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A 61-year-old female, previously treated for lung cancer, presented with a rare case of metastasis directly to the optic chiasm manifesting as visual deficits. Magnetic resonance imaging revealed a suprasellar mass similar to an optic glioma. At surgery, the optic chiasm appeared swollen with hypervascularity over the surface. The bilateral optic nerves and the pituitary stalk appeared normal. A small incision was made on the superior surface of the chiasm and biopsy specimens were taken. The histological diagnosis was adenocarcinoma, which was consistent with the primary lung cancer. She received whole brain irradiation, resulting in mild improvement of her vision. Suprasellar metastatic tumors to the pituitary gland, pituitary stalk, and hypothalamus are well documented, but solitary metastasis within the optic chiasm should be considered as one of several differential diagnoses of suprasellar tumors, in patients with or without a history of treated cancer.

Neurofibomatosis (NF1) patients are susceptible to multiple tumors of the nervous system including neurofibromas, optic glioma, malignant peripheral nerve sheath tumors (MPNSTs), and astrocytoma. The Nf1+/—;Trp53+/— (NPcis) mouse model of NF1 spontaneously develops astrocytoma and MPNSTs that are very similar to human NF1 tumors. To use this model for testing potential therapeutics, we have developed systems that take advantage of bioluminescent reporters of tumor growth. We have generated E2F1 promoter—driving luciferase (ELUX) reporter mice to detect proliferating tumors in NPcis mice in vivo using bioluminescence. The power of this system is that it enables looking at tumor evolution and detecting spontaneous tumors at early stages of development as they evolve within their natural haploinsufficient microenvironment. This system can be used to identify tumors at different stages of tumorigenesis and to examine where spontaneous NF1 tumors initiate. The ability to rapidly screen multiple animals at a time increases the potential for use of this model in preclinical trials. This model will be valuable for the characterization of spontaneous NF1 tumors and will be important for studying the treatment and prevention of NF1 tumors in vivo.

Individuals with neurofibromatosis type 1 (NF1) are prone to develop optic pathway gliomas that can result in significant visual impairment. To explore the cellular basis for the reduced visual function resulting from optic glioma formation, we used a genetically engineered mouse model of Nf1 optic glioma (Nf1+/-(GFAP)CKO mice). We performed multimodal functional and structural analyses both before and after the appearance of macroscopic tumors. At 6 weeks of age, before obvious glioma formation, Nf1+/-(GFAP)CKO mice had decreased visual-evoked potential amplitudes and increased optic nerve axon calibers. By 3 months of age, Nf1+/-(GFAP)CKO mice exhibited pronounced optic nerve axonopathy and apoptosis of neurons in the retinal ganglion cell layer. Magnetic resonance diffusion tensor imaging showed a progressive increase in radial diffusivity between 6 weeks and 6 months of age in the optic nerve proximal to the tumor indicating ongoing deterioration of axons. These data suggest that optic glioma formation results in early axonal disorganization and damage, which culminates in retinal ganglion cell death. Collectively, this study shows that Nf1+/-(GFAP)CKO mice can provide a useful model for defining mechanisms of visual abnormalities in children with NF1 and lay the foundations for future interventional studies aimed at reducing visual loss.

Neurofibromatosis type 1 (NF1) is an inherited autosomal dominant disorder characterized by numerous cutaneous features, including café-au-lait macules, skinfold freckling and iris hamartomas. In addition, individuals with NF1 are prone to the development of both benign and malignant tumors. The most common CNS tumor in children and adults with NF1 is the glioma. In childhood, gliomas are primarily located in the optic pathway, and less frequently in the hypothalamus and brainstem. Regular ophthalmologic evaluations in children are essential for the effective management of these tumors in patients with NF1. Adults, in contrast, are more likely to develop higher grade gliomas, which are treated in a similar fashion as their sporadic counterparts.

The classical clinical presentation of optic nerve sheath meningiomas is painless, slowly progressive, unilateral optic neuropathy with a swollen and/or pale optic disc. It affects middle-aged women more frequently than men. Optic nerve sheath meningiomas occur frequently in patients with neurofibromatosis type 2. This association parallels the well known link between neurofibromatosis type 1 and optic gliomas. Due to advances in neuroimaging, management decisions have to be made in patients with excellent visual function. Fractionated conformal stereotactic radiotherapy holds the best potential to improve, prevent or at least delay severe visual loss in patients with optic nerve sheath meningiomas.

Optic glioma is a rare benign tumour predominantly occurring in childhood, frequently associated with Neurofibromatosis Type 1 (NF1). It threatens vision and—if extending suprachiasmatically—the life of the patient. Symptoms are visual loss, orbital signs including motility disorders and/or nystagmus in suprachiasmatic lesions. There is no therapy approved in studies with highest evidence. Radiotherapy is most effective in stopping tumour progression but has serious side effects, such as brain developmental anomalies, moya moya syndrome and secondary tumours. Therefore in children younger than 9 and patients with NF1, chemotherapy with vincristine and carboplatine is preferred. Surgery plays only a role in the debulking of large tumours, cosmetic correction or definitive removal if visual function is lost. Therapeutic decisions should be based on reliable function testing.

Neurofibromatosis-1 (NF1) is a common tumor predisposition syndrome in which affected individuals develop benign and malignant tumors. Previous studies from our laboratory and others have shown that benign tumor formation in Nf1 genetically engineered mice (GEM) requires a permissive tumor microenvironment. In the central nervous system, Nf1 loss in glia is insufficient for glioma formation unless coupled with Nf1 heterozygosity in the brain. Our subsequent studies identified Nf1+/− microglia as a critical cellular determinant of optic glioma growth in Nf1 GEM. Using NF1 as an experimental paradigm to further characterize the role of microglia in glioma growth, we first examined the properties of Nf1+/− microglia in vitro and in vivo. Nf1+/− microglia exhibit increased proliferation and motility and express elevated levels of genes associated with microglia activation. We further show that Nf1+/− microglia harbor high levels of activated c-Jun-NH2-kinase (JNK) without any significant changes in Akt, mitogen-activated protein kinase (MAPK), or p38-MAPK activity. In contrast, Nf1−/− astrocytes do not exhibit increased JNK activation. SP600125 inhibition of JNK activity in Nf1+/− microglia results in amelioration of the increased proliferation and motility phenotypes and reduces the levels of expression of activated microglia-associated transcripts. Moreover, SP600125 treatment of Nf1 optic glioma–bearing GEM results in reduced optic glioma proliferation in vivo. Collectively, these findings suggest that Nf1+/− microglia represent a good model system to study the role of specialized microglia in brain tumorigenesis and identify a unique Nf1 deregulated pathway for therapeutic studies aimed at abrogating microenvironmental signals that promote brain tumor growth. [Cancer Res 2008;68(24):10358–66]

We report a rare case of atypical teratoid/rhabdoid tumor that presented with imaging findings similar to those of optic pathway glioma. The diagnosis of atypical teratoid/rhabdoid tumor was determined following surgical resection of the tumor by collective histologic and immunohistochemical staining, and cytogenetic analysis. We describe the clinical presentation, neuroimaging findings and pathology, and compare them to those of optic gliomas.

Mouse models of human cancers afford unique opportunities to evaluate novel therapies in preclinical trials. For this purpose, we analyzed three genetically engineered mouse (GEM) models of low-grade glioma resulting from either inactivation of the neurofibromatosis-1 (Nf1) tumor suppressor gene or constitutive activation of KRas in glial cells. Based on tumor proliferation, location, and penetrance, we selected one of these Nf1 GEM models for preclinical drug evaluation. After detection of an optic glioma by manganese-enhanced magnetic resonance imaging, we randomized mice to either treatment or control groups. We first validated the Nf1 optic glioma model using conventional single-agent chemotherapy (temozolomide) currently used for children with low-grade glioma and showed that treatment resulted in decreased proliferation and increased apoptosis of tumor cells in vivo as well as reduced tumor volume. Because neurofibromin negatively regulates mammalian target of rapamycin (mTOR) signaling, we showed that pharmacologic mTOR inhibition in vivo led to decreased tumor cell proliferation in a dose-dependent fashion associated with a decrease in tumor volume. Interestingly, no additive effect of combined rapamycin and temozolomide treatment was observed. Lastly, to determine the effect of these therapies on the normal brain, we showed that treatments that affect tumor cell proliferation or apoptosis did not have a significant effect on the proliferation of progenitor cells within brain germinal zones. Collectively, these findings suggest that this Nf1 optic glioma model may be a potential preclinical benchmark for identifying novel therapies that have a high likelihood of success in human clinical trials. [Cancer Res 2008;68(5):1520–8]

A 68-year-old man presented with a history of a right optic glioma. Eighteen months ago he underwent a lateral orbitotomy at another institution for removal of an optic nerve mass. At that time histology revealed that the tumor was an optic nerve glioma with a pilocytic pattern. No further treatment was instituted and one year after surgery he noticed that his right eye was proptotic again. Magnetic resonance imaging of the orbit showed that his right orbit was almost completely filled with a mass which extended through the optic canal to the chiasma. The tumor was excised by a combined neurosurgical and orbital approach. Histology proved that the neoplasm was a low grade pilocytic astrocytoma of the optic nerve.

Astrocytoma (glioma) formation in neurofibromatosis type 1 (NF1) occurs preferentially along the optic pathway during the first decade of life. The molecular basis for this unique pattern of gliomagenesis is unknown. Previous studies in mouse Nf1 optic glioma models suggest that this patterning results from cooperative effects of Nf1 loss in glial cells and the action of factors derived from the surrounding Nf1+/− brain. Because CXCL12 is a stroma-derived growth factor for malignant brain tumors, we tested the hypothesis that CXCL12 functions in concert with Nf1 loss to facilitate NF1-associated glioma growth. Whereas CXCL12 promoted cell death in wild-type astrocytes, it increased Nf1−/− astrocyte survival. This increase in Nf1−/− astrocyte survival in response to CXCL12 was due to sustained suppression of intracellular cyclic AMP (cAMP) levels. Moreover, the ability of CXCL12 to suppress cAMP and increase Nf1−/− astrocyte survival was a consequence of mitogen-activated protein/extracellular signal-regulated kinase kinase–dependent inhibition of CXCL12 receptor (CXCR4) desensitization. In support of an instructive role for CXCL12 in facilitating optic glioma growth, we also show that CXCL12 expression along the optic pathway is higher in infant children and young mice and is associated with low levels of cAMP. CXCL12 expression declines in multiple brain regions with increasing age, correlating with the age-dependent decline in glioma growth in children with NF1. Collectively, these studies provide a mechanism for the unique pattern of NF1-associated glioma growth. [Cancer Res 2007;67(18):8588–95]

One of the major limitations to preclinical mouse therapeutic evaluation is the inherent difficulty in imaging small tumors in vivo. We present a rapid and reliable method to detect optic glioma (OPG) in a mouse neurofibromatosis-1 model (Nf1flox/mutGFAP-Cre mice) in vivo using Manganese-Enhanced Magnetic Resonance Imaging (MEMRI). In a blinded study, twenty-three mice were chosen randomly from a cohort of Nf1flox/mutGFAP-Cre mice and two sets of age-matched controls. In all cases, OPG presence or absence was correctly identified. In addition, the OPG size and shape was accurately measured in vivo, facilitating the use of this model for preclinical drug studies.

The tumor microenvironment is considered to play an important role in tumor formation and progression by providing both negative and positive signals that influence tumor cell growth. We and others have previously shown that brain tumor (glioma) formation in Nf1 genetically engineered mice requires a microenvironment composed of cells heterozygous for a targeted Nf1 mutation. Using NF1 as a model system to understand the contribution of the tumor microenvironment to glioma formation, we show that Nf11 /2 brain microglia produce specific factors that promote Nf12 /2 astrocyte growth in vitro and in vivo and identify hyaluronidase as one of these factors in both genetically engineered Nf1 mouse and human NF1-associated optic glioma. We further demonstrate that blocking hyaluronidase ameliorates the ability of Nf11 /2 microglia to increase Nf12 /2 astrocyte proliferation and that hyaluronidase increases Nf12 /2 astrocyte proliferation in an MAPK-dependent fashion. Lastly, inhibiting microglia activation in genetically engineered Nf1 mice significantly reduces mouse optic glioma proliferation in vivo. Collectively, these studies identify Nf11 /2 microglia as an important stromal cell type that promotes Nf12 /2 astrocyte and optic glioma growth relevant to the pathogenesis of NF1-associated brain tumors and suggest that future brain therapies might be directed against paracrine factors produced by cells in the tumor microenvironment.

Optic pathway glioma (OPG), seen in 15% to 20% of individuals with neurofibromatosis type 1 (NF1), account for significant morbidity in young children with NF1. Overwhelmingly a tumor of children younger than 7 years, OPG may present in individuals with NF1 at any age. Although many OPG may remain indolent and never cause signs or symptoms, others lead to vision loss, proptosis, or precocious puberty. Because the natural history and treatment of NF1-associated OPG is different from that of sporadic OPG in individuals without NF1, a task force composed of basic scientists and clinical researchers was assembled in 1997 to propose a set of guidelines for the diagnosis and management of NF1-associated OPG. This new review highlights advances in our understanding of the pathophysiology and clinical behavior of these tumors made over the last 10 years. Controversies in both the diagnosis and management of these tumors are examined. Finally, specific evidence-based recommendations are proposed for clinicians caring for children with NF1.

Orbital tumors constitute a group of diverse lesions with a low incidence in the population. Tumors affecting the eye and ocular adnexa may also secondarily invade the orbit. Lack of accumulation of a sufficient number of cases with a specific diagnosis at various orbital centers, the paucity of prospective randomized studies, animal model studies, tissue bank, and genetic studies led to the development of various myths regarding the diagnosis and treatment of orbital lesions in the past. These myths continue to influence the diagnosis and treatment of orbital lesions by orbital specialists. This manuscript discusses some of the more common myths through case summaries and a review of the literature. Detailed genotypic analysis and genetic classification will provide further insight into the pathogenesis of many orbital diseases in the future. This will enable targeted treatments even for diseases with the same histopathologic diagnosis. Phenotypic variability within the same disease will be addressed using targeted treatments.

Purpose: To examine the incidence, presentation, and outcome of optic gliomas in children with neurofibromatosis type 1 (NF1) in Southern California Kaiser Permanente. Methods: The authors queried the Southern California Kaiser Permanente electronic medical record database to find patients diagnosed as having NF1. Genetics, ophthalmology, and imaging medical records of patients with optic glioma were reviewed. Results: A total of 708 patients younger than 21 years had a diagnosis of NF1 in Southern California Kaiser Permanente and 30 (4.2%) had a diagnosis of optic glioma. The average age of diagnosis was 5 years, with a range of 18 months to 12 years. Half (15 of 30) of the patients diagnosed as having optic glioma presented with symptoms (eg, vision loss, proptosis, and precocious puberty). Eight of 15 of the symptomatic patients were treated with surgery and/or chemotherapy. Symptomatic children were diagnosed later than those diagnosed through routine screening (5.7 vs 3.9 years old). The oldest child presented with symptoms at age 12 years. One asymptomatic patient had prophylactic chemotherapy. Sixty-three percent (19 of 30) of the gliomas were bilateral, 23% (7 of 30) were right-sided, and 13% (4 of 30) were left-sided. Fifty-three percent (17 of 30) of the gliomas involved the optic chiasm. Conclusions: Screening practices for optic glioma are inconsistent. Most children with NF1 at risk for optic glioma do not have even one visit with an ophthalmologist. Children with NF1 can develop asymptomatic optic glioma as early as age 1 year. Annual ophthalmologic examination and screening for precocious puberty in children with NF1 is important for early diagnosis of optic gliomas and may reduce morbidity. [ J Pediatr Ophthalmol Strabismus . 2016;53(6):334–338.]

Investigators from Cincinnati Children's Hospital, OH, analysed retrospectively the utility of screening brain/orbital MRIs in 826 children with NF1 (ages 1-9 years; 402 female, 424 male) seen over a 20-year period between 1990 and 2010.

Neurofibromatosis type 1 (NF1) is a common neurogenetic condition characterized by significant clinical heterogeneity. A major barrier to developing precision medicine approaches for NF1 is an incomplete understanding of the factors that underlie its inherent variability. To determine the impact of the germline NF1 gene mutation on the optic gliomas frequently encountered in children with NF1, we developed genetically engineered mice harboring two representative NF1-patient-derived Nf1 gene mutations (c.2542G>C;p.G848R and c.2041C>T;p.R681X). We found that each germline Nf1 gene mutation resulted in different levels of neurofibromin expression. Importantly, only R681X(CKO) but not G848R(CKO), mice develop optic gliomas with increased optic nerve volumes, glial fibrillary acid protein immunoreactivity, proliferation and retinal ganglion cell death, similar to Nf1 conditional knockout mice harboring a neomycin insertion (neo) as the germline Nf1 gene mutation. These differences in optic glioma phenotypes reflect both cell-autonomous and stromal effects of the germline Nf1 gene mutation. In this regard, primary astrocytes harboring the R681X germline Nf1 gene mutation exhibit increased basal astrocyte proliferation (BrdU incorporation) indistinguishable from neo(CKO) astrocytes, whereas astrocytes with the G848R mutation have lower levels of proliferation. Evidence for paracrine effects from the tumor microenvironment were revealed when R681X(CKO) mice were compared with conventional neo(CKO) mice. Relative to neo(CKO) mice, the optic gliomas from R681X(CKO) mice had more microglia infiltration and JNK(Thr183/Tyr185) activation, microglia-produced Ccl5, and glial AKT(Thr308) activation. Collectively, these studies establish that the germline Nf1 gene mutation is a major determinant of optic glioma development and growth through by both tumor cell-intrinsic and stromal effects.

Objective: Optic gliomas are for the vast majority of cases no surgical tumors in NF1 due to their diffuse nature and involvement of optic nerve, chiasm and optic tract/hypothalamus. An exception are unilateral intraorbital to pre-chiasmatic tumors in case of blindness associated with increasing[for full text, please go to the a.m. URL], 66. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC)

Neurofibromatosis type 1 (NF1) is a genetic multisystemic disorder involving the skin, the central and peripheral nervous systems, bones, and the cardiovascular and endocrine systems. This condition is caused by inherited or de novo mutations of the NF1 gene at the 17q11.2 chromosomal region, a gene that codes for the protein neurofibromin. Neurofibromin is particularly expressed in neural cells and inhibits the RAS pathway, which regulates cellular proliferation and differentiation. The typically age-dependent emergence of diagnostic signs and the risk for severe complications in the first years of life simultaneously makes a precocious diagnosis crucial and makes the management of children with suspected NF1 challenging. Currently, no standardized specific treatments for NF1 and its complications are available. However, in recent years, increasing knowledge of the pathogenetic mechanisms has motivated the scientific search behind targeted biological agents that might change the course of the disease. Numerous clinical trials for the treatment of the most typical NF1 complications, such as plexiform neurofibromas (Ns) and NF1-related tumors, have been conducted. Consequently, encouraging in vitro and in vivo results are emerging. Insufficient efficacy and safety in in vivo data do not permit the routine use of these drugs in clinical practice. Radiotherapy appears to be indicated only for high-grade soft-tissue sarcomas, whereas surgical approaches should be considered for malignant peripheral nerve sheath tumors (MPNSTs) and Ns, optic pathway gliomas, and bone dystrophic changes because they might improve quality of life. Further prospective studies, however, are needed to confirm the efficacy, safety, and cost/benefit ratio of new therapeutic approaches and the optimal timing for their use in patients with NF1.

Purpose Optic pathway gliomas (OPGs) are the most common CNS tumor in neurofibromatosis 1 (NF1) patients. We evaluated the long-term risk of second tumors in NF1-related OPGs after radiotherapy. Patients and Methods We reviewed 80 NF1 OPG patients from two NF1 clinics to evaluate the long-term risk of developing subsequent nervous system tumors, with or without radiotherapy. Results Fifty-eight patients were assessable for second tumors. Nine (50%) of 18 patients who received radiotherapy after their OPGs developed 12 second tumors in 308 person-years of follow-up after radiotherapy. Eight (20%) of 40 patients who were not treated with radiotherapy developed nine tumors in 721 person-years of follow-up after diagnosis of their OPGs. The relative risk of second nervous system tumor after radiotherapy was 3.04 (95% CI, 1.29 to 7.15). Conclusion There is a significantly increased risk of second nervous system tumors in those NF1 patients who received radiotherapy for their OPGs, especially when treated in childhood. Thus radiotherapy should only be used if absolutely essential in children with NF1.

A 51-year-old male presented with a 5-year history of progressive right exophthalmos and visual loss. Magnetic resonance imaging showed a right intraorbital lesion. [18F]fluorodeoxyglucose positron emission tomography ([18F]FDG-PET) revealed high uptake in the tumor. No FDG was accumulated in the remaining optic tract. He underwent removal of the tumor. The histological diagnosis was optic glioma. Six months after the operation, the tumor recurred, and a second operation was performed to spare the visual acuity of the other eye, which remained stable for 1.5 years after the first operation. However, the patient died 2 years after the first operation of liver dysfunction. Adult optic glioma tends to rapidly extend into the surrounding tissue and to affect the contralateral visual pathway. Early diagnosis and surgical intervention are imperative. In the present case, [18F]FDG-PET was valuable for evaluating malignancy to determine whether radical surgery was indicated to preserve the remaining visual acuity.

The gene responsible for neurofibromatosis type 1 (NF1) encodes a tumor suppressor that functions as a negative regulator of the Ras proto-oncogene. Individuals with germline mutations in NF1 are predisposed to the development of benign and malignant tumors of the peripheral and central nervous system(CNS). Children with this disease suffer a high incidence of optic gliomas, a benign but potentially debilitating tumor of the optic nerve; and an increased incidence of malignant astrocytoma, reactive astrogliosis and intellectual deficits. In the present study, we have sought insight into the molecular and cellular basis of NF1-associated CNS pathologies. We show that mice genetically engineered to lack NF1 in CNS exhibit a variety of defects in glial cells. Primary among these is a developmental defect resulting in global reactive astrogliosis in the adult brain and increased proliferation of glial progenitor cells leading to enlarged optic nerves. As a consequence, all of the mutant optic nerves develop hyperplastic lesions, some of which progress to optic pathway gliomas. These data point to hyperproliferative glial progenitors as the source of the optic tumors and provide a genetic model for NF1-associated astrogliosis and optic glioma.

Von Hippel-Lindau disease (VHL) and neurofibromatosis type 1 (NF 1) are hereditary multitumor syndromes that show associated ocular manifestations. Capillary retinal angioma, a benign vascular tumor, is the classical ocular lesion in VHL. It often appears as the first manifestation of the disease and may thus lead to the diagnosis of VHL. Since small angiomas can be treated easily by laser photocoagulation, a regular ocular screening of VHL patients is recommended. Ocular manifestations of NF 1 are more diverse as compared to VHL. Lisch nodules of the iris are an important diagnostic criteria of NF 1 since they can be found in almost every affected patient. Optic glioma can occur both intraorbitally and intracranially. The intraorbital form causes progressive protrusion of the globe and eventually blindness. Extension of the tumor beyond the chiasm worsens the prognosis quoad vitam. The hallmark of NF 1, namely cutaneous neurofibroma can cause visual impairment when affecting the skin of the eyelids. The rare intraorbital pexiform neurofibroma is associated with abnormal development of the orbital bones and infantile glaucoma. It may result in orbital mass effects and therefore may need surgical excision.

✓ Tumors involving the optic nerve (optic glioma, optic nerve sheath meningioma) are benign but difficult to treat. Gamma knife surgery (GKS) may be a useful treatment. The authors present data obtained in three such cases and record the effects of GKS.

A 12-year-old girl with neurofibromatosis type 1 presented with headache, visual acuity and visual field disturbance. Computed tomography and magnetic resonance imaging revealed an enhanced solid mass involving her right optic nerve and optic chiasm, and a cystic lesion in the pineal region that had resulted in obstructive hydrocephalus. An open biopsy of the right optic nerve tumour was performed, and it was histologically identified as a pilocytic astrocytoma. Local irradiation of 50 Gy to the optic pathway tumour was performed, and the tumour has remained stable for more than 29 months. On the contrary, the pineal cystic mass that was also histologically identified as a pilocytic astrocytoma showed marked enlargement within 5 months after a subtotal resection. Chemotherapy with cisplatin and vincristine was performed after a second surgery, and the pineal tumour has not re-grown in 18 months. To our knowledge, this is the first case report to describe synchronous optic and pineal pilocytic astrocytomas associated with neurofibromatosis type 1.

Gliomas of the optic pathways are rare childhood central nervous system tumors. The treatment approach is controversial because of its rarity and the slow and unpredictable growth rates of these lesions.We reviewed 50 patients with the diagnosis of optic pathway low-grade gliomas treated between January 1980 and December 1995 at King Faisal Specialist Hospital and Research Center, Saudi Arabia. Thirty-five patients presented with chiasmatic/hypothalamic (posterior tumors), and 15 with optic nerve gliomas with or without chiasmal involvement (anterior tumors). Evidence of neurofibromatosis was present in 18 patients. Twenty-nine patients underwent surgery (total or partial resection), and 12 of these received postoperative radiotherapy (RT). Sixteen patients were treated with primary RT. The radiation dose varied between 42 and 54 Gy (median dose 50).The overall actuarial survival rate was 87.5% at 5 years and 75% at 10 years, and the corresponding progression-free survival (PFS) rates were 69% and 62%. Patients with anterior tumors fared better than those with posterior tumors, with a 10-year PFS rate of 72% and 58%, respectively; the difference, however, was not statistically significant (p = 0.58). A PFS advantage was found in favor of patients with posterior tumors treated with RT (primary or postoperative) compared with no RT, with 5-year PFS rates of 68% vs. 42% (p = 0.03). This, however, did not translate into a survival advantage because of the success of salvage treatment.In multivariate analysis, age (3 vs.3 years) emerged as the only significant determinant for PFS with patients3 years old faring worse (p = 0.03). Neurologic and endocrine dysfunction are significant problems that need to be addressed.

OBJECTIVE AND IMPORTANCE Vascular malformations in the optic pathway are rare. Only one case of pathologically confirmed arteriovenous malformation (AVM) of the optic nerve has been reported previously. We document the case of a patient with an optic nerve AVM who presented with optic apoplexy that was diagnosed with the use of magnetic resonance imaging. CLINICAL PRESENTATION A 15-year-old girl developed left visual disturbance of sudden onset while playing badminton. A magnetic resonance imaging scan disclosed left optic nerve swelling and intraoptical hemorrhage, although an angiogram did not reveal abnormal vessels. INTERVENTION The patient underwent total removal of the hematoma and tangles of the abnormal vessels in the left optic nerve, which was diagnosed pathologically as an AVM. The patient recovered visual acuity, but the left visual field defect remained unchanged. CONCLUSION Along with cavernous malformations and optic gliomas, AVMs can be a rare cause of optic nerve apoplexy. T2-weighted magnetic resonance imaging is useful in rendering the diagnosis of an optic nerve AVM, observed as a mass lesion consisting of serpiginous, tangled, low-intensity bands. Early surgical treatment is recommended to obtain a rapid recovery.

Unidentified bright objects are commonly observed on magnetic resonance imaging in young neurofibromatosis 1 patients, but their clinical and pathologic significance is largely unknown. Diagnostic features of neurofibromatosis 1 include café-au-lait spots, intertriginous freckling, Lisch nodules, neurofibromas, bony lesions, and optic glioma. We investigated the relationship between unidentified bright objects and other features of neurofibromatosis 1. Data from the National Neurofibromatosis Foundation International Database included 523 neurofibromatosis 1 patients between 2 and 20 years of age who had cranial magnetic resonance imaging examinations. The presence or absence of unidentified bright objects, diagnostic features of neurofibromatosis 1, and central nervous system neoplasms was known in these patients. Logistic regressive models were used to measure associations between unidentified bright objects and the other features while controlling for age. The occurrence of unidentified bright objects was associated with the number of diagnostic features, but most significantly with central nervous system neoplasms other than optic gliomas [odds ratio (OR) = 9.0, 95% confidence interval (CI) = 1.2-70], optic gliomas (OR = 2.1, 95% CI = 1.2-3.6), subcutaneous neurofibromas (OR = 2.0, 95% CI = 1.3-3.1), and Lisch nodules (OR = 1.6, 95% CI = 1.1-2.3). These findings suggest a common causal mechanism between unidentified bright objects and these cardinal clinical features in children with neurofibromatosis 1.

PURPOSE: Optic gliomas are brain tumors characterized by slow growth, progressive loss of vision and limited therapeutic options. Optic gliomas contain various amount of myxoid matrix, which can represent majority of the tumor mass. We sought to investigate biological function and protein structure of the myxoid matrix in optic gliomas to identify novel therapeutic targets. EXPERIMENTAL DESIGN: We reviewed histological features of 120 optic gliomas, clinical imaging properties of 10 optic gliomas, analyzed vasculature by immunohistochemistry and electron microscopy of 12 optic gliomas and performed Liquid Chromatography–Mass Spectrometry on 10 snap-frozen age-, sex- and BRAF status- matched Nf1 wild-type optic gliomas, which varied in the amount of myxoid matrix. RESULTS: Optic gliomas contain varying amounts of myxoid matrix and are indistinguishable on imaging. Microvascular network of pilomyxoid astrocytoma, a subtype of optic glioma with abundant myxoid matrix, is characterized by the presence of endothelium-free channels in the myxoid matrix. Channels are connected to the main vascular network, show normal perfusion and lack thrombosis, likely due to extravasation of fibrin. The myxoid matrix is composed predominantly of the proteoglycan versican (VCAN) and its linking protein, a vertebrate Hyaluronan And Proteoglycan Link Protein 1 (HAPLN1). These proteins may limit effective delivery of chemotherapy to the tumor. CONCLUSIONS: Pediatric optic pathway gliomas maintain blood supply without endothelial cells by using invertebrate-like channels, which we termed “primitive myxoid vascularization.” Channels are formed within myxoid matrix, which lacks endothelium and absorbs fibrin. Targeting the optic glioma matrix enzymatically, similar to storage disorders, may decrease the tumor mass directly, as well as provide improved access of chemotherapy and molecularly targeted therapy to the tumor cells, providing increased treatment efficacy.

Background Malignant optic glioma of adulthood is a rare, invasive neoplasm of the anterior visual pathway. In this article, the clinical features of a case series of 3 malignant optic nerve glioblastomas (World Health Organization grade IV) are presented, and the modalities of treatment and their associated survivals are discussed through a review of the existing literature to date. Methods A retrospective case series study was led for 3 patients diagnosed with primary optic nerve and chiasm glioblastoma, coming from 2 referral neurosurgical centers. An electronic search was conducted on MEDLINE via PUBMED, COCHRANE, from October 1973 to April 2016. Cohort, case reports, and case series were screened for investigating treatment and overall survival (OS) of malignant optic nerve gliomas. Pooled means and 95% confidence intervals of OS for each treatment were generated. Results From our retrospective case series, all patients had initial visual impairment (2 women and 1 man). The histologic diagnosis was done by biopsy. The patients' mean age was 67.3 years (standard deviation [SD] 18.5). The disease was rapidly lethal for all patients: median OS was 5 months (SD: 15.1). Two patients underwent chemotherapy by single cure of temozolomide, while the third one was treated with a radiochemotherapy protocol. Due to the fact that there is no gold standard treatment as first-choice treatment, a large heterogeneity in first-choice oncologic treatment is observed. However, we did not find any significant differences for OS between World Health Organization grade III and grade IV optic gliomas. Conclusion Malignant optic glioma is a rare and fatal disease in adults. Despite the modalities of treatment, the treatment outcomes remain unsatisfactory. There is no significant difference in the median OS of patients with malignant optic nerve, as compared with those diagnosed with other supratentorial glioblastoma. Chemoradiotherapy with temozolomide currently remains the best treatment in terms of OS. Advances in the understanding of tumor biology have yet failed to translate into effective treatment regimens.

Neurofibromatosis type 1 (NF1) is one of the most common inherited cancer syndromes in which affected individuals develop brain tumors.1 As such, children with NF1 are at risk for the formation of low-grade glial neoplasms involving the optic pathway (optic nerve, chiasm, and postchiasmal tracts; optic pathway glioma [OPG]),2,3 which can lead to visual impairment.4,5 Since surgery is not an option because of permanent nerve damage, and radiation therapy is associated with an increased incidence of fatal secondary high-grade glioma,6 the mainstay of treatment has been chemotherapy. For the past 25 years, the treatment of NF1-OPG has largely employed anti-neoplastic agents used for sporadic low-grade glioma7,8 with varying success. Genetically engineered mouse (GEM) models provide unprecedented opportunities to identify and critically evaluate therapies specifically targeted to NF1-OPG. To this end, Nf1+/− mice with neuroglial progenitor Nf1 loss develop low-grade gliomas of the prechiasmatic optic nerves and chiasm with many similarities to their human counterparts.9,10 As observed in human NF1-OPG, these murine tumors harbor low proliferative indices, microglia infiltration, nuclear pleomorphism, cellular atypia, and bipolar neoplastic glial cells. Nf1 optic glioma mice have been previously employed to demonstrate that increased cell growth results from loss of Nf1 protein (neurofibromin) regulation of Ras in neuroglial progenitors, leading to elevated Ras and Ras pathway activation.11 The critical role of deregulated Ras signaling in Nf1 optic glioma formation is further underscored by the finding that Nf1+/− mice with constitutively active KRas expression in neuroglial progenitors develop optic glioma.12 Ras transmits its growth regulatory signal through downstream signaling intermediates, including protein kinase-B (Akt) and mitogen activated protein kinase (ERK). While previous studies from our laboratory have identified the Akt/mammalian target of rapamycin (mTOR) effector arm as a major regulator of Nf1 optic glioma growth,11,13 recent reports have demonstrated that ERK is the primary driver of tumor growth in other NF1-associated cancers.14,15 These observations have prompted recent clinical trials employing inhibitors of mitogen-activated protein kinase kinase (MEK) for the treatment of plexiform neurofibromas (NCT01362803) and brain tumors (NCT01885195) in individuals with NF1. In this report, we sought to critically establish which Ras effector pathway is responsible for maintaining Nf1 optic glioma growth. Using a series of pharmacologic studies on Nf1-deficient astrocytes in vitro and Nf1 murine optic gliomas in vivo, we demonstrate that both phosphatidylinositol-3 kinase (PI3K)/Akt and MEK/ERK signaling pathways are responsible for neurofibromin regulation of mTOR activity, such that sustained inhibition of either PI3K or MEK activity suppresses Nf1 optic glioma proliferation and retinal ganglion cell (RGC) death in vivo. Together, these data provide further support for the use of agents that target mTOR as biologically based NF1-OPG treatments.

Primary optic nerve gliomas are most commonly benign pilocytic astrocytomas (World Health Organization [WHO] Grade I) occurring in childhood and following an indolent course. Malignant optic gliomas occur in adulthood and follow an extremely aggressive course, with rapid infiltration of the chiasm, blindness, and death typically within months. A third category of optic glioma, occurring in adulthood, histopathologically benign (WHO Grade I-II) but following an aggressive course, has been rarely reported. The authors describe clinical and histopathologic features of clinically aggressive but histopathologically benign optic nerve gliomas of adulthood. Retrospective review of cases of biopsy-proven optic nerve glioma in the neuro-ophthalmology division of the Jules Stein Eye Institute from 1990 to 2011 was carried out. Cases following an aggressive course were selected for review of clinical, neuroradiologic, and histopathologic features. Three cases were selected for detailed study. Ages ranged from 31 to 45 years. All were initially diagnosed with optic nerve inflammation or benign neoplasm based on clinical and neuroradiologic features, but all suffered neuroradiologic extension and rapid deterioration of vision in the affected eye to no light perception over 3-8 weeks. Optic nerve biopsies were undertaken for the suspicion of malignancy. Features ranged from WHO Grade I (pilocytic astrocytoma, ganglioglioma) in two cases, to WHO Grade II in one case (diffuse astrocytoma, histopathologically benign, but associated with aggressive features such as high p53 [13-21%] and Ki-67 [40%]). The diffuse astrocytoma case subsequently developed extensive intracranial extension suspicious for malignant transformation. These findings indicate that benign optic nerve glioma in adults may be initially misdiagnosed as inflammation, be clinically aggressive, and require excision to prevent further intracranial involvement.

Neurofibromatosis type 1 (NF1) is one of the most common genetic etiologies for pediatric brain tumors.1,2 As such, 15%–20% of children with NF1 develop low-grade glial neoplasms (pilocytic astrocytomas [PAs]) arising along the optic pathway (optic nerve, chiasm, and postchiasmal tracts; optic pathway glioma [OPG]).3,4 In some children with these NF1-OPGs, there may also be associated visual impairment5,6 or hypothalamic dysfunction.7 Since surgery and radiation therapy are not used due to the risk of permanent nerve damage and secondary malignancy,8 respectively, the treatment of NF1-OPG has largely employed agents (vincristine and carboplatin) in routine use for sporadic low-grade glioma.9,10 Because NF1-OPGs are rarely biopsied for pathological diagnosis, there have been few analyses of the molecular changes that drive tumorigenesis in this condition. Immunohistochemical and whole genome (NexGen) sequencing studies have demonstrated biallelic inactivation of both NF1 genes,11 resulting in loss of NF1 protein (neurofibromin) expression in these NF1-associated brain tumors.12,13 To model the human condition in which children with NF1 are born with one functional and one nonfunctional (germline NF1 gene mutation) copy of the NF1 gene, Nf1+/− mice with biallelic astroglial progenitor Nf1 gene loss were generated.14,15 These mice develop low-grade gliomas of the prechiasmatic optic nerves and chiasm with many similarities to their human counterparts.14,16,17 As observed in human NF1-OPGs, these murine optic gliomas have low proliferative indices, increased microglia infiltration, and bipolar neoplastic glial cells with nuclear pleiomorphism and cellular atypia.14,16,17 While complete NF1 gene inactivation is the rule for NF1-PA tumors, recent studies have revealed the presence of additional molecular changes in NF1-OPGs.18,19 In some of these NF1-OPGs, heterozygous PTEN deletion (1/4 tumors) and KIAA1549:BRAF duplication (1/4 tumors) were detected, raising the intriguing possibility that genetic cooperativity between these molecular alterations and neurofibromin loss might lead to more biologically aggressive tumors. To address this clinically relevant issue, we generated Nf1 genetically engineered mouse (GEM) strains that harbor Pten reduction or KIAA1549:BRAF expression in addition to Nf1 gene loss in neuroglial progenitors in vivo. Using these novel strains, we demonstrated that heterozygous Pten loss, but not KIAA1549:BRAF expression, cooperates with Nf1 gene inactivation to increase murine optic glioma growth and retinal nerve defects.

Gangliogliomas involving the optic apparatus are rare, with only 23 cases described in the literature to our knowledge. Because of their location, they are resistant to gross total resection and command careful consideration of adjuvant treatment. Here, we review the existing literature describing these cases, along with our own additional patient. Most patients (91.3%) with optic gangliogliomas presented with progressive visual disturbances, and the majority were male (69.6%), as with gangliogliomas in general. Ophthalmological evaluation is warranted in these patients, followed by neurological imaging (preferably MRI). Screening for neurofibromatosis type 1 (NF1) is essential, as NF1 patients represent a disproportionate number of optic ganglioglioma cases (13.0%). Gross total resection should be attempted only if vision is beyond salvage, as this can be curative. Otherwise, when serviceable vision remains, subtotal resection with adjuvant radiation should be carried out when feasible. Despite treatment, the prognosis remains mixed, with roughly one-third of patients progressing.

Optic pathway cavernous malformations (CMs) are extremely rare, accounting for less than 1 % of all intracranial CMs. We report a case of optic pathway CM mimicking optic glioma because the initial magnetic resonance (MR) images did not disclose hemorrhagic findings such as popcorn-like lesion or hemosiderin ring. A 20-year-old woman presented with subacute left visual acuity loss and visual field defect and was referred to our hospital. Initial MR imaging findings were suggestive of optic glioma. Second MR imaging demonstrated hemorrhagic findings, but the hemorrhage was considered to be intratumoral hemorrhage from left optic pilocytic astrocytoma. She underwent radiochemotherapy and intravenous administration of corticosteroids but her symptoms deteriorated. Third and fourth MR imaging revealed enlargement of the hematoma. Therefore, the radiation therapy was interrupted at a delivered dose of 16.2 Gy, and craniotomy was performed to preserve residual right visual field. The lesion was totally removed and the histological diagnosis was CM. Her right visual field was preserved, but not improved. The present case and previous cases suggest that optic pathway CMs sometimes do not initially manifest with signs of hemorrhage, so CMs should be included in the differential diagnosis of optic pathway lesions. Histological confirmation with preparation for total resection should be considered for rapidly progressive cases even if the neuroimaging findings are compatible with optic glioma.

Background: Arachnoid proliferation, although rare, is known to occur in association with optic gliomas. However, chondroid and chordoid metaplasia has not been reported previously. Case Description: A 27‑year‑old male presented with progressive, painless loss of vision in right eye, associated with vomiting and headache for one and a half months. Computed tomography (CT) scan revealed a contrast enhancing mass arising from planum sphenoidale. Perioperative findings showed the tumor adherent to the right optic nerve and attached to basal dura and falx. A clinical impression of an intradural, optic nerve sheath meningioma was made. Histopathological examination revealed a glial tumor with adjacent areas displaying marked fibroblastic and arachnoid cell proliferation with chondroid as well as chordoid differentiation along with myxoid change and dense collagenisation. Reticulin stain, immunochemistry with glial fibrillary acid protein (GFAP), epithelial membrane antigen (EMA), and S‑100 helped to arrive at the final diagnosis of optic glioma displaying exuberant arachnoid proliferation with cartilaginous metaplasia. Conclusion: We report a case of optic nerve glioma displaying extensive arachnoid proliferation, chordoid, and cartilaginous metaplasia, which mimicked chondrosarcoma or chordoid meningioma, posing a diagnostic dilemma. A clinical feedback, simple reticulin stain, and GFAP staining is of immense value in such cases to arrive at the correct diagnosis.

BACKGROUND: We assessed the effects on visual function of murine nerve growth factor (NGF) administered as eye drop in children with optic pathway glioma (OPG) and visual impairment. METHODS: A prospective randomized double-blind controlled study was conducted in 18 pts (median age 10 yrs) with OPG-induced visual impairment. All patients were off-therapy and with stable disease by MRI. NGF eye-drop was prepared by University Hospital Pharmacy according to standard required for human use. Patients were evaluated by visual acuity, visual field, optical coherence tomography of the optic nerve fiber layer, Ganzfeld electroretinograms photopic negative response (PhNR), an indirect index of retinal ganglion cell function, and visual evoked potentials (VEPs). All patients were assesed at baseline and 15, 30, 90 and 180 days post treatment. Brain MRI was performed at baseline and at 180 days after NGF treatment. Patients received a 10-day course of 1 mg murine NGF topical administration and placebo, respectively. Based on the evidence of statistically significant drug effect, a cross over treatment with NGF was given, in open label, to patients receiving placebo. RESULTS: Ten pts received placebo and eight NGF. In treated pts there was an improvement of visual field by 40% ( p = 0.02) and 50% (p = 0.05) at 30 and at 90 days post-treatment respectively, compared to a 14% and 5% increase in the placebo group. An increase of the mean PhNR amplitude till 90 days was observed in the treated eyes (25%, p < 0.06), compared to placebo group. There was a median VEP amplitude increase from baseline, compared to placebo group, at 30 days (p < 0.05). In placebo group visual field and VEP amplitudes improved from either baseline or from the values recorded after placebo treatment. CONCLUSIONS: NGF administration appears an effective and safe therapy in patients with OPG-associated visual impairment.

BACKGROUND: We assessed the effects on visual function of murine nerve growth factor (NGF) administered as eye drop in children with optic pathway glioma (OPG) and visual impairment. METHODS: A prospective randomized double-blind controlled study was conducted in 18 pts (median age 10 yrs) with OPG-induced visual impairment. All patients were off-therapy and with stable disease by MRI. NGF eye-drop was prepared by University Hospital Pharmacy according to standard required for human use. Patients were evaluated by visual acuity, visual field, optical coherence tomography of the optic nerve fiber layer, Ganzfeld electroretinograms photopic negative response (PhNR), an indirect index of retinal ganglion cell function, and visual evoked potentials (VEPs). All patients were assesed at baseline and 15, 30, 90 and 180 days post treatment. Brain MRI was performed at baseline and at 180 days after NGF treatment. Patients received a 10-day course of 1 mg murine NGF topical administration and placebo, respectively. Based on the evidence of statistically significant drug effect, a cross over treatment with NGF was given, in open label, to patients receiving placebo. RESULTS: Ten pts received placebo and eight NGF. In treated pts there was an improvement of visual field by 40% ( p = 0.02) and 50% (p = 0.05) at 30 and at 90 days post-treatment respectively, compared to a 14% and 5% increase in the placebo group. An increase of the mean PhNR amplitude till 90 days was observed in the treated eyes (25%, p < 0.06), compared to placebo group. There was a median VEP amplitude increase from baseline, compared to placebo group, at 30 days (p < 0.05). In placebo group visual field and VEP amplitudes improved from either baseline or from the values recorded after placebo treatment. CONCLUSIONS: NGF administration appears an effective and safe therapy in patients with OPG-associated visual impairment.

The most effective method for the screening and monitoring of optic pathway gliomas in children with neurofibromatosis type 1 remains a dilemma. Children less than 6 years of age are the group at highest risk for the development of optic pathway gliomas. Although an annual ophthalmologic examination currently is recommended as the most efficient method to screen for optic pathway gliomas, this method is often unreliable and inaccurate in young children. Magnetic resonance imaging remains the most sensitive test; however, cost and the need for sedation or general anaesthetic preclude its use as a routine screening test. We previously have recommended visual-evoked potentials (VEPs) as a possible alternative or aid in the assessment of optic pathway gliomas in this group of patients. The aims of this study were to ascertain the sensitivity of VEPs in detecting optic pathway gliomas and to determine whether VEPs are useful in monitoring the progress of optic pathway gliomas. This study provides further evidence of the sensitivity of VEPs in detecting optic pathway gliomas. In addition, VEPs may provide additional useful information concerning the progression of optic pathway gliomas once they have been detected.

Management of low grade optic glioma in children and adolescents remains controversial. Treatment with chemotherapy may delay or eliminate the need for radiation therapy. Children with newly diagnosed optic chiasm glioma were eligible for enrollment in this phase II trial and received intravenous carboplatin (CBDCA) (560 mg/m2) every four weeks. Patients were monitored closely for toxicity and tumor status. Twelve children were enrolled. Six patients had stable disease, four a partial response and two progressed on therapy. Overall progression free survival was 83 +/- 11%. The median duration of follow-up was 38.6 months (range 18-63 months). No deaths were noted in our series. Thrombocytopenia was the major toxicity, and two patients required platelet transfusions. One child developed an urticarial reaction requiring discontinuation of therapy. Another child developed unilateral high frequency hearing loss. No renal toxicity was encountered. We have demonstrated that carboplatin can eliminate or delay radiation therapy in children and adolescents with low grade optic glioma. CBDCA deserves further investigation in larger clinical trials as a treatment for children with optic chiasm glioma.

Advances have recently been made in the use of chemotherapy for pediatric brain tumors. Chemotherapy increases disease-free survival in high-risk primitive neuroectodermal tumor/medulloblastoma patients and enables the reduction of radiation therapy in standard-risk patients. Radiation can be significantly delayed and neurotoxicity ameliorated in many infants using chemotherapy. Chemotherapy can cause reduction in size of low-grade glioma, optic glioma, and oligodendroglioma. High-grade glioma and ependymoma are relatively chemoresistant. Physicians caring for children with brain tumors are encouraged to participate in controlled studies, so that objective information can be gathered and the role of chemotherapy in these tumors can be better defined.

The first case is presented of an exophytic chiasmatic-hypothalamic glioma causing progressive hemidystonia in an 8-year-old boy, and all 24 reported cases of intraaxial cerebral tumours resulting in symptomatic hemidystonia are reviewed.