Matthias Spranger

Moderate Hypothermia in the Treatment of Patients With Severe Middle Cerebral Artery Infarction

BACKGROUND AND PURPOSE Animal research and clinical studies in head trauma patients suggest that moderate hypothermia may improve outcome by attenuating the deleterious metabolic processes in neuronal injury. Clinical studies on moderate hypothermia in the treatment of acute ischemic stroke patients are still lacking. METHODS Moderate hypothermia was induced in 25 patients with severe ischemic stroke in the middle cerebral artery (MCA) territory for therapy of postischemic brain edema. Hypothermia was induced within 14+/-7 hours after stroke onset and achieved by external cooling with cooling blankets, cold infusions, and cold washing. Patients were kept at 33 degreesC body-core temperature for 48 to 72 hours, and intracranial pressure (ICP), cerebral perfusion pressure, and brain temperature were monitored continuously. Outcome at 4 weeks and 3 months after the stroke was analyzed with the Scandinavian Stroke Scale (SSS) and Barthel index. The side effects of induced moderate hypothermia were analyzed. RESULTS Fourteen patients survived the hemispheric stroke (56%). Neurological outcome according to the SSS score was 29 (range, 25 to 37) 4 weeks after stroke and 38 (range 28 to 48) 3 months after stroke. During hypothermia, elevated ICP values could be significantly reduced. Herniation caused by a secondary rise in ICP after rewarming was the cause of death in all remaining patients. The most frequent complication of moderate hypothermia was pneumonia in 10 of the 25 patients (40%). Other severe side effects of hypothermia could not be detected. CONCLUSIONS Moderate hypothermia in the treatment of severe cerebral ischemia is not associated with severe side effects. Moderate hypothermia can help to control critically elevated ICP values in severe space-occupying edema after MCA stroke and may improve clinical outcome in these patients.

Intraventricular Brain-Derived Neurotrophic Factor Reduces Infarct Size after Focal Cerebral Ischemia in Rats

Brain-derived neurotrophic factor (BDNF), acting through the high-affinity receptor tyrosine kinase (TrkB), is widely distributed throughout the central nervous system and displays in vitro trophic effects on a wide range of neuronal cells, including hippocampal, cerebellar, and cortical neurons. In vivo, BDNF rescues motorneurons, hippocampal, and substantia nigral dopaminergic cells from traumatic and toxic brain injury. After transient middle cerebral artery occlusion (MCAO), upregulation of BDNF-mRNA in cortical neurons suggests that BDNF potentially plays a neuroprotective role in focal cerebral ischemia. In the current study, BDNF (2.1 μg/d) in vehicle or vehicle alone (controls) was delivered intraventricularly for 8 days, beginning 24 hours before permanent middle cerebral artery occlusion by intraluminal suture in Wistar rats (n = 13 per group). There were no differences in physiological variables recorded during surgery for the two groups. Neurological deficit (0 to 4 scale), which was assessed on a daily basis, improved in BDNF-treated animals compared with controls (P < 0.05; analysis of variance and Scheffes test). There were no significant differences in weight in BDNF-treated animals and controls during the experiment. After elective killing on day 7 after MCAO, brains underwent 2,3,5-triphenyltetrazolium chloride staining for calculation of the infarct volume and for histology (hematoxylin and eosin and glial fibrillary acid protein). The mean total infarct volume was 83.1 ± 27.1 mm3 in BDNF-treated animals and 139.2 ± 56.4 mm3 in controls (mean ± SD; P < 0.01, unpaired, two-tailed t-test). The cortical infarct volume was 10.8 ± 7.1 mm3 in BDNF-treated animals and 37.9 ± 19.8 mm3 in controls (mean ± SD; P < 0.05; unpaired, two-tailed t-test), whereas ischemic lesion volume in caudoputaminal infarction was not significantly different. These results show that pretreatment with intraventricular BDNF reduces infarct size after focal cerebral ischemia in rats and support the hypothesis of a neuroprotective role for BDNF in stoke.

Brain temperature monitoring and modulation in patients with severe MCA infarction

Article abstract-Background: Brain temperature has been measured only occasionally in humans. After head trauma, a temperature gradient in brain temperature compared with body temperature of up to 3 degrees C degrees higher in the brain has been reported. Elevated temperature facilitates neuronal injury after ischemia. At present, no information concerning changes in brain temperature after acute stroke is available. Methods: In 15 patients who had suffered severe ischemic stroke in the MCA territory, intracerebral temperature was recorded with use of two different thermocouples, with intraventricular, epidural, and parenchymatous measurements. Body-core temperature (Foley catheter temperature) and jugular bulb temperature (n = 5) were recorded simultaneously. Measures for reducing brain temperature were compared. Results: In all patients, brain temperature exceeded body-core temperature by at least up to 1 degrees C (range, 1.0 to 2.1 degrees C). Temperature in the ventricles exceeded epidural temperature by up to 2.0 degrees C. Brain temperature modulation was independent of single pharmacologic (paracetamol, metamizol) treatments. Only systemic cooling was effective and sustained hypothermic (33 to 34 degrees C) brain temperatures. Conclusion: After MCA stroke, human intracerebral temperature is higher than central body-core temperature. There is also a temperature gradient within the brain, with the ventricles warmer than the surface. Mild hypothermia in the treatment of severe cerebral ischemia with use of cooling blankets is both easy to perform and effective in the therapy of severe hemispheric infarction. NEUROLOGY 1997;48: 762-767

Inhibition of caspases prevents cell death of hippocampal CA1 neurons, but not impairment of hippocampal long-term potentiation following global ischemia.

An essential role for caspases in programmed neuronal cell death has been demonstrated in various in vitro studies, and synthetic caspase inhibitors have recently been shown to prevent neuronal cell loss in animal models of focal cerebral ischemia and traumatic brain injury, respectively. The therapeutic utility of caspase inhibitors, however, will depend on preservation of both structural and functional integrity of neurons under stressful conditions. The present study demonstrates that expression and proteolytic activity of caspase-3 is up-regulated in the rat hippocampus after transient forebrain ischemia. Continuous i.c.v. infusion of the caspase inhibitor N-benzyloxycarbonyl-Asp(OMe)-Glu(OMe)-Val-Asp(OMe)-fluoromethyl ketone significantly attenuated caspase-3-like enzymatic activity, and blocked delayed cell loss of hippocampal CA1 neurons after ischemia. Administration of N-benzyloxycarbonyl-Asp(OMe)-Glu(OMe)-Val-Asp(OMe)-fluoromethyl ketone, however, did not prevent impairment of induction of long-term potentiation in post-ischemic CA1 cells, suggesting that caspase inhibition alone does not preserve neuronal functional plasticity.

Superoxide Dismutase Activity in Serum of Patients With Acute Cerebral Ischemic Injury: Correlation With Clinical Course and Infarct Size

BACKGROUND AND PURPOSE Superoxide dismutase (SOD) is one of the major free radical scavenging systems that might play a role in both degenerative and acute diseases of the central nervous system. METHODS We measured SOD activity in the serum of 41 patients with acute ischemic stroke with a chemiluminometric assay based on the generation of oxygen free radicals by xanthine and xanthine oxidase. RESULTS SOD activity was significantly lower in patients with ischemic stroke than in age-matched control patients with nonvascular, neurological illnesses (n = 24; P < .034, Wilcoxon rank test). The activity was inversely correlated with the size of infarction on CT (P = .01, Spearman correlation) and the severity of neurological deficits (P < .001, Spearman correlation). The decreased SOD activity recovered within 5 days after stroke to values found in serum of control patients. CONCLUSIONS Our data suggest that the SOD activity in serum is reduced in stroke patients, and replacement of antioxidative activity could be beneficial in the acute treatment of cerebral ischemia.

Brain-Derived Neurotrophic Factor Improves Long-Term Potentiation and Cognitive Functions after Transient Forebrain Ischemia in the Rat

We investigated the effect of brain-derived neurotrophic factor (BDNF) on hippocampal long-term potentiation (LTP) and cognitive functions after global cerebral ischemia in the rat. After four-vessel occlusion, BDNF was administered via an osmotic minipump continuously over 14 days intracerebroventricularly. Electrophysiological experiments were performed 14 days after cerebral ischemia. Test stimuli and tetanization were delivered to the Schaffer collaterals of the hippocampus and field excitatory postsynaptic potentials (fEPSP) were recorded in the CA1 region. Cognitive impairment was analyzed repeatedly with a passive avoidance test, a hole-board test, and with an activity center on the same animal. In sham-operated animals, LTP was consistantly induced after delivering a tetanus (increase of initial slope of fEPSP to 173 +/- 12% of baseline; n = 6). After transient forebrain ischemia LTP could not be induced (117 +/- 4% of baseline; n = 7). In ischemic animals treated with BDNF, LTP could be induced (168 +/- 28% of baseline; n = 8). Transient forebrain ischemia resulted in a significant decrease in spatial discrimination performance but not of associative memory. The ratios for working memory (WM) and reference memory (RM) 15 days after ischemia were lower in the ischemic rats (n = 10) than in the sham-operated control animals (n = 10; WM: 22 +/- 6 vs 72 +/- 7; RM: 30 +/- 7 vs 72 +/- 5). Postischemic intracerebroventricular BDNF infusion increased both WM (63 +/- 4; n = 10) and RM (58 +/- 5; n = 10). The spontaneous locomotor activity did not differ significantly in the three groups. These data indicate a protective effect of BDNF for synaptic transmission and cognitive functions after transient forebrain ischemia.

Bradykinin induces interleukin-6 expression in astrocytes through activation of nuclear factor-κB

Abstract : Bradykinin, a mediator of inflammation, is produced in the brain during trauma and stroke. It is thought to open the blood‐brain barrier, although the mechanism is unclear. We have investigated, therefore, the effect of bradykinin on the expression of interleukin‐6 (IL‐6), a putative modulator of the blood‐brain barrier, in astrocytes. IL‐6 gene transcription was evaluated by transient transfection of the human IL‐6 promoter linked to the luciferase gene. In murine astrocytes, bradykinin stimulated IL‐6 secretion and gene transcription. The effect of bradykinin was blocked by KN‐93, an inhibitor of Ca2+/calmodulin‐dependent protein kinases, and by bisindolyl‐maleimide I, an inhibitor of protein kinase C, suggesting the involvement of these protein kinases. Mutations in the multiple response element and the binding site for nuclear factor‐κB (NF‐κB), but not in other known elements of the IL‐6 promoter, interfered with induction of IL‐6 transcription. The involvement of NF‐κB was supported further by the binding that overexpression of nmIκBα, a stable inhibitor of NF‐κB, inhibited the induction of IL‐6 by bradykinin. Bradykinin activated NF‐κB in primary astrocytes as shown by increased DNA binding of NF‐κB. These data demonstrate that bradykinin stimulates IL‐6 expression through activation of NF‐κB, which may explain several inflammatory effects of bradykinin.

Brain‐derived neurotrophic factor prevents neuronal death and glial activation after global ischemia in the rat

The expression of brain‐derived neurotrophic factor (BDNF) and its receptor tyrosine kinase B are both increased after global ischemia. Therefore, a protective action of BDNF against the delayed degeneration of vulnerable neurons has been suggested. We have investigated the neuroprotective action of BDNF in global ischemia induced by a four‐vessel occlusion in the rat. Following reperfusion, 0.06 μg/hr BDNF was continuously administered intracerebroventricularly with an osmotic minipump. Rats were sacrificed up to 7 days after ischemia and neuronal degeneration was identified by terminal transferase and biotin‐dUTP nick end labeling (TUNEL) staining. Additionally, the glial reaction was investigated immunohistochemically and by measuring the activation of immunological nitric oxide synthase protein expression. Postischemic intracerebroventricular infusion of BDNF prevented neuronal death in the vulnerable CA1 region of the hippocampus. Additionally, astroglial activation and macrophage infiltration, which were observed in association with neuronal death, were inhibited by BDNF. This was paralleled by an inhibition of inducible nitric oxide synthase (iNOS) expression in the hippocampus. Thus, the observed neuroprotective effects of continuous BDNF administration after reperfusion suggest a therapeutic potential for BDNF in cerebral ischemia. J. Neurosci. Res. 56:21–27, 1999. 

Stimulation of Interleukin‐6 Secretion and Gene Transcription in Primary Astrocytes by Adenosine

Abstract: During cerebral ischemia, the expression of interleukin‐6 (IL‐6), which has neuroprotective properties, increases. To understand the underlying mechanism, the regulation of IL‐6 expression by neurotransmitters that accumulate during cerebral ischemia was investigated. Adenosine stimulated IL‐6 secretion in primary astrocytes four‐ to 10‐fold. The effect was concentration dependent, the EC50 being ∼8 µM. Although the nonselective analogue 2‐chloroadenosine (2CA) increased IL‐6 secretion to a similar extent, the A1‐selective agonist N6‐cyclopentyladenosine or the A2a agonist CGS‐21680 had only a marginal effect on IL‐6 secretion. IL‐6 secretion stimulated by 2CA (10 µM) was inhibited by the nonselective adenosine antagonist 8‐(p‐sulfophenyl)theophylline, whereas the A1‐selective antagonist 8‐cyclopentyl‐1,3‐dipropylxanthine or the A2a‐selective antagonist 8‐(3‐chlorostyryl)caffeine had no effect, to a concentration of 0.1 µM. Transcription of the IL‐6 gene was investigated by transfecting primary astrocytes with a reporter fusion gene containing the human IL‐6 promoter (−179/+12). 2CA stimulated IL‐6 gene transcription 2.5‐fold. Mutations of the binding site for NF‐κB or NF‐IL6 abrogated the response to 2CA. Thus, an increase of extracellular adenosine during focal cerebral ischemia may stimulate IL‐6 expression via A2b receptors. The induction of IL‐6 expression appears to involve a transcriptional effect that depends on NF‐κB and NF‐IL6.

Craniectomy: An aggressive treatment approach in severe encephalitis

Article abstract-Background and objective: Focal encephalitis may be associated with brain edema, which is often fatal. The control of intracranial pressure (ICP) is therefore crucial for further therapeutic strategies in space-occupying edema following encephalitis. However, aggressive treatment strategies such as hemicraniectomy have not been described in a larger series of patients. Patients and methods: We describe the clinical course and outcome in six patients who developed severe brain edema associated with acute encephalitis. All received maximum medical treatment for elevated ICP, but with signs of brainstem compression emerging, hemicraniectomy was performed to control ICP. Results: All patients had a very severe encephalitic syndrome and were treated over the course of weeks in the neurocritical care unit (NCCU). However, all patients recovered almost completely and showed only mild or no neurologic deficit when reexamined after 4 months to 3 years. Conclusion: Hemicraniectomy should be considered in patients with severe brain edema following encephalitis as a potentially lifesaving therapeutic measure. Moreover, the initial neurologic deficit seems to have no impact on the long-term clinical outcome. NEUROLOGY 1997;48 412-417