Primary spinal glioblastoma multiforme. Single center experience and literature review

Abstract Objectives Spinal glioblastomas represent a rare entity accounting for ca 1–3% of all intramedullary tumors; data about survival, prognostic factors and therapeutic protocols are quite poor. Even with an aggressive multimodal management the spinal glioblastoma patients' survival remains poor, with rapid progression of the disease. This study reports our experience with the management of the primary intramedullary glioblastomas, also in regard to the current literature data. Patients and Methods We retrospectively analyzed the medical records of 5 patients treated at the Department for Neuro-oncology and Spine Surgery of the Clinical Center of Belgrade, Serbia, between January 2007 and December 2016 for a primary intramedullary glioblastoma. Demographic characteristics, pre-operative data and post-operative results were then compared with previous literature regarding spinal GBMs and attempt to identify potential prognostic factors. Results Gross total resection was achieved in two patients, while a subtotal resection was performed in the latter 3 cases; as per protocol, all patients underwent to surgery, followed by radio and chemotherapy. There were no intraoperative complications and no patients developed a new postoperative neurological defect; the median overall survival was 6 months. Progression or recurrence of disease was noted in all patients at the 3-months follow-up, despite the adjuvant treatments. Conclusions To the date, there is a lack of consensus on specific management of spinal glioblastomas: the extent of resection can play an important role, but it appears to be not preeminent. A shorter interval between symptoms onset and treatment and a smaller extension of the tumor seem to be correlated with better outcomes and a longer overall survival. However, there is not an adjunctive viable standardized postoperative therapy yet, which results in concrete and persistent improvement of overall survival and progression free survival

Distribution and role of metals in sclerotic hippocampi of patients with mesial temporal lobe epilepsy

The accumulating evidence on the relation between the disturbed metal homeostasis and epilepsy urges the need for data regarding the total metal concentrations, as well as metal distribution in the brain itself, in order to indicate where to direct the potential therapy, to metal supplementation or chelation. This paper summarizes our results on the measurements of some important essential metals in hippocampi of patients with mesial temporal lobe epilepsy (mTLE) who underwent amigdalohippocampectomy. The key findings point out that levels of copper and manganese are deficient in hippocampi of mTLE patients, and that their concentrations correlated positively with neuronal loss in affected regions of sclerotic hippocampus. In addition, the Cu concentration was decreased in the areas of total neuronal loss. Iron and zinc total hippocampal levels were neither accumulated nor deficient compared to control. Our results contribute to deeper insight of metals biology in the epilepsy and may represent the initial point of new and non-invasive therapy of drug resistant epilepsy

Relationship Between Regional Distributions of Cytochrome C Oxidase and Copper-Delivering Chaperones in Sclerotic Hippocampi of Epilepsy Patients

Aims: A drop in copper level and the loss of energy homeostasis are both portrayed in mesial temporal lobe epilepsy (mTLE) with hippocampal sclerosis (HS) patients. Cytochrome c oxidase (COX) represents a crossroad of energy and copper metabolism; it is a key component of mitochondrial machinery and contains two copper centers. Our aim here was to examine the link between COX activity and the copper transporting system in HS. COX activity and the levels of mRNA of selected chaperones - COX11, COX17, Sco1 and Sco2 were determined in 13 anatomically distinct hippocampal regions. Methods: Study was performed on seven hippocampal samples, four of which had been acquired during the course of amygdalohippocampectomy treatment of medically intractable epilepsy and three control postmortem samples. Adjacent slices were used for Nissl staining, COX activity assay and mRNA in situ hybridization with autoradiography. Densitometry was performed using ImageJ. Results: Overall COX activity was decreased in HS compared to controls (P = 0.0003). However, 5 regions showed significantly lower COX activity in HS and 8 did not. Subiculum showed slightly higher activity in HS. The levels of mRNA levels were lowered in HS in 6 regions for COX11, 10 regions for COX17, two regions for Sco1 and 11 regions for Sco2. Conclusions: Our findings suggest the loss of energy homeostasis in HS may be related to pathological changes in specific components of copper delivery to COX, and that the impact may vary between different hippocampal regions

Imaging and regional distribution of copper, zinc, manganese and iron in sclerotic hippocampi of patients with mesial temporal lobe epilepsy

Mesial temporal lobe epilepsy (mTLE) represents the most common subtype of human focal epilepsies and perhaps the best-characterized disorder of this type 1 . Hippocampal sclerosis (HS) is the most common histopathologic abnormality found in adults with drugresistant mTLE 2 . The histopathologic hallmark of HS is segmental pyramidal cell loss, which can affect any field of the cornu Ammonis (CA1-4). Hippocampal neuronal cell loss is always associated with a severe pattern of astrogliosis 3 . Therewithal, disturbed homeostasis of metals is implicated in the pathology of mTLE-HS. Zinc has been considered to play a major role in epileptogenesis in relation to its involvement in the modulation of excitability and synaptic plasticity 4,5. Further, it has been shown that epileptogenic hippocampi are exposed to oxidative stress and that the development of prooxidative conditions in the CNS usually involves the loss of homeostasis of iron 6,7. Low brain levels of copper and manganese have been reported in patients with Menkes disease and in animal models of epilepsy, and linked to seizure development 8,9. Ristić et al. were the first to conduct a case-control study of total concentration of metals in tissue of human HS, and report lower concentrations of copper and manganese 10

Metallome of sclerotic hippocampi in patients with drug-resistant mesial temporal lobe epilepsy

Altered hippocampal metallome is strongly implicated in the pathology of mesial temporal lobe epilepsy with hippocampal sclerosis (mTLE-HS). We aimed to determine sodium, potassium, calcium, magnesium, iron, copper, manganese, and zinc concentration in epileptic human hippocampi

The importance of copper in pathology of mesial temporal lobe epilepsy

More and more studies are identifying the regulation of metal homeostasis as one of the key points of central nervous system’s well-being. Epilepsy is a particularly interesting neurological condition when viewed in terms of the correlation between the amount of metals and the development of a seizure. This lecture will present contribution of our group to the field of metal biology in epilepsy by mapping brain metals in sclerotic hippocampus resected from drug resistant mesial temporal lobe epilepsy (mTLE) patients as surgical therapeutic approach. Direct insight into this epileptogenic area, by two powerful techniques, optical emission and mass spectrometry, has led us to investigation of copper turnover. Namely, among the examined metals, we found the deficiency of copper in sclerotic hippocampus on two levels: (i) in whole structure (ii) and locally in the areas of neuronal loss, with significant correlation between copper concentration and neuron density. Furthermore, analysis of copper metalloproteins showed: (i) significant increase or decrease in levels of protein that is participating in copper transport into the cell (CTR1) depending on the degree of hippocampal neuronal loss; (ii) and lower activity of an enzyme in which copper is part of the active site, cytochrome c oxidase, in sclerotic hippocampi of patients compared to control tissue. In our further investigations it remained to be determined whether changes in copper concentrations and copper metalloproteins are causal to pathology of mTLE or they represent epiphenomenon

Metal maps of sclerotic hippocampi of patients with mesial temporal lobe epilepsy.

The loss of metal homeostasis has been implicated in the pathophysiology of mesial temporal lobe epilepsy associated with hippocampal sclerosis (mTLE-HS). Here we applied laser ablation inductively coupled plasma mass spectrometry imaging to establish the spatial distribution of Zn, Fe, Cu and Mn in coronal sections of hippocampi of four patients with drug-resistant mTLE-HS who underwent amygdalohippocampectomy. Detailed maps of the metal concentrations in the different morphological areas/layers were built and analyzed. The highest level of Zn (>20 μg g(-1)) was found in mossy fiber-rich regions - cornu ammonis field 4 (CA4), gyrus dentatus, and CA3. The distribution of Fe appears to reflect the routes of the main intrahippocampal blood vessels. The highest concentrations of Cu (>10 μg g(-1)) and Mn (>15 μg g(-1)) were observed in regions/layers with neuron somata - subiculum, CA4, gyrus dentatus, and stratum pyramidale (SPy) in CA1 and CA2. Alveus and other regions with axons and dendrites generally showed lower levels of Zn, Cu, and Mn. The Cu concentration was decreased in the areas of total neuronal loss in SPy in CA1 (9.73 ± 0.91 μg g(-1)), compared to the subiculum (13.32 ± 1.29 μg g(-1); p = 0.043). The Cu and Mn concentrations correlated positively with neuron density in the SPy in CA1 (R = 0.629, p < 0.001; and R = 0.391, p = 0.004). These results provide a deeper insight into hippocampal metabolism of metals, and pave the road for identifying the components of the mechanism of epileptogenesis among Cu and Mn transporters and metalloproteins.Metallomics (2017), 9(2): 141-14