Neuroglucopenia and Metabolic Distress in Two Patients with Viral Meningoencephalitis: A Microdialysis Study.

INTRODUCTION: Viral encephalitis is an emerging disease requiring intensive care management in severe cases. Underlying pathophysiologic mechanisms are incompletely understood and may be elucidated using invasive multimodal neuromonitoring techniques in humans. METHODS: Two otherwise healthy patients were admitted to our neurological intensive care unit with altered level of consciousness necessitating mechanical ventilation. Brain imaging and laboratory workup suggested viral encephalitis in both patients. Invasive neuromonitoring was initiated when head computed tomography revealed generalized brain edema, including monitoring of intracranial pressure, brain metabolism (cerebral microdialysis; CMD), brain tissue oxygen tension (in one patient), and cerebral blood flow (in one patient). RESULTS: Brain metabolism revealed episodes of severe neuroglucopenia (brain glucose <0.7 mM/l) in both patients, which were not attributable to decreased cerebral perfusion or hypoglycemia. CMD-glucose levels changed depending on variations in insulin therapy, nutrition, and systemic glucose administration. The metabolic profile, moreover, showed a pattern of non-ischemic metabolic distress suggestive for mitochondrial dysfunction. Both patients had a prolonged but favorable clinical course and improved to a modified Rankin Scale Score of 1 and 0 three months later. CONCLUSION: Invasive multimodal neuromonitoring is feasible in poor-grade patients with viral meningoencephalitis and may help understand pathophysiologic mechanisms associated with secondary brain injury. The detection of neuroglucopenia and mitochondrial dysfunction may serve as treatment targets in the future.

Cerebral tau is elevated after aneurysmal subarachnoid haemorrhage and associated with brain metabolic distress and poor functional and cognitive long-term outcome.

BACKGROUND: Recent evidence suggests axonal injury after aneurysmal subarachnoid haemorrhage (aSAH). The microtubule-associated protein, tau, has been shown to be elevated in the cerebrospinal fluid after aSAH, however, brain extracellular tau levels and their relation to long-term neurological and cognitive outcomes have not been investigated. METHODS: Serial cerebral microdialysis (CMD) samples were collected from 22 consecutive aSAH patients with multimodal neuromonitoring to determine CMD-total-tau by ELISA. CMD-total-tau was analysed considering other brain metabolic parameters, brain tissue oxygen tension (PbtO2), and functional and neuropsychological outcome at 12 months. All outcome models were analysed using generalised estimating equations with an autoregressive working correlation matrix to account for multiple measurements of brain extracellular proteins per subject. RESULTS: CMD-total-tau levels positively correlated with brain extracellular fluid levels of lactate (r=0.40, p<0.001), glutamate (r=0.45, p<0.001), pyruvate (r=0.26, p<0.001), and the lactate-pyruvate ratio (r=0.26, p<0.001), and were higher in episodes of hypoxic (PbtO2<20 mm Hg) brain extracellular lactate elevation (>4 mmol/L) (p<0.01). More importantly, high CMD-total-tau levels were associated with poor functional outcome (modified Rankin Scale ≥4) 12 months after aSAH even after adjusting for disease severity and age (p=0.001). A similar association was found with 3/5 neuropsychological tests indicative of impairments in cognition, psychomotor speed, visual conceptualisation and frontal executive functions at 1 year after aSAH (p<0.01). CONCLUSIONS: These results suggest that CMD-total tau may be an important biomarker for predicting long-term outcome in patients with severe aSAH. The value of axonal injury needs further confirmation in a larger patient cohort, preferably combined with advanced imaging techniques.

Early brain injury after aneurysmal subarachnoid hemorrhage: a multimodal neuromonitoring study.

INTRODUCTION: There is a substantial amount of evidence from animal models that early brain injury (EBI) may play an important role for secondary brain injury after aneurysmal subarachnoid hemorrhage (aSAH). Cerebral microdialysis (CMD) allows online measurement of brain metabolites, including the pro-inflammatory cytokine interleukin-6 (IL-6) and matrix metalloproteinase-9 (MMP-9), which is indicative for disruption of the blood-brain barrier. METHODS: Twenty-six consecutive poor-grade aSAH patients with multimodal neuromonitoring were analyzed for brain hemodynamic and metabolic changes, including CMD-IL-6 and CMD-MMP-9 levels. Statistical analysis was performed by using a generalized estimating equation with an autoregressive function. RESULTS: The baseline cerebral metabolic profile revealed brain metabolic distress and an excitatory response which improved over the following 5 days (P <0.001). Brain tissue hypoxia (brain tissue oxygen tension of less than 20 mm Hg) was common (more than 60% of patients) in the first 24 hours of neuromonitoring and improved thereafter (P <0.05). Baseline CMD-IL-6 and CMD-MMP-9 levels were elevated in all patients (median = 4,059 pg/mL, interquartile range (IQR) = 1,316 to 12,456 pg/mL and median = 851 pg/mL, IQR = 98 to 25,860 pg/mL) and significantly decreased over days (P <0.05). A higher pro-inflammatory response was associated with the development of delayed cerebral ischemia (P = 0.04), whereas admission disease severity and early brain tissue hypoxia were associated with higher CMD-MMP-9 levels (P <0.03). Brain metabolic distress and increased IL-6 levels were associated with poor functional outcome (modified Rankin Scale of more than 3, P ≤0.01). All models were adjusted for probe location, aneurysm securing procedure, and disease severity as appropriate. CONCLUSIONS: Multimodal neuromonitoring techniques allow insight into pathophysiologic changes in the early phase after aSAH. The results may be used as endpoints for future interventions targeting EBI in poor-grade aSAH patients.

Cerebral Taurine Levels are Associated with Brain Edema and Delayed Cerebral Infarction in Patients with Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND: Cerebral edema and delayed cerebral infarction (DCI) are common complications after aneurysmal subarachnoid hemorrhage (aSAH) and associated with poor functional outcome. Experimental data suggest that the amino acid taurine is released into the brain extracellular space secondary to cytotoxic edema and brain tissue hypoxia, and therefore may serve as a biomarker for secondary brain injury after aSAH. On the other hand, neuroprotective mechanisms of taurine treatment have been described in the experimental setting. METHODS: We analyzed cerebral taurine levels using high-performance liquid chromatography in the brain extracellular fluid of 25 consecutive aSAH patients with multimodal neuromonitoring including cerebral microdialysis (CMD). Patient characteristics and clinical course were prospectively recorded. Associations with CMD-taurine levels were analyzed using generalized estimating equations with an autoregressive process to handle repeated observations within subjects. RESULTS: CMD-taurine levels were highest in the first days after aSAH (11.2 ± 3.2 µM/l) and significantly decreased over time (p < 0.001). Patients with brain edema on admission or during hospitalization (N = 20; 80 %) and patients developing DCI (N = 5; 20 %) had higher brain extracellular taurine levels compared to those without (Wald = 7.3, df = 1, p < 0.01; Wald = 10.1, df = 1, p = 0.001, respectively) even after adjusting for disease severity and CMD-probe location. There was no correlation between parenteral taurine supplementation and brain extracellular taurine (p = 0.6). Moreover, a significant correlation with brain extracellular glutamate (r = 0.82, p < 0.001), lactate (r = 0.56, p < 0.02), pyruvate (r = 0.39, p < 0.01), potassium (r = 0.37, p = 0.01), and lactate-to-pyruvate ratio (r = 0.24, p = 0.02) was found. CONCLUSIONS: Significantly higher CMD-taurine levels were found in patients with brain edema or DCI after aneurysmal subarachnoid hemorrhage. Its value as a potential biomarker deserves further investigation.

Higher brain extracellular potassium is associated with brain metabolic distress and poor outcome after aneurysmal subarachnoid hemorrhage.

INTRODUCTION: Elevated brain potassium levels ([K+]) are associated with neuronal damage in experimental models. The role of brain extracellular [K+] in patients with poor-grade aneurysmal subarachnoid hemorrhage (aSAH) and its association with hemorrhage load, metabolic dysfunction and outcome has not been studied so far. METHODS: Cerebral microdialysis (CMD) samples from 28 poor grade aSAH patients were analyzed for CMD [K+] for 12 consecutive days after ictus, and time-matched to brain metabolic and hemodynamic parameters as well as corresponding plasma [K+]. Statistical analysis was performed using a generalized estimating equation with an autoregressive function to handle repeated observations of an individual patient. RESULTS: CMD [K+] did not correlate with plasma [K+] (Spearman's ρ = 0.114, P = 0.109). Higher CMD [K+] was associated with the presence of intracerebral hematoma on admission head computed tomography, CMD lactate/pyruvate ratio >40 and CMD lactate >4 mmol/L (P < 0.05). In vitro retrodialysis data suggest that high CMD [K+] was of brain cellular origin. Higher CMD [K+] was significantly associated with poor 3-month outcome, even after adjusting for age and disease severity (P < 0.01). CONCLUSIONS: The results of this pilot study suggest that brain extracellular [K+] may serve as a biomarker for brain tissue injury in poor-grade aSAH patients. Further studies are needed to elucidate the relevance of brain interstitial K+ levels in the pathophysiology of secondary brain injury after aSAH.

Parenteral diclofenac infusion significantly decreases brain-tissue oxygen tension in patients with poor-grade aneurysmal subarachnoid hemorrhage.

INTRODUCTION: Diclofenac, a nonsteroidal antiinflammatory drug, is commonly used as antipyretic therapy in intensive care. The purpose of this study was to investigate the effects of parenteral diclofenac infusion on brain homeostasis, including brain-tissue oxygen tension (PbtO2) and brain metabolism after aneurysmal subarachnoid hemorrhage (aSAH). METHODS: We conducted a prospective, observational study with retrospective analysis of 21 consecutive aSAH patients with multimodal neuromonitoring. Cerebral perfusion pressure (CPP), mean arterial pressure (MAP), intracranial pressure (ICP), body temperature, and PbtO2 were analyzed after parenteral diclofenac infusion administered over a 34-minute period (20 to 45 IQR). Data are given as mean ± standard error of mean and median with interquartile range (IQR), as appropriate. Time-series data were analyzed by using a general linear model extended by generalized estimation equations (GEEs). RESULTS: One-hundred twenty-three interventions were analyzed. Body temperature decreased from 38.3°C ± 0.05°C by 0.8°C ± 0.06°C (P < 0.001). A 10% decrease in MAP and CPP (P < 0.001) necessitated an increase of vasopressors in 26% (n = 32), colloids in 33% (n = 41), and crystalloids in 5% (n = 7) of interventions. PbtO2 decreased by 13% from a baseline value of 28.1 ± 2.2 mm Hg, resulting in brain-tissue hypoxia (PbtO2 <20 mm Hg) in 38% (n = 8) of patients and 35% (n = 43) of interventions. PbtO2 <30 mm Hg before intervention was associated with brain-tissue hypoxia after parenteral diclofenac infusion (likelihood ratio, 40; AUC, 93%; 95% confidence interval (CI), 87% to 99%; P < 0.001). Cerebral metabolism showed no significant changes after parenteral diclofenac infusion. CONCLUSIONS: Parenteral diclofenac infusion after aSAH effectively reduces body temperature, but may lead to CPP decrease and brain-tissue hypoxia, which were both associated with poor outcome after aSAH.

High dose erythropoietin increases brain tissue oxygen tension in severe vasospasm after subarachnoid hemorrhage.

BACKGROUND: Vasospasm-related delayed cerebral ischemia (DCI) significantly impacts on outcome after aneurysmal subarachnoid hemorrhage (SAH). Erythropoietin (EPO) may reduce the severity of cerebral vasospasm and improve outcome, however, underlying mechanisms are incompletely understood. In this study, the authors aimed to investigate the effect of EPO on cerebral metabolism and brain tissue oxygen tension (PbtO2). METHODS: Seven consecutive poor grade SAH patients with multimodal neuromonitoring (MM) received systemic EPO therapy (30.000 IU per day for 3 consecutive days) for severe cerebral vasospasm. Cerebral perfusion pressure (CPP), mean arterial blood pressure (MAP), intracranial pressure (ICP), PbtO2 and brain metabolic changes were analyzed during the next 24 hours after each dose given. Statistical analysis was performed with a mixed effects model. RESULTS: A total of 22 interventions were analyzed. Median age was 47 years (32-68) and 86 % were female. Three patients (38 %) developed DCI. MAP decreased 2 hours after intervention (P < 0.04) without significantly affecting CPP and ICP. PbtO2 significantly increased over time (P < 0.05) to a maximum of 7 ± 4 mmHg increase 16 hours after infusion. Brain metabolic parameters did not change over time. CONCLUSIONS: EPO increases PbtO2 in poor grade SAH patients with severe cerebral vasospasm. The effect on outcome needs further investigation.

Multimodal neuromonitoring in a patient with aneurysmal subarachnoid hemorrhage associated with aortic coarctation.

BACKGROUND: Aortic coarctation (AC) rarely remains undiagnosed until adulthood. Intracranial aneurysms and spontaneous subarachnoid hemorrhage (SAH) are more frequent in patients with AC than in the general population. METHODS: The purpose of this report is to describe the management of a poor grade SAH patient with previously undiagnosed AC using advanced monitoring techniques of the brain and the cardiovascular system. RESULTS: A 28-year-old man with previously unknown AC was admitted with aneurysmal SAH WFNS grade 5. Head computed tomography demonstrated thick blood filling the basal cisterns, mild hydrocephalus, and global cerebral edema. The ruptured aneurysm of the anterior communicating artery was successfully coiled on the same day. Echocardiography revealed high grade isthmus stenosis with a pressure gradient of 60 mm Hg. Hospital course was complicated by prerenal failure and severe vasospasm. Neuromonitoring data (cerebral metabolism, brain tissue oxygenation, cerebral blood flow and intracranial pressure) were used as endpoint to define the optimal blood pressure to meet the cerebral metabolic and oxygen demand in each phase. CONCLUSIONS: Cerebral aneurysm rupture associated with coarctation of the aorta is rare. The aim of this report is to call attention to AC in, particularly, young patients presenting with SAH and to discuss advanced multimodal neuromonitoring techniques used to optimize intensive care management.

Accuracy of stereotactic electrode placement in deep brain stimulation by intraoperative computed tomography.

The purpose of this study was to evaluate the accuracy of stereotactic electrode placement in patients undergoing deep brain stimulation by using pre- and postoperative computed tomography (CT). Twenty-three patients with movement disorders (Parkinson's disease (n=7), tremor (n=9), dystonia (n=7)) treated with bilateral deep brain stimulation (DBS) (overall 46 target points) were investigated. The target point of the electrode was planned stereotactically in combination with a preoperative stereotactic helical computed tomography (CT). A postoperative CT, which was carried out still in the operating room while the patient had the stereotactic frame on the head, was performed in order to control the position of the electrodes in relation to the previously planned target point. The position of the four electrode contacts was measured according to the Talairach space (AC-PC line) and compared with the coordinates of the planned target point. The mean spatial distance of planned target perpendicular to the electrode was 1.32+/-0.75mm. These results show the high accuracy of stereotactic implantation of DBS electrodes assisted by pre- and postoperative image fusion with computed tomography (CT).

Refractory intracranial hypertension in traumatic brain injury: Proposal for a novel score to assess the safety of lumbar cerebrospinal fluid drainage.

BACKGROUND: Cerebrospinal fluid (CSF) drainage via ventricular puncture is an established therapy of elevated intracranial pressure (ICP). In contrast, lumbar CSF removal is believed to be contraindicated with intracranial hypertension. METHODS: We investigated the safety and efficacy of lumbar CSF drainage to decrease refractory elevated ICP in a small cohort of patients with traumatic brain injury (TBI). A score (0-8 points) was used to assess computed tomography (CT) images for signs of herniation and for patency of the basal cisterns. All patients received lumbar CSF drainage either as a continuous drainage or as a single lumbar puncture (LP). Type and method of CSF drainage, mean ICP 24 h prior and after CSF removal, and adverse events were documented. Outcome was assessed after 3 months (with dichotomized Glasgow outcome scale). RESULTS: Eight patients were evaluated retrospectively. n = 5 suffered a moderate, n = 2 a severe TBI (one Glasgow coma score not documented). The CT score was ≥5 in all patients prior to LP and decreased after puncture without clinical consequences in two patients. The amount of CSF removal did not correlate with score changes (P = 0.45). CSF drainage led to a significant reduction of mean ICP (from 22.3 to 13.9 mmHg, P = 0.002). Continuous drainage was more effective than a single LP. Three of eight patients reached a favorable outcome. CONCLUSIONS: Lumbar CSF removal for the treatment of intracranial hypertension is effective and safe, provided the basal cisterns are discernible, equivalent to ≥5 points in the proposed new score. The score needs further validation.

Neuroinflammation is Associated with Brain Extracellular TAU-Protein Release After Spontaneous Subarachnoid Hemorrhage.

INTRODUCTION: Animal data suggest an association between neuroinflammation and secondary brain injury including axonal injury after aneurysmal subarachnoid hemorrhage (aSAH). We sought to study the association between brain extracellular interleukin (IL)-6 and TAU-protein levels as a surrogate marker for neuroinflammation and axonal injury in patients with poor grade aSAH. METHODS: Prospectively collected data from 26 consecutive poor-grade aSAH patients with multimodal neuromonitoring including cerebral microdialysis (CMD) were retrospectively analyzed. IL-6 and TAU-protein levels were analyzed using ELISA from a single CMD-sample every 24 hours and correlated with brain metabolic and hemodynamic parameters. Patients were dichotomized to highgrade (N=10) or low-grade (N=16) neuroinflammation according to their median CMD-IL-6 levels. Data were analyzed using generalized estimating equations to account for multiple within-subject measurements. RESULTS: Perilesional probe location (P=0.02) and aSAH related intracerebral hemorrhage (aICH) volume (P=0.003) at admission were associated with high-grade neuroinflammation. Brain extracellular TAU-protein levels (P=0.001), metabolic distress and delayed cerebral infarction (DCI; P=0.001) were linked to high-grade neuroinflammation. Relative or absolute phosphor-TAU levels were not correlated with CMD-IL-6 levels. High-grade neuroinflammation was a predictor for worse outcome three months after ictus, independently from probe location, initial Hunt&Hess grade and age (P=0.01). CONCLUSION: Neuroinflammation after aSAH is associated with intraparenchymal bleeding, deranged cerebral metabolism and TAU-protein release. The impact of potential anti-inflammatory treatment strategies on secondary brain injury after aSAH has to be investigated in future studies.

Frame-based vs frameless placement of intrahippocampal depth electrodes in patients with refractory epilepsy: a comparative in vivo (application) study.

BACKGROUND: Despite progress in imaging technologies, documentation of unifocal electrical excitability is pivotal in patient selection for epilepsy surgery. OBJECTIVE: To compare the application accuracy of the Vogele-Bale-Hohner system (VBH), a maxillary fixation system with an external fiducial frame permitting frameless stereotactic guidance, with that of conventional frame-based stereotaxy for placement of intrahippocampal depth electrodes (DEs) in patients with refractory epilepsy. METHODS: Retrospective study. Comparison of two patient cohorts with DEs implanted along the occipitotemporal axis (group A, VBH; group B, frame-based stereotaxy). In vivo accuracy (lateral target localization error [TLE]), determined postoperatively by measuring the normal distance between virtual target and real electrode position at the tip and at 4cm from the tip, number of electrode contacts within the target structure, and diagnostic quality of electroencephalogram recordings were compared. RESULTS: Seventeen DEs (A, 6 electrodes, 60 contacts; B, 11 electrodes, 90 contacts) were placed. electroencephalogram recordings via DEs supported further treatment decisions in all patients. TLE was 2.433 ± 0.977 mm (SD) (95% confidence interval [CI], 1.715-3.214 mm) (A) and 1.803 ± 0.392 mm (SD) (95% CI,1.511-2.195 mm) (B) (P = .185). Maximal error was 4 mm (A) and 3.2 mm (B). TLE 4 cm from the tip was 2.166 ± 2.188 mm (SD) (95% CI,0.438-3.916 mm) (A) and 1.372 ± 0.548 mm (SD) (95% CI,1.049-1.695 mm) (B) (P = .39). Maximal error 4 cm from the tip was 6.4 mm (A) and 2.14 mm (B). On average, 7 (A) and 5 (B) electrode contacts were placed in the target region. CONCLUSION: The VBH and frame-based systems offer similar in vivo accuracy for intrahippocampal DE placement. With frame-based methods, accuracy is higher but the number of contacts per side is lower. This does not translate to clinically important differences.