Daniel N. Hertle

Clusters of Spreading Depolarizations Are Associated With Disturbed Cerebral Metabolism in Patients With Aneurysmal Subarachnoid Hemorrhage

Background and Purpose— We studied the dynamics of extracellular brain tissue concentrations of glucose, lactate, pyruvate, and glutamate during the occurrence of spreading depolarizations (SDs) in patients with aneurysmal subarachnoid hemorrhage. Methods— In this prospective observational study, patients with aneurysmal subarachnoid hemorrhage received multimodal cerebral monitoring, including intracranial pressure, cerebral microdialysis, and subdural electrocorticography. Results— Seven of the 17 recruited patients had intracerebral hemorrhage, acute ischemia and severe brain oedema leading to acute ischemic neurological deficits associated with early disturbance of metabolism at the recording site. They displayed a total of 130 SDs. The remaining 10 patients without acute ischemic neurological deficits exhibited 138 single SDs and 68 SDs in clusters. In patients without acute ischemic neurological deficits, clustered SDs were associated with a significant transient decrease in glucose and increase in lactate compared with baseline during the first 140 minutes after SDs. Moreover, the number of clustered SDs correlated with the outcome (R=−0.659; P<0.01). Conclusion— SDs can propagate in nonischemic human brain tissue. Clusters of SDs are related to metabolic changes suggestive of ongoing secondary damage in primarily nonischemic brain tissue.

Recording, analysis, and interpretation of spreading depolarizations in neurointensive care: Review and recommendations of the COSBID research group

Spreading depolarizations (SD) are waves of abrupt, near-complete breakdown of neuronal transmembrane ion gradients, are the largest possible pathophysiologic disruption of viable cerebral gray matter, and are a crucial mechanism of lesion development. Spreading depolarizations are increasingly recorded during multimodal neuromonitoring in neurocritical care as a causal biomarker providing a diagnostic summary measure of metabolic failure and excitotoxic injury. Focal ischemia causes spreading depolarization within minutes. Further spreading depolarizations arise for hours to days due to energy supply-demand mismatch in viable tissue. Spreading depolarizations exacerbate neuronal injury through prolonged ionic breakdown and spreading depolarization-related hypoperfusion (spreading ischemia). Local duration of the depolarization indicates local tissue energy status and risk of injury. Regional electrocorticographic monitoring affords even remote detection of injury because spreading depolarizations propagate widely from ischemic or metabolically stressed zones; characteristic patterns, including temporal clusters of spreading depolarizations and persistent depression of spontaneous cortical activity, can be recognized and quantified. Here, we describe the experimental basis for interpreting these patterns and illustrate their translation to human disease. We further provide consensus recommendations for electrocorticographic methods to record, classify, and score spreading depolarizations and associated spreading depressions. These methods offer distinct advantages over other neuromonitoring modalities and allow for future refinement through less invasive and more automated approaches.

Clinical review: Traumatic brain injury in patients receiving antiplatelet medication

As the population ages, emergency physicians are confronted with a growing number of trauma patients receiving antithrombotic and antiplatelet medication prior to injury. In cases of traumatic brain injury, pre-injury treatment with anticoagulants has been associated with an increased risk of posttraumatic intracranial haemorrhage. Since high age itself is a well-recognised risk factor in traumatic brain injury, this population is at special risk for increased morbidity and mortality. The effects of antiplatelet medication on coagulation pathways in posttraumatic intracranial haemorrhage are not well understood, but available data suggest that the use of these agents increases the risk of an unfavourable outcome, especially in cases of severe traumatic brain injury. Standard laboratory investigations are insufficient to evaluate platelet activity, but new assays for monitoring platelet activity have been developed. Commonly used interventions to restore platelet activity include platelet transfusion and application of haemostatic drugs. Nevertheless, controlled clinical trials have not been carried out and, therefore, clinical practice guidelines are not available. In addition to the risks of the acute trauma, patients are at risk for cardiac events such as life-threatening stent thrombosis if antiplatelet therapy is withdrawn. In this review article, we summarize the pathophysiologic mechanisms of the most commonly used antiplatelet agents and analyse results of studies on the effects of this treatment on patients with traumatic brain injury. Additionally, we focus on opportunities to counteract antiplatelet effects in those patients as well as on considerations regarding the withdrawal of antiplatelet therapy. In those chronically ill patients, an interdisciplinary approach involving intensivists, neurosurgeons as well as cardiologists is often mandatory.

Spreading depolarizations in a case of migraine-related stroke

Background: Cortical spreading depolarization (CSD) has been implicated in the pathophysiology of migraine with aura. Patients that suffer from this type of migraine have shown a higher risk of developing an ischaemic stroke. Case: A 42-year-old female exhibited reoccurring migraine attacks for the first time 1 month before suffering an ischaemic infarction. Imaging studies revealed an occlusion in the right middle cerebral artery. Other possible disorders were excluded. It was possible to register 20 CSDs, of which 12 coincided with high levels of glutamate and lactate/pyruvate ratio. Loss of electrocorticographic activity was observed for 89 hours after the 8th depolarization. Conclusions: Migraine with aura symptoms may be induced by CSDs triggered by hypoperfusion states. Our case supports the idea of the migraine with aura–stroke continuum.

Cerebral metabolism after early decompression craniotomy following controlled cortical impact injury in rats

Abstract After traumatic brain injury, a cascade of metabolic changes promotes the development of secondary brain damage. In this study, we examined metabolic changes in rats in the acute stage after trauma. Furthermore, we investigated the effect of a very early decompression craniotomy on intracranial pressure (ICP) and on metabolic parameters. For this study, a moderate controlled cortical impact injury (CCII) on rats was performed. The observation time was 180 minutes after trauma. ICP was measured continuously and microdialysate samples were collected every 30 minutes from the peri-contusional region. As representative metabolic parameters, glutamate, lactate, lactate/pyruvate ratio (L/P ratio), and glucose concentrations were measured. Compared to sham-operated animals, a significant, sustained decrease in glucose concentration and increase in L/P ratio occurred immediately after CCII. Additionally, delayed increase in lactate and glutamate concentrations occurred 60 minutes after trauma. After this initial peak, glutamate concentrations declined continuously via the observation time and reached levels comparable to sham-operated animals. In our model, thus we could detect a very early deterioration of glucose utilization and energy supply after trauma that recovered, due to the moderate intensity of the trauma, within 60 minutes without leading to ischemia in the peri-contusional region. Following decompression craniotomy, the increase of intracranial pressure could be reduced significantly. Any significant beneficial effects on metabolic changes, however, could not be proven in this very early stage after moderate CCII.

Cerebral Microdialysis in Acutely Brain-Injured Patients with Spreading Depolarizations

Multimodal cerebral monitoring was utilized to examine the relationship between pathological changes in microdialysis parameters and the occurrence of spreading depolarizations (SD) in brain-injured patients. SD are a relatively newly discovered phenomenon in man found to be linked to secondary insults and infarct growth and they can be detected via electrocorticography (ECoG). A total of 24 brain-injured patients (mean age: 52±11 years) requiring craniotomy took part in this prospective observational study. Each patient was monitored with a linear strip electrode for ECoG data and a cerebral microdialysis probe. SD were detected in 13 of the 24 patients. Pathological concentrations of glucose and lactate in brain parenchyma were significantly correlated with various time points prior to and/or immediately following the SD. Severe systemic hyperglycemia and systemic hypoglycemia were also found to be correlated with the occurrence of SD. The present study shows a clear relationship between SD and pathological changes in cerebral metabolism; further studies are needed to elucidate these complex interactions with the ultimate goal of developing therapeutic strategies for improving outcome in brain-injured patients.

Endogenous nitric-oxide synthase inhibitor ADMA after acute brain injury.

Previous results on nitric oxide (NO) metabolism after traumatic brain injury (TBI) show variations in NO availability and controversial effects of exogenous nitric oxide synthase (NOS)-inhibitors. Furthermore, elevated levels of the endogenous NOS inhibitor asymmetric dimethylarginine (ADMA) were reported in cerebro-spinal fluid (CSF) after traumatic subarachnoid hemorrhage (SAH). Therefore, we examined whether ADMA and the enzymes involved in NO- and ADMA-metabolism are expressed in brain tissue after TBI and if time-dependent changes occur. TBI was induced by controlled cortical impact injury (CCII) and neurological performance was monitored. Expression of NOS, ADMA, dimethylarginine dimethylaminohydrolases (DDAH) and protein-arginine methyltransferase 1 (PRMT1) was determined by immunostaining in different brain regions and at various time-points after CCII. ADMA and PRMT1 expression decreased in all animals after TBI compared to the control group, while DDAH1 and DDAH2 expression increased in comparison to controls. Furthermore, perilesionally ADMA is positively correlated with neuroscore performance, while DDAH1 and DDAH2 are negatively correlated. ADMA and its metabolizing enzymes show significant temporal changes after TBI and may be new targets in TBI treatment.

The use of danaparoid to manage coagulopathy in a neurosurgical patient with heparin-induced thrombocytopenia type II and intracerebral haemorrhage.

This study presents a case of bifrontal intracerebral haemorrhage in a patient with heparin-induced thrombocytopenia type II (HIT II). HIT II was induced by treatment with low-molecular-weight heparin for recurrent deep vein thrombosis caused by essential thrombocytosis and accompanied by hepatic thromboembolism. This patient was treated with platelet substitution and neurosurgical haematoma evacuation. Anticoagulation with 2500 units danaparoid per day was sufficient for therapy of thrombosis and no rebleeding occurred.

Changes in electrocorticographic beta frequency components precede spreading depolarization in patients with acute brain injury

OBJECTIVE Spreading depolarization (SD) occurs after traumatic brain injury, subarachnoid hemorrhage, malignant hemispheric stroke and intracranial hemorrhage. SD has been associated with secondary brain injury, which can be reduced by ketamine. In this present study frequency bands of electrocorticographic (ECoG) recordings were investigated with regards to SDs. METHODS A total of 43 patients after acute brain injury were included in this retrospective and explorative study. Relative delta 0.5-4Hz, theta 4-8Hz, alpha 8-13Hz and beta 13-40Hz bands were analyzed with regards to SD occurrence and analgesic and sedative administration. Higher frequencies, including gamma 40-70Hz, fast gamma 70-100Hz and high frequency oscillations 100-200Hz were analyzed in a subset of patients with a sampling rate of up to 400Hz. RESULTS A close association of relative beta frequency and SD was found. Relative beta frequency was suppressed up to two hours prior to SD when compared to hours with no SD. This finding was partially explained by administration of ketamine. Even after removal of all patient data during administration of ketamine, SDs occurred predominantly during times with low relative beta frequency in a patient-independent analysis. CONCLUSION Suppression of beta frequency by ketamine or without ketamine is associated with low SD counts. SIGNIFICANCE Alteration of beta frequency might help to predict occurrence of SDs in acutely brain injured patients.

Reversible occlusion (on-off) valves in shunted tumor patients.

The first commercially produced adjustable valve for shunted hydrocephalus patients was introduced by H. Portnoy and R. Schulte in 1973. This valve is still in use and known as reversible occlusion or on–off valve. The reversible occlusion valve is mainly used in conjunction with an existing shunt in patients receiving intraventricular cytostatic therapy. The valve has a simple mechanical lock that is closed by external pressure application with a single finger. The study method is a retrospective clinical series of 15 patients undergoing a total of 16 valve implantations between 2003 and 2010 was carried out, and the valve was tested in vitro. We report a high incidence of accidental occlusions leading to a loss of consciousness in five patients (33.3%). We furthermore demonstrate in vitro that accidental occlusions can occur. The reversible occlusion valve is needed in shunted tumor patients receiving intrathecal administration of cytostatica. The mechanism works as long as no external pressure compresses the valve. However, head positions pose significant risks for unintentional occlusions. We stress the importance of: (1) a position near the midline avoiding the retroauricular or occipital regions, (2) a handling training for nurses and doctors, (3) instruction of patients and relatives, and (4) removal of the device after intrathecal cytostatic treatment.