Characterization of rebound depolarization in hippocampal neurons.

Rebound depolarization (RD) following hyperpolarizing pulses is found in several neuronal cell types where it takes part in the regulation of neuronal firing behavior. During whole-cell current and voltage clamp recordings in slice preparations, we investigated the modulation of RD by different stimulation patterns and its underlying ionic currents in rat CA1 pyramidal cells. RD was mainly carried by the hyperpolarization-activated cation current I(h) (about two-third) and T-type calcium currents (about one-third), respectively. RD increased with increasing hyperpolarizing amplitude and stimulation frequency, whereas RD substantially decreased with longer pulse duration and, less pronounced, with increasing pulse number. The pulse duration-related decrease of RD was due to a decrease of the driving force of I(h). In conclusion, we showed that RD is differentially modulated by precedent hyperpolarization. Since RD amplitude was high enough to generate action potentials, RD may serve, even under physiologic conditions, as an inhibition-excitation converter.

Blood-brain barrier disruption by low-frequency ultrasound.

BACKGROUND AND PURPOSE: A recent study showed a dramatic increase in cerebral hemorrhage comprising atypical locations with low-frequency ultrasound-mediated recombinant tissue plasminogen activator-thrombolysis in humans. Here, we provide a possible explanation for this phenomenon by a side effect observed in a study using the similar ultrasound device. METHODS: The study was originally undertaken to investigate by transcranial Doppler sonography, positron emission tomography and perfusion MRI whether transcranial application of wide-field low-frequency ultrasound (300 kHz) improves cerebral hemodynamics in patients with cerebral small vessel disease. RESULTS: Showing no clear positive effect on cerebral hemodynamics in 4 patients and on cerebral perfusion (positron emission tomography) in 2 patients, the study has been terminated early because of a remarkable side effect in the first patient (a 62 year-old man) undergoing perfusion-MRI: detection of frontoparietal extravasation of Gadolinium contrast agent (applied during MRI perfusion imaging preinsonation) on MRI immediately postinsonation. CONCLUSIONS: Abnormal permeability of the human blood-brain barrier can be induced by wide-field low-frequency insonation. The observed excessive bleeding rate with low-frequency sonothrombolysis might thus be attributable to primary blood-brain barrier disruption by ultrasound.

Safety and therapeutical benefit of hemicraniectomy combined with mild hypothermia in comparison with hemicraniectomy alone in patients with malignant ischemic stroke.

INTRODUCTION: Both for hemicraniectomy and for hypothermia, several reports describe a beneficial effect in patients with malignant supratentorial cerebral ischemia. We compared the safety and the clinical outcome in patients with a malignant supratentorial infarction who were treated with hemicraniectomy alone (HA) or received a combination therapy with hemicraniectomy and hypothermia of 35 degrees C (HH), respectively. METHODS: In a prospective and randomized study, 25 consecutive patients were treated after an ischemic infarction of more than two thirds of one hemisphere by HA (n=13 patients) or the HH combination therapy (n=12 patients). Safety parameters were compared between both treatment groups, the clinical outcome was assessed during treatment and after 6 months. RESULTS: Age, cranial CT or MRI findings, initial National institutes of Health Stroke Scale Score (NIHSSS) and level of consciousness were not significantly different between both groups. Hemicraniectomy was performed within 15+/- 6 h after the ischemic event. Hypothermia was induced immediately after surgery. Overall mortality was 12% (2/13 vs. 1/12 in the two groups), but none of these 3 patients died due to treatment-related complications. There were no severe side effects of hypothermia. Duration of need for intensive care or for mechanical ventilation and infectious status did not differ significantly between both groups, but the need for catecholamine application was increased in the HH group. The clinical outcome showed a tendency for a better outcome in the HH compared with the HA group with respect to status after 6 months, as assessed by the NIHSSS (10+/-1 vs. 11+/-3, p<0.08). DISCUSSION: The present study suggests that a combined therapy of mild hypothermia and hemicraniectomy in malignant brain infarction does not imply additional risks by side effects and improves functional outcome as compared with hemicraniectomy alone.

Transcranial low-frequency ultrasound-mediated thrombolysis in brain ischemia: increased risk of hemorrhage with combined ultrasound and tissue plasminogen activator: results of a phase II clinical trial.

BACKGROUND: Clinical studies using ultrasound at diagnostic frequencies in transcranial Doppler devices provided encouraging results in enhancing thrombolysis with tissue plasminogen activator (tPA) in acute stroke. Low-frequency ultrasound does not require complex positioning procedures, penetrates through the skull better, and has been demonstrated to accelerate thrombolysis with tPA in animal experiments in wide cerebrovascular territories without hemorrhagic side effects. We therefore conducted the first multicenter clinical trial to investigate safety of tPA plus low-frequency ultrasound (300 kHz). METHODS: Acute stroke patients within a 6-hour time window were included (National Institutes of Health Stroke Scale scores >4). Magnetic resonance imaging (MRI) was used to document vascular occlusion and to rule out cerebral hemorrhage. Patients were allocated to combination therapy alternately; the first patient received tPA only, the second patient received tPA plus ultrasound, etc. Follow-up included serial MRI directly thereafter and 24 hours later to confirm recanalization and tissue imaging. Clinical recovery was measured after treatment and 3 months later. RESULTS: 26 patients (70.4+/-9.7 years) entered the trial (12 tPA, 14 tPA plus ultrasound). The study was prematurely stopped because 5 of 12 patients from the tPA only group but 13 of 14 patients treated with the tPA plus ultrasound showed signs of bleeding in MRI (P<0.01). Within 3 days of treatment, 5 symptomatic hemorrhages occurred within the tPA plus ultrasound group. At 3 months, neither morbidity nor treatment-related mortality or recanalization rates differed between both groups. CONCLUSIONS: This study demonstrated bioeffects from low-frequency ultrasound that caused an increased rate of cerebral hemorrhages in patients concomitantly treated with intravenous tPA.

Separating functional and structural damage in persistent vegetative state using combined voxel-based analysis of 3-D MRI and FDG-PET.

Functional and structural damage in postanoxic persistent vegetative state (PVS) was analysed using 18fluorodeoxyglucose PET (FDG-PET) coregistered to 3-D MRI in combination with morphometric 3-D MRI analysis (voxel-based morphometry, VBM). In five patients in late stages of non-traumatic PVS, combined analysis using statistical parametric mapping (SPM2) was performed to compare metabolic impairment and structural loss. FDG-PET showed widespread hypometabolism at p<0.001 (corrected) in the parietal, parietooccipital and frontotemporal cortices, cingulum, frontal medial and precentral gyrus, and within the bilateral thalamus. VBM revealed multilocal structural loss at p<0.001 (corrected) in the inferior parietal and superior/medial frontal cortices, insula and operculum, superior and medial temporal lobes, cingulum and fusiform gyrus, caudate, midbrain, dorsal pons, and the cerebellum, but to a lesser extent in the thalamus. The selective vulnerability of the brain in a sample of PVS patients could be mapped in vivo, indicating that a complex structural and functional lesion pattern of the cerebral networks seems to be associated with this condition.

Activation of a residual cortical network during painful stimulation in long-term postanoxic vegetative state: a 15O-H2O PET study.

Survivors of prolonged cerebral anoxia often remain in the persistent vegetative state (PVS). In this study, long-term PVS patients were investigated by 15O-H(2)O PET to analyze their central processing of pain. The study was approved by the local Ethics Committee, the experiments were performed in accordance with the Helsinki Declaration of 2000. Seven patients remaining in PVS of anoxic origin for a mean of 1.6 years (range 0.25-4 years) were investigated. We performed functional PET of the brain using 15O-labelled water during electrical nociceptive stimulation. Additionally, a brain metabolism study using 18F-fluorodeoxyglucose (FDG) PET and multi-sequence MRI (including a 3-D data set) were acquired in all patients. PET data were analyzed by means of Statistical Parametric Mapping (SPM99) and coregistered to a study-specific brain template. MRI and FDG PET showed severe cortical impairment at the structural and the functional level, that is, general atrophy of various degrees and a widespread significant hypometabolism, respectively. Pain-induced activation (hyperperfusion) was found in the posterior insula/secondary somatosensory cortex (SII), postcentral gyrus/primary somatosensory cortex (SI), and the cingulate cortex contralateral to the stimulus and in the posterior insula ipsilateral to the stimulus (P<0.05, small-volume-corrected). No additional areas of the complex pain-processing matrix were significantly activated. In conclusion, the regional activity found at the cortical level indicates that a residual pain-related cerebral network remains active in long-term PVS patients.

[Clinical symptomatology, diagnostics, and treatment in patients with tuberculous meningoencephalitis]. / Tuberkulöse Meningoenzephalitis: klinisches Bild, Diagnostik und Behandlung.

BACKGROUND: Tuberculous meningoencephalitis (TBM) is still associated with a high mortality. The relative rareness of TBM in Western European countries and the accompanying heterogeneous and unspecific clinical symptoms often result in a delayed diagnosis. PATIENTS AND METHODS: We present six HIV-negative patients (age 37-72 years) with a laboratory-confirmed or clinically probable diagnosis of TBM. The diagnosis could be confirmed in three patients by culture of the cerebrospinal fluid (CSF), in one patient by positive tracheal aspirate culture. In the cases with probable TBM, the diagnosis was confirmed by the combination of clinical symptoms, CSF analysis, and magnetic resonance imaging (MRI). DISCUSSION: The diagnostic and therapeutic problems in TBM are discussed. Moreover, the neurologic complications are presented which developed in all patients during the clinical course despite immediate antituberculous therapy.

Primary stenting as emergency therapy in acute basilar artery occlusion.

In three patients with acute occlusion of the basilar artery intra-arterial fibrinolysis resulted in only partial recanalization and revealed severe stenosis as the underlying cause. Application of micro-stents without previous dilatation resulted in vessel re-opening. Two patients had an excellent clinical outcome. One patient died 10 days after the stroke due to brainstem infarction. Emergency primary stent application may improve the outcome in acute basilar artery occlusion, if intra-arterial thrombolysis fails to re-establish a sufficient flow.

Transcranial color-coded sonography in basilar artery stenting.

Basilar artery (BA) stenting is an emerging technique with promising results in revascularization of severe arteriosclerotic stenoses. Because of the limitations associated with other noninvasive techniques, we applied transcranial color-coded sonography (TCCS) in the follow-up. Successful stent application in two cases of acute basilar occlusion caused by thrombosis on pre-existing severe midbasilar stenoses was initially confirmed by angiography. Later recanalization was controlled noninvasively by magnetic resonance angiography (MRA), computed tomographic angiography (CTA) and TCCS. Ultrasound (US) was performed through the transtemporal bone window; a contrast-enhancing agent had to be used in one case. TCCS showed an orthograde flow in the distal BA in both patients without signs of severe stenoses. Transtemporal TCCS was demonstrated to be a noninvasive bedside technique in monitoring the patency of the BA after stenting.