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.
Glioma; neurofibromatosis 1; optic radiations
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.
Apoptosis; Magnetic resonance imaging; Neurofibromatosis-1; Optic pathway glioma; Retinal ganglion cell; Visual evoked potential
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.
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.
A 32-year-old woman who died suddenly during pregnancy as a result of an adrenal phaeochromocytoma also suffered from von Recklinghausen's disease. 21 years earlier she had an optic nerve glioma successfully removed. The association between von Reckinghausen's disease and optic nerve glioma/phaeochromocytoma is well established. So far as is known, the present case is the first ever published with the triad: von Recklinghausen's disease, optic nerve glioma, and phaeochromocytoma.
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.
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.
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.
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.
Optic nerve neoplasms; Benign optic nerve sheath neoplasm; Meningioma
Thirty-one patients presenting as orbital optic nerve glioma have been reviewed with maximum follow-up of 14 years. Sixteen of these patients have been reported on previously and further follow-up is provided. Sixteen patients had a stable clinical course with little change over a period of up to 13.5 years. Neurofibromatosis was relatively common in this group (11/16). Fifteen patients had progressive enlargement of the tumour; the incidence of neurofibromatosis in this group was low (4/15). Eleven of these patients were explored neurosurgically and the optic nerve totally excised in 10 of them. The proximal cut end was normal in six patients and the chiasm has apparently remained free of tumour in all of them. We suggest a method of management of primary optic nerve tumours, both meningiomas and gliomas, in young patients.
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.
neurofibromatosis-1; optic glioma; astrocyte; retinal ganglion cell; microglial cell; electron microscope tomography
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.
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.
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.
BRAF; Fluorescence in situ hybridization (FISH); Glioma; MAPK; Neurofibromatosis; Optic nerve; Pilocytic astrocytoma
Seventeen patients thought to have orbital optic nerve gliomas when first seen have been reviewed after up to 12 years. Enlargement of the optic canal was present in 15 of the 16 patients examined, but this finding was unreliable as an indicator of the posterior extent of the tumour. Nine patients had a stable course with little change over a period of up to 8 years; there was optic atrophy in all and neurofibromatosis was relatively common (7/9). Eight patients showed progressive enlargement of the tumour; 6 had swollen discs, and the incidence of neurofibromatosis was relatively low (3/8). The optic nerve was excised in 7 of the latter group. Biopsies of the optic nerve taken from the region of maximal enlargement were difficult to interpret and unhelpful in planning management. Radical surgery should be reserved for the minority of patients in whom there is progressively enlarging tumour without evidence of chiasmal involvement.
Neurofibromatosis (NF) is divided into two types, NF type 1 and NF type 2. Optic nerve gliomas have a high degree of association with NF type 1. NF 2, less commonly seen, is a complex of cutaneous and deep neural tumors. It is an autosomal dominant familial disorder in which CNS is affected in about 15% of the cases. Bilateral acoustic neuromas are pathognomonic of NF type 2 which may be associated with meningiomas or ependymomas.
Typical clinical manifestations of neurofibromatosis are cafe-au-lait spots and multiple cutaneous tumors. There is bone involvement as scoliosis, pseudoarthrosis of long bones, scalloping of vertebral bodies, abnormal rib tubulation and defective ossification of the skull. Extraskeletal manifestations of neurofibromatosis include optic nerve gliomas, pheochromocytoma, aneurysms of cerebral and renal arteries, acoustic neurilemmoma and superficial skin nodular neurofibromas.
Here, we intend to present images of several cases of neurofibromatosis with different patterns of body involvement.
Neuro fibromatosis; Glioma; Schwannoma; Neurinoma
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.
We present a case of sarcoidosis in a 14-year-old girl who presented with a short history of visual disturbance. Computed tomography and magnetic resonance imaging (MRI) demonstrated enlargement of the optic chiasm and prechiasmic optic nerves. Post-contrast MRI showed marginal enhancement of the affected areas of the optic pathways. A diagnosis of optic nerve glioma and arachnoid gliomatosis was made; surgical confirmation was not sought due to the risk to vision associated with biopsy. A rapid clinical deterioration led to repeat MRI which demonstrated extensive enhancing soft tissue throughout the basal cisterns with extension into the brain. Biopsy confirmed a diagnosis of sarcoidosis.
Recent evidence indicates differences in neural stem cell (NSC) biology in different brain regions. For example, we demonstrated that neurofibromatosis-1 (NF1) tumor suppressor gene inactivation leads to increased NSC proliferation and gliogenesis in the optic chiasm and brainstem, but not in the cerebral cortex. The differential effect of Nf1 inactivation in the optic nerve and brainstem (in which gliomas commonly form in children with NF1) vs. the cortex (in which gliomas rarely develop) suggests the existence of distinct ventricular zones for gliomagenesis in children and adults. Here, we characterized the third ventricle subventricular zone (tv-SVZ) in young and adult mice and human brains. In children but not adult humans the tv-SVZ contains nestin-positive, glial fibrillary acidic protein (GFAP)-positive, brain fatty acid binding protein-positive and sox2-positive cells with radial processes and prominent cilia. In contrast, the tv-SVZ in young mice contains sox2-positive progenitor cells and ciliated ependymal lining cells, but lacks GFAP-positive, nestin-positive radial glia. As in the lateral ventricle SVZ (lv-SVZ), proliferation in the human and murine tv-SVZ decreases with age. The tv-SVZ in adult mice lacks the hypocellular subventricular zone observed in adult human specimens. Collectively, these data indicate the existence of a subventricular zone relevant to our understanding of glioma formation in children and will assist interpretation of genetically engineered mouse glioma models.
Germinal zone; Third ventricle
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.
Neurofibromatosis type 1; Optic glioma; Glial progenitor; Astrocyte; Tumor suppressor gene; Mouse
Aim: To study the maturation of multifocal visual evoked potentials (multifocal VEP) in normal children between the ages of 5 and 16 years and to apply the results clinically in selected cases to the diagnosis of optic pathway diseases.
Method: 70 normal children were recruited from the community and multifocal VEP (Accumap ObjectiVision, Sydney, Australia) was recorded. The waveform of the evoked responses, the latency and amplitude were analysed. Using these data, an age matched comparison was made with three children with advanced optic nerve disease; two had optic nerve glioma and one had congenital glaucoma.
Results: The full field amplitude did not correlate with age and varied greatly within each age group (coefficient of variability 28%). When scaled with respect to the background electroencephalogram the intra-age group variability decreased to 15% and a sigmoid relation was found between amplitude and age. The scaled amplitude remained largely unchanged till 11 years, between 11 and 13 years there was a rapid increase (40%), and remained stable thereafter. This relation was seen at all eccentricities tested. The latency decreased gradually with age and plateaued at 13 years. In the three children with vision abnormalities this test was able to detect scotomas consistent with their condition.
Conclusion: Multifocal VEP perimetry shows an age related maturation in the visual pathway, characterised by distinctive timeframe of development for amplitude and latency. It can be performed by children as young as 5 years of age and holds promise as a diagnostic test capable of documenting children’s visual fields objectively, even before they are able to perform subjective field tests.
multifocal VEP; children
A case of uveal malignant melanoma and contralateral optic nerve glioma is described in a 53-year-old Caucasian male with multiple uveal melanocytic hamartomas and neurofibromatosis. The eye was enucleated, and histologically the melanoma was found to consist of 70% epithelioid cells, with many bizarre, multinucleated forms. CT scan demonstrated a non-enhancing, fusiform enlargement of the contralateral optic nerve with enlargement of the optic canal and intracranial extension. This combination of tumours has not previously been reported in a patient with neurofibromatosis and serves to emphasise the common neuroectodermal origin of tumours in this autosomal dominant condition.
To investigate the visual pathway in normal subjects and patients with lesion involved by diffusion tensor imaging (DTI) and diffusion tensor tractography (DTT).
Thirty normal volunteers, 3 subjects with orbital tumors involved the optic nerve (ON) and 33 subjects with occipital lobe tumors involved the optic radiation (OR) (10 gliomas, 6 meningiomas and 17 cerebral metastases) undertook routine cranium magnetic resonance imaging (MRI), DTI and DTT. Visual pathway fibers were analyzed by DTI and DTT images. Test fractional anisotropy (FA) and mean diffusivity (MD) values in different part of the visual pathway.
The whole visual pathway but optic chiasm manifested as hyperintensity in FA maps and homogenous green signal in the direction encoded color maps. The optic chiasm did not display clearly. There was no significant difference between the bilateral FA values and MD values of normal visual pathway but optic chiasm, which the FA values tested were much too low (all P>0.05). The ONs of subjects with orbital tumors were compressed and displaced. Only one subject had lower FA values and higher MD values. OR of 9 gliomas subjects were infiltrated, with displacement in 2 and disruption in 7 subjects. All OR in 6 meniongiomas subjects were displaced. OR in 17 cerebral metastases subjects all developed displacement while 7 of them had disruption also.
MR-DTI is highly sensitive in manifesting visual pathway. Visual pathway can be analyzed quantitatively in FA and MD values. DTT supplies accurate three dimensional conformations of visual pathway. But optic chiasm's manifestation still needs to improve.
visual pathway; human; diffusion tensor imaging; diffusion tensor tractography
A newborn boy was noted by his mother to have a prominent left eye at birth, but an eye examination was delayed until age 7 months, at which time his ophthalmologist diagnosed exophthalmos. Computed tomography was interpreted as showing mild, diffuse, optic nerve thickening bilaterally suggestive of optic nerve gliomas. Subsequent examination in our clinic revealed pseudoproptosis secondary to retraction of the left upper eyelid. Magnetic resonance imaging demonstrated normal orbital structures. The mother was noted to be clinically hyperthyroid, and abnormal thyroid function tests confirmed the diagnosis. Although the infant was euthyroid, neonatal Graves' ophthalmopathy was diagnosed. He was managed by close observation while his mother was treated for her hyperthyroidism.
Malignant optic nerve glioma (MONG) is a rare but uniformly fatal disease that remains poorly understood. We describe a notable case of this rare disease occurring in the optic chiasm. Normal brain imaging and normal ophthalmic examination two years prior to diagnosis provide evidence for de novo genesis of MONG in our patient. Early response to steroids highlights the degree to which MONG can initially mimic inflammatory optic neuropathies and chiasmal syndromes. Our case also demonstrates a poor outcome with MONG even with current advanced therapy for glioblastoma including radiotherapy plus concomitant and adjuvant temozolomide (the EORTC/NCIC regimen) and bevacizumab.
Glioblastoma is the most common and most malignant intrinsic human brain tumor, characterized by extensive invasion and proliferation of glial (astrocytic) tumor cells, frequent activation of tyrosine kinase receptor signaling pathways, relative resistance to chemotherapy and radiotherapy, and poor prognosis. Using the Gal4-UAS system, we have produced glioma models in Drosophila by overexpressing homologs of human tyrosine kinase receptors under control of the glia-specific promoter reversed polarity (repo). Glial overexpression of activated epidermal growth factor receptor (EGFR) resulted in enhanced proliferation and migration of larval glial cells with increased numbers in the eye imaginal disc, diffuse tumor-like enlargement of the optic stalk, and marked ectopic invasion of glial cells along the optic nerve. Glial overexpression of the downstream kinase PI3K showed similar pathology. Overexpression of activated pvr (platelet-derived growth factor receptor/vascular endothelial growth factor receptor homolog) led to migration of glial cells along the optic nerve, whereas expression of activated htl (fibroblast growth factor receptor 1 homolog) and INR (insulin receptor) showed markedly elevated numbers of glial cells in the optic stalk. The EGFR/phosphatidylinositol 3-phosphate kinase (PI3K) phenotype was partly reverted by the administration of the EGFR tyrosine kinase inhibitor gefitinib and completely rescued by the PI3K inhibitor wortmannin and the Akt inhibitor triciribine. We suggest that Drosophila models will be useful for deciphering signaling cascades underlying abnormal behavior of glioma cells for genetic screens to reveal interacting genes involved in gliomagenesis and for experimental therapy approaches.
A 13-year-old girl with a right intraorbital optic nerve glioma (ONG) was referred to our glaucoma clinic because of uncontrolled intraocular pressure (IOP) in her right eye. The IOP reached as high as 80 mmHg. Several months earlier, she had undergone stereotactic image-guided robotic radiosurgery using the CyberKnife for her ONG; the mass had become smaller after treatment. Her visual acuity was no light perception. Slit lamp examination revealed rubeosis iridis, a swollen pale optic disc, and vitreous hemorrhage. After medical treatment, the IOP decreased to 34 mmHg, and no pain was reported. Although the mass effect of an ONG can cause neovascular glaucoma (NVG), this case shows that stereotactic radiosurgery may also cause NVG, even after reducing the mass of the tumor. Patients who undergo radiosurgery targeting the periocular area should be followed carefully for complications.
Neovascular glaucoma; Optic nerve glioma; Radiosurgery