Wolfgang R. Lanksch

Presentation of a new magnetic field therapy system for the treatment of human solid tumors with magnetic fluid hyperthermia

Magnetic fluid hyperthermia (MFH) selectively heats up tissue by coupling alternating current (AC) magnetic fields to targeted magnetic fluids, so that boundaries of different conductive tissues do not interfere with power absorption. In this paper, a new AC magnetic field therapy system for clinical application of MFH is described. With optimized magnetic nanoparticle preparations it will be used for target-specific glioblastoma and prostate carcinoma therapy.

Genetic Signature of Oligoastrocytomas Correlates with Tumor Location and Denotes Distinct Molecular Subsets

Oligoastrocytomas are heterogeneous tumors that have molecular features that overlap with either oligodendrogliomas or astrocytomas. Differences in the frequency of chromosomal losses of 1p and 19q in oligodendrogliomas are related to tumor location, with a low rate of allelic loss in tumors of the temporal and a high rate in tumors of the frontal, parietal, and occipital lobes. To test the possibility of regional molecular heterogeneity in oligoastrocytoma, we examined a series of 203 gliomas including 68 oligoastrocytomas and two control groups of 73 oligodendrogliomas and 62 astrocytomas for allelic losses of chromosomal arms 1p and 19q, and TP53 mutations, and compared these data with tumor localization. Common molecular alterations were found in oligodendrogliomas and oligoastrocytomas arising in extratemporal sites. In respect to the molecular parameters analyzed, temporal oligoastrocytomas were either indistinguishable from astrocytoma or similar to temporal oligodendrogliomas. Oligodendroglial neoplasms can thus be separated into three molecular subsets, two of which include lesions with the morphological features of oligodendrogliomas and oligoastrocytomas and one resembling temporal oligoastrocytoma. Molecular subclassification thus unifies previous findings about prognosis, behavior, response to therapy, genotype, and location in oligodendroglial tumors.

Bedside microdialysis: a tool to monitor cerebral metabolism in subarachnoid hemorrhage patients?

ObjectiveTo analyze the time course and changes of cerebral microdialysis parameters after aneurysmal subarachnoid hemorrhage (SAH) in respect to the clinical course (asymptomatic, delayed, and acute ischemic neurologic deficits) to evaluate the method of bedside microdialysis in these patients. DesignProspective, controlled study during a 3-yr period. SettingNeurosurgical intensive care unit at a primary level university hospital, supervised and staffed by members of both the department of neurosurgery and the department of anesthesiology and intensive care medicine. PatientsNinety-seven patients (51 females/21 males; 52 ± 13 yrs; World Federation of Neurological Surgeons Scale grades 0–5) after aneurysmatic SAH. Measurements and Main ResultsA microdialysis catheter (CMA 100) was inserted into the region most likely to be affected by vasospasm directly after aneurysm clipping, connected to a pump, and perfused with Ringer solution (0.3 &mgr;L/min). The dialysates were collected hourly and analyzed at the bedside for glucose, lactate, lactate-pyruvate ratio, glutamate, and glycerol (CMA 600). Patients were classified according to clinical presentation as being asymptomatic or having acute (AIND) or delayed (DIND) ischemic neurologic deficits. DIND patients (n = 18) had significantly higher lactate and glutamate concentrations on days 1–8 post-SAH and a higher lactate-pyruvate ratio on days 3–8 post-SAH compared with asymptomatic patients (n = 57;p < .025). Glucose and glycerol levels did not differ in asymptomatic and DIND patients. AIND patients (n = 22) had the worst metabolic pattern: the extracellular glucose concentration was low, whereas the lactate, lactate-pyruvate ratio, glutamate, and glycerol levels were significantly elevated compared with asymptomatic and DIND patients. In 83% of the DIND patients, the changes in metabolites indicative of cerebral ischemia preceded the onset of symptomatic vasospasm. All DIND patients clinically improved in their Glasgow Coma Scale scores with induced hypertension, intentional hypervolemia, and/or hemodilution therapy (p = .01). ConclusionCerebral bedside microdialysis is a safe and promising technique for monitoring (impending) regional cerebral ischemia. The dialysate changes can indicate early the onset of delayed neurologic deterioration and are in good accordance with the clinical course of SAH patients. In the future, this technique may be used to monitor the efficacy of the intensive care therapy of these patients.

Early IL-6 plasma concentrations correlate with severity of brain injury and pneumonia in brain-injured patients

BACKGROUND Brain injury as well as early inflammatory and endocrine responses were found to be indicators for infectious complications in patients with multiple injuries. In this context, brain-derived inflammatory response as well as centrally triggered neuroendocrine activation and systemic immunodepression seem to be of major importance. Therefore, we hypothesize that a circulating index of inflammatory or endocrine function measured soon after brain injury (in patients with admission Glasgow Coma Scale [GCS] score of 4-7) would discriminate severe from moderate injury as indexed by GCS status on postinjury day 7. METHODS In a retrospective study, 25 patients with either acute traumatic brain injury or cerebral hemorrhage and an initial GCS score of 4 to 7 were examined. Blood samples were obtained at different time points, and different immune variables and neuroendocrine hormones were determined. According to the GCS score on day 7, patients were divided into two groups (GCS score > or = 8, moderate brain injury; and GCS score < 8, severe brain injury or patients who died within the first week) for comparison of variables. Concluding from the results of this retrospective analysis, in a prospective study patients (n = 26) were divided into two groups according to their interleukin (IL)-6 plasma concentrations on day 1 (IL-6 > or = 100 pg/mL and IL 6 < 100 pg/mL). After 7 days, the GCS score, the infection rate, and the mortality were compared between these two groups. RESULTS In the retrospective study, we could show that severe brain injury (as assessed by GCS score and mortality on day 7) was associated with high plasma levels of pro- and anti-inflammatory cytokines, acute phase proteins, and neuroendocrine hormones within 2 to 6 hours after the acute event. Among the investigated variables, elevated IL-6 plasma concentrations were stable up to 1 day after the acute event with a high predictive value with regard to the short-term prognosis and incidence of infectious complications within the first week. Because of this stability during the first 24 hours, we selected IL-6 for further studies. In the prospective study with a calculated cut-off IL-6 plasma concentration of 100 pg/mL on day 1, the predictive value of this parameter regarding the severity of the brain injury was fully confirmed (positive predictive value, 0.94; this value represents the observed pretest probability of 0.62). All patients who died (n = 5) or developed infectious complications within the first week (n = 8) showed plasma IL-6 levels > or = 100 pg/mL on day 1. CONCLUSION The IL-6 plasma level 1 day after the acute event with a cut-off of 100 pg/mL (Immulite) seems to be a predictor for short-term prognosis and infectious complications in brain-injured patients.

Multimodal monitoring in patients with head injury: evaluation of the effects of treatment on cerebral oxygenation.

BACKGROUND Recently, invasive intensive care unit monitoring of cerebral oxygenation has become feasible. The purpose of this study was to investigate the effects of standard therapeutic interventions used in the treatment of intracranial hypertension on cerebral oxygenation and other physiologic parameters in comatose patients. METHODS In the neurosurgical intensive care unit, Ptio2, and jugular bulb oxygen saturation (Sjvo2), arterial blood pressure, intracranial pressure (ICP), and cerebral perfusion pressure (CPP) were prospectively studied (0.1 Hz acquisition rate) with a multimodal monitoring system in 21 patients with severe traumatic brain injury during various treatment modalities: dopamine and mannitol infusion, head positioning, and induced arterial hypocapnia. RESULTS For baseline CPP values below 40 mm Hg, dopamine infusion was more effective in decreasing ICP and improving Ptio2 and Sjvo2 than for initial CPP values above 60 mm Hg. Treatment with mannitol, although improving CPP and lowering ICP, did not affect Ptio2 and Sjvo2. CPP in this group, however, was always above 60 mm Hg. Forced hyperventilation to an end-tidal Pco2 of 21 mm Hg normalized ICP and CPP, but significantly reduced cerebral oxygenation. CONCLUSION A CPP > 60 mm Hg emerges as the crucial factor guaranteeing sufficient brain oxygenation. Any intervention used to further elevate CPP does not improve cerebral oxygenation, to the contrary, forced hyperventilation even bears the risk of inducing brain ischemia.

Secondary insults in severe head injury: Do multiply injured patients do worse?

Objectives To study the occurrence of secondary insults and the influence of extracranial injuries on cerebral oxygenation and outcome in patients with closed severe head injury (Glasgow Coma Scale score ≤8). Design Two-year prospective, clinical study. Setting Two intensive care units in a level III trauma center. Patients We studied 119 patients. Eighty patients had severe head injury and were divided into two categories: “isolated” severe head injury patients (n = 36, Injury Severity Score <30), and severe head injury patients with associated extracranial injuries (n = 44, Injury Severity Score >29). Thirty-nine patients with extracranial injuries and no head injury served as the control group. Interventions After patients were admitted to the intensive care unit, we began continuous multimodal cerebral monitoring of intracranial pressure, mean arterial blood pressure, cerebral perfusion pressure, end-tidal Co2 , brain tissue Po2 (Licox), jugular bulb oxyhemoglobin saturation in severe head injury patients, and mean arterial blood pressure in the control group. Targets of management included intracranial pressure <20 mm Hg, cerebral perfusion pressure >60 mm Hg, Paco2 > 30 mm Hg, control of cerebral oxygenation, and delayed surgery for non-life-threatening extracranial lesions. Measurements and Main Results Data were analyzed for critical thresholds. The occurrence of secondary insults (intracranial pressure >20 mm Hg, mean arterial blood pressure <70 mm Hg, cerebral perfusion pressure <60 mm Hg, end-tidal Co2 <30 torr, brain tissue Po2 <10 torr, jugular bulb oxyhemoglobin saturation <50%) was comparable in patients with isolated severe head injury and those with severe head injury with associated extracranial lesions (Abbreviated Injury Scale score ≤5). The duration of intracranial hypertension and arterial hypotension significantly correlated with an unfavorable outcome, independent of the Injury Severity Score. In patients with severe head injury, 1-yr outcome was 29% dead or vegetative, 17% severely disabled, and 54% moderate or good outcome. This was similar to patients with severe head injury and extracranial injuries (31% dead or vegetative, 14% severely disabled, and 56% moderate or good outcome) and was independent of the Injury Severity Score. Patients with no head injury had less secondary insults (mean arterial blood pressure <70 mm Hg, p < .01) and a better outcome compared with both severe head injury groups (p < .044). Conclusions In patients with severe head injury who have targeted management including intracranial pressure- and cerebral perfusion pressure-guided therapy and delayed surgery for extracranial lesions, the occurrence of secondary insults in the intensive care unit and long-term neurological outcome were comparable and independent of the presence of extracranial lesions (Abbreviated Injury Severity level ≤5). A severe head injury is still a major contributor predicting an unfavorable outcome in multiply injured patients.

Decompressive Craniectomy Following Traumatic Brain Injury: ICP, CPP and Neurological Outcome

Decompressive craniectomy is often the final option in the management of posttraumatic intracranial hypertension. Aim of this study was to investigate the effect of secondary decompression on intracranial pressure (ICP), cerebral perfusion pressure (CPP) and neurological outcome. 62 patients decompressed after severe head injury were included in the retrospective study. Decompression was performed when ICP could not be controlled by non-surgical treatment. Mean age was 36.6 yrs, 77.4% were male. Initial Glasgow Coma Score (GCS) was 6. Outcome was determined 6 months after trauma according to the Glasgow Outcome Scale (GOS) and the functional Barthel-Index (BI). In the last hour before decompression ICP was 40.5 +/- 1.6 mmHg and CPP was 65.3 +/- 2.1 mmHg (being maintained, if necesary, by catecholamines). ICP was significantly reduced to 9.8 +/- 1.3 mmHg by surgery and CPP improved to 78.2 +/- 2.3 mmHg. 12 hrs following decompression mean ICP rose to 21.6 +/- 1.7 mmHg again (CPP: 73.6 +/- 1.7 mmHg), but in the following period ICP could be kept below 25 mmHg in the majority of patients. 6 months after trauma 22.5% of the patients had died (except one all these patients were aged more than 50 yrs). 48.4% of patients survived with an unfavourable outcome (GOS 2 + 3), while 29.1% had a favourable outcome (GOS 4 + 5). Decompressive craniectomy is highly effective to treat otherwise uncontrollable intracranial hypertension and improves CPP. A satisfactory outcome, however, is only achieved under strict consideration of negative predictors (e.g. age).

Treatment of a cavernous sinus dural arteriovenous fistula by deep orbital puncture of the superior ophthalmic vein

Abstract In a patient with progressive ophthalmological problems, including uncontrolled intraocular pressure related to a cavernous sinus dural arteriovenous fistula, urgent intervention may be necessary to prevent permanent visual loss. We report a case in which inadequate transarterial embolisation and lack of access for transvenous catheterisation, including a direct approach through the superior ophthalmic vein, preceded percutaneous puncture of the superior ophthalmic vein deep within the orbit, permitting venous occlusion without complications. This case demonstrates that deep orbital puncture of the vein is feasible for occlusion of a cavernous sinus dural arteriovenous fistula.

Influence of Hyperventilation on Brain Tissue-PO2, PCO2, and pH in Patients with Intracranial Hypertension

A harmful effect of prolonged hyperventilation on outcome has been shown in comatose patients after severe head injury. The purpose of this study was to assess the acute effect of moderate hyperventilation for treatment of intracranial hypertension (ICP < 20 mmHg) on invasively measured brain tissue-PO2 (PtiO2), PCO2 (PtiCO2) and pH (tipH) in severely head injured patients. 15 severely head injured patients (GCS < or = 8) were prospectively studied. Intracranial pressure (ICP), mean arterial blood pressure (MABP), cerebral perfusion pressure (CPP), endtidal CO2 (ETCO2), PtiO2, PtiCO2 and tipH (Paratrend or Licox microsensors) were continuously recorded using multimodal monitoring. Following a baseline period of 15 minutes, patients were hyperventilated for 10 minutes. Arterial blood gas analysis was done before, during and after hyperventilation. At least three hyperventilation maneuvers were performed per patient. For statistical analysis the Friedman test was used. Hyperventilation (paCO2: 32.4 +/- 0.6 to 27.7 +/- 0.5 mmHg) significantly reduced ICP from 25.3 +/- 1.5 to 14.2 +/- 1.9 mmHg (p < 0.01). As a consequence, CPP increased by 9.6 +/- 3.4 mmHg to 76.8 +/- 3.2 mmHg. Brain tissue PCO2 decreased from 37.5 +/- 1.3 to 34.6 +/- 1.2 while tipH increased from 7.13 to 7.16. In all patients, hyperventilation led to a reduction of brain tissue PO2 (PtiO2/Licox: 24.6 +/- 1.4 to 21.9 +/- 1.7 mmHg, n.s.; PtiO2/Paratrend: 35.8 +/- 4.3 to 31.9 +/- 4.0 mmHg, n.s.). In one case hyperventilation even had to be stopped after 7 min because the drop in brain tissue PO2 below 10 mmHg signalized imminent hypoxia. As well known, hyperventilation improves CPP due to a reduction in ICP. However, this does not ameliorate cerebral oxygenation as demonstrated by the decrease in PtiO2. This underlines that hyperventilation should only be used with caution in the treatment of intracranial hypertension.

Brain-IL-1β induces local inflammation but systemic anti-inflammatory response through stimulation of both hypothalamic–pituitary–adrenal axis and sympathetic nervous system

Abstract It is well established that systemic inflammation induces a counter-regulatory anti-inflammatory response particularly resulting in deactivation of monocytes/macrophages. However, recently we demonstrated a systemic anti-inflammatory response without preceding signs of systemic inflammation in patients with brain injury/surgery and release of cytokines into the cerebrospinal fluid (CSF). In order to analyze the mechanisms and pathways of systemic immunodepression resulting from sterile cerebral inflammation we established an animal model using continuous intra-cerebroventricular (i.c.v.) or intra-hypothalamic (i.h.) infusion of rat recombinant (rr) tumor necrosis factor (TNF)-α and interleukin (IL)-1β for 48 h. Controls received intra-venous (i.v.) cytokine administration. Interestingly, i.c.v. and i.h. infusion of IL-1β but not TNF-α produced distinct signs of central nervous system (CNS) inflammation. Correspondingly, i.c.v. infusion of IL-1β particularly diminished the TNF-α but increased the IL-10 concentration in whole blood cultures after endotoxin stimulation. All parameters normalized within 48 h after termination of the infusion. Blocking the hypothalamic–pituitary–adrenal (HPA) axis by hypophysectomy (HPX) led to complete recovery of the diminished TNF-α concentration and temporarily inhibited the IL-10 increase. Blocking the sympathetic nervous system (SNS) transmission by application of the β 2 -adrenoreceptor antagonist propranolol not only inhibited the increase but further downregulated the endotoxin induced IL-10 concentration in the media of whole blood cell cultures, whereas the TNF-α decrease was only partially prevented. Interestingly, HPX and propranolol also diminished the cell invasion into the CSF. In summary, activation of both the HPA axis and the SNS plays an important role in systemic anti-inflammatory response resulting from cytokines in brain and cerebral inflammation.