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An 11-year-old boy affected by neurofibromatosis type 1 is presented with severely impaired vision on the right eye (0.1). MRI demonstrated a 2.3 x 1.8 cm tumour of the optic chiasma. After open biopsy cytogenetic analysis was performed on primary cultures of this optic glioma (grade I). A clonal translocation t(10;21)(q21.2;21.1) was detected in 66% of the metaphases analysed. The boy received fractioned irradiation with a total tumour dose of 60 Gy. The ultimate MRI taken 18 months after radiotherapy showed no residual tumour. The vision on the right improved to 0.2, but decreased on the left to 0.6. The patient attends high school with no impairment in his daily life.

Brain tumors (gliomas) are composed of heterogeneous populations of neoplastic and non-neoplastic cells. While the neoplastic cells have classically been the target of therapeutic drug design, recent studies have demonstrated a critical role for non-neoplastic cells in brain tumor growth. The importance of non-neoplastic (stromal) cells is underscored by genetically-engineered mouse (GEM) models of Neurofibromatosis type 1 (NF1)-associated optic glioma. Whereas mice lacking Nf1 gene expression in GFAP+ glial cells do not develop brain tumors, nearly 100% of Nf1+/− mice with GFAP+ cell Nf1 inactivation form optic gliomas. These observations establish an obligate role for Nf1+/− non-neoplastic cells in gliomagenesis. One of the non-neoplastic cell types found in both mouse and human NF1-associated gliomas is microglia, a resident population of macrophage-like cells. To prove that microglia are essential drivers of glioma formation, we generated Nf1 optic glioma mice with reduced expression of the microglial chemokine receptor CX3CR1 (Nf1+/−GFAPCKO-cx3cr1+/GFP mice). Consistent with the critical role of CX3CR1 in microglial function, Nf1+/−GFAPCKO-cx3cr1+/GFP mice had reduced numbers of Iba1+ microglia in the optic nerve. Moreover, Nf1+/−GFAPCKO-cx3cr1+/GFP mice had optic glioma proliferative indices and optic nerve volumes comparable to those found in wild-type mice, demonstrating that microglia are necessary for optic nerve gliomagenesis. Collectively, these findings establish an obligate role for microglia in glioma formation and suggest that CX3CR1 is a potential target for future therapeutic drug design. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1530. doi:1538-7445.AM2012-1530

Solid tumors are complex ecosystems, composed of a heterogeneous ensemble of cells that comprise the tumor mass (neoplastic compartment) and the surrounding stroma (non-neoplastic compartment). Currently, research efforts are aimed at defining the individual contributions of each cell type to tumor development and maintenance. Previous studies using a genetically-engineered mouse model of Neurofibromatosis type 1 (NF1)-associated optic glioma have underscored the critical role of one stromal cell type (microglia) in the growth of these tumors. In the current study, we analyze neoplastic cell heterogeneity and demonstrate that two distinct proliferating populations of neoplastic cells exist in the tumor. These distinct cell types, neuroglial progenitors and differentiated astrocytes, are distinguished by their sensitivity to rapamycin. The molecular basis for this differential sensitivity to rapamycin reflects dramatic differences in mammalian target of rapamycin (mTOR) complex protein expression and basal mTOR activation. We leverage this cell type-specific sensitivity to target neuroglial progenitor cells in the tumor and inhibit optic glioma formation in vivo. Collectively, these findings emphasize the importance of cellular diversity in glioma formation and growth, and highlight the importance of developing novel treatment strategies that co-target multiple cell populations for maximal therapeutic benefit. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2498. doi:1538-7445.AM2012-2498

Optic nerve gliomas and meningiomas, which remain puzzling to clinicians, are reviewed with special attention to natural history, magnetic resonance findings, and appropriate management. New histopathological insights established the true neoplastic nature of optic nerve gliomas considered by most clinicians to be benign hamartomas. Unusual presenting manifestations and therapeutic alternatives of optic glioma have been also considered. Since the association of optic nerve gliomas and meningiomas with neurofibromatosis has long been recognized, special attention has been drawn to clinical, genetic, and ophthalmologic aspects of neurofibromatosis. New and unusual presenting manifestations, diagnostic and treatment opportunities concerning optic nerve involvement in metastatic disease, and lymphomatous proliferation are also described.

Twenty-five asymptomatic patients with neurofibromatosis type 1 (NF 1), aged 6–21 years, underwent the following examinations: intracranial magnetic resonance testing (MRI), visual acuity testing, ophthalmoscopy, and visual field and pattern reversal visual evoked potentials (VEPs). MRI showed enlargement of one or both optic nerves in six children, with bilateral involvement in three. VEPs were normal in all these patients; two of them had abnormalities on other visual examinations, although there were no subjective visual disturbances. These results show that VEPs cannot be considered as a screening test for optic pathway lesions in children with NF 1, as previously stated, and that other types of visual function examination may be more sensitive. These data may contribute to the establishment of more precise guidelines for the evaluation and treatment of children with NF 1.

A case of linear sebaceous nevus syndrome (sebaceous nevus of Jadassohn) in an infant is reported. The clinical manifestation and the radiological features of the central nervous system abnormalities associated with this neurocutaneous syndrome are presented. We believe that this is the first reported case of this syndrome in combination with optic glioma.

Optic gliomas occur in 15% of patients with neurofibromatosis type 1 (NF 1) and are a significant cause of morbidity. Of these tumors, 20-30% become symptomatic, usually before age 10 years. Previous studies have suggested that visual evoked potentials (VEPs) are a sensitive method for the detection of asymptomatic optic gliomas. Because routine neuroimaging of children with NF 1 is currently not recommended, the role of pattern-shift VEPs (PS VEPs) as a screening test for optic gliomas was evaluated. PS VEPs were performed on 10 children with NF 1 and optic gliomas and 20 children with NF 1 and normal visual pathways (as defined on MRI). PS VEPs had 90% sensitivity for detecting optic gliomas, with an increase in sensitivity to 100% when hemifield stimulation was used. The specificity of the test was 60%. Four of 20 children without optic gliomas had thickened optic nerves on computed tomography which represented dural ectasia with normal visual pathways on MRI; PS VEPs were normal in these patients. The efficacy of PS VEPs as a routine screen for optic gliomas is limited by the age at which children will cooperate with the test procedure and the high incidence of false-positive results; however, VEPs do provide a useful adjunct to routine clinical ophthalmologic assessment in the detection of optic gliomas in children with NF 1. Abnormal test results provide a stronger indication for neuroimaging. The early detection of optic gliomas allows for close monitoring of tumor progression and earlier intervention prior to significant visual loss.

Three children with optic pathway gliomas who developed ascites following ventriculoperitoneal shunt placement are presented. In all 3 cases there was an elevated cerebrospinal fluid (CSF) protein level at the time of initial shunt placement. At the time of developing ascites following placement of the ventriculoperitoneal shunt, none of the patients had evidence of infection or tumor seeding in the peritoneal cavity. The ascites completely resolved in each instance after converting the shunt to a ventriculoatrial system. Ascites following ventriculoperitoneal shunt insertion is an uncommon complication. A review of the literature and discussion of the possible etiologic factors in the development of ascites after ventriculoperitoneal shunt placement are presented. For patients diagnosed with optic gliomas, it is suggested that because the tumor is widely exposed to the CSF space, protein exuded by the mass into the subarachnoid space will cause an elevated CSF protein concentration. The elevated CSF protein may then lead to ascites as a result of poor absorption of CSF in the peritoneal cavity after placement of a ventriculoperitoneal shunt. Although ascites following ventriculoperitoneal shunt placement is not typical in patients with optic gliomas, attention should be given to CSF protein levels documented at the time of CSF diversion for hydrocephalus, recognizing that ascites may occur as a result of poor CSF absorption in the periotoneum, subsequently requiring a ventriculoatrial shunt in patients who develop hydrocephalus.

Supratentorial astrocytomas accounted for 36% of all pediatric brain tumors in the SEER registry review of 1973–1980 (25% low-grade astrocytomas and 11% high-grade astrocytomas) (Duffner et al. 1986). No predilection for either sex has been noted. Age at time of presentation ranges from infancy to 20 years, with the median at 12.7 years.

We report the results of the reevaluation of 24 patients with neurofibromatosis type 1 (NF1) using central nervous system (CNS) imaging techniques. The first examination by computed tomography (CT) or magnetic resonance imaging (MRI) indicated the presence of optic glioma in three cases, “unidentified bright objects” (UBOs) in six, and a suspected right frontal tumor in one. In two patients optic glioma and UBOs were both present and in one of them a bulbar tumor was also suspected. Later imaging examinations revealed the appearance of optic glioma in three more cases and UBOs in nine. In two of these patients both optic glioma and UBOs were present. This study indicates that the likelihood of detecting imaging abnormalities in patients with NF1 increases when systematic follow-up is performed. Optic gliomas are characteristic of pediatric patients; they rarely give rise to clinical manifestations (1/6 cases) and in general progress very slowly. For these reasons, therapeutic strategy must be carefully considered and individually decided. UBOs are very frequent findings in pediatric patients with NF 1 and therefore they must be considered diagnostically relevant. They are not related to clinical manifestations and spontaneous regression has been observed. The nature of these imaging abnormalities is still unknown, but because they do not behave like tumors, useless and dangerous therapeutic procedures should not be employed.

The biological nature of optic gliomas is controversial, with some considering them benign hamartomatous lesions, and others believing them to be true neoplasms. We evaluated the use of colloid silver impregnation of nucleolar organizer region-associated proteins (AgNORs) in making this distinction. Thirty-one optic gliomas, 14 optic nerve meningiomas, and a single case of giant cell glioblastoma multiforme (monstrocellular glioma) of the optic chiasm were stained for AgNORs and counted in a masked fashion. The optic gliomas contained 2.01 +/- 0.09 AgNORs per nucleus, similar to that of optic nerve meningiomas (2.15 +/- 0.15) and our previously reported counts for diffuse fibrillary astrocytoma (2.22 +/- 0.10), and significantly more than that of reactive astrocytosis (1.18 +/- 0.02). Six of the seven optic gliomas examined had compound AgNORs, a feature associated with malignancy in other tumour types. AgNOR counts did not correlate with clinical features, including those seen during the post-operation course. These data suggest that optic gliomas may be true neoplasms, and not benign hamartomas.

A 14-year-old girl was diagnosed as having acute lymphoblastic leukemia following 5000 cGy cranial radiotherapy for treatment of optic glioma. In the absence of underlying predisposing factors, development of acute leukemia was attributed to the oncogenic effect of radiation.

Although bilateral optic nerve gliomas are commonly found in patients with neurofibromatosis I, extensive gliomas involving the entire visual tracts, bilaterally are relatively rare. Usually the optic radiations are spared. We report a case of a 2-year-old child with extensive disease of bilateral visual pathways with involvement of the hypothalamus manifesting as obesity.

We reviewed the magnetic resonance images of four children with neurofibromatosis 1 and orbital optic gliomas. The images showed double-intensity tubular thickening characteristic of perineural arachnoidal gliomatosis, elongation of the nerves, and downward kinking of the nerves in the midorbit. We believe these findings typify the orbital gliomas in patients with this disease.

Optic nerve glioma is a rare tumor usually occurring in small children. How these tumors should be treated, is a matter of controversy. Recommended treatment ranges from a wait-and-see policy to radical excision with or without subsequent radio- or chemotherapy. Comparative data on these lesion are limited, as there are no randomized investigations and long-term studies reported in the literature. In 11 patients interstitial radiotherapy was carried out, by the implantation of J-125 seeds following confirmation of the histological diagnosis. The results are compared with those of 10 patients who underwent only biopsy for histological confirmation. CT-stereotactic biopsy to verify the diagnosis with subsequent interstitial irradiation is presented as an alternative therapy for optic gliomas.

Brain tumors can only be treated by the combined efforts of neurosurgeons, radiotherapists, and medical oncologists. This holds especially true in children, where close cooperation with other specialists in mandatory, i.e., the child neurologist for timely diagnosis and follow-up, the neuropsychologist for assessment of treatment effects, and so on. Since standard treatment — surgery and radiotherapy — is not sufficient in a lot of cases, while on the other hand the results of chemotherapy in brain tumors are far from satisfactory, multimodality treatment protocols become more and more necessary for adequate management of brain tumors.

Pilocytic astrocytomas occupy an exceptional position among the tumors of astrocytic differentiation because of the characteristically very low age of patients and the predilection of the tumors for the midline and infratentorial regions. As a rule these tumors grow very slowly and patients have a relatively good prognosis [1, 5, 7]. The question then arises whether this slow growth in comparison to other glioma types can be quantified in biopsy material, and whether it will be possible to define subtypes of pilocytic astrocytoma on this basis.

INTRODUCTION: Neurofibromatosis von Recklinghausen type 1 (NF1) is characterized by the following National Institutes of Health (NIH) diagnostic criteria: café au lait spots, freckling, neurofibromas, Lisch nodules, optic glioma, distinct osseous lesions, and first-degree relative with NF1. Focal areas of high-signal intensity (FASI) in white matter and deep gray matter are typical brain MRI findings in children with NF1. OBJECTIVE: This study evaluated the frequency of FASI and the possibility of using FASI as a diagnostic criterion. METHODS: In a group of 160 children, the diagnosis of NF1 was confirmed in keeping with the NIH criteria. All children had MRI examination of the brain. The MRI findings of FASI in the children with NF1 were compared both with the brain MRI findings of the control group of 160 children with different diagnoses and with frequencies of the NIH diagnostic criteria. RESULTS: In 137 (86%) patients with NF1, ≥1 FASI were found. The difference between frequency of FASI in the NF1 group and in the control group (14 [9%]) is highly significant. The frequencies of the diagnostic criteria were as follows: café au lait spots: 157 (98%); freckling: 123 (77%); neurofibromas: 112 (70%); NF1 relatives: 89 (56%); Lisch nodules: 71 (44%); optic glioma: 45 (28%); and osseous lesions: 15 (9%; only partial examination of the group). CONCLUSIONS: The findings of FASI in T2-weighted images of the brain MRI are significantly frequent in children with NF1. Frequency of FASI is comparable with frequency of NIH diagnostic criteria. FASI could be proposed as an additional or new criterion for the NF1, mainly in childhood.

A 5 1/2-year-old boy developed a huge cyst in his chiasmal glioma 4 years after radiation therapy. The cyst produced obtundation but was successfully treated.

The cerebral hemisphere gliomas are found most often in adults, and thus childhood cerebral gliomas have not been extensively reviewed and reported, as have the other common pediatric intracranial tumors such as medullo-blastoma, brainstem glioma, optic glioma, and cerebellar astrocytoma. In some reported series, the pediatric cerebral gliomas of a particular histology are included together with the same histological types of other sites such as the infratentorial region. Sometimes, series have been reported in which many different histological types have been included in the category of cerebral or hemispheric tumor without separately reporting data on the various histological types. Often, childhood cerebral gliomas have been included in reported series compiled of mainly adult patients.

Tumors of the visual pathways — optic nerve, optic chiasm and optic tract — may have a long natural history. Controversies exist as to their appropriate management. Some believe therapy should be reserved until a patient has progressive symptoms, although others argue for early treatment to minimize visual deterioration. Depending on the location of the tumor, surgery, combined modalities and radiotherapy alone may be used in the treatment of this disorder. Some argue that attempt at surgical removal, even just biopsy, may make vision worse. Most of the literature recommends radiation doses of at least 4500–5000 rad. Improvements in vision are frequently seen following radiotherapy. Vascular occlusion is a late risk of high fractionated dose and high total dose radiation. Ninety-one percent of radiation oncologists would treat optic glioma according to the national survey.

2087 Background: To evaluate longitudinally the relationship between brain imaging and functional findings in childhood optic gliomas (OG) by comparing over time magnetic resonance imaging (MRI) with flicker visual evoked potential (FVEP) changes. Methods: Fourteen children (median age 3 yrs, range: 2–7) suffering from OGs involving chiasm and retro-chiasmatic visual pathways underwent serial MRI and FVEP examinations over a median follow-up time of 38 months (range 12–76). FVEPs were monocularly recorded in response to 8 Hz sine-wave flicker stimuli presented in a mini-Ganzfeld according to a published technique (Trisciuzzi et al., Clin. Neurophysiol., 2004). MRI examinations were performed according to standard procedures. Longitudinal results of both tests were examined in a blind fashion by independent evaluators. FVEPs were judged to be improved, stable or worsened if changes in the amplitude and/or phase of the fundamental response component exceeded the limits of test-retest variability (±90th percentile) established in the same patients. MRI results were judged to show regression, stabilization or progression of OG based on its changes in size (±20%) or extension. Two to seven pairs (< one month apart) of FVEP/MRI examinations per patient (median: 4, range 2–7) were collected. Agreement between test changes over time were evaluated by K-statistics. Results: Based on a total of 38 pairs of longitudinal FVEP/MRI examinations, both tests agreeed in showing worsening (progression), stabilization and improvement (regression) in 5, 10 and 15 cases, respectively. In 3 cases, FVEPs showed a worsening and MRI a stabilization, while in 5 cases FVEPs showed an improvement and MRI a stabilization. Agreement between FVEP and MRI changes was 78.9% (95% CI: ± 37%, K = 0.67, p < 0.001). Conclusions: The results indicate that changes over time in FVEPs, an objective and non-invasive test of visual function, can accurately predict associated changes in OG size and extension as assessed by MRI, and suggest that the latter changes may have a significant impact on visual function during developmental age. No significant financial relationships to disclose.

A 25-year-old man presented for evaluation of aphasia and generalized seizures. Examination revealed cafe au lait macules, axillary freckling, and bilateral Lisch nodules. Surgical history included excision of an upper extremity plexiform neurofibroma and optic glioma resection followed by …

Objective and importance Intracranial giant optic nerve gliomas, usually presumed as optic chiasmatic gliomas, are much less common. The architectural tumor form of optic nerve glioma without neurofibromatosis type 1 is usually the expansile-intraneural pattern. The exophytic optic nerve gliomas without neurofibromatosis type 1 are relatively uncommon. Surgical decompression for intracranial optic gliomas frequently leads to clinical improvement, but obvious improvement of vision is rare. We report a case that demonstrated significant recovery of visual function after removal of the intracranial giant optic nerve glioma, revealing exophytic growth. Clinical presentation A 13-year-old boy presented with visual impairment in both eyes. Magnetic resonance images (MRI) disclosed a 6 cm diameter mass in the suprasellar area. On heavily T2-reversed MRIs, it was obvious that the intracranial portion of right optic nerve was enlarged, and optic tracts were shifted to the left by the tumor. The relationship of the tumor to the chiasma could not be affirmed on MRIs. Intervention A right frontotemporal craniotomy for decompression of the optic apparatus was performed. After the majority of the tumor was resected, it became clear that the tumor originated in the right optic nerve. The tumor exophytically grew and dislocated the optic chiasma and optic tracts. Significant improvement of visual functions began from the first week after surgery and continued gradually thereafter. The histological diagnosis was pilocytic astrocytoma. A follow-up MRI taken 4 years after surgery showed no regrowth of the residual tumor. Conclusion Giant exophytic gliomas without neurofibromatosis type 1 may arise from the intracranial portion of an isolated optic nerve. Direct visualization of optic component by heavily T2-reversed MRI could more precisely delineate the relationship of the intracranial optic nerve glioma to the optic apparatus. Surgery may be indicated in giant exophytic intracranial optic nerve gliomas and preoperative postulated optic chiasmatic gliomas. Microsurgical resection can induce postoperative visual improvement without regrowth of the residual tumor.

Children with optic gliomas should benefit from better management after a study has established how different gliomas behave. Aggressive treatment is recommended for sporadic gliomas and early monitoring for gliomas associated with neurofibromatosis type 1 (NF1). Seventeen cases in the study were of optic glioma associated with NF1 and …

The natural history of sporadic optic gliomas was compared with that of optic gliomas associated with neurofibromatosis type 1 (NF1) in a study using a Children’s Tumor Registry (CTR) and an NF1 Database (NF1DB) at St Mary’s Hospital, Manchester, UK.

Objective To demonstrate spontaneous regression of large, clinically symptomatic optic pathway gliomas in patients with and without neurofibromatosis type 1 (NF-1). Methods Patient cases were collected through surveys at 2 consecutive annual meetings of the North American Neuro-Ophthalmology Society (NANOS) and through requests on the NANOSNET Internet listserv. Serial documentation of tumor signal and size, using magnetic resonance imaging in 11 patients and computed tomography in 2 patients, was used to evaluate clinically symptomatic optic pathway gliomas. All tumors met radiologic criteria for the diagnosis of glioma and 4 patients had biopsy confirmation of their tumors. In 3 patients, some attempt at therapy had been made many years before regression occurred. In one of these, radiation treatment had been given 19 years before tumor regression, while in another, chemotherapy had been administered 5 years before signal changes in the tumor. In the third patient, minimal surgical debulking was performed 1 year before the tumor began to shrink. Results Spontaneous tumor shrinkage was noted in 12 patients. Eight patients did not have NF-1. In an additional patient without NF-1, a signal change within the tumor without associated shrinkage was detected. Tumor regression was associated with improvement in visual function in 10 of 13 patients, stability of function in 1, and deterioration in 2. Conclusions Large, clinically symptomatic optic gliomas may undergo spontaneous regression. Regression was seen in patients with and without NF-1. Regression may manifest either as an overall shrinkage in tumor size, or as a signal change on magnetic resonance imaging. A variable degree of improvement in visual function may accompany regression. The possibility of spontaneous regression of an optic glioma should be considered in the planning of treatment of patients with these tumors.

Most of the clinical manifestations of NF1 are thought to occur in similar frequencies in different ethnic groups. One exception to this assumption may be optic glioma, which has been reported to be less common in African-Americans. We have compared the manifestations of NF1 in a retrospective analysis of 55 individuals with NF1, including 39 Caucasians and 16 African-Americans in the first part of the study. All patients met the NIH consensus criteria for NF1. The diagnosis of NF1 was established at the mean age of 11.1 years in African-Americans and 8.3 years in Caucasians (±SD 6.9 years for African-Americans and 12.3 years for Caucasians; p

We welcome the study by Wolkenstein et al 1 of the usefulness of screening investigations in neurofibromatosis type 1 (NF1). Because of the high incidence of NF1 (up to 1 case in 2500 births), this work is of great practical significance for the practicing dermatologist. We have performed similar work 2 to evaluate the necessity of screening for the presence of optic glioma at the time of diagnosis of NF1 ( Figure 1 ). In this study, our aims were to define the prevalence and clinical significance of optic gliomas in patients presenting to the Dermatology Outpatient Department, Beaumont Hospital, Dublin, Ireland, to determine what proportion of gliomas were symptomatic and to evaluate screening modalities. In addition, the patients with optic gliomas detected by screening were followed up closely for 5 years. Standard diagnostic criteria for NF1 were applied. 1 Any symptoms of diplopia, headache, seizure, neurologic deficit, or visual deterioration were

Magnetic resonance (MR) imaging plays an important role in evaluation of ocular and orbital lesions. Ocular tumors can be distinguished and delineated from adjacent fluid collections. Demonstration of internal septa within a well-defined mass leads to the diagnosis of cavernous hemangioma, whereas vascularity and internal lobulations are the hallmark of capillary hemangiomas. MR is the procedure of choice for evaluation of the optic nerve sheath complex. It precisely delineates and characterizes optic neuritis, optic gliomas, and perioptic meningiomas.

We describe a young girl with neurofibromatosis and enlargement of the optic chiasm and intracranial left optic nerve. Serial MRIs over 32 months demonstrated spontaneous, marked reduction in the size of these lesions. Spontaneous regression must be considered in evaluating therapies for optic glioma.