Elisabeth Ronne-Engström

Seizure related elevations of extracellular amino acids in human focal epilepsy

Intracerebral microdialysis combined with electrocorticographic recordings was used in a patient subjected to epilepsy surgery. The patient developed a series of partial seizures during an 8 min period. Marked elevations of aspartate (79-fold), glycine (21-fold), glutamate (16-fold) and serine (8-fold) dialysate concentrations occurred in association with onset of the period with seizures. Recurrent seizures occurred, in spite of normalizing amino acid levels. Other amino acids analyzed (aspargine, threonine, arginine, alanine, taurine, tyrosine, phenylalanine, isoleucine and leucine) showed less pronounced changes (1-5 times the basal levels).

Epileptic seizure activity in the acute phase following cortical impact trauma in rat

The aim of this investigation was to determine the incidence of seizure activity in the acute phase following traumatic brain injury. Compression contusion trauma was produced in the right parietal cortex in 19 artificially ventilated rats. Electroencephalographic recordings were carried out in 17 of the animals for 2 h following the impact. The extracellular levels of neuroactive amino acids were simultaneously monitored in 9 of the experiments using microdialysis. In 14 of the 17 animals a generalized seizure activity with an average duration of 59 s (range 30-101 s) was recorded. The mean time lag between trauma and seizure onset was 67 s (range 26-90 s). The seizure activity was consistently followed by post-ictal depression. The trauma was accompanied by a transient increase of aspartate, taurine, glutamate and glycine, in decreasing rank order. The seizure activity occurred when the levels of these neuroactive amino acids were elevated. It is concluded that the high incidence of seizure activity observed may be an important factor contributing to secondary ischemia after traumatic brain injury. Aspartate and glutamate, potentiated by glycine, may play a role in post-traumatic seizure activity.

Intracerebral Microdialysis of Extracellular Amino Acids in the Human Epileptic Focus

Extracellular levels of aspartate (ASP), glutamate (GLU), serine (SER), asparagine (ASN), glycine (GLY), threonine (THR), arginine (ARG), alanine (ALA), taurine (TAU), tyrosine (TYR), phenylalanine (PHE), isoleucine (ILEU), and leucine (LEU) were monitored by using intracerebral microdialysis in seven patients with medically intractable epilepsy, undergoing epilepsy surgery. In association with focal seizures, dramatic increases of the extracellular ASP, GLU, GLY, and SER concentrations were observed. The other amino acids analyzed, including TAU, showed small changes. The results support the hypothesis that ASP, GLU, GLY, and possibly SER, play an important role in the mechanism of seizure activity and seizure-related brain damage in the human epileptic focus.

Continuous monitoring of cerebral metabolism in traumatic brain injury: a focus on cerebral microdialysis.

Purpose of reviewThis review highlights recent advances in cerebral microdialysis as a tool for neurochemical monitoring of patients with traumatic brain injury. Recent findingsProgress in microdialysis research has come from validation studies of microdialysis biomarkers and clinical outcome in large cohorts of traumatic brain injury patients and by combining microdialysis with other methods, such as positron emission tomography, magnetic resonance spectroscopy, brain tissue oximetry and electrophysiology. The combination of rapid-sampling microdialysis and electrocorticography has revealed complex, transient fluctuations of microdialysis glucose and lactate and depolarization-like events that may affect the secondary injury process. The use of microdialysis to monitor global cerebral metabolic events (related to intracranial hypertension or reduced cerebral perfusion pressure for example) as opposed to focal events in peri-lesional brain tissue need to be clearly distinguished and the microdialysis catheter location verified by neuroimaging to ensure proper data interpretation. Differences in microdialysis biomarker levels between grey and white matter following traumatic brain injury need clarification. SummaryMicrodialysis is established as a neurochemical research tool in neurointensive care, particularly in combination with other monitoring methods, and contributes to a growing knowledge of secondary injury mechanisms in traumatic brain injury. The value of microdialysis as a tool in routine neurointensive care decision-making remains unclear.

Monitoring of brain interstitial total tau and beta amyloid proteins by microdialysis in patients with traumatic brain injury.

OBJECT Damage to axons contributes to postinjury disabilities and is commonly observed following traumatic brain injury (TBI). Traumatic brain injury is an important environmental risk factor for the development of Alzheimer disease (AD). In the present feasibility study, the aim was to use intracerebral microdialysis catheters with a high molecular cutoff membrane (100 kD) to harvest interstitial total tau (T-tau) and amyloid beta 1-42 (Abeta42) proteins, which are important biomarkers for axonal injury and for AD, following moderate-to-severe TBI. METHODS Eight patients (5 men and 3 women) were included in the study; 5 of the patients had a focal/mixed TBI and 3 had a diffuse axonal injury (DAI). Following the bedside analysis of the routinely measured energy metabolic markers (that is, glucose, lactate/pyruvate ratio, glycerol, and glutamate), the remaining dialysate was pooled and two 12-hour samples per day were used to analyze T-tau and Abeta42 by enzyme-linked immunosorbent assay from Day 1 up to 8 days postinjury. RESULTS The results show high levels of interstitial T-tau and Abeta42 postinjury. Patients with a predominantly focal lesion had higher interstitial T-tau levels than in the DAI group from Days 1 to 3 postinjury (p < 0.05). In contrast, patients with DAI had consistently higher Abeta42 levels when compared with patients with focal injury. CONCLUSIONS These results suggest that monitoring of interstitial T-tau and Abeta42 by using microdialysis may be an important tool when evaluating the presence and role of axonal injury following TBI.

Consensus statement from the 2014 International Microdialysis Forum

Microdialysis enables the chemistry of the extracellular interstitial space to be monitored. Use of this technique in patients with acute brain injury has increased our understanding of the pathophysiology of several acute neurological disorders. In 2004, a consensus document on the clinical application of cerebral microdialysis was published. Since then, there have been significant advances in the clinical use of microdialysis in neurocritical care. The objective of this review is to report on the International Microdialysis Forum held in Cambridge, UK, in April 2014 and to produce a revised and updated consensus statement about its clinical use including technique, data interpretation, relationship with outcome, role in guiding therapy in neurocritical care and research applications.

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.

Cerebral perfusion pressure between 50 and 60 mmHg may be beneficial in head-injured patients: a computerized secondary insult monitoring study.

OBJECTIVE To describe the occurrence of secondary insults using a computerized monitoring data collecting system and to investigate their relationship to outcome when the neurointensive care was dedicated to avoiding secondary insults. METHODS Patients 16 to 79 years old admitted to the neurointensive care unit between August 1998 and December 2002 with traumatic brain injury and 54 hours or more of valid monitoring within the first 120 hours after trauma (one value/min) were included. Monitoring of intracranial pressure (ICP), cerebral perfusion pressure (CPP), systolic blood pressure (BPs), and mean blood pressure (BPm) was required, and insult levels were defined (ICP >25/>35, BPs <100/<90/>160/>180, BPm <80/<70/>110/>120, and CPP <60/<50/>70/>80 mm Hg). Insults were quantified as proportion of valid monitoring time at the insult level. Logistic regression analyses were performed with admission and secondary insult variables as explanatory variables and favorable outcome as dependent variable. RESULTS Eighty-one patients, 63 men and 18 women, with a mean age of 43.0 years, fulfilled the inclusion criteria. Seventy-two patients (89%) had Glasgow Coma Scale scores of 8 or less. Thirty-one patients (38%) had diffuse injury, and 50 (62%) had mass lesions. Mean Injury Severity Score was 26.6. After 6 months, 54% of the patients had achieved a favorable outcome. Most patients spent 5% or less of the monitoring time at the insult level except for CPP greater than 70 mm Hg. Low age, high Glasgow Coma Scale motor score, low Injury Severity Score, and CPP less than 60 mm Hg insults were significant predictors of favorable outcome in the final multiple logistic regression model. CONCLUSION Overall, the secondary insults were rare, except for high CPP. The results suggest that patients with traumatic brain injury might benefit from a CPP slightly less than 60 mm Hg.

Early cerebral hyperglycolysis after subarachnoid haemorrhage correlates with favourable outcome

Summary. Background: Intracerebral microdialysis (MD) was applied in patients with severe subarachnoid haemorrhage treated in a neurosurgical intensive care unit in order to explore their cerebral energy metabolism. Method: Brain MD fluid levels of glucose, lactate and pyruvate were measured for 3 to 12 days in 20 patients and 2,635 hourly samples were analysed. The MD data were related to computerized tomography and clinical outcome, assessed by the Glasgow Outcome Scale. Findings: The study showed that most patients who made a good recovery had a specific curve pattern when plotting the studied metabolites over time, characterised by a distinct decrease in MD-glucose and a parallel increase in both MD-lactate and pyruvate. Patients who had an unfavourable outcome lacked this distinct curve pattern and exhibited more irregular changes, including increased levels of both MD-glucose and lactate and low MD-pyruvate levels. Interpretation: This exploratory study suggests that accumulation of interstitial lactate and pyruvate, together with decreasing levels of glucose is a favourable prognostic pattern presumably reflecting increased glucose metabolism. Such hyperglycolysis may be elicited in patients with recovery potential to cope with an extreme metabolic demand set in motion by a brain insult to restore brain cell homeostasis and integrity.

Decreased cortical levels of astrocytic glutamate transport protein GLT-1 in a rat model of posttraumatic epilepsy.

The extracellular homeostasis of glutamate in the brain is maintained by the efficient uptake into astroglial cells. The high extracellular glutamate levels seen during seizures are therefore probably a result of both an increased synaptic release and a deranged glutamate uptake. In this study we used immuno-blotting technique to measure the cortical levels of the astrocytic glutamate transport protein (GLT-1) and of the glutamate and aspartate transporting protein (GLAST) in an epilepsy model induced by ferrous chloride injection in the cortex of rats. The levels of GLT-1 were lower in epileptic rats than in controls, day 1 and 5 after induction, but not at 3 months. Glial fibrillary protein (GFAP) levels increased with time in the epileptic model, whereas GLAST and beta-tubulin III remained unchanged compared to controls. The results suggest that the transient decrease of GLT-1 could play a role in epileptogenesis, while recurrent seizure activity may be maintained by other mechanisms.