What predicts survival in glioblastoma? A population-based study of changes in clinical management and outcome.

Background: Glioblastoma is the most common and most aggressive primary brain tumor in adults. Despite multimodal treatment, the median survival time is 15-16 months and 5-year survival rate 5%-10%. The primary goal of this study was to identify prognostic factors for survival in an unselected population of patients operated for glioblastoma. The secondary goal was to explore changes in outcome and the clinical management of this patient group over time. Methods: We identified 222 consecutive adults operated for glioblastoma between November 2012 and June 2016 at the Department of Neurosurgery, Sahlgrenska University Hospital in Gothenburg, serving a health care region in the western part of Sweden with 1.900.000 inhabitants. Clinical variables were identified and tested as predictors for prognosis in extended Poisson regression models. The results were compared with a previously published cohort from 2004 to 2008, before current standard of care based on molecular tumor diagnosis was fully implemented. Results: Median overall survival was 1.07 years, which was significantly longer than in the 2004-2008 cohort (1.07 vs. 0.73 y, age- and sex adjusted HR = 1.89, p < 0.0001). Variables associated with longer survival in the multivariable model were MGMT promoter hypermethylation, non-central tumor location, complete resection of enhancing tumor, WHO performance status 0-1, unilateral tumor location, fewer lobes involved, younger age and no comorbidities. Conclusion: The median survival for patients with glioblastoma treated according to current standard treatment has moderately but significantly increased, with MGMT promoter hypermethylation as the strongest predictor for survival.

Prognostic factors for glioblastoma patients--a clinical population-based study.

OBJECTIVES: To address in a retrospective and population-based study prognostic factors for survival time after diagnosis and surgery for glioblastoma multiforme (GBM). MATERIAL AND METHODS: During the study period, 430 patients were identified at the multidisciplinary team conferences as newly diagnosed GBM, 201 of these were considered not to benefit from surgery, and thus, a total of 229 consecutive adult patients with GBM were operated between January 2004 and December 2008 at Sahlgrenska University Hospital and were retrospectively analyzed. Potential predictors of survival were statistically analyzed using Poisson regression models. RESULTS: Median survival was 0.73 years. Multivariable analysis showed the following factors to positively influence survival: younger age at surgery, secondary tumor genesis, unifocal tumor location (vs multifocal), resection (vs biopsy only), radiotherapy, and combination of radiotherapy and chemotherapy. CONCLUSION: This population-based study supports the importance of surgery instead of biopsy only, followed by radiotherapy and chemotherapy, a finding which has also been stated in earlier non-population-based reports. However, it is obvious that the solution is not just surgical radicality followed by optimal oncological treatment. It is of great importance to seek further subclassifications, biomarkers, and new treatment modalities to make a significant change in survival for individuals.

High-Sensitive Troponin T and N-Terminal Pro B-Type Natriuretic Peptide for Early Detection of Stress-Induced Cardiomyopathy in Patients with Subarachnoid Hemorrhage.

BACKGROUND: Patients developing stress-induced cardiomyopathy (SIC) after subarachnoid hemorrhage (SAH) have increased risk of vasospasm, delayed cerebral ischemia and death. We evaluated whether high-sensitive troponin T (hsTnT) and N-terminal pro B-type natriuretic peptide (NTproBNP) are useful biomarkers for early detection of SIC after SAH. METHODS: Medical records of all patients admitted to our NICU with suspected or verified SAH from January 2010 to August 2014 were reviewed. Patients in whom echocardiography was performed and blood samples for measurements of hsTnT and/or NTproBNP were obtained, within 72 and 48 h, respectively, after onset of symptoms, were included. SIC was defined as reversible left ventricular segmental hypokinesia diagnosed by echocardiography. RESULTS: A total of 502 SAH patients were admitted during the study period, 112 patients fulfilled inclusion criteria and 25 patients fulfilled SIC criteria. Peak levels of hsTnT and NTproBNP were higher in patients with SIC (p < 0.001). hsTnT had its peak on admission, while NTproBNP peaked at days 2-4 after onset of symptoms. A hsTnT > 89 ng/l or a NTproBNP > 2,615 ng/l obtained within 48 h after onset of symptoms had a sensitivity of 100% and a specificity of 79% in detecting SIC. CONCLUSIONS: The cardiac biomarkers, hsTnT and NTproBNP, are increased early after SAH and levels are considerably higher in patients with SIC. These biomarkers are useful for screening of SIC, which could make earlier diagnosis and treatment of SIC in SAH patients possible.

Plateau waves and baroreflex sensitivity in patients with head injury: a case study.

The study aimed to investigate baroreceptor reflex sensitivity in a patient with head injury for whom plateau waves of intracranial pressure (ICP) were recorded. Baroreflex sensitivity index was separately estimated on top of plateau waves and during intermediate intervals between two consecutive waves. The EuroBaVar data set was utilized to verify and validate the results. A very high baroreflex sensitivity associated with dominant parasympathetic activity was observed spontaneous to the acute elevations of ICP. The high vagal afferent discharge was found to be suggestive for the high firing rate of carotid baroreceptors and probably an active Cushing reflex mechanism during plateau waves.

Pulse wave velocity in patients with severe head injury a pilot study.

The study aimed to determine the potential of pulse wave velocity measurements to reflect changes in compliant cerebral arteries/arterioles in head injured patients. The approach utilizes the electrocardiogram and intracranial pressure signals to measure the wave transit time between heart and cranial cavity. Thirty five clinical records of nineteen head injured patients, with different levels of cerebrovascular pressure-reactivity response, were investigated through the study. Results were compared with magnitude of normalized transfer function at the fundamental cardiac frequency. In patients with intact cerebrovascular pressure-reactivity, magnitude of normalized transfer function at the fundamental cardiac component was found to be highly correlated with pulse wave transit time.

Normalized power transmission between ABP and ICP in TBI.

A new approach to study the pulse transmission between the cerebrovascular bed and the intracranial space is presented. In the proposed approach, the normalized power transmission between ABP and ICP has got the main attention rather than the actual power transmission. Evaluating the gain of the proposed transfer function at any single frequency can reveal how the percentage of contribution of that specific frequency component has been changed through the cerebrospinal system. The gain of the new transfer function at the fundamental cardiac frequency was utilized to evaluate the state of the brain in three TBI patients. Results were assessed using the reference evaluations achieved by a novel CT scan-based scoring scheme. In all three study cases, the gain of the transfer function showed a good capability to follow the trend of the CT scores and describe the brain state. Comparing the new transfer function with the traditional one and also the index of compensatory reserve, the proposed transfer function was found more informative about the state of the brain in the patients under study.

Retinoids and activation of PKC induce tissue-type plasminogen activator expression and storage in human astrocytes.

BACKGROUND: Emerging data demonstrate important roles for tissue-type plasminogen activator (t-PA) in the central nervous system (CNS). In contrast to endothelial cells, little is known about the regulation of t-PA gene expression and secretion in astrocytes. OBJECTIVES: The aims of the present study were to investigate whether t-PA gene expression is regulated by retinoids and the protein kinase C (PKC) activator phorbol 12-myristate 13-acetate (PMA) in human astrocytes, and to study whether t-PA is stored and subject to regulated release from these cells, as with endothelial cells. METHODS: Native human astrocytes were treated with RA and/or PMA. mRNA was quantified by real-time RT-PCR and protein secretion determined by ELISA. Intracellular t-PA immunoreactivity in astrocytes was examined by immunocyto- and histochemistry. RESULTS: RA and/or PMA induced a time-dependent increase in t-PA mRNA and protein levels in astrocytes, reaching 10-fold after combined treatment. This was associated with increased amounts of t-PA storage in intracellular granular structures. Both forskolin and histamine induced regulated release of t-PA. The presence of t-PA in reactive astrocytes was confirmed in human brain tissue. CONCLUSIONS: These data show that RA and PKC activation induce a strong up-regulation of t-PA expression in astrocytes, and increased intracellular storage pools. Moreover, a regulated release of t-PA can be induced from these cells. This raises the possibility that astrocytes contribute to the regulation of extracellular t-PA levels in the CNS.

Health status and life satisfaction after decompressive craniectomy for malignant middle cerebral artery infarction.

OBJECTIVES: To study the long-term outcome in patients with malignant middle cerebral artery (MCA) infarction treated with decompressive craniectomy. The outcome is described in terms of survival, impairment, disabilities and life satisfaction. MATERIALS AND METHODS: Patients were examined at a minimum of 1 year (mean 2.9, range 1-6) after the surgery and classified according to the Glasgow Outcome Scale (GOS), the National Institutes of Health Stroke scale (NIHSS), the Barthel Index (BI), the short-form health survey (SF-36) and the life satisfaction checklist (LiSat-11). RESULTS: Eighteen patients were included. The long-term survival was 78%. The mean NIHSS score was 13.8 (range 6-20). No patient was left in a vegetative state. The mean BI was 63.9 (5-100). The SF-36 scores showed that the patients' view of their health was significantly lower in most items compared with that of a reference group. According to the LiSat checklist, 83% found their life satisfying/rather satisfying and 17% found their life rather dissatisfying/dissatisfying. CONCLUSION: We conclude that the patients remained in an impaired neurological condition, but had fairly good insight into their limitations. Although their life satisfaction was lower compared with that of the controls, the majority felt that life in general could still be satisfying.

Long-term follow-up of a patient with traumatic brain injury using diffusion tensor imaging.

This case report describes a patient who sustained severe head trauma with diffuse axonal injury (DAI). Examination with magnetic resonance diffusion tensor imaging (MRDTI), 6 days post-injury, showed a severe reduction in fractional anisotropy (FA) in the rostral pons containing the corticospinal tract, which correlated to the patient's severe hemiparesis. By 18 months post-accident, the patient had recovered completely and conventional MRI showed no pathology. However, although her FA values in the rostral pons had increased, they were still not normalized. It seems that a complete normalization of the FA values is not required to achieve clinical recovery, and that MR-DTI seems to be more sensitive to DAI compared to conventional MRI.

Outcome after severe brain damage, what makes the difference?

OBJECTIVE: To assess and compare the consequences for outcome in terms of the dimensions of activity and participation for two groups: group A, which received early formalized rehabilitation, and group B, which received late or no formalized rehabilitation. RESEARCH DESIGN: A cross-sectional study. PROCEDURE: Twenty-six patients (A: n = 14 and B: n = 12) with severe brain damage were included. The participants were assessed a mean of 26.6 months (SD 7.1, median 25, range 14-41) after the incident using the structured form for the Swedish Neuro database, the Glasgow Outcome Scale (GOS), the Extended Glasgow Outcome Scale (GOSE) and the Functional Independence Measure (FIM). RESULTS: The study reveals a better outcome for group A. No patient remained in a vegetative state in group A as compared with three in group B. In group A, 50% were independent as compared with 17% in group B. The frequency of return to work was 43% in group A, but no patient in group B had returned to work.

Parenchymal lesions in pharmacoresistant temporal lobe epilepsy: dual and multiple pathology.

OBJECTIVES: Dual pathology is reported in 5-30% of temporal lobe resections performed in pharmacoresistant epilepsy. Dual pathology may be of importance for surgical planning and also for the understanding of the pathogenesis of epilepsy. We describe the frequency of dual or multiple pathology, i.e. more than one histopathological diagnosis, in adults with temporal lobe resections. MATERIAL AND METHODS: Surgical specimens from 33 consecutive patients with resections including mesial as well as neocortical temporal structures were reviewed. All histopathological findings were recorded. Post-mortem specimens from 11 control subjects were also reviewed. RESULTS: Dual or multiple pathology was found in almost half of the epilepsy patients (48%). Hippocampal sclerosis was found in 25 patients (76%), malformations of cortical development in 15 (46%), of which 12 (36%) were microdysgenesis, and low-grade tumours in seven (21%). Apart from mild gliosis, there were no histopathological changes in the control specimens. CONCLUSION: Dual or multiple pathology was a common finding in this group of adults with temporal lobe resections. In order to increase our understanding of how aetiological factors may combine in the development of seizures, we consider it relevant and important to report all histopathological findings in epilepsy surgery series.

Visual field defects after temporal lobectomy -- comparing methods and analysing resection size.

OBJECTIVES: The frequency of visual field defects (VFD) after temporal lobe resections (TLR) was compared for two types of TLR and VFD frequency was correlated to resection size. METHODS: Pre- and post-operative perimetry results were analysed for 50 patients with TLR for medically intractable epilepsy. Thirty-three patients had a classical TLR and 17 had a TLR with less lateral extension. Post-operative MRIs were studied in 34 patients by scoring resection size in 12 compartments in the temporal lobe. RESULTS: Twenty-five patients developed a VFD. In the classical TLR group, 16 of 33 developed a VFD, compared with nine of 17 in the other group. The resection points were higher for the VFD group in the most anterior compartment studied, in the superior temporal gyrus. CONCLUSIONS: There was no clearcut difference in VFD frequency between the surgical methods studied. However, the compartmentalized analysis disclosed a relation between the extent of resection in the anterior part of the superior temporal gyrus and VFD frequency.

Herpesviral DNA in brain tissue from patients with temporal lobe epilepsy.

OBJECTIVES: Presence of DNA from six herpesviruses were examined in brain tissue from patients operated for temporal lobe epilepsy. MATERIAL AND METHODS: A total of 19 Canadian patients (I) with a median age of 22 years, 17 Swedish patients (II) with a median age of 14 years and a reference group comprising 12 individuals were studied. Presence of herpesviral DNA was detected by nested polymerase chain reaction. RESULTS: Of three children with Rasmussen's encephalitis, Cytomegalovirus (CMV) DNA was found in two, and human herpesvirus type 6 DNA in two. In six children with ganglioglioma, Epstein-Barr virus (EBV) was detected in four. CMV DNA was found significantly more in group I compared with II, while the reverse occurred with EBV DNA. Malformations of cortical development were found significantly more in group II compared with I. CONCLUSION: Detection of DNA from some herpesviruses in epileptic brain tissue may possibly be associated with distinct clinical conditions, but factors such as age and malformations of cortical development should also be considered.

Sympathetic nervous activation following subarachnoid hemorrhage: Influence of intravenous clonidine.

BACKGROUND: Subarachnoid hemorrhage is often accompanied by systemic complications and cerebral vasospasm. Elevated levels of circulating catecholamines may be involved in the pathophysiology behind these events. The alpha-2-agonist clonidine inhibits sympathetic outflow by a central mechanism. Unrestricted sympathoexcitation may be detrimental and administration of clonidine may be beneficial in these patients. METHODS: Using isotope dilution methodology, norepinephrine kinetic determinations, comprising determination of arterial norepinephrine concentration and rates of norepinephrine spillover to and removal, or clearance, from plasma, were performed on three occasions during the first week after subarachnoid hemorrhage in 25 patients. Eleven of these patients received clonidine (continuous i.v. infusion 5.8 +/- 0.7 microg x kg(-1) x 24 h(-1)) and the remainder, standard therapy. Initial results were compared with 17 healthy age-matched subjects and eight patients suffering from severe traumatic brain injury without traumatic subarachnoid hemorrhage. RESULTS: Subarachnoid hemorrhage patients exhibited markedly elevated arterial plasma norepinephrine concentrations [3.74 +/- 0.48, P < 0.001 vs. healthy subjects (1.59 +/- 0.11 nmol/L) and P < 0.05 vs. head trauma patients (1.94 +/- 0.29 nmol/L)]. The rate of clearance of norepinephrine from plasma in the subarachnoid patients was also significantly greater than that observed in the healthy subjects (2.66 +/- 0.15 vs. 2.14 +/- 0.15 L/min, P < 0.05) and the head trauma patients (2.00 +/- 0.12 L/min, P < 0.05). Compared with both control groups, on admission the rate of spillover of norepinephrine to plasma following subarachnoid hemorrhage was markedly elevated (9.11 +/- 1.12, P < 0.001). Clonidine treatment (continuous i.v. infusion 5.8 +/- 0.7 microg x kg(-1) x 24 h(-1)) did not reduce the increased rate of spillover of norepinephrine to plasma following subarachnoid hemorrhage. CONCLUSION: Sympathetic nervous activity is markedly elevated following subarachnoid bleeding. Clonidine had no effect on the rate of norepinephrine spillover to, or clearance from, plasma in these patients. Clearly, further studies are required to elucidate the mechanisms responsible for generating sympathetic nervous activation following subarachnoid hemorrhage.

Widespread microdysgenesis in therapy-resistant epilepsy--a case report on post-mortem findings.

Microdysgenesis is a subtle malformation, which is often found in specimens from epilepsy surgery. It is, however, not clear whether the changes are focal or diffuse. A recent autopsy case offered an opportunity to investigate whether microdysgenesis found after temporal lobe surgery was focal or widespread in the brain. The entire brain of a 20-year-old patient who died suddenly and unexpectedly was examined histologically. Microdysgenesis had previously been diagnosed after a left temporal lobectomy performed because of therapy-resistant seizures. A light microscopic examination was performed on specimens stained with Luxol-fast blue-cresyl violet and polyclonal antibodies to glial fibrillary acidic protein. Widespread microdysgenesis with irregular nerve cell distribution in the cortex and an increased number of nerve cells in cortical layer I and in the white matter was found in the right temporal and parietal lobes and bilaterally in the frontal and occipital lobes. The post-mortem examination confirmed the previous diagnosis of microdysgenesis and showed that the changes were widespread in a patient who was operated on because of focal epilepsy.

Complications of epilepsy surgery after 654 procedures in Sweden, September 1990-1995: a multicenter study based on the Swedish National Epilepsy Surgery Register.

OBJECTIVE: To present the first national multicenter study on complications after epilepsy surgery procedures to include all epilepsy surgery centers in Sweden: Göteborg, Linköping, Lund, Stockholm, Umeå, and Uppsala. METHODS: Every epilepsy surgery procedure in Sweden is reported to the Swedish National Epilepsy Surgery Register. The report includes relevant social and medical items and complications. A complication is defined as minor if it resolves within 3 months and major if it affects activities of daily living and lasts longer than 3 months. Follow-up data are recorded for 2 years after the operation. Intrinsic checkpoints and external revision validate the register data. RESULTS: During the inclusion period (September 1990-December 1995), 654 surgical procedures were performed (age range, 6 mo-67 yr). Of these, 205 were invasive electrode procedures (182 first investigations and 23 reinvestigations), and 449 were therapeutic procedures (375 first operations and 74 reoperations). After invasive electrode procedures, only minor complications were reported (6.3%). For all 449 therapeutic procedures (including reoperations), minor complications were reported in 8.9% and major complications in 3.1 %. Only one major complication was reported in a patient under the age of 35 years. CONCLUSION: This is the first national multicenter study on complications after epilepsy surgery. It demonstrates that these procedures as performed at six different centers in Sweden are safe, but also that risk is related to age. In patients younger than age 35 years, the risk for a major complication after invasive subdural strip electrode investigation and epilepsy surgery is low.

[Well-integrated chain of care results in better prognosis in severe brain injury]. / Sammanhållen vårdkedja ger bättre prognos vid svår hjärnskada.

The result of a project in the western region of Sweden regarding a multi- and interdisciplinary approach to patients with severe traumatic brain injury/subarachnoid bleeding is reported. The importance of early structured intervention and long-range follow-up by a rehabilitation team is stressed. The goal is to afford patients and their families/caregivers optimal care and support from the time of injury through rehabilitation. The project has resulted in an established clinical routine. Results indicate that patients treated in this manner attain a higher level of performance in a shorter period of time. Furthermore, results from one-year post-injury evaluation demonstrate a high degree of Life Satisfaction (Fugl-Meyer questionnaire) for most patients. This is a long-range study which will monitor patients for at least four years.

Increased sympathetic nervous activity in patients with nontraumatic subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: Activation of the sympathetic nervous system, which leads to elevation of circulating catecholamines, is implicated in the genesis of cerebral vasospasm and cardiac aberrations after subarachnoid hemorrhage. To this juncture, sympathetic nervous testing has relied on indirect methods only. METHODS: We used an isotope dilution technique to estimate the magnitude and time course of sympathoadrenal activation in 18 subarachnoid patients. RESULTS: Compared with 2 different control groups, the patients with subarachnoid hemorrhage exhibited an approximately 3-fold increase in total-body norepinephrine spillover into plasma within 48 hours after insult (3.2+/-0.3 and 4.2+/-0.7 versus 10.2+/-1.4 nmol/L; P<0.05 versus both). This sympathetic activation persisted throughout the 7- to 10-day examination period and was normalized at the 6-month follow-up visit. CONCLUSIONS: The present study has established that massive sympathetic nervous activation occurs in patients after subarachnoid hemorrhage. This overactivation may relate to the well-known cardiac complications described in subarachnoid hemorrhage.

Microdysgenesis in surgical specimens from patients with epilepsy: occurrence and clinical correlations.

Malformations of cortical development are commonly associated with epilepsy. In the first 139 consecutive patients in the Göteborg epilepsy surgery series, parenchymal malformations were found in 56. 1% of the children and in 23.1% of the adults. Microdysgenesis (MDG), which was the most common parenchymal malformation, was found in 35. 1% of the children and in 16.7% of the adults. The aim of this study was to identify clinical characteristics of patients with MDG. Mental retardation was found to be significantly more common in patients with major parenchymal malformations and in patients with MDG compared with patients without parenchymal malformations. Patients with major parenchymal malformations as well as patients with MDG also had a significantly earlier onset of seizures than patients without parenchymal malformations, also when adjusting for mental retardation. Patients with MDG were in these clinical aspects shown to closely resemble patients with major malformations. These findings suggest that MDG is a pathoanatomical entity of clinical relevance, with implications both in mental retardation and in epileptogenesis.