IDH1 mutation is associated with seizures and protoplasmic subtype in patients with low-grade gliomas.

OBJECTIVE: The isocitrate dehydrogenase 1 (IDH1) R132H mutation is the most common mutation in World Health Organization (WHO) grade II gliomas, reported to be expressed in 70-80%, but only 5-10% of high grade gliomas. Low grade tumors, especially the protoplasmic subtype, have the highest incidence of tumor associated epilepsy (TAE). The IDH1 mutation leads to the accumulation of 2-hydroxyglutarate (2HG), a metabolite that bears a close structural similarity to glutamate, an excitatory neurotransmitter that has been implicated in the pathogenesis of TAE. We hypothesized that expression of mutated IDH1 may play a role in the pathogenesis of TAE in low grade gliomas. METHODS: Thirty consecutive patients with WHO grade II gliomas were analyzed for the presence of the IDH1-R132H mutation using immunohistochemistry. The expression of IDH1 mutation was semiquantified using open-source biologic-imaging analysis software. RESULTS: The percentage of cells positive for the IDH1-R132H mutation was found to be higher in patients with TAE compared to those without TAE (median and interquartile range (IQR) 25.3% [8.6-53.5] vs. 5.2% [0.6-13.4], p = 0.03). In addition, we found a significantly higher median IDH1 mutation expression level in the protoplasmic subtype of low grade glioma (52.2% [IQR 19.9-58.6] vs. 13.8% [IQR 3.9-29.4], p = 0.04). SIGNIFICANCE: Increased expression of the IDH1-R132H mutation is associated with seizures in low grade gliomas and also with the protoplasmic subtype. This supports the hypothesis that this mutation may play a role in the pathogenesis of both TAE and low grade gliomas.

Tumour associated epilepsy and glutamate excitotoxicity in patients with gliomas.

Tumour associated epilepsy (TAE) is common, debilitating and often not successfully controlled by surgical resection of the tumour and administration of multiple anti-epileptic drugs. It represents a cause of significant lost quality of life in an incurable disease and is therefore an important subject for ongoing research. The pathogenesis of TAE is likely to be multifactorial and involve, on the microscopic level, the interaction of genetic factors, changes in the peritumoural microenvironment, alterations in synaptic neurotransmitter release and re-uptake, and the excitotoxic effects of glutamate. On a macroscopic level, the occurrence of TAE is likely to be influenced by tumour size, location and interaction with environmental factors. The optimal treatment of TAE requires a multi-disciplinary approach with input from neurosurgeons, neurologists, radiologists, pathologists and basic scientists. This article reviews the current literature regarding the incidence, treatment, and aetiology of TAE.

Malignant potential of pleomorphic xanthoastrocytoma.

Pleomorphic xanthoastrocytoma (PXA) is a low-grade astrocytic tumour that occasionally progresses to a higher grade. We have extensively reviewed the literature on the potential for malignant transformation of PXA. An illustrative case of a PXA transforming to glioblastoma multiforme is presented.

Pilocytic astrocytoma with neoplastic gemistocytes undergoing spontaneous transformation to glioblastoma multiforme without prior radiotherapy.

Pilocytic astrocytoma, the most common glioma of childhood, is considered a clinically benign tumour. Malignant transformation of this tumour is rare and thought to occur almost exclusively in the setting of prior radiotherapy. We describe a patient with mixed pilocytic and gemistocytic astrocytoma which transformed into a glioblastoma multiforme, leading to rapid deterioration and death of the patient, without prior radiotherapy.

Management of recurrent craniopharyngioma.

Craniopharyngioma accounts for approximately 1.2% to 4.6% of all intracranial tumours. Their close proximity to vital structures such as the hypothalamic-pituitary axis and optic apparatus makes them one of the most challenging and controversial management dilemmas in neurosurgery. Recurrence following initial transcranial resection is reported as 9% to 51% at a median time of 26 months to 96 months. Treatment options for recurrent craniopharyngioma include repeat surgery, radiotherapy, radiosurgery and intracystic therapies. We present a series of 54 recurrent craniopharyngiomas treated at The Royal Melbourne Hospital between 1991 and 2008 and discuss the management options now available.

Management of recurrent Cushing's disease.

The management of patients with Cushing's disease remains a major challenge. The remission rate for initial transsphenoidal surgery is reported as 69-94% while the recurrence rate following initially successful transsphenoidal surgery is 2-27%. Treatment options for Cushing's disease after failed initial therapy or recurrence include repeat transsphenoidal surgery, radiotherapy, medical therapy and bilateral adrenalectomy. Management options following unsuccessful initial surgery or recurrence are presented and discussed.

Treatment of persistent and recurrent acromegaly.

Acromegaly is a chronic insidious disease characterised by growth hormone (GH) hypersecretion, typically from a pituitary adenoma. Effective treatment of acromegaly is vital because it is associated with a mortality rate more than twice that of the general population, an increased prevalence of colonic malignancy and many significant co-morbidities. Transsphenoidal adenoma resection is still the best first-line treatment for acromegaly but persistence (43%) or recurrence (2% to 3%) of GH hypersecretion after surgery remains a problem. Treatment options for acromegaly after failed initial therapy or recurrence include further surgery, radiotherapy, radiosurgery or medical therapies, including somatostatin analogues, dopamine agonists and growth hormone receptor antagonists. There has been a progressive lowering of the accepted GH level defining cure in acromegaly. This article reviews the efficacy and safety of the various treatment options for persistent or recurrent acromegaly and the changing definition of cure.

Primary melanocytic neoplasms of the central nervous system.

Primary melanocytic neoplasms of the central nervous system (CNS) are rare lesions arising from melanocytes of the leptomeninges. They include diffuse leptomeningeal melanocytosis or melanomatosis, melanocytoma and primary malignant melanoma. We have reviewed the English literature regarding these lesions, which consists of case reports and a small number of larger case series. The presenting features, radiological, surgical and histological findings are reviewed, as are current management options and prognosis. We also present illustrative case reports of diffuse leptomeningeal melanocytosis and primary melanoma of the CNS.

Tailored cortical resection following image guided subdural grid implantation for medically refractory epilepsy.

The aim of this study was to report the safety and efficacy of tailored cortical resection based on image guided subdural electrode implantations in eight patients with medically refractory epilepsy. The patients were selected for multimodality image guided subdural grid implantation, inpatient invasive electroencephalography video monitoring and surgical resection of epileptogenic foci. All patients had frequent disabling, medically refractory seizures pre-operatively. At a minimum of 10 months post-resection all patients had a worthwhile improvement in seizure frequency, with 7 of the 8 (87.5%) having an excellent outcome (Engel Class I). Short-term complications of grid implantation were: one patient with a post-operative subdural haemorrhage and one patient with a transient fluctuating dysphasia. The only long-term complication was a mild, non-disabling dysarthria following resection near eloquent speech cortex in one patient. We conclude that tailored cortical resection following image-guided insertion of subdural grids is a reliable, safe and highly effective method for the treatment of medically refractory epilepsy in carefully selected patients.