The 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 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
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).
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 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 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).
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 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 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).
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 cross-section, 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 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).
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 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).
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 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 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). 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.
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
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 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).
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 normal-appearing 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 widely among authors but is approximately 30% (6,63), whereas approximately 18% of patients with NF1 have an OCG (24).
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 T2-weighted images (24,53,63,66,80). As in the case of ONGs, OCGs almost always show enhancement after intravenous contrast material.
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).
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 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).
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 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 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, double-masked, 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 statistically significant improvement in all parameters in subjects receiving NGF. Visual field worsening occurred only in subjects who had received placebo.
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
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, 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) 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 NF1-unrelated 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.
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 normal-appearing 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 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.
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.
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