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1.  Akt- or MEK-mediated mTOR inhibition suppresses Nf1 optic glioma growth 
Neuro-Oncology  2014;17(6):843-853.
Children with neurofibromatosis type 1 (NF1) develop optic pathway gliomas, which result from impaired NF1 protein regulation of Ras activity. One obstacle to the implementation of biologically targeted therapies is an incomplete understanding of the individual contributions of the downstream Ras effectors (mitogen-activated protein kinase kinase [MEK], Akt) to optic glioma maintenance. This study was designed to address the importance of MEK and Akt signaling to Nf1 optic glioma growth.
Primary neonatal mouse astrocyte cultures were employed to determine the consequence of phosphatidylinositol-3 kinase (PI3K)/Akt and MEK inhibition on Nf1-deficient astrocyte growth. Nf1 optic glioma–bearing mice were used to assess the effect of Akt and MEK inhibition on tumor volume, proliferation, and retinal ganglion cell dysfunction.
Both MEK and Akt were hyperactivated in Nf1-deficient astrocytes in vitro and in Nf1 murine optic gliomas in vivo. Pharmacologic PI3K or Akt inhibition reduced Nf1-deficient astrocyte proliferation to wild-type levels, while PI3K inhibition decreased Nf1 optic glioma volume and proliferation. Akt inhibition of Nf1-deficient astrocyte and optic glioma growth reflected Akt-dependent activation of mammalian target of rapamycin (mTOR). Sustained MEK pharmacologic blockade also attenuated Nf1-deficient astrocytes as well as Nf1 optic glioma volume and proliferation. Importantly, these MEK inhibitory effects resulted from p90RSK-mediated, Akt-independent mTOR activation. Finally, both PI3K and MEK inhibition reduced optic glioma–associated retinal ganglion cell loss and nerve fiber layer thinning.
These findings establish that the convergence of 2 distinct Ras effector pathways on mTOR signaling maintains Nf1 mouse optic glioma growth, supporting the evaluation of pharmacologic inhibitors that target mTOR function in future human NF1–optic pathway glioma clinical trials.
PMCID: PMC4483119  PMID: 25534823
MEK; mTOR; neurofibromin; optic glioma; PI3K/Akt
2.  Aggressive Low-Grade Optic Nerve Glioma in Adults 
Neuro-Ophthalmology  2014;38(6):297-309.
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.
PMCID: PMC5131714  PMID: 27928317
Adult optic glioma; ganglioglioma; pilocytic astrocytoma; WHO Grade I–II
3.  Optic Nerve Tortuosity in Individuals with Neurofibromatosis Type 1 
Pediatric radiology  2013;43(10):1336-1343.
Optic nerve tortuosity is often reported in children with neurofibromatosis type 1 (NF1). We describe quantitative and subjective criteria to determine the degree of optic nerve tortuosity in individuals with NF1.
To employ quantitative and subjective criteria to assess optic nerve tortuosity in individuals with NF1.
Materials and methods
A retrospective study over a period of 8 years was performed on children with NF1, with and without optic pathway glioma, compared to children without NF1. A tortuosity index was computed for the optic nerve in each subject using a high resolution 3D T1-weighted magnetization-prepared rapid gradient echo sequence, which was averaged and compared across groups.
The tortuosity index for subjects with NF1, regardless of an optic pathway glioma, was greater than those without NF1. There was no difference in the tortuosity index between NF1 subjects with optic pathway glioma and NF1 subjects without optic pathway glioma. There was also no correlation between subjective measures of tortuosity and the quantitative scoring (tortuosity index), or between the degree of tortuosity and subject age or gender.
Individuals with NF1 have increased optic nerve tortuosity relative to unaffected individuals. Quantitative tortuosity index is a superior measure to subjective assessment in the evaluation of optic nerve tortuosity in children with NF1.
PMCID: PMC3904184  PMID: 23636538
NF1; optic glioma; MRI; brain tumor; cancer predisposition syndrome
4.  Acquired bilateral myelinated retinal nerve fibers after unilateral optic nerve sheath fenestration in a child with idiopathic intracranial hypertension 
To report the unusual development of bilateral myelinated retinal nerve fibers (MRNF) adjacent to the optic nerve in a child after treatment of idiopathic intracranial hypertension (IIH) with unilateral optic nerve sheath fenestration (ONSF) and to discuss the etiology of acquired MRNF.
The patient’s clinical history, including visual acuity, refractive error, ocular alignment, fundus examination, and optic nerve photographs, was retrospectively reviewed. A literature review was performed for acquired MRNF in children using PubMed. The results of the demographic and clinical findings of our patient were compared with those of previously reported cases.
The child developed bilateral MRNF adjacent to the optic nerve 5 months after unilateral ONSF. In reviewing the literature, 8 of 10 cases of acquired MRNF in children had prior abnormalities of the optic nerve, 4 of 10 had associated bilateral optic nerve head drusen, 3 of 10 had associated optic nerve glioma, and 3 of 10 had a history of significant increased intracranial pressure requiring surgical intervention.
While the etiology of acquired MRNF is uncertain, this case plus a review of the literature suggest that it may be related to changes in the lamina cribosa combined with possible optic nerve injury caused by optic nerve head drusen, optic nerve glioma, or elevated intracranial pressure, and that it can occur months to years after intervention.
PMCID: PMC3535484  PMID: 23237749
5.  Atypical clinical presentation and long-term survival in a patient with optic nerve medulloepithelioma: a case report 
Medulloepithelioma is a rare congenital tumor of the primitive medullary neuroepithelium. A significant proportion of patients with medulloepithelioma arising from the optic nerve die from intracranial spread or cerebral metastasis. Because it has no known distinct clinical features and because of its low frequency, this tumor presents within the first two to six years of life and is usually misdiagnosed clinically as a different type of optic nerve tumor. Here, we describe a new and atypical case of medulloepithelioma of the optic nerve in a 12-year-old boy. To the best of our knowledge, he is the oldest reported patient to present with this disease and, now as an adult, has the longest documented period of disease-free survival.
Case presentation
A 12-year-old Caucasian boy with headache and unilateral amaurosis was referred for a presumed optic nerve glioma to our hospital. A computed tomography scan showed optic nerve enlargement, and fundoscopy showed a whitish mass at the optic disc. Our patient had been followed at his local hospital for four years for an 'optic disc cyst' with no change or progression. He experienced mild progressive visual impairment during that period. He was admitted for resection, and a histopathological analysis revealed a medulloepithelioma of the optic nerve. Supplemental orbital radiotherapy was performed. He remained disease-free for 25 years.
Medulloepithelioma of the optic nerve can clinically mimic more common pediatric tumors, such as optic glioma, meningioma, or retinoblastoma. Thus, medulloepithelioma should be included in the differential diagnoses of pediatric optic nerve lesions. Fundoscopy in these patients may provide relevant information for diagnosis. Anterior optic nerve medulloepitheliomas may behave differently from and have a better prognosis than medulloepitheliomas that have a more posterior location. Our case report illustrates that long-term survival can be achieved in patients with this malignant tumor.
PMCID: PMC3359171  PMID: 22571440
6.  The impact of coexisting genetic mutations on murine optic glioma biology 
Neuro-Oncology  2014;17(5):670-677.
Children with the neurofibromatosis type 1 (NF1) tumor predisposition syndrome are prone to the development of optic pathway gliomas resulting from biallelic inactivation of the NF1 gene. Recent studies have revealed the presence of other molecular alterations in a small portion of these NF1-associated brain tumors. The purpose of this study was to leverage Nf1 genetically engineered mouse strains to define the functional significance of these changes to optic glioma biology.
Nf1+/− mice were intercrossed with Nf1flox/flox mice, which were then crossed with Nf1flox/flox; GFAP-Cre mice, to generate Nf1flox/mut; GFAP-Cre (FMC) mice. These mice were additionally mated with conditional KIAA1549:BRAF knock-in or Ptenflox/wt mice to generate Nf1flox/mut; f-BRAF; GFAP-Cre (FMBC) mice or Nf1flox/mut; Ptenflox/wt; GFAP-Cre (FMPC) mice, respectively. The resulting optic gliomas were analyzed for changes in tumor volume, proliferation, and retinal ganglion cell loss.
While KIAA1549:BRAF conferred no additional biological properties on Nf1 optic glioma, FMPC mice had larger optic gliomas with greater proliferative indices and microglial infiltration. In addition, all 3 Nf1 murine optic glioma strains exhibited reduced retinal ganglion cell survival and numbers; however, FMPC mice had greater retinal nerve fiber layer thinning near the optic head relative to FMC and FMBC mice.
Collectively, these experiments demonstrate genetic cooperativity between Nf1 loss and Pten heterozygosity relevant to optic glioma biology and further underscore the value of employing genetically engineered mouse strains to define the contribution of discovered molecular alterations to brain tumor pathogenesis.
PMCID: PMC4482850  PMID: 25246427
BRAF; neurofibromatosis; neurofibromin; pediatric brain tumor; PTEN
7.  Optic glioma of childhood: clinical, histopathological, and histochemical observations. 
This report documents the long-term clinical and histopathological behaviour of eight intraorbital and 16 intracranial optic nerve gliomas and relates the therapeutic data to the prognosis for both visual acuity and survival. The mean age at onset of symptoms was 8.6 years and at the diagnosis 10.9 years. It is generally held that proptosis is mild in intraorbital glioma, but we encountered marked proptosis ranging from 7 to 12 mm in six of the eight intraorbital gliomas, which contained abundant Alcian-blue-positive mucoid material. Of the patients with intracranial optic nerve gliomas 37.5% survived for a mean of eight years after treatment with radiotherapy or surgery combined with radiotherapy. At follow-up ranging from five months to 11 years only one of the six patients with intracranial gliomas had full visual acuity. Our observations emphasise that, although optic nerve gliomas are benign hamartomas, the prognosis for visual acuity and survival is unfavourable in cases which are diagnosed and treated late. Histopathological and histochemical observations suggest that increase in the amount of mucoid material may contribute to rapid enlargement of intraorbital and intracranial optic gliomas.
PMCID: PMC1041895  PMID: 2818994
8.  RNA Sequencing of Tumor-Associated Microglia Reveals Ccl5 as a Stromal Chemokine Critical for Neurofibromatosis-1 Glioma Growth1 
Neoplasia (New York, N.Y.)  2015;17(10):776-788.
Solid cancers develop within a supportive microenvironment that promotes tumor formation and growth through the elaboration of mitogens and chemokines. Within these tumors, monocytes (macrophages and microglia) represent rich sources of these stromal factors. Leveraging a genetically engineered mouse model of neurofibromatosis type 1 (NF1) low-grade brain tumor (optic glioma), we have previously demonstrated that microglia are essential for glioma formation and maintenance. To identify potential tumor-associated microglial factors that support glioma growth (gliomagens), we initiated a comprehensive large-scale discovery effort using optimized RNA-sequencing methods focused specifically on glioma-associated microglia. Candidate microglial gliomagens were prioritized to identify potential secreted or membrane-bound proteins, which were next validated by quantitative real-time polymerase chain reaction as well as by RNA fluorescence in situ hybridization following minocycline-mediated microglial inactivation in vivo. Using these selection criteria, chemokine (C-C motif) ligand 5 (Ccl5) was identified as a chemokine highly expressed in genetically engineered Nf1 mouse optic gliomas relative to nonneoplastic optic nerves. As a candidate gliomagen, recombinant Ccl5 increased Nf1-deficient optic nerve astrocyte growth in vitro. Importantly, consistent with its critical role in maintaining tumor growth, treatment with Ccl5 neutralizing antibodies reduced Nf1 mouse optic glioma growth and improved retinal dysfunction in vivo. Collectively, these findings establish Ccl5 as an important microglial growth factor for low-grade glioma maintenance relevant to the development of future stroma-targeted brain tumor therapies.
PMCID: PMC4656811  PMID: 26585233
9.  NG2-cells are not the cell of origin for murine neurofibromatosis-1 (Nf1) optic glioma 
Oncogene  2013;33(3):289-299.
Low-grade glial neoplasms (astrocytomas) represent one of the most common brain tumors in the pediatric population. These tumors frequently form in the optic pathway (optic pathway gliomas; OPGs), especially in children with the Neurofibromatosis Type 1 (NF1) inherited tumor predisposition syndrome. To model these tumors in mice, we have previously developed several Nf1 genetically-engineered mouse (GEM) strains that form optic gliomas. However, there are three distinct macroglial cell populations in the optic nerve (astrocytes, NG2+ cells and oligodendrocytes). The presence of NG2+ cells in the optic nerve raises the intriguing possibility that these cells could be the tumor-initiating cells, as has been suggested for adult glioma. In this report, we used a combination of complementary in vitro and novel GEM strains in vivo to determine whether NG2+ cells could give rise to Nf1 optic glioma. First, we show that Nf1 inactivation results in a cell-autonomous increase in GFAP+, but not NG2+, cell proliferation in vitro. Second, similar to the GFAP-Cre transgenic strain that drives Nf1 optic gliomagenesis, NG2-expressing cells also give rise to all three macroglial lineages in vivo. Third, in contrast to the GFAP-Cre strain, Nf1 gene inactivation in NG2+ cells is not sufficient for optic gliomagenesis in vivo. Collectively, these data demonstrate that NG2+ cells are not the cell of origin for mouse optic glioma and support a model in which gliomagenesis requires Nf1 loss in specific neuroglial progenitors during embryogenesis.
PMCID: PMC3874418  PMID: 23318450
genetically-engineered mice; NG2; optic glioma; neurofibromatosis type 1
10.  Optic Nerve Dysfunction in a Mouse Model of Neurofibromatosis-1 Optic Glioma 
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 employed a genetically engineered mouse model of Nf1 optic glioma (Nf1+/−GFAPCKO mice). We performed multi-modal functional and structural analyses both before and after the appearance of macroscopic tumors. At 6 weeks of age, prior to obvious glioma formation, Nf1+/−GFAPCKO mice had decreased visual evoked potential amplitudes and increased optic nerve axon calibers. By 3 months of age, Nf1+/−GFAPCKO 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 that culminates in retinal ganglion cell death. The Nf1+/−GFAPCKO mice 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.
PMCID: PMC2746323  PMID: 19525901
Apoptosis; Magnetic resonance imaging; Neurofibromatosis-1; Optic pathway glioma; Retinal ganglion cell; Visual evoked potential
11.  Ultrastructural Characterization of the Optic Pathway in a Mouse Model of Neurofibromatosis-1 Optic Glioma 
Neuroscience  2010;170(1):178-188.
The purpose of this study was to investigate the progression of changes in retinal ganglion cells and optic nerve glia in neurofibromatosis-1 (NF1) genetically-engineered mice with optic glioma. Optic glioma tumors were generated in Nf1+/− mice lacking Nf1 expression in GFAP+ cells (astrocytes). Standard immunohistochemistry methods were employed to identify astrocytes (GFAP, S100β), proliferating progenitor cells (sox2, nestin), microglia (Iba1), endothelial cells (CD31) and retinal ganglion cell (RGC) axons (Neurofilament 68k) in Nf1+/−, Nf1GFAPCKO (wild-type mice with Nf1 loss in glial cells), and Nf1+/−GFAPCKO (Nf1+/− mice with Nf1 loss in glial cells) mice. Ultrastructural changes in the optic chiasm and nerve were assessed by electron microscopy (EM). RGC were counted in whole retina preparations using high-resolution, mosaic confocal microscopy following their delineation by retrograde FluoroGold labeling. We found that only Nf1+/−GFAPCKO mice exhibited gross pre-chiasmatic optic nerve and chiasm enlargements containing aggregated GFAP+/nestin+ and S100β+/sox2+ cells (neoplastic glia) as well as increased numbers of blood vessels and microglia. Optic gliomas in Nf1+/−GFAPCKO mice contained axon fiber irregularities and multilamellar bodies of degenerated myelin. EM and EM tomographic analyses showed increased glial disorganization, disoriented axonal projections, profiles of degenerating myelin and structural alterations at nodes of Ranvier. Lastly, we found reduced RGC numbers in Nf1+/−GFAPCKO mice, supporting a model in which the combination of optic nerve Nf1 heterozygosity and glial cell Nf1 loss results in disrupted axonal-glial relationships, subsequently culminating in the degeneration of optic nerve axons and loss of their parent RGC neurons.
PMCID: PMC2926211  PMID: 20600672
neurofibromatosis-1; optic glioma; astrocyte; retinal ganglion cell; microglial cell; electron microscope tomography
12.  Neurofibromatosis-1 Heterozygosity Increases Microglia in a Spatially- and Temporally-Restricted Pattern Relevant to Mouse Optic Glioma Formation and Growth 
While carcinogenesis requires the acquisition of driver mutations in progenitor cells, tumor growth and progression is heavily influenced by the local microenvironment. Previous studies from our laboratory have employed Neurofibromatosis-1 (NF1) genetically engineered mice to characterize the role of stromal cells and signals to optic glioma formation and growth. Previously, we have shown that Nf1+/- microglia in the tumor microenvironment are critical cellular determinants of optic glioma proliferation. To define the role of microglia in tumor formation and maintenance further, we employed CD11b-TK mice, in which resident brain microglia (CD11b+, CD68+, Iba1+, CD45low cells) can be ablated at specific times following ganciclovir (GCV) administration. GCV-mediated microglia reduction reduced Nf1 optic glioma proliferation during both tumor maintenance and tumor development. We identified the developmental window during which microglia are increased in the Nf1+/- optic nerve and demonstrated that this accumulation reflected delayed microglia dispersion. The increase in microglia in the Nf1+/- optic nerve was associated with reduced expression of the chemokine receptor, CX3CR1, such that reduced Cx3cr1 expression in Cx3cr1-GFP heterozygous knockout mice led to a similar increase in optic nerve microglia. These results establish a critical role for microglia in the development and maintenance of Nf1 optic glioma.
PMCID: PMC3044783  PMID: 21157378
Astrocytoma; Chemokine; Fractalkine receptor; Microenvironment; Optic glioma; Stroma
13.  Retinal Nerve Fiber Layer Thickness in Children with Optic Pathway Gliomas 
American journal of ophthalmology  2011;151(3):542-549.e2.
To determine the relation of high-contrast visual acuity (VA) and low-contrast letter acuity with retinal nerve fiber layer (RNFL) thickness in children with optic pathway gliomas.
Cross-sectional convenience sample, with prospective data collection, from a tertiary care children’s hospital of patients with optic pathway gliomas associated with Neurofibromatosis type 1, sporadic OPG and Neurofibromatosis type 1 without OPG.
Patients performed best corrected VA testing using surrounded HOTV optotypes and low-contrast letter acuity (5%, 2.5% and 1.25% low contrast Sloan letter charts). Mean RNFL thickness (microns) was measured by a Stratus optical coherence tomography (Carl Zeiss Meditec, Dublin, CA) using the fast RNFL thickness protocol. Eyes were classified as having abnormal vision if they had high-contrast VA > 0.1 logMAR or visual field loss. The association of subject age, glioma location and RNFL thickness with both VA and low-contrast letter acuity scores was evaluated by one-way analysis of variance and linear regression, using the generalized estimating equation approach to account for within-patient intereye correlations.
Eighty-nine eyes of patients with optic pathway gliomas were included and 41 were classified as having abnormal VA or visual field loss. Reduced RNFL thickness was significantly associated with higher logMAR scores for both VA (P < 0.001) and all low-contrast letter acuity charts (P < 0.001) when accounting for age and glioma location.
Eyes of most children with optic pathway gliomas and decreased RNFL thickness had abnormal visual acuity or visual field loss.
PMCID: PMC3053008  PMID: 21232732
14.  A case of neurofibromatosis 1 presenting with optic pathway glioma with an early onset and an aggressive course 
Indian Journal of Ophthalmology  2008;56(2):161-162.
Optic pathway glioma associated with neurofibromatosis 1 has a classically indolent course. However, involvement of the optic radiations is relatively rare and is associated with a more aggressive course. A three-year-old girl presented with strabismus and loss of vision in the left eye with relative afferent pupillary defect and optic disc pallor. She had multiple café au lait spots. Visually evoked potential was suggestive of an optic nerve conduction defect and magnetic resonance imaging of the brain was suggestive of an optic pathway glioma involving the optic nerves, the optic chiasma and the optic tracts. The optic radiations and the dentate nuclei had hamartomas. Optic nerve biopsy confirmed pilocytic astrocytoma. Radical radiotherapy under general anesthesia was subsequently given. This case report aims to highlight the involvement of the optic radiations and the unusually aggressive clinical course in this case.
PMCID: PMC2636080  PMID: 18292634
Glioma; neurofibromatosis 1; optic radiations
15.  High-Dose Intravenous Vitamin C Treatment of a Child with Neurofibromatosis Type 1 and Optic Pathway Glioma: A Case Report 
Patient: Male, 1
Final Diagnosis: Optic glioma
Symptoms: Visual problems
Medication: —
Clinical Procedure: Intravenous vitamin C
Specialty: Oncology
Unusual clinical course
In neurofibromatosis type 1 (NF1) disease, the loss of the tumor suppressor function of the neurofibromin gene leads to proliferation of neural tumors. In children, the most frequently identified tumor is the optic pathway glioma.
Case Report:
We describe the case of a 5-year-old child who was diagnosed with NF1 and optic pathway tumor onset at the age of 14 months. Because of the tumor progression, chemotherapy with carboplatin and vincristine was prescribed at this early age and continued for one year. As the progression of disease continued after chemotherapy, the child, at the age of 2.8 years, was started on high-dose intravenous vitamin C (IVC) treatment (7–15 grams per week) for 30 months. After 30 months, the results of IVC treatments demonstrated reduction and stabilization of the tumors in the optic chiasm, hypothalamus, and left optic nerve according to radiographic imaging. The right-sided optic nerve mass seen before IVC treatment disappeared by the end of the treatment.
This case highlights the positive effects of treating NF1 glioma with IVC. Additional studies are necessary to evaluate the role of high-dose IVC in glioma treatment.
PMCID: PMC5081233  PMID: 27773919
Ascorbic Acid; Neurofibromatosis 1; Optic Nerve Glioma
16.  Inactivation of NF1 in CNS causes increased glial progenitor proliferation and optic glioma formation 
Development (Cambridge, England)  2005;132(24):5577-5588.
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.
PMCID: PMC2760350  PMID: 16314489
Neurofibromatosis type 1; Optic glioma; Glial progenitor; Astrocyte; Tumor suppressor gene; Mouse
17.  Defective Cyclic AMP Generation Underlies the Sensitivity of Central Nervous System Neurons to Neurofibromatosis-1 Heterozygosity 
Individuals with the Neurofibromatosis-1 (NF1) inherited cancer syndrome exhibit neuronal dysfunction that predominantly affects the central nervous system (CNS). In this report, we demonstrate a unique vulnerability of CNS neurons, but not peripheral nervous system (PNS) neurons, to reduced Nf1 gene expression. Unlike dorsal root ganglion neurons, Nf1 heterozygous (Nf1+/−) hippocampal and retinal ganglion cell (RGC) neurons have decreased growth cone areas and neurite lengths, and increased apoptosis compared to their wild-type counterparts. These abnormal Nf1+/− CNS neuronal phenotypes do not reflect Ras pathway hyperactivation, but rather result from impaired neurofibromin-mediated cAMP generation. In this regard, elevating cAMP levels with forskolin or rolipram treatment, but not MEK or PI3-K inhibition, reverses these abnormalities to wild-type levels in vitro. In addition, Nf1+/− CNS, but not PNS, neurons exhibit increased apoptosis in response to excitotoxic or oxidative stress in vitro. Since children with NF1-associated optic gliomas often develop visual loss and Nf1 genetically-engineered mice with optic glioma exhibit RGC neuronal apoptosis in vivo, we further demonstrate that RGC apoptosis resulting from optic glioma in Nf1 genetically-engineered mice is attenuated by rolipram treatment in vivo. Similar to optic glioma-induced RGC apoptosis, the increased RGC neuronal death in Nf1+/− mice following optic nerve crush injury is also attenuated by rolipram treatment in vivo. Together, these findings establish a distinctive role for neurofibromin in CNS neurons with respect to vulnerability to injury, define a CNS-specific neurofibromin intracellular signaling pathway responsible for neuronal survival, and lay the foundation for future neuroprotective glioma treatment approaches.
PMCID: PMC2864934  PMID: 20410111
Neurofibromin; cAMP; neuronal survival; optic glioma; CNS neurons; neurite extension
18.  Reduced microglial CX3CR1 expression delays neurofibromatosis-1 glioma formation 
Annals of neurology  2013;73(2):303-308.
While traditional models of carcinogenesis have largely focused on neoplastic cells, converging data have revealed the importance of non-neoplastic stromal cells in influencing tumor growth and progression. Leveraging a genetically-engineered mouse model of NF1-associated optic glioma, we now demonstrate that stromal microglia express the CX3CR1 chemokine receptor, such that reduced CX3CR1 expression decreases optic nerve microglia. Moreover, genetic reduction of Cx3cr1 expression in Nf1 optic glioma mice delays optic glioma formation. Coupled with previous findings demonstrating that microglia maintain optic glioma growth, these new findings provide a strong preclinical rationale for the development of future stroma-directed glioma therapies in children.
PMCID: PMC3608848  PMID: 23424002
genetically-engineered mice; monocyte; astrocytoma; brain tumor; fractalkine
19.  Optic Nerve Sheath Meningioma in the First Decade of Life: Case Report and Review of the Literature 
Case Reports in Ophthalmology  2012;3(2):270-276.
Tumors of the optic nerve are mostly either optic nerve gliomas or optic nerve sheath meningiomas (ONSMs). While gliomas occur in children, most meningiomas are slow-growing tumors affecting middle-aged individuals with progressive visual loss, proptosis, disc edema and optociliary veins on fundus examination. ONSMs are extremely rare in children, with only 14 cases reported in children under the age of 10 years. The purpose of this study is to describe an additional case and review clinical, radiologic and histopathological findings that can help differentiate such tumors in children and allow an early and accurate diagnosis.
Case Report
An 8-year-old girl had a 2-year history of progressive proptosis and total visual loss on the right side. A computed tomography scan revealed a well-defined intraconal mass with perioptic calcification. Magnetic resonance imaging showed a tumor surrounding the optic nerve and extending intracranially, with enhancement following gadolinium injection. The patient was submitted to fronto-orbital craniotomy for complete tumor excision. Histological studies identified the neoplasm as ONSM.
Though unusual, ONSMs may occur in children and, in these cases, present a much more aggressive behavior than in adults. ONSM should therefore be differentiated from optic glioma in children because of its aggressive behavior and need for different treatment modalities.
PMCID: PMC3457045  PMID: 23071466
Optic nerve neoplasms; Benign optic nerve sheath neoplasm; Meningioma
20.  CyberKnife® enhanced conventionally fractionated chemoradiation for high grade glioma in close proximity to critical structures 
With conventional radiation technique alone, it is difficult to deliver radical treatment (≥ 60 Gy) to gliomas that are close to critical structures without incurring the risk of late radiation induced complications. Temozolomide-related improvements in high-grade glioma survival have placed a higher premium on optimal radiation therapy delivery. We investigated the safety and efficacy of utilizing highly conformal and precise CyberKnife radiotherapy to enhance conventional radiotherapy in the treatment of high grade glioma.
Between January 2002 and January 2009, 24 patients with good performance status and high-grade gliomas in close proximity to critical structures (i.e. eyes, optic nerves, optic chiasm and brainstem) were treated with the CyberKnife. All patients received conventional radiation therapy following tumor resection, with a median dose of 50 Gy (range: 40 - 50.4 Gy). Subsequently, an additional dose of 10 Gy was delivered in 5 successive 2 Gy daily fractions utilizing the CyberKnife® image-guided radiosurgical system. The majority of patients (88%) received concurrent and/or adjuvant Temozolmide.
During CyberKnife treatments, the mean number of radiation beams utilized was 173 and the mean number of verification images was 58. Among the 24 patients, the mean clinical treatment volume was 174 cc, the mean prescription isodose line was 73% and the mean percent target coverage was 94%. At a median follow-up of 23 months for the glioblastoma multiforme cohort, the median survival was 18 months and the two-year survival rate was 37%. At a median follow-up of 63 months for the anaplastic glioma cohort, the median survival has not been reached and the 4-year survival rate was 71%. There have been no severe late complications referable to this radiation regimen in these patients.
We utilized fractionated CyberKnife radiotherapy as an adjunct to conventional radiation to improve the targeting accuracy of high-grade glioma radiation treatment. This technique was safe, effective and allowed for optimal dose-delivery in our patients. The value of image-guided radiation therapy for the treatment of high-grade gliomas deserves further study.
PMCID: PMC2891601  PMID: 20534128
21.  Optic nerve glioma: A great mimicker 
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.
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.
PMCID: PMC3927089  PMID: 24575324
Arachnoid hyperplasia; chondroid; chordoid; glioma; optic nerve
22.  Reproducibility of Circumpapillary Retinal Nerve Fiber Layer Measurements Using Handheld Optical Coherence Tomography in Sedated Children 
American journal of ophthalmology  2014;158(4):780-787.e1.
To determine the intra- and intervisit reproducibility of circumpapillary retinal nerve fiber layer (RNFL) measures using handheld optical coherence tomography (OCT) in sedated children.
Prospective cross-sectional and longitudinal study
Children undergoing sedation for a clinically indicated MRI for an optic pathway glioma and or Neurofibromatosis type 1 (NF1) had multiple 6 × 6 mm volumes (isotropic 300×300 or non-isotropic 1000×100 samplings) acquired over the optic nerve. Children with two handheld OCT sessions within 6 months were included in the intervisit cohort. The intra- and inter-visit coefficient of variation (CV) and intraclass correlation coefficient (ICC) were calculated for the average and anatomic quadrant circumpapillary RNFL thickness.
Fifty-nine subjects (mean age 5.1 years, range 0.8–13.0 years) comprised the intravisit cohort and 29 subjects (mean age 5.7 years, range 1.8–12.7 years) contributed to the intervisit cohort. Forty-nine subjects had an optic pathway glioma and 10 subjects had NF1 without an optic pathway glioma. The CV was comparable regardless of imaging with an isotropic and non-isotropic volume in both the intra- and intervisit cohorts. The average circumpapillary RNFL demonstrated the lowest CV and highest ICC compared to the quadrants. For the intervisit cohort, the average ICC was typically higher while the CV was typically lower, but not statistically different compared to the other quadrants.
Circumpapillary RNFL measures acquired with handheld OCT during sedation demonstrate good intra- and intervisit reproducibility. Handheld OCT has the potential to monitor progressive optic neuropathies in young children who have difficulty cooperating with traditional OCT devices.
PMCID: PMC4165732  PMID: 24983792
23.  BRAF Duplications and MAPK Pathway Activation Are Frequent in Gliomas of the Optic Nerve Proper 
Optic pathway gliomas represent a specific subtype of astrocytoma with unique clinicopathologic and biological properties but studies of tumors in the optic nerve proper have been hampered by limited tissue availability. We analyzed optic nerve gliomas of 59 patients (median age 9 years, range = 3 months to 66 years; 33 female; 26 male) using formalin-fixed paraffin embedded material in tissue microarrays. Seven patients had the clinical diagnosis of neurofibromatosis type 1 (NF1). Fluorescence in situ hybridization studies were performed for BRAF, PTEN, CDKN2A (p16), and NF1. Immunohistochemistry was performed for glial fibrillary acidic protein, phospho-ERK and mutant IDH1R132H protein. BRAF duplication was present in 11 (of 15) (73%) evaluable tumors including 1 NF1 patient (1 of 4 tested, 25%). The single tumor lacking BRAF duplication or NF1-association had histologic features of a ganglioglioma. Conversely, heterozygous PTEN deletions were present in 2 (of 25) (8%) evaluable cases, one of which was BRAF-duplicated and the other NF1-associated. CDKN2A and NF1 deletions were absent in all tumors tested. Phospho-ERK immunoreactivity was present in 55 (of 57) (96%) tumors, and was mostly strong and diffuse (80%). Only 1 case (of 53) expressed IDH1R132H. Thus, optic nerve gliomas demonstrated molecular alterations typical of pilocytic astrocytomas, including the universal presence of either BRAF duplication or NF1-association and common MAPK pathway activation, but very rare mutant IDH1 expression.
PMCID: PMC3429698  PMID: 22892521
BRAF; Fluorescence in situ hybridization (FISH); Glioma; MAPK; Neurofibromatosis; Optic nerve; Pilocytic astrocytoma
24.  High resolution magnetic resonance imaging of the anterior visual pathway in patients with optic neuropathies using fast spin echo and phased array local coils. 
High resolution MRI of the anterior visual pathways was evaluated using frequency selective fat suppressed fast spin echo (FSE) sequences in conjunction with phased array local coils in patients with optic neuropathies. Fifteen normal controls and 57 patients were examined. Coronal T2 weighted fat suppressed FSE images were obtained in 11 minutes with an in plane resolution of 0.39 x 0.39 mm. The optic nerve and its sheath containing CSF were clearly differentiated. Central retinal vessels were often visible. In demyelinating optic neuritis and in anterior ischaemic optic neuropathy high signal within the nerve was readily delineated. Meningiomas and gliomas involving the optic nerve were precisely visualised both in the orbit and intracranially. Extrinsic compression of the optic nerves was readily visualised in carotid artery ectasia and dysthyroid eye disease. Enlarged subarachnoid spaces around the optic nerves were demonstrated in benign intracranial hypertension. High resolution MRI of the anterior visual pathway represents an advance in the diagnosis and management of patients presenting with optic neuropathy.
PMCID: PMC1073486  PMID: 7745403
25.  Arachnoid hyperplasia in optic nerve glioma: confusion with orbital meningioma. 
A case is reported of an optic nerve glioma with a marked degree of arachnoid hyperplasia which was initially diagnosed as an optic nerve meningioma. Hyperplasia of the arachnoid was also the underlying cause for expansion of the optic canal. The relationship between arachnoid hyperplasia in optic nerve glioma and meningioma of the optic nerve sheath in childhood is discussed.
PMCID: PMC1043565  PMID: 486377

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