Maria Zetterling

Cerebral glutamine and glutamate levels in relation to compromised energy metabolism : a microdialysis study in subarachnoid hemorrhage patients

Astrocytic glutamate (Glt) uptake keeps brain interstitial Glt levels low. Within the astrocytes Glt is converted to glutamine (Gln), which is released and reconverted to Glt in neurons. The Glt–Gln cycle is energy demanding and impaired energy metabolism has been suggested to cause low interstitial Gln/Glt ratios. Using microdialysis (MD) measurements from visually noninjured cortex in 33 neurointensive care patients with subarachnoid hemorrhage, we have determined how interstitial Glt and Gln, as a reflection of the Glt–Gln cycle turnover, relate to perturbed energy metabolism. A total of 3703 hourly samples were analyzed. The lactate/pyruvate (L/P) ratios correlated to the Gln/Glt ratios (r = −0.66), but this correlation was not stronger than the correlation between L/P and Glt (r = 0.68) or the correlation between lactate and Glt (r = 0.65). A novel observation was a linear relationship between interstitial pyruvate and Gln (r = 0.52). There were 13 periods (404 h) of ‘energy crisis’, defined by L/P ratios above 40. All were associated with high interstitial Glt levels. Periods with L/P ratios above 40 and low pyruvate levels were associated with decreased interstitial Gln levels, suggesting ischemia and failing astrocytic Gln synthesis. Periods with L/P ratios above 40 and normal or high pyruvate levels were associated with increased interstitial Gln levels, which may represent an astrocytic hyperglycolytic response to high interstitial Glt levels. The results imply that moderately elevated L/P ratios cannot always be interpreted as failing energy metabolism and that interstitial pyruvate levels may discriminate whether or not there is sufficient astrocytic capacity for Glt–Gln cycling in the brain.

Depression and post-traumatic stress disorder after aneurysmal subarachnoid haemorrhage in relation to lifetime psychiatric morbidity

Introduction. Little is known about the roles that lifetime psychiatric disorders play in psychiatric and vocational outcomes of aneurysmal subarachnoid haemorrhage (SAH). Materials and methods. Eighty-three SAH patients without apparent cognitive dysfunction were assessed using the Structured Clinical Interview for DSM-IV axis I disorders (SCID-I) after their SAH. Diagnoses were assessed for three time periods, ‘lifetime before SAH’, ‘12 months before SAH’ and ‘7 months after SAH’. Results. Forty-five percentage of patients with SAH reported at least one lifetime psychiatric disorder. After SAH, symptoms of depression and/or post-traumatic stress disorder (PTSD) were seen in 41%, more often in those with a psychiatric history prior to SAH (p = 0.001). In logistic regressions, depression after SAH was associated with a lifetime history of major depression, or of anxiety or substance use disorder, as well as with lifetime psychiatric comorbidity. Subsyndromal or full PTSD was predicted by a lifetime history of major depression. After the SAH, 18 patients (22%) had received psychotropic medication and/or psychological treatment, 13 of whom had a disorder. Those with a lifetime history of major depression or treatment with antidepressants before SAH had lower return to work rates than others (p = 0.019 and p = 0.031, respectively). This was also true for those with symptoms of depression and/or PTSD, or with antidepressant treatment after SAH (p = 0.001 and p = 0.031, respectively). Conclusions. Depression and PTSD are present in a substantial proportion of patients 7 months after SAH. Those with a history of psychiatric morbidity, any time before the SAH, are more at risk and also constitute a risk group for difficulties in returning to work.

Brain energy metabolism in patients with spontaneous subarachnoid hemorrhage and global cerebral edema

BACKGROUNDPrevious studies of spontaneous subarachnoid hemorrhage (SAH) have shown that global cerebral edema on the first computed tomography scan is associated with a more severe initial injury and is an independent predictor of poor outcome. Effects of secondary ischemic events also influence outcome after SAH. OBJECTIVEThis study demonstrates that early global edema is related to markers of an increased cerebral energy metabolism as measured with intracerebral microdialysis, which could increase vulnerability to adverse events. METHODSFifty-two patients with microdialysis monitoring after spontaneous SAH were stratified according to the occurrence of global cerebral edema on the first computed tomography scan taken a median of 2 hours after the initial bleed. Microdialysis levels of glucose, lactate, and pyruvate were compared between the global edema (n = 31) and no global edema (n = 21) groups. Clinical outcome was assessed with the Glasgow Outcome Scale score at ≥ 6 months. RESULTSPatients with global edema showed significantly elevated lactate and pyruvate levels 70 to 79 hours after SAH and marginally significantly higher levels of lactate 60 to 69 hours and 80 to 89 hours after SAH. There was a trend toward worse outcome in the edema group. CONCLUSIONPatients with global cerebral edema have higher interstitial levels of lactate and pyruvate. The edema group may have developed a cerebral hypermetabolism to meet the increased energy demand in the recovery phase after SAH. This stress would make the brain more vulnerable to secondary insults, increasing the likelihood of energy failure.

Extension of diffuse low-grade gliomas beyond radiological borders as shown by the coregistration of histopathological and magnetic resonance imaging data

OBJECTIVE Magnetic resonance imaging tends to underestimate the extent of diffuse low-grade gliomas (DLGGs). With the aim of studying the presence of tumor cells outside the radiological border, the authors developed a method of correlating MRI findings with histological data in patients with suspected DLGGs in whom en bloc resections were performed. METHODS Five patients with suspected DLGG suitable for en bloc resection were recruited from an ongoing prospective study. Sections of the entire tumor were immunostained with antibodies against mutated IDH1 protein (IDH1-R132H). Magnetic resonance images were coregistered with corresponding IDH1 images. The growth pattern of tumor cells in white and gray matter was assessed in comparison with signal changes on corresponding MRI slices. RESULTS Neuropathological assessment revealed DLGG in 4 patients and progression to WHO Grade III glioma in 1 patient. The tumor core consisted of a high density of IDH1-R132H-positive tumor cells and was located in both gray and white matter. Tumor cells infiltrated along the peripheral fibers of the white matter tracts. In all cases, tumor cells were found outside the radiological tumor border delineated on T2-FLAIR MRI sequences. CONCLUSIONS The authors present a new method for the coregistration of histological and radiological characteristics of en bloc-removed infiltrative brain tumors that discloses tumor invasion at the radiological tumor borders. This technique can be applied to evaluate the sensitivity of alternative imaging methods to detect scattered tumor cells at tumor borders. Accurate methods for detection of infiltrative tumor cells will improve the possibility of performing radical tumor resection. In future studies, the method could also be used for in vivo studies of tumor invasion.

High intraoperative blood loss may be a risk factor for postoperative hematoma.

Summary: The authors studied the incidence of postoperative intracranial hematoma to improve care after intracranial surgery. Five years (1995–1999) of surgical records were analyzed retrospectively. Patients were included if evacuation of an intracranial postoperative hematoma was reported. A control group was randomly selected. Forty-nine patients (0.8%) had postoperative hematomas requiring evacuation. The amount of intraoperative blood loss was significantly larger in the hematoma group (762 ± 735 mL [median 500 mL]) than in the control group (415 ± 403 mL; median 300 mL) (P = 0.004). Clinical deterioration occurred within the first 24 hours in 80%, within 6 hours in 51%, and within 1 hour in 12% of the patients. Those who deteriorated within 24 hours had a faster and more life-threatening deterioration than those who had a hematoma after 24 hours. A decreased level of consciousness was found in 61% and increased focal neurologic signs were found in 33% of the patients. An elevated intracranial pressure was seen significantly more often in the hematoma group (9/10 patients, 90%) than in the control group (1/8 patients, 12.5%) (P = 0.001). In this study, a large amount of intraoperative blood loss and elevated intracranial pressure were warning signs of postoperative hematoma and should alert the clinician to the increased risk. Most hematomas occurred within 24 hours after surgery, and in this time period the deterioration was more severe compared with the hematomas that occurred later.

Relation between brain interstitial and systemic glucose concentrations after subarachnoid hemorrhage

OBJECT The aim in the present investigation was to study the relation between brain interstitial and systemic blood glucose concentrations during the acute phase after subarachnoid hemorrhage (SAH). The authors also evaluated the effects of insulin administration on local brain energy metabolism. METHODS Nineteen patients with spontaneous SAH were prospectively monitored with intracerebral microdialysis (MD). The relation between plasma glucose and MD-measured interstitial brain glucose concentrations as well as the temporal pattern of MD glucose, lactate, pyruvate, glutamate, and glycerol was studied for 7 days after SAH. Using a target plasma glucose concentration of 5-10 mmol/L, the effect of insulin injection was also evaluated. RESULTS The mean (± SD) correlation coefficient between plasma glucose and MD glucose was 0.27 ± 0.27 (p = 0.0005), with a high degree of individual variation. Microdialysis glucose, the MD/plasma glucose ratio, and MD glutamate concentrations decreased in parallel with a gradual increase in MD pyruvate and MD lactate concentrations. There were no significant changes in the MD L/P ratio or MD glycerol levels. Insulin administration induced a decrease in MD glucose and MD pyruvate. CONCLUSIONS After SAH, there was a positive correlation between plasma and MD glucose concentrations with a high degree of individual variation. A gradual decline in MD glucose and the MD/plasma glucose ratio and an increase in MD pyruvate and MD lactate concentrations during the 1st week after SAH suggest a transition to a hyperglycolytic state with increased cerebral glucose consumption. The administration of insulin was related to a lowering of MD glucose and MD pyruvate, often to low levels even though plasma glucose values remained above 6 mmol/L. After SAH, the administration of insulin could impede the glucose supply of the brain.

Human Cytomegalovirus Tegument Protein pp65 Is Detected in All Intra- and Extra-Axial Brain Tumours Independent of the Tumour Type or Grade

Human cytomegalovirus (HCMV) has been indicated being a significant oncomodulator. Recent reports have suggested that an antiviral treatment alters the outcome of a glioblastoma. We analysed the performance of commercial HCMV-antibodies applying the immunohistochemical (IHC) methods on brain sample obtained from a subject with a verified HCMV infection, on samples obtained from 14 control subjects, and on a tissue microarray block containing cores of various brain tumours. Based on these trials, we selected the best performing antibody and analysed a cohort of 417 extra- and intra-axial brain tumours such as gliomas, medulloblastomas, primary diffuse large B-cell lymphomas, and meningiomas. HCMV protein pp65 immunoreactivity was observed in all types of tumours analysed, and the IHC expression did not depend on the patients age, gender, tumour type, or grade. The labelling pattern observed in the tumours differed from the labelling pattern observed in the tissue with an active HCMV infection. The HCMV protein was expressed in up to 90% of all the tumours investigated. Our results are in accordance with previous reports regarding the HCMV protein expression in glioblastomas and medulloblastomas. In addition, the HCMV protein expression was seen in primary brain lymphomas, low-grade gliomas, and in meningiomas. Our results indicate that the HCMV protein pp65 expression is common in intra- and extra-axial brain tumours. Thus, the assessment of the HCMV expression in tumours of various origins and pathologically altered tissue in conditions such as inflammation, infection, and even degeneration should certainly be facilitated.

Cortisol and adrenocorticotropic hormone dynamics in the acute phase of subarachnoid haemorrhage

Abstract Objective. An adequate response of hypothalamic–pituitary–adrenal (HPA) axis is important for survival and recovery after a severe disease. The hypothalamus and the pituitary glands are at risk of damage after subarachnoid haemorrhage (SAH). A better understanding of the hormonal changes would be valuable for optimising care in the acute phase of SAH. Patients. Fifty-five patients with spontaneous SAH were evaluated regarding morning concentrations of serum (S)-cortisol and P-adrenocorticotropic hormone (ACTH) 7 days after the bleeding. In a subgroup of 20 patients, the diurnal changes of S-cortisol and P-ACTH were studied and urine (U)-cortisol was measured. The relationships of hormone concentrations to clinical and radiological parameters and to outcome were assessed. Results. S-cortisol and P-ACTH were elevated the day of SAH. S-cortisol concentrations below reference range were uncommon. Early global cerebral oedema was associated with higher S-cortisol concentrations at admission and a worse World Federation of Neurological Surgeons (WFNS) and Reaction Level Scale 85 grade. Global cerebral oedema was shown to be a predictor of S-cortisol at admittance. Patients in better WFNS grade displayed higher U-cortisol. All patients showed diurnal variations of S-cortisol and P-ACTH. A reversed diurnal variation of S-cortisol was more frequently found in mechanically ventilated patients. Periods of suppressed P-ACTH associated with S-cortisol peaks occurred especially in periods of secondary brain ischaemia. Conclusion. There was an HPA response acutely after SAH with an increase in P-ACTH and S-cortisol. Higher U-cortisol in patients in a better clinical grade may indicate a more robust response of the HPA system. Global cerebral oedema was associated with higher S-cortisol at admission and was a predictor of S-cortisol concentrations. Global cerebral oedema may be the result of the stress response initiated by the brain injury. Periods of suppressed P-ACTH occurred particularly in periods of brain ischaemia, indicating a possible connection between brain ischaemia and ACTH suppression.

Survey on current cognitive practices within the European Low-Grade Glioma Network: towards a European assessment protocol

BackgroundThe European Low-Grade Glioma network indicated a need to better understand common practices regarding the managing of diffuse low-grade gliomas. This area has experienced great advances in recent years.MethodA general survey on the managing of diffuse low-grade gliomas was answered by 21 centres in 11 European countries. Here we focused on specific questions regarding perioperative and intraoperative cognitive assessments.ResultsMore centres referred to the same speech and language therapist and/or neuropsychologist across all assessments; a core of assessment tools was routinely used across centres; fluency tasks were commonly used in the perioperative stages, and object naming during surgery; tasks that tapped on attention, executive functions, visuospatial awareness, calculation and emotions were sparsely administered; preoperative assessments were performed 1 month or 1 week before surgery; timing for postoperative assessments varied; finally, more centres recommended early rehabilitation, whenever needed.ConclusionsThere is an emerging trend towards following similar practices for the management of low-grade gliomas in Europe. Our results are descriptive and formalise current discussions in our group. Also, they contribute towards the development of a European assessment protocol.

Neurological Impairment Linked with Cortico-Subcortical Infiltration of Diffuse Low-Grade Gliomas at Initial Diagnosis Supports Early Brain Plasticity.

Diffuse low-grade gliomas (DLGG) are slow-growing brain tumors that in spite of an indolent behavior at onset show a continuous expansion over time and inevitably transform into malignant gliomas. Extensive tumor resections may be performed with preservation of neurological function due to neuroplasticity that is induced by the slow tumor growth. However, DLGG prefer to migrate along subcortical pathways, and white matter plasticity is considerably more limited than gray matter plasticity. Whether signs of functional decompensating white matter that may be found as early as at disease presentation has not been systematically studied. Here, we examined 52 patients who presented with a DLGG at the time of radiological diagnosis. We found a significant correlation between neurological impairment and eloquent cortico-subcortical tumor localization, but not between neurological function and tumor volume. These results suggest that even small tumors invading white matter pathways may lack compensatory mechanisms for functional reorganization already at disease presentation.