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The kallikrein-kinin system as mediator in vasogenic brain edema

Part 1: Cerebral exposure to bradykinin and plasma

Andreas Unterberg and Alexander J. Baethmann

✓ Plasma and bradykinin were perfused into the ventricular system of mongrel dogs to investigate whether either or both induce brain edema. Formation of cerebral edema was determined by measurement of cerebral water and electrolytes in periventricular white matter, cerebral cortex, and caudate nucleus. The response of cerebral tissue to exposure to bradykinin or to plasma, as a carrier of kininogens, was analyzed by assessment of the perfusate composition after ventricle passage. The authors report that cerebral administration of bradykinin induces cerebral edema. Ventricular perfusion with plasma also led to an increase of cerebral water content which was restricted to the white matter, but involved all brain tissue areas, if bradykinin was used. Ventricular perfusion with plasma was associated with consumption of the kinin precursor (kininogens) indicative of formation of kinins. Significant consumption of the precursor was found in five out of nine animals subjected to plasma perfusion of the ventricular system. In these animals a close correlation between the increase of white matter water content and kininogen-consumption as a measure of kinin-formation was obtained. Marked kinin-degrading activity was observed during ventricular perfusion with bradykinin as concluded from a considerable decrease of bradykinin concentration in the cisternal effluent compared to the inflowing perfusate concentration. Ventricular perfusion with plasma was associated with a decrease of K+ clearance capacity with continued duration, and in two animals with a release of glutamate into the plasma perfusate, suggesting an involvement of cytotoxic mechanisms.

These findings provide support for the hypothesis of a mediator function of the kallikrein-kinin (KK) system in vasogenic brain edema. The next question that needs to be answered to complete the picture — does spontaneous activation of the KK system occur in conditions leading to vasogenic edema? — is studied in a subsequent report.

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Stepan Fedorko, Klaus Zweckberger, and Andreas W. Unterberg

OBJECTIVE

Pineal region tumors are a rare and heterogeneous group of lesions. The optimal therapeutic approach is currently a topic of controversy, particularly in light of the potential operative risks and complications. The potential beneficial effects of surgery have already been described, but information about neurological outcome and, in particular, health-related quality of life (HRQOL) is still lacking in the literature. The aim of this study was to assess the therapeutic effect of resection of pineal region lesions, emphasizing grade of tumor resection, neurological outcome, quality of life, and the necessity of additional shunt procedures.

METHODS

The authors performed a prospective study of HRQOL in 32 patients who had undergone surgical treatment of lesions in the pineal region (20 tumors and 12 cysts) between 2008 and 2014. All patients had at least 6 months of follow-up, with reexamination including standardized neurological assessment, an evaluation of dependency using the modified Rankin Scale, and an evaluation of HRQOL. The authors retrospectively examined patient charts and collected information regarding imaging studies, neurological status prior to surgery, surgical strategies used, any complications, and histological diagnoses.

RESULTS

In this study, there was no surgery-associated mortality or major morbidity. Permanent minor morbidity was reported for 4 patients (13%). Comparing pre- and postoperative neurological symptoms, 75% of tumor patients had either complete resolution or improvement of preoperative symptoms; symptoms were unchanged in 10% of tumor patients and deteriorated in 15%. In patients with pineal cysts, long-term follow-up showed that 42% of patients were free of any symptoms and 58% experienced improvement of their preoperative symptoms. These outcomes were also reflected in the modified Rankin Scale scores, which demonstrated significant improvement following resection of pineal region lesions. Furthermore, significant improvements in HRQOL scores occurred in global health status, in all functional scales, and in pain, nausea and vomiting, fatigue, and insomnia (p < 0.0001). Moreover, a significant reduction in the necessity for permanent shunt procedures was observed after gross-total tumor resection compared with subtotal resection (p = 0.035) of pineal cysts.

CONCLUSIONS

Despite potential risks, (radical) surgery is a highly effective and safe treatment option for pineal region lesions and should be considered for the majority of patients.

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Henrik Giese, Benjamin Haenig, Anna Haenig, Andreas Unterberg, and Klaus Zweckberger

OBJECTIVE

Craniopharyngiomas are rare and benign tumors of the sellar and/or parasellar region. Primary treatment involves resection followed by adjuvant radiotherapy. While the grade of resection was frequently analyzed following surgery, the neurological outcome and especially neuropsychological deficits and quality of life have been neglected for many decades. Therefore, the authors retrospectively analyzed their patient series and prospectively assessed neuropsychological outcome and quality of life following resection of craniopharyngiomas in adults.

METHODS

In total, 71 patients (39 men and 32 women) with a mean age of 49 years were enrolled in the retrospective analysis. In addition, 36 of the 71 patients were included in the prospective arm of the study and underwent neurological and neuropsychological testing as well as quality of life (36-Item Short-Form Health Survey; SF-36) assessment. Factors influencing outcome were identified and correlations calculated.

RESULTS

Resection was performed mostly using a pterional (41.6%, 47/113 surgical procedures) or bifrontal translamina terminalis (30.1%, 34/113 surgical procedures) approach. Following surgery, visual acuity was significantly improved (> 0.2 diopters) in 32.4% (23/71) of patients, or remained stable in 45.1% (32/71) of patients. During long-term follow up, 80.3% (57/71) of patients developed pituitary insufficiency, particularly involving the corticotropic and thyrotrophic axes. In total, 75% (27/36) of patients showed neuropsychological deviations in at least 1 test item. In particular, attentiveness, cognitive speed, and short-term memory were affected. Referring to the SF-36 score, quality of life was affected in both the mental and physical score in 19.4% (7/36) and 33.3% (12/36), respectively. The risk factors that were identified were a tumor volume larger than 9 cm3, tumor extension toward/into the third ventricle or the brainstem, and resection using a bifrontal translamina terminalis or left-sided approach.

CONCLUSIONS

This study demonstrated that resection of craniopharyngiomas is frequently associated with postoperative neuropsychological deficits and hence an impaired quality of life. In addition to tumor size and extension toward/into the third ventricle or the brainstem, selection of the surgical approach may play a crucial role in the patient’s neuropsychological outcome and quality of life.

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Miriam Ratliff, Andreas Unterberg, and Heidi Bächli

The authors present the unusual case of a 4-year-old boy who had a complex history of posthemorrhagic hydrocephalus and who underwent more than 40 surgeries related to this condition. In the course of trying to treat his condition, ventriculoperitoneal, ventriculoatrial, and ventriculopleural shunts were inserted and failed.

The child presented with a dysfunction of his shunt system. A ventriculopleural shunt was inserted, but within days the patient developed dyspnea as a clinical symptom of pleural effusion that required repeated thoracentesis. A bipleural drainage system was inserted, and no relevant pleural effusions developed during the follow-up period.

Although the authors’ experience is based on a single case, they do suggest bipleural drainage in patients with clinically relevant pleural effusions when the more common alternatives are not a good choice. Bipleural drainage might particularly be an option in children, who are prone to pleural effusion because of the smaller absorbing pleural surface. The authors reviewed the English-language literature on PubMed dating back to 1952. To their knowledge, this is the only published case in which a patient was treated with a ventriculo-bipleural shunt.

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The kallikrein-kinin system as mediator in vasogenic brain edema

Part 3: Inhibition of the kallikrein-kinin system in traumatic brain swelling

Andreas Unterberg, Claudia Dautermann, Alexander Baethmann, and Werner Müller-Esterl

✓ Evidence has previously been provided that administration of kinins to the cerebrum causes edema and opening of the blood-brain barrier. It has further been shown that these highly active compounds are formed in the brain under pathophysiological conditions. Their formation was enhanced when cerebral blood flow became compromised by an increase in intracranial pressure. Final evidence, however, was not available as to whether specific inhibition of the kallikrein-kinin (KK) system has a therapeutic function in acute head injury. The authors have demonstrated in rabbits that inhibition of the activating enzyme kallikrein by aprotinin or by aprotinin plus soybean trypsin inhibitor (SBTI), which interfere with plasma and tissue kallikrein, is associated with a decrease in formation of posttraumatic swelling after a standardized cold lesion to the brain. Saline-treated control animals with cerebral cold-induced injury had an increase in hemispheric weight 24 hours later of 13.0% ± 0.8% (standard error of the mean) in the damaged hemisphere compared to the contralateral nondamaged hemisphere. Administration of aprotinin or aprotinin plus SBTI led to a significant reduction of hemispheric swelling of 10.1% ± 0.7% or 10.4% ± 0.7%, respectively. In animals receiving SBTI only, hemispheric swelling evolving from cold injury was not significantly reduced. Therapeutic reduction of brain edema by aprotinin cannot be attributed to a nonspecific effect on the blood pressure, which in the experimental groups remained almost normal as compared to the control animals. Failure of SBTI to influence posttraumatic brain swelling may have resulted from disturbances in intravascular coagulation. Measurements of aprotinin in plasma and tissue demonstrate that the inhibitor doses employed are within an effective therapeutic range. Attenuation of brain edema by specific inhibition of the KK system provides evidence for a mediator role of kinins in vasogenic edema. Clinical trials with inhibitors of the KK system in acute forms of traumatic lesions associated with vasogenic edema appear worthwhile.

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Andreas W. Unterberg, Bruce J. Andersen, Geoff D. Clarke, and Anthony Marmarou

✓ Clinical and experimental evidence suggests that head injury can cause alterations of cerebral energy metabolism. However, the etiology of this metabolic perturbation is not known. The objective of this study was to determine the effect of fluid-percussion trauma on cerebral energy metabolism. Seven ventilated, chloralose-anesthetized cats were subjected to a 3.2-atm fluid-percussion brain injury. Before and for 8 hours after trauma, continuous phosphorus-31 magnetic resonance spectrography was obtained to noninvasively monitor tissue pH, phosphocreatine (PCr), and inorganic phosphate (Pi) levels. Measurement of cerebral blood flow (CBF) by the radioactive microsphere technique and calculation of oxygen and glucose consumption (CMRO2 and CMRGl) were also performed before trauma as well as 30 minutes and 1,2,4, and 8 hours after trauma. The data showed a moderate decrease in tissue pH from 7.04 to 6.89 at 30 minutes following trauma with return to control levels by 3 hours posttrauma. During the 8-hour observation period, CBF, CMRO2, and CMRGl remained at control levels. Tissue PCr and Pi levels were also unchanged.

Fluid-percussion trauma at the 3.2-atm level in ventilated cats causes a moderate and transient decrease in tissue pH that returns to control levels after trauma. No other metabolic changes are seen later than 30 minutes posttrauma. This indicates that a mild metabolic disturbance occurs after trauma in the ventilated animal and quickly returns to normal.

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John F. Stover, Nils-Kristian Dohse, and Andreas W. Unterberg

Object. Identification of new therapeutic agents aimed at attenuating posttraumatic brain edema formation remains an unresolved challenge. Among others, activation of bradykinin B2 receptors is known to mediate the formation of brain edema. The purpose of this study was to investigate the protective effect of the novel nonpeptide B2 receptor antagonist, LF 16-0687Ms, in brain-injured rats.

Methods. Focal contusion was produced by controlled cortical impact injury. Five minutes after trauma, the rats received a single dose of no, low- (3 mg/kg body weight), or high- (30 mg/kg) dose LF 16-0687Ms. After 24 hours, the amount of brain swelling and hemispheric water content were determined. Low and high doses of LF 16-0687Ms significantly reduced brain swelling by 25% and 27%, respectively (p < 0.03). Hemispheric water content tended to be increased in the nontraumatized hemisphere.

In a subsequent series of 10 rats, cisternal cerebrospinal fluid (CSF) samples were collected to determine whether changes in substances associated with edema formation could clarify why LF 16-0687Ms increases water content. For this, the volume regulator amino acid taurine, the excitatory transmitter glutamate, and the adenosine triphosphate degradation products hypoxanthine and xanthine were measured. In CSF, the levels of taurine, hypoxanthine, and xanthine were significantly decreased following a single administration of LF 16-0687Ms (p < 0.005); the level of glutamate, however, was double that found in control animals (p < 0.05).

Conclusions. Using the present study design, a single administration of LF 16-0687Ms successfully reduced posttraumatic brain swelling. The decreased levels of taurine, hypoxanthine, and xanthine may reflect reduced posttraumatic brain edema, whereas the increased level of glutamate could account for the elevated water content observed in the nontraumatized hemisphere.

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Bruce J. Andersen, Andreas W. Unterberg, Geoff D. Clarke, and Anthony Marmarou

✓ Cerebral energy metabolism was studied in cats subjected to fluid-percussion brain trauma followed immediately by 30 minutes of controlled hypoventilation for the purpose of simulating a more realistic model of human head injury. The cerebral blood flow (CBF) and cerebral metabolic rates of oxygen (CMRO2) and glucose (CMRGl) were measured, with simultaneous phosphorus-31 magnetic resonance spectroscopy quantifications of cerebral tissue pH, phosphocreatine (PCr), and inorganic phosphate (Pi). Hypoventilation alone did not produce marked changes in CMRGl, tissue pH, or PCr:Pi ratios. When hypoventilation was combined with trauma, marked alterations in CBF, CMRGl, PCr:Pi ratio, and tissue pH were seen, indicating relative ischemia. The alterations of cerebral energy metabolism produced by combining trauma and hypoventilation are more severe than those caused by fluid-percussion trauma alone, and may provide a more realistic model of human head injury.

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Ibn Sina (Avicenna)

Historical vignette

Asita S. Sarrafzadeh, Nuri Sarafian, Almut von Gladiss, Andreas W. Unterberg, and Wolfgang R. Lanksch

Ibn Sina (often known by his last name in Latin, Avicenna; 980–1037 A.D.) was the most famous physician and philosopher of his time. His Canon of Medicine, one of the most famous books in the history of medicine, surveyed the entire medical knowledge available from ancient and Muslim sources and provided his own contributions. In this article the authors present a unique picture of the neurosurgical technique of Ibn Sina and briefly summarize his life and work.