Faculty Bibliography

INTRODUCTION: : Glutamic acid decarboxylase (GAD) is the rate-limiting enzyme converting glutamate into gamma-aminobutyric acid. Impaired GAD function can alter motor, cognitive, and behavioral function. Anti-GAD antibodies (GADAbs) can cause several neurological disorders. However, the association between anti-GADAbs and pure psychosis, without seizures or focal neurological deficits, is not well defined. CASE REPORT: : A 19-year-old woman with recent-onset psychotic disorder was diagnosed with schizophrenia. Brain magnetic resonance imaging and cerebrospinal fluid analysis were normal. Serum anti-GADAb titers were elevated. Brain biopsy showed subcortical gliosis and microglia-macrophage infiltration. The clinical syndrome improved with immune therapy. CONCLUSIONS: : Severe psychosis and mild cognitive decline without other neurological features, meeting the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision diagnostic criteria for schizophrenia, can result from brain inflammation associated with elevated serum anti-GADAbs.

Medulloblastoma, the most common malignant paediatric brain tumour, arises in the cerebellum and disseminates through the cerebrospinal fluid in the leptomeningeal space to coat the brain and spinal cord. Dissemination, a marker of poor prognosis, is found in up to 40% of children at diagnosis and in most children at the time of recurrence. Affected children therefore are treated with radiation to the entire developing brain and spinal cord, followed by high-dose chemotherapy, with the ensuing deleterious effects on the developing nervous system. The mechanisms of dissemination through the cerebrospinal fluid are poorly studied, and medulloblastoma metastases have been assumed to be biologically similar to the primary tumour. Here we show that in both mouse and human medulloblastoma, the metastases from an individual are extremely similar to each other but are divergent from the matched primary tumour. Clonal genetic events in the metastases can be demonstrated in a restricted subclone of the primary tumour, suggesting that only rare cells within the primary tumour have the ability to metastasize. Failure to account for the bicompartmental nature of metastatic medulloblastoma could be a major barrier to the development of effective targeted therapies.

Object The presence of angiogenesis is a hallmark of glioblastoma (GBM). Vascular endothelial growth factor (VEGF), which drives angiogenesis, provides an additional target for conventional therapy. The authors conducted a prospective clinical trial to test the effectiveness of bevacizumab, an inhibitor of VEGF, in newly diagnosed GBM. Methods From 2006 through 2010, 51 eligible patients with newly diagnosed GBM were treated with involved-field radiation therapy and concomitant temozolomide (75 mg/m(2) daily for 42 days) along with bevacizumab (10 mg/kg every 2 weeks), starting 29 days after surgery. This was followed by 6 cycles of adjuvant temozolomide therapy (150 mg/m(2) on Days 1-7 of a 28-day cycle) with bevacizumab administered at 10 mg/kg on Days 8 and 22 of each 28-day cycle. Results The 6- and 12-month progression-free survival (PFS) rates were 85.1% and 51%, respectively. The 12- and 24-month overall survival (OS) rates were 85.1% and 42.5%, respectively. Grade III/IV toxicities were noted in 10 patients (19.6%). No treatment-related deaths were observed. Asymptomatic intracranial bleeding was noted in 5 patients. Conclusions The addition of bevacizumab to conventional therapy in newly diagnosed GBM appears to improve both PFS and OS in patients with newly diagnosed GBM, with acceptable morbidity. A shift toward diffuse relapse was noted in a significant number of patients. Ongoing Phase III clinical trials will show the true benefit of this antiangiogenic approach.

PURPOSE: Local recurrence is the dominant pattern of relapse in high-grade glioma (HGG) after conventional therapy. The recent use of antiangiogenic therapy has shown impressive radiologic and clinical responses in adult HGG. The preclinical data suggesting increased invasiveness after angiogenic blockade have necessitated a detailed analysis of the pattern of recurrence after therapy. METHODS AND MATERIALS: A total of 162 consecutive patients with HGG, either newly diagnosed (n = 58) or with recurrent disease (n = 104) underwent therapy with bevacizumab at 10 mg/kg every 2 weeks and conventional chemotherapy with or without involved field radiotherapy until disease progression. The pattern of recurrence and interval to progression were the primary aims of the present study. Diffuse invasive recurrence (DIR) was defined as the involvement of multiple lobes with or without crossing the midline. RESULTS: At a median follow-up of 7 months (range, 1-37), 105 patients had recurrence, and 79 patients ultimately developed DIR. The interval to progression was similar in the DIR and local recurrence groups (6.5 and 6.3 months, p = .296). The hazard risk of DIR increased exponentially with time and was similar in those with newly diagnosed and recurrent HGG (R(2) = 0.957). The duration of bevacizumab therapy increased the interval to recurrence (p < .0001) and improved overall survival (p < .0001). However, the pattern of relapse did not affect overall survival (p = .253). CONCLUSION: Along with an increase in median progression-free survival, bevacizumab therapy increased the risk of DIR in HGG patients. The risk of increased invasion with prolonged angiogenic blockade should be addressed in future clinical trials

Recent studies highlight the importance of BRAF alterations resulting in mitogen activated protein kinase (MAK/ERK) pathway activation in low-grade CNS tumors. We studied 106 low-grade CNS neoplasms in a cohort of primarily pediatric patients to identify the prevalence and clinicopathologic significance of these alterations. Polymerase chain reaction testing identified KIAA1549:BRAF fusions in 51 (48%) tumors overall, including 42 (60%) pilocytic astrocytomas, 4 (17%) unclassifiable low-grade gliomas, 4 (36%) low-grade glioneuronal/neuroepithelial tumors, 0 (of 5) pleomorphic xanthoastrocytomas, 0 (of 4) diffuse astrocytomas (World Health Organization grade II), and 1 (of 3, 33%) pilomyxoid astrocytoma. KIAA1549:BRAF gene fusions confirmed by sequencing included the previously reported ones involving exons 1-16/9-18 (49%), 1-15/9-18 (35%), and 1-16/11-18 (8%) and 2 fusions with novel breakpoints: 1-15/11-18 (6%) and 1-17/10-18 (1%). DNA sequencing identified BRAF mutations in 8% of tumors. BRAF mutations were absent. KIAA1549:BRAF fusions were significantly more frequent in infratentorial (57%) and optic pathway (59%) tumors versus supratentorial (19%) tumors (p = 0.001). We did not identify significantly improved progression-free survival in tumors with fusions. In summary, KIAA1549:BRAF fusions predominate in pilocytic astrocytomas but are also present in some low-grade unclassifiable gliomas and glioneuronal tumors. The prognostic and therapeutic significance of this alteration is unclear and merits further study.

Paraganglioma (PGL) of the filum terminale is a rare tumor of extra-adrenal paraganglia. The reported cases of filum terminale and cauda equina PGLs often present with low-back pain and sciatica. While sensory or motor deficits and paraplegia may occur, the incidence is relatively low. We present a case of a 51-year old male with hemorrhagic paraganglioma of the filum terminale. He presented with acute paraplegia and was treated via emergent laminectomy, evacuation of hematoma, and resection of tumor. The patient had a significant but incomplete neurological recovery. The clinical, radiologic, and histopathological characteristics of the condition are described

Nonparaneoplastic glutamic acid decarboxylase antibody (GADAb)-related autoimmune encephalitis is a syndrome characterized by refractory seizures, progressive cognitive deficits, and psychiatric manifestations. The limbic subtype is well described, has characteristic affective and memory disturbances, and typical mesial temporal MRI abnormalities. We found only one single case report of the extralimbic subtype. We report clinical, radiological, and pathological findings of two additional cases with contrast-enhancing lesions. One of our cases presented as vasculitis, and the other imitated a tumor. Pathological evidence of both vasculitis and encephalitis has never been previously reported in any inflammatory condition affecting the brain. Our cases confirm prior reports that immune therapy can better control seizures associated with GADAb autoimmune encephalitis, and support the rationale for assaying for GADAb titers in patients with etiologically unclear extralimbic lesions and refractory epilepsy, independent of seizure types

Purpose: The role of invasion as a prognostic factor in high-grade gliomas (HGG) remains controversial. An apparent increase in invasiveness following anti-angiogenic therapy makes this question clinically relevant. The goal of this study is to assess survival differences in patients with newly diagnosed HGG who present with diffuse invasive disease compared to those who did not, but went on to develop diffuse invasive disease following bevacizumab therapy. Materials and Methods: Twenty-three patients presented as newly diagnosed diffuse invasive HGG. All patients underwent surgical resection with radiation therapy and temozolomide for one year. Progression-free survival (PFS) and overall survival (OS) were compared to a control of 58 patients with focal high-grade glioma who received similar therapy, but that included bevacizumab at 10 mg/kg given every two weeks. Results: The patient characteristics were similar in each group. The median PFS and OS for invasive HGG patients were 6 and 13 months and for the focal HGG patients, 11 and 24 months, respectively (P=0.092 and P=0.071). In the subgroup of invasive HGG that showed significant angiogenesis, the median PFS and OS were 3 and 9 months, respectively. 56% of the focal HGG patients recurred as diffuse invasive relapse. For patients with focal HGG who recurred as invasive disease, the median PFS and OS were 9 and 21 months respectively. Conclusions: Presence of diffuse invasive disease not accompanied by angiogenesis either prior to therapy or subsequent to anti-angiogenic therapy does not seem to have prognostic significance. However, invasion accompanied by angiogenesis in newly diagnosed HGG may confer a poor prognosis