1560-1567. Miller: J Neuro-Ophthalmol 2016; 36: 460-473 17. Avery RA, Liu GT, Fisher MJ, Quinn GE, Belasco JB, Phillips PC, Maguire MG, Balcer LJ. Retinal nerve fiber layer thickness in children with optic pathway gliomas. Am J Ophthalmol. 2011;151:542-549. 18. Gu S, Glaug N, Cnaan A, Packer RJ, Avery RA. Ganglion cell layer-inner plexiform layer thickness and vision loss in young children with optic pathway gliomas. Invest Ophthalmol Vis Sci. 2014;55:1402-1408. 19. Listernick R, Ferner RE, Liu GT, Gutmann DH. Optic pathway gliomas in neurofibromatosis-1: controversies and recommendations. Ann Neurol. 2007;61:189-198. 20. Lewis RA, Gerson LP, Axelson KA, Riccardi VM, Whitford RP. Von Recklinghausen neurofibromatosis: II. Incidence of optic gliomata. Ophthalmology. 1984;91:929-935. 21. Di Mario FJ, Ramsby G, Greenstein R. Neurofibromatosis type I: resonance imaging findings. J Child Neurol. 1993;8:32-39. 22. Schindera C, Wingeier K, Goeggel Simonetti B, Diebold M, Nauer CB, Fleischauer J, Steinlin M. Macrocephaly in neurofibromatosis type 1: a sign post for optic pathway gliomas? Childs Nerv Syst. 2011;27:2107-2111. 23. Imes RK, Hoyt WF. Magnetic resonance imaging signs of optic nerve gliomas in neurofibromatosis 1. Am J Ophthalmol. 1991;111:729-734. 24. Prada CE, Hufnagel RB, Hummel TR, Lovell AM, Hopkin RJ, Saal HM, Schorry EK. The use of magnetic resonance imaging screening for optic pathway gliomas in children with neurofibromatosis type 1. J Pediatr. 2015;167:851- 856. 2015. 25. Holman CB. Roentgenologic manifestations of glioma of the optic nerve and chiasm. Am J Roentgenol Radium Ther Nucl Med. 1959;82:462-471. 26. Revere KE, Katowitz WR, Katowitz JA, Rorke-Adams L, Fisher MJ, Liu GT. Childhood optic nerve glioma: vision loss due to biopsy. Ophthal Plast Reconstr Surg. [published ahead of print April 4, 2016] doi: 10.1097/IOP.0000000000000687. 27. Yanoff M, Davis RL, Zimmerman LE. Juvenile pilocytic astrocytoma ("glioma") of the optic nerve: clinicopathologic study of 63 cases. In: Jakobiec FA, ed. Ocular and Adnexal Tumors. Birmingham, AL: Aesculapius, 1978:685-707. 28. Spicer GJ, Kazim M, Glass LR, Harris GJ, Miller NR, Rootman J, Sullivan TJ. Accuracy of MRI in defining tumor-free margin in optic nerve glioma surgery. Ophthal Plast Reconstr Surg. 2013;29:277-280. 29. Cutarelli PE, Roessmann UR, Miller RH, Specht CS, Grossniklaus HE. Immunohistochemical properties of human optic nerve glioma. Invest Ophthalmol Vis Sci. 1991;32:2521-2524. 30. Parsa CF. Why optic gliomas should be called hamartomas. Ophthal Plast Reconstr Surg. 2010;26:497. 31. Miller NR. Optic pathway gliomas are tumors! Ophthal Plast Reconstr Surg. 2008;24:433. 32. Liu GT, Katowitz JA, Rorke-Adams LB, Fisher MJ. Optic pathway gliomas neoplasms, not hamartomas. JAMA Ophthalmol. 2013;131:646-650. 33. Cummings TJ, Provenzale JM, Hunter SB, Friedman AH, Klintworth GK, Bigner SH, McLendon RE. Gliomas of the optic nerve: histological immunohistochemical (MIB-1 and P53), and MRI analysis. Acta Neuropathol. 2000;99:563-570. 34. Yeung SN, White VA, Nimmo M, Rootman J. Optic nerve gliomas: role of KI-67 staining of tumour and margins in predicting long-term outcome. Br J Ophthalmol. 2011;95:1077-1081. 35. Charles NC, Nelson L, Brookner AR, Lieberman N, Breinin GM. Pilocytic astrocytoma of the optic nerve with hemorrhage and extreme cystic degeneration. Am J Ophthalmol. 1981;92:691-695. 36. Borit A, Richardson EP Jr. The biological and clinical behaviour of pilocytic astrocytomas of the optic pathways. Brain. 1982;105:161-187. 37. Zimmerman LE. Arachnoid hyperplasia in optic nerve glioma. Br J Ophthalmol. 1980;64:638-639. 471 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Jacobson Lecture 38. Cooling RJ, Wright JE. Arachnoid hyperplasia in optic nerve glioma: confusion with orbital meningioma. Br J Ophthalmol. 1979;63:596-599. 39. Seiff S, Brodsky MC, MacDonald G. Orbital optic glioma in neurofibromatosis: magnetic resonance diagnosis of perineural arachnoidal gliomatosis. Arch Ophthalmol. 1987;105:1689-1692. 40. Yeung SN, Heran MK, Smith A, White VA, Rootman J. Perineural gliomatosis associated with isolated optic nerve gliomas. Br J Ophthalmol. 2009;93:839-841. 41. Stern J, Jakobiec FA, Housepian EM. The architecture of optic nerve gliomas with and without neurofibromatosis. Arch Ophthalmol. 1980;98:505-511. 42. Brodsky MC. The "pseudo-CSF" signal of orbital optic glioma on magnetic resonance imaging: a signature of neurofibromatosis. Surv Ophthalmol. 1993;38:213-218. 43. Parsa CF, Givrad S. Juvenile pilocytic astrocytomas do not undergo spontaneous malignant transformation: grounds for designation as hamartomas. Br J Ophthalmol. 2008;92:40-46. 44. Frohman LP, Epstein F, Kupersmith MJ. Atypical visual prognosis with an optic nerve glioma. J Clin Neuroophthalmol. 1985;5:90-94. 45. Parsa CF, Hoyt CS, Lesser RL, Weinstein JM, Strother CM, MuciMendoza R, Ramella M, Manor RS, Fletcher WA, Repka MX, Garrity JA, Ebner RN, Monteiro ML, McFadzean RM, Rubtsova IV, Hoyt WF. Spontaneous regression of optic gliomas: 13 cases documented by serial neuroimaging. Arch Ophthalmol. 2001;119:516-529. 46. McDonnell P, Miller NR. Chiasmatic and hypothalamic extension of optic nerve glioma. Arch Ophthalmol. 1983;101:1412-1415. 47. Gayre GS, Scott IU, Feuer W, Saunders TG, Siatkowski RM. Long-term visual outcome in patients with anterior visual pathway glioma. J Neuroophthalmol. 2001;21:1-7. 48. North American Study Group for Optic Glioma. Tumor spread in unilateral optic glioma: study report No 2. Neurofibromatosis. 1989;2:195-203. 49. Fisher MJ, Loguidice M, Gutmann DH, Listernick R, Ferner RE, Ullrich NJ, Packer RJ, Tabori U, Hoffman RO, Ardern-Holmes SL, Hummel TR, Hargrave DR, Bouffet E, Charrow J, Bilaniuk LT, Balcer LJ, Liu GT. Visual outcomes in children with neurofibromatosis type 1-associated optic pathway glioma following chemotherapy: a multicenter retrospective analysis. Neuro Oncol. 2012;14:790-797. 50. Diggs-Andrews KA, Brown JA, Gianino SM, Rubin JB, Wozniak DF, Gutmann DH. Sex is a major determinant of neuronal dysfunction in neurofibromatosis type 1. Ann Neurol. 2014;75:309-316. 51. Fisher MJ, Avery RA, Allen JC, Ardern-Holmes SL, Bilaniuk LT, Ferner RE, Gutmann DH, Listernick R, Martin S, Ullrich NJ, Liu GT; for the REINS International Collaboration. Functional outcome measures for NF1-associated optic pathway glioma clinical trials. Neurology. 2013;81(21 suppl 1):S14-S24. 52. Avery RA, Cnaan A, Schuman JS, Trimboli-Heidler C, Chen CL, Packer RJ, Ishikawa H. Longitudinal change of circumpapillary retinal nerve fiber layer thickness in children with optic pathway gliomas. Am J Ophthalmol. 2015;160:944-952. 53. Avery RA, Fisher MJ, Liu GT. Optic pathway gliomas. J Neuroophthalmol. 2011;31:269-278. 54. Wolter JR. Large optic nerve glioma removed by the transconjunctival approach. J Pediatr Ophthalmol. 1973;10:142-146. 55. Althekair FY. Debulking optic nerve gliomas for disfiguring proptosis: a globe-sparing approach by lateral orbitotomy alone. Poster presented at: 42nd Annual Meeting of the North American Neuro-Ophthalmology Society; February 28, 2016; Tucson, AR. 56. Vanderveen DK, Nihalani BR, Barron P, Anderson RL. Optic nerve sheath fenestration for an isolated optic nerve glioma. J AAPOS. 2009;13:88-90. 57. Chen A, Yoon MK, Haugh S, Phan LT, Song J, McCulley TJ. Surgical management of an optic nerve glioma with perineural 472 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70. 71. 72. 73. 74. 75. 76. 77. 78. 79. arachnoidal gliomatosis growth pattern. J Neuroophthalmol. 2013;33:51-53. Marwaha G, Macklis R, Singh AD. Radiation therapy: orbital tumors. Dev Ophthalmol. 2013;52:94-101. Taveras JM, Mount LA, Wood EH. The value of radiation therapy in the management of glioma of the optic nerves and chiasm. Radiology. 1956;66:518-528. Throuvalas N, Bataini P, Ennuyer A. Les gliomes du chiasma et du nerf optique: L'apport de la radiotherapie transcutanée dans leur traitement. Bull Cancer. 1969;56:231-264. Parentin F, Rabusin M, Zannaro F, Orth DC, Pensiero S. Chemotherapy for optic nerve glioma in a child with neurofibromatosis type-1. Neuroophthalmology. 2008;32:159-162. Falsini B, Chiaretti A, Barone G, Piccardi M, Pierri F, Colosimo C, Lazzareschi I, Ruggiero A, Parisi V, Fadda A, Balestrazzi E, Riccardi R. Total nerve growth factor as a visual rescue strategy in pediatric optic gliomas: a pilot study including electrophysiology. Neurorehabil Neurol Repair. 2011;25:512-520. Binning MJ, Liu JK, Kestle JR, Brockmeyer DL, Walker ML. Optic pathway gliomas: a review. Neurosurg Focus. 2007;23:1-8. Miller NR, Iliff WJ, Green WR. Evaluation and management of gliomas of the anterior visual pathways. Brain. 1974;97:743-754. Jamshidi S, Korengold M, Kobrine AI. Computed tomography of an optic chiasm glioma in an elderly patient. Surg Neurol. 1984;21:83-87. Shofty B, Ben-Sira L, Kesler A, Constantini S. Optic pathway gliomas. Adv Tech Stand Neurosurg. 2015;42:123-146. Cartwright SC. Concordant optic glioma in a pair of monozygotic twins with neurofibromatosis. Clin Pediatr. 1982;21:236-238. Crawford MJ, Buckler JM. Optic glioma affecting twins with neurofibromatosis. Dev Med Child Neurol. 1983;25:367-373. Roh S, Mawn LA, Hedges TR. Juvenile pilocytic astrocytoma masquerading as amblyopia. Am J Ophthalmol. 1997;123:692-694. Maitland CG, Abiko S, Hoyt WF, Wilson CB, Okamura T. Chiasmal apoplexy: report of four cases. J Neurosurg. 1982;56:118-122. Hill JD, Rhee MS, Edwards JR, Hagen MC, Fulkerson DH. Spontaneous intraventricular hemorrhage from low-grade optic glioma: case report and review of the literature. Childs Nerv Syst. 2012;28:327-330. Kupersmith MJ, Siegel IM, Carr RE, Ransohoff J, Flamm E, Shakin E. Visual-evoked potentials in chiasmal gliomas in four adults. Arch Neurol. 1981;38:362-365. Doganis D, Pourtsidis A, Tsakiris K, Baka M, Kouri A, Douhoutsou D, Varvoutsi M, Servitzoglou M, Dana H, Kosmidis H. Optic pathway glioma in children: 10 years of experience in a single institution. Pediatr Hematol Oncol. 2016;33:102-108. Lavery MA, O'Neill JF, Chu FC, Martyn LJ. Acquired nystagmus in early childhood: a presenting sign of intracranial tumor. Ophthalmology. 1984;91:425-435. Newman SA, Hedges TR III, Wall M, Sedwick LA. Spasmus nutans-or is it? Surv Ophthalmol. 1990;34:453-454. Brodsky MC, Keating GE. Chiasmal glioma in spasmus nutans: a cautionary note. J Neuroophthalmol. 2014;34:274-275. Gan HW, Phipps K, Aquilina K, Gaze MN, Hayward R, Spoudeas HA. Neuroendocrine morbidity after pediatric optic gliomas: a longitudinal analysis of 166 children over 20 years. J Clin Endocrinol Metab. 2015;100:3787-3799. Kim A, Moon JS, Yang HR, Chang JY, Ko JS, Seo JK. Diencephalic syndrome: a frequently neglected cause of failure to thrive in infants. Korean J Pediatr. 2015;58:28-32. García García E, Márquez Vega C, Fajardo Cascos M, Venegas Moreno E, Soto Moreno A. Optic chiasm glioma in children: endocrine disorders in 14 cases. Med Clin (Barc). 2016;146:446-449. Miller: J Neuro-Ophthalmol 2016; 36: 460-473 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Jacobson Lecture 80. Lambron J, Rakotonjanahary J, Loisel D, Frampas E, De Carli E, Delion M, rialland X, Toulgoat F. Can we improve accuracy and reliability of MRI interpretation in children with optic pathway glioma? Proposal for a reproducible image classification. Neuroradiology. 2016;58:197-208. 81. Hoyt WF, Baghdassarian SB. Optic glioma of childhood: natural history and rationale for conservative management. Br J Ophthalmol. 1969;53:793-798. 82. Imes RK, Hoyt WF. Childhood chiasmal gliomas: update on the fate of patients in the 1969 San Francisco Study. Br J Ophthalmol. 1986;70:179-182. 83. Liu GT, Lessell S. Spontaneous visual improvement in chiasmal gliomas. Am J Ophthalmol. 1992;114:193-201. 84. Brzowski AE, Bazan C III, Mumma JV, Ryan SG. Spontaneous regression of optic glioma in a patient with neurofibromatosis. Neurology. 1992;42:679-681. 85. Takenchi H, Kabuto M, Sato K, Kubota T. Chiasmal gliomas with spontaneous regression: proliferation and apoptosis. Childs Nerv Syst. 1997;13:229-233. 86. Pruzan NL, de Alba Campomanes A, Gorovoy IR, Hoyt C. Spontaneous regression of a massive sporadic chiasmal optic pathway glioma. J Child Neurol. 2015;30:1196-1198. 87. El Beltagy MA, Reda M, Enayet A, Zaghloul MS, Awad M, Zekri W, Taha H, El-Khateeb N. Treatment and outcome in 65 children with optic pathway gliomas. World Neurosurg. 2016;89:525-534. 88. Wilson WB, Feinsod M, Hoyt WF, Nielsen SL. Malignant evolution of childhood chiasmal pilocytic astrocytoma. Neurology. 1976;26:322-325. 89. Nishio S, Takeshita I, Fukui M, Yamashita M, Tateishi J. Anaplastic evolution of childhood optico-hypothalamic pilocytic astrocytoma: report of an autopsy case. Clin Neuropathol. 1988;7:254-258. 90. Bruggers CS, Friedman HS, Phillips PC, Wiener MD, Hockenberger B, Oakes WJ, Buckley EG. Leptomeningeal dissemination of optic pathway gliomas in three children. Am J Ophthalmol. 1991;111:719-723. 91. Trigg ME, Swanson JD, Letellier MA. Metastasis of an optic glioma through a ventriculoperitoneal shunt. Cancer. 1983;52:599-601. 92. Kocks W, Kalff R, Reinhardt V. Spinal metastasis of pilocytic astrocytoma of the chiasma opticum. Childs Nerv Syst. 1989;5:118-120. 93. Lloyd L. Gliomas of the optic nerve and chiasm in childhood. Trans Am Ophthalmol Soc. 1973;71:488-535. 94. Goodden J, Pizer B, Pettorini B, Williams D, Blair J, Didi M, Thorp N, Mallucci C. The role of surgery in optic pathway/ hypothalamic gliomas in children. J Neurosurg Pediatr. 2014;13:1-12. 95. Debus J, Kocagoncu KO, Hoss A, Wenz F, Wannenmacher M. Fractionated stereotactic radiotherapy (FSRT) for optic glioma. Int J Radiat Oncol Biol Phys. 1999;44:243-248. 96. Liang CL, Lu K, Liliang PC, Chen HJ. Gamma knife surgery for optic glioma. Report of 2 cases. J Neurosurg. 2010;113 (suppl l):101-103. 97. Kelly JP, Leary S, Khanna P, Weiss AH. Longitudinal measures of visual function, tumor volume, and prediction of visual outcomes after treatment of optic pathway gliomas. Ophthalmology. 2012;119:1231-1237. 98. Avery RA, Hwang EI, Jakacki RI, Packer RJ. Marked recovery of vision in children with optic pathway gliomas treated with bevacizumab. JAMA Ophthalmol. 2014;132:111-114. 99. Ater JL, Xia C, Mazewski CM, Booth TN, Freyer DR, Packer RJ, Sposto R, Vezina G, Pollack IF. Nonrandomized comparison of neurofibromatosis type 1 and non-neurofibromatosis type 1 children who received carboplatin and vincristine for progressive low-grade glioma: a report from the Children's Oncology Group. Cancer. 2016;122:1928-1936. 100. Falsini B, Chiaretti A, Rizzo D, Piccardi M, Ruggiero A, Manni L, Soligo M, Dickmann A, Federici M, Salerni A, Miller: J Neuro-Ophthalmol 2016; 36: 460-473 101. 102. 103. 104. 105. 106. 107. 108. 109. 110. 111. 112. 113. 114. 115. 116. Timelli L, Guglielmi G, Lazzareschi I, Caldarelli M, Galli-Resta L, Colosimo C, Riccardi R. Nerve growth factor improves visual loss in childhood optic gliomas: a randomized, double-blind, phase II clinical trial. Brain. 2016;139:404-414. Rodriguez FJ, Lim KS, Bowers D, Eberhart CG. Pathological and molecular advances in pediatric low-grade astrocytoma. Annu Rev Pathol. 2013;8:361-379. Houshmandi SS, Gutmann DH. All in the family: using inherited cancer syndromes to understand deregulated cell signaling in brain tumors. J Cell Biochem. 2007;102:811-819. Warrington NM, Gianino SM, Jackson E, Goldhoff P, Garbow JR, Piwnica-Worms D, Gutmann DH, Rubin JB. Cyclic AMP suppression is sufficient to induce gliomagenesis in a mouse model of neurofibromatosis-1. Cancer Res. 2011;70:5717-5727. Bajenaru ML, Hernandez MR, Perry A, Zhu Y, Parada LF, Garvow JR, Gutmann DH. Optic nerve glioma in mice requires astrocyte Nf1 gene inactivation and Nf1 brain heterozygosity. Cancer Res. 2003;63:8573-8577. Zhu Y, Harada T, Liu L, Lush ME, Guignard F, Harada C, Burns DK, Bajenaru ML, Gutmann DH, Parada LF. Inactivation of NF1 in CNS causes increased glial progenitor proliferation and optic glioma formation. Development. 2005;132:5577-5588. Toonen JA, Anastasaki C, Smithson LJ, Gianino SM, Li LK, Kesterson RA, Gutmann DH. NF1 germline mutation differentially dictates optic glioma formation and growth in neurofibromatosis type-1. Hum Mol Genet. 2016;25:1703-1713. Pfister S, Janzarik WG, Remke M, Ernst A, Werft W, Becker N, Toedt G, Wittmann A, Kratz C, Olbrich H, Ahmadi R, Thieme B, Joos S, Radlwimmer B, Kulozik A, Pietsch T, Herold-Mende C, Gnekow A, Reifenberger G, Korshunov A, Scheurlen W, Omran H, Lichter P. BRAF gene duplication constitutes a mechanism of MAPK pathway activation in low-grade astrocytomas. J Clin Invest. 2008;118:1739-1749. Yu J, Deshmukh H, Gutmann RJ, Emnett RJ, Rodriguez FJ, Watson MA, Nagarajan R, Gutmann DH. Alterations of BRAF and HIPK2 loci predominate in sporadic pilocytic astrocytoma. Neurology. 2009;73:1526-1531. Rodriguez FJ, Ligon AH, Horkayne-Szakaly I, Rushing EJ, Ligon KL, Vena N, Garcia DI, Cameron JD, Eberhart CG. BRAF duplications and MAPK pathway activation are frequent in gliomas of the optic nerve proper. J Neuropathol Exp Neurol. 2012;71:789-794. Hoyt WF, Meshel LG, Lessell S, Schatz NJ, Suckling RD. Malignant optic glioma of adulthood. Brain. 1973;96:121-132. Rudd A, Rees JE, Kennedy P, Weller RO, Blackwood W. Malignant optic nerve gliomas in adults. J Clin Neuroophthalmol. 1985;5:238-243. Nagaishi M, Sugiura Y, Takano I, Tanaka Y, Suzuki K, Yokoo H, Hyodo A. Clinicopathological and molecular features of malignant pathway glioma in an adult. J Clin Neurosci. 2015;22:207-209. Traber GL, Pangalu A, Neumann M, Costa J, Weller M, HunaBaron R, Landau K. Malignant optic glioma-the spectrum of disease in a case series. Graefes Arch Clin Exp Ophthalmol. 2015;253:1187-1194. Dumas-Stoeckel S, Gambrelle J, Cornut PL, El Chehab H, Vighetto A, Denis P. Central retinal vein and artery occlusions related to intraocular involvement of an anaplastic optochiasmatic glioma [in French]. J Fr Ophtalmol. 2010;33:564-567. Woiciechowsky C, Vogel S, Meyer R, Lehmann R. Magnetic resonance imaging of a glioblastoma of the optic chiasm. J Neurosurg. 1995;83:923-925. Albers GW, Hoyt WF, Forno LS, Shratter LA. Treatment response in malignant optic glioma of adulthood. Neurology. 1988;38:1071-1074. 473 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.