A. Kampfl

Attenuated Corticomedullary Contrast: An Early Cerebral Computed Tomography Sign Indicating Malignant Middle Cerebral Artery Infarction: A Case-Control Study

BACKGROUND AND PURPOSEnNo neuroradiological markers have been characterized that support a timely decision for decompressive surgery in malignant middle cerebral artery (MCA) infarction (mMCAI). This case-control study was designed to analyze whether early cerebral CT (CCT) scanning provides reliable information for the prospective selection of stroke patients at risk of developing mMCAI.nnnMETHODSnThirty-one pairs (n=62) were formed with cases (mMCAI) and controls (acute but not malignant MCA infarction) closely matched in terms of age, sex, and stroke etiology. CCT was performed within 18 hours of stroke onset and analyzed by a blinded neuroradiologist according to a defined panel of 12 CCT criteria.nnnRESULTSnIn terms of predicting mMCAI, the criteria of extended MCA territory hypodensities >67% and >50%, hemispheric brain swelling, midline shift, and hyperdense MCA sign exhibited high specificity (100%, 93. 5%, 100%, 96.7%, and 83.9%, respectively) but low sensitivity (45.2%, 58.1%, 12.9%, 19.4%, and 70.9%, respectively). Two criteria yielded high sensitivity (subarachnoid space compressed, 100%; cella media compressed, 80.6%) but low specificity (29% and 74.2%, respectively). The criterion of attenuated corticomedullary contrast yielded both high specificity (96.8%) and sensitivity (87.1%). The latter remained as the crucial criterion [Exp(B)=90.8; 95% CI, 5.8 to 1427. 5] in a 2-tailed logistic regression analysis with the strongest correlating parameters (Spearman correlation factor >/=0.6 or </=-0.6).nnnCONCLUSIONSnThe analysis of CCT scans within 18 hours of stroke onset revealed an attenuated corticomedullary contrast as the crucial CCT criterion, which, with both sufficient sensitivity and specificity, predicted mMCAI with 95% certainty.

Sphingosine-1-phosphate induces apoptosis of cultured hippocampal neurons that requires protein phosphatases and activator protein-1 complexes

In this study, we report that mobilization of internal Ca2+ by sphingosine-1-phosphate, a metabolite of ceramide, induces apoptosis in cultured hippocampal neurons. This sphingosine-1-phosphate-induced apoptosis is dependent upon the activation of protein phosphatases, possibly calcineurin and phosphatase 2A (or a related phosphatase). In addition, pretreatment of neurons with double-stranded oligonucleotides containing the metallothionein phorbol-12-myristate-13-acetate response element sequence as transcription factor decoys suppressed apoptosis. In contrast, double-stranded oligonucleotides containing either the c-jun or SV40 phorbol-12-myristate-13-acetate response element sequences were ineffective. Electrophoretic mobility shift assays and supershift assays revealed that c-Fos-containing activator protein- complexes preferentially bound the metallothionein phorbol-12-myristate-13-acetate response element sequence-containing oligonucleotides. Furthermore, antisense oligonucleotides to c-fos and c-jun were also protective. The apoptotic death of hippocampal neurons has been hypothesized to contribute to the cognitive impairments observed following insults to the brain. While increases in intracellular calcium are thought to be key mediators of neuronal apoptosis, the biochemical cascade(s) activated as a result of increased Ca2+ which mediates apoptosis of hippocampal neurons is (are) not well understood. The findings presented in this study suggest that mobilization of internal calcium via prolonged exposure of sphingosine-1-phosphate induces apoptosis of hippocampal neurons in culture. Sustained increases in intracellular calcium activate a phosphatase cascade that includes calcineurin and a phosphatase 2A-like phosphatase, and leads to the expression of genes containing metallothionein phorbol-12-myristate-13-acetate response element (TGAGTCA)-type enhancer sequences. The expression of genes containing TGAGTCA-type enhancer sequences appears to be essential for sphingosine-1-phosphate-induced apoptosis of hippocampal neurons.

Cerebral vasospasm and ischaemic infarction in clipped and coiled intracranial aneurysm patients

The influence of the treatment modalities (clipping/coiling) on the incidence of vasospasm and ischaemic infarction in aneurysm patients is still judged controversially. The purpose of this study was to analyse and compare retrospectively cerebral vasospasm and ischaemic infarction, as well as neurological deficits and outcome within a large population of clipped and coiled patients with ruptured and unruptured aneurysms. Within a 2‐year period, a total of 144 interventions (53 clipping/91 coiling) entered the study. Daily bilateral transcranial Doppler sonographic monitoring was performed to observe vasospasm development. All cerebral computed tomography (cCT) and magnetic resonance imaging (MRI) scans were reviewed with respect to occurrence and localization of ischaemic infarctions. Focal neurological deficits were recorded and clinical outcome was evaluated using the Glasgow Outcome Scale. Statistical analysis included the use of multivariate logistic regression models to find determinants of vasospasm, ischaemic infarction and neurological deficits. Altogether, vasospasm was detected after 77 (53.5%) interventions, 61.8% in females (Pu2003<u20030.01). Clipped patients significantly more often exhibited vasospasms (69.8 vs. 44.0%, Pu2003<u20030.005) and were treated 1u2003week longer at the intensive care unit (Pu2003<u20030.005). Seventy‐seven patients (53.5%) developed ischaemic infarctions, 62.3% after clipping and 48.4% after coiling (Pu2003>u20030.05). In the multivariate analysis, aneurysm‐rupture was the strongest predictor for vasospasm and vasospasm was the strongest predictor for infarction. Neurological deficits at discharge (46.5%) were independent of treatment modality, the same applied for the mean Glasgow Outcome Scores. There was no significant difference in mortality between surgical and endovascular treatment (9.4 vs. 12.1%). Whilst the vasospasm incidence was significantly higher after surgical treatment, ischaemic infarctions were only slightly more frequent. The incidence of neurological deficits and clinical outcome was similar in both treatment groups.

Cerebrospinal Fluid (CSF) Pharmacokinetics of Intraventricular Vancomycin in Patients with Staphylococcal Ventriculitis Associated with External CSF Drainage

We studied the efficacy and pharmacokinetics of intraventricularly administered vancomycin in three patients with shunt-associated staphylococcal ventriculitis. We instilled 10 mg of the drug intraventricularly every 24 hours. Cerebrospinal fluid (CSF) levels were measured 1 hour after instillation and then every 2 hours. Peak vancomycin levels reached a mean of 292.9 microg/mL. The mean trough levels, measured immediately before readministration of vancomycin, were 7.6 microg/mL; this level has proved to be sufficient for maintaining the necessary steady-state serum concentration of vancomycin. All three patients were cured clinically and bacteriologically, and CSF parameters returned to normal within 5-13 days. No side effects were observed. Our results suggest that intraventricularly administered vancomycin is a valuable therapeutic strategy for treating shunt-associated staphylococcal ventriculitis. In addition, we provide evidence that 10 mg of vancomycin, administered intraventricularly every 24 hours, allows maintenance of therapeutic drug levels in the CSF for at least 24 hours.

Light and confocal microscopic studies of evolutionary changes in neurofilament proteins following cortical impact injury in the rat

Previous studies have shown that traumatic brain injury (TBI) produces progressive degradation of cytoskeletal proteins including neurofilaments (e.g., neurofilament 68 [NF68] and neurofilament 200 [NF200]) within the first 24 h after injury. Thus, we employed immunofluorescence (light and confocal microscopy) to study the histopathological correlates of progressive neurofilament protein loss observed at 15 min, 3 h, and 24 h following unilateral cortical injury in rats. TBI produced significant alterations in NF68 and NF200 immunolabeling in dendrites and cell bodies at contusion sites ipsilateral to injury, as well as in the noncontused contralateral cortex. Changes in immunolabeling were associated with, but not exclusively restricted to, regions previously shown to contain dark shrunken neurons labeled by hematoxylin and eosin staining, a morphopathological response to injury suggesting impending cell death. Immunofluorescence microscopic studies of neurofilament proteins in the ipsilateral cerebral cortex detected prominent fragmentation of apical dendrites of pyramidal neurons in layers 3-5 and loss of fine dendritic arborization within layer 1. While modest changes were observed 15 min following injury, more pronounced loss of dendritic neurofilament immunofluorescence was detected 3 and 24 h following injury. Confocal microscopy also revealed progressive alterations in NF68 immunoreactivity in dendrites following TBI. While some evidence of structural alterations was observed 15 min following TBI, dendritic breaks were readily detected in confocal micrographs from 3 to 24 h following injury. However, disturbances in axonal NF68 by immunofluorescence microscopy in the corpus callosum were not detected until 24 h after injury. These studies confirmed that derangements in dendritic neurofilament cytoskeletal proteins are not exclusively restricted to sites of impact contusion. Moreover, changes in dendritic cytoskeletal proteins are progressive and not fully expressed within the first 15 min following impact injury. These progressive dendritic disruptions are characterized by disturbances in the morphology of neurofilament proteins, resulting in fragmentation and focal loss of NF68 immunofluorescence within apical dendrites. In contrast, alterations in axonal cytoskeletal proteins are more restricted and delayed with no pronounced changes until 24 h after injury.

Subcellular localization and duration of μ-calpain and m-calpain activity after traumatic brain injury in the rat : A casein zymography study

Casein zymographic assays were performed to identify changes in μ-calpain and m-calpain activity in naive, sham-injured, and injured rat cortex at 15 minutes, 3 hours, 6 hours, and 24 hours after unilateral cortical impact brain injury. Cortical samples ipsilateral and contralateral to the site of injury were separated into cytosolic and total membrane fractions. Marked increases in μ-calpain activity in cytosolic fractions in the ipsilateral cortex occurred as early as 15 minutes, became maximal at 6 hours, and decreased at 24 hours to levels observed at 15 minutes after injury. A similar temporal profile of cytosolic μ-calpain activity in the contralateral cortex was observed, although the increases in the contralateral cortex were substantially lower than those in the ipsilateral cortex. Differences were also noted between cytosolic and total membrane fractions. The detection of a shift in μ-calpain activity to the total membrane fraction first occurred at 3 hours after traumatic brain injury and became maximal at 24 hours after traumatic brain injury. This shift in μ-calpain activity between the two fractions could be due to the redistribution of μ-calpain from the cytosol to the membrane. m-Calpain activity was detected only in cytosolic fractions. m-Calpain activity in cytosolic fractions did not differ significantly between ipsilateral and contralateral cortices, and increased in both cortices from 15 minutes to 6 hours after injury. Relative magnitudes of m-calpain versus μ-calpain activity in cytosolic fractions differed at different time points after injury. These studies suggest that traumatic brain injury can activate both calpain isoforms and that calpain activity is not restricted to sites of focal contusion and cell death at the site of impact injury but may represent a more global response to injury.

Immunoblot Analyses of the Relative Contributions of Cysteine and Aspartic Proteases to Neurofilament Breakdown Products Following Experimental Brain Injury in Rats

Analyses using either one or two-dimensional gel electrophoresis were performed to identify the contribution of several proteases to lower molecular weight (MW) neurofilament 68 (NF68) break down products (BDPs) detected in cortical homogenates following unilateral cortical impact injury in rats. One dimensional immunoblot of BDPs obtained from in vitro cleavage of enriched neurofilaments (NF) by purified μ-calpain, m-calpain, cathepsin, B, cathepsin D, and CPP32 (caspase-3) were compared to in vivo samples from rats following traumatic brain injury (TBI). Comparison of these blots provided information on the relative contribution of different cysteine or aspartic proteases to NF loss following brain injury. As early as 3 hrs post-injury, cortical impact resulted in the presence of several lower MW NF68 immunopositive bands having patterns similar to those previously reported to be produced by calpain mediated proteolysis of neurofilaments. Only μ-calpain and m-calpain in vitro digestion of enriched neurofilaments contributed to the presence of the low MW 57 kD NF68 break down product (BDP) detected in post-TBI samples. Cathepsin B, cathepsin D, and caspase-3 failed to produce either the 53 kD or 57 kD NF BDPs. Further, 1 and 2 dimensional peptide maps containing a 1:1 ratio of in vivo and in vitro tissue samples showed complete comigration of lower MW immunopositive spots produced by TBI or in vitro incubation with m-calpain, thus providing additional evidence for the potential role of calpain activation to the production of NF68 BDPs following TBI. More importantly, 2-dimensional gel electrophoresis detected that immunopositive NF68 spots shifted to the basic pole (+) suggesting that dephosphorylation of the NF68 subunit pool may be associated with NF protein loss following TBI, an observation not previously noted in any model of experimental brain injury.

Refractory status epilepticus due to acute hepatic porphyria in a pregnant woman: induced abortion as the sole therapeutic option?

A 22‐years old, 55u2003kg female patient in the twelfth week of pregnancy developed neuropsychiatric syndromes and in the following status epilepticus. Raised porphyrines and porphyrine precursors were found in the patients urine. Despite intravenous glucose infusions and appropriate medication no reduction in seizure‐frequency and neuropsychiatric syndromes was observed. An abortion was induced. After the interruption and starting of haem arginate therapy, seizure activity stopped and porphyrine precursors returned to normal levels, and after 6u2003weeks the patient was discharged in excellent clinical condition. This report describes a status epilepticus caused by acute hepatic porphyria, triggered by pregnancy, in a 22‐years old woman. To our knowledge this is the first report of induced abortion as successful treatment in acute hepatic porphyria induced status epilepticus.

Traumatic intracranial hemorrhages in facial fracture patients: review of 2,195 patients

ObjectivePatients sustaining facial fractures are at risk for accompanying traumatic intracranial hematomas, which are a major cause of morbidity and mortality. Prompt recognition is crucial in improving patient survival and recovery. This study examined which simple clinical signs identify facial fracture patients at risk for intracranial hemorrhage before the performance of computed tomography.Design and methodsRetrospective study of 2,195 patients with facial fractures during a period of 7xa0years. By means of univariate and multivariate analysis clinical features potentially predictive for (a) intracranial hemorrhage and (b) surgery for intracranial hemorrhage were identified.SettingCritical care units of anesthesiology and neurology, general traumatology, and oral and maxillofacial surgery in a level I trauma university hospital.ResultsSeizures (OR 22.1) and vomiting/nausea (OR 20.2) were the strongest independent predictors of intracranial bleeding in facial fracture patients. For intracranial hemorrhages requiring surgical intervention closed head injuries (OR 9.75) and cranial vault fractures (OR 5.0) were the most significant risk factors. However, among those patients without vomiting/nausea and without seizures and without closed head injury (n=1,628), 20 patients (1.2%) suffered intracranial hemorrhage, and six (0.37%) of them required surgical intervention.ConclusionsSimple clinical symptoms, such as seizures, vomiting/nausea, history of a closed head injury or cranial vault fractures are strong predictors for intracranial hemorrhage in facial fracture patients. The early consideration of such important indicators allows us to detect patients at elevated risk of an intracranial hematoma requiring surgical intervention.

Syndrome of the anterior spinal artery as the primary manifestation of aspergillosis

SummaryAspergillosis of the central nervous system (CNS) is an uncommon infection, mainly occurring in immunocompromised patients. Beside cerebral involvement spinal cord lesions are extremely rare. To our knowledge, aspergillosis initially presenting with acute paraplegia due to mycotic thrombosis of the anterior spinal artery in a formerly healthy patient has, so far, not been reported. Neither a primary focus nor an underlying disease had been detected.ZusammenfassungEine Aspergillose des zentralen Nervensystems (vorwiegend cerebrum) ist eine ungewöhnliche Infektion, die hauptsächlich bei immunkompromittierten Patienten vorkommt. Eine Aspergillose, die sich initial als akutes A. spinalis anterior Syndrom präsentiert — bei mykotischer Thrombose — wurde bis jetzt noch nicht mitgeteilt. In diesem sonst gesunden Patienten war kein Fokus gefunden worden.Aspergillosis of the central nervous system (CNS) is an uncommon infection, mainly occurring in immunocompromised patients. Beside cerebral involvement spinal cord lesions are extremely rare. To our knowledge, aspergillosis initially presenting with acute paraplegia due to mycotic thrombosis of the anterior spinal artery in a formerly healthy patient has, so far, not been reported. Neither a primary focus nor an underlying disease had been detected. Eine Aspergillose des zentralen Nervensystems (vorwiegend cerebrum) ist eine ungewöhnliche Infektion, die hauptsächlich bei immunkompromittierten Patienten vorkommt. Eine Aspergillose, die sich initial als akutes A. spinalis anterior Syndrom präsentiert — bei mykotischer Thrombose — wurde bis jetzt noch nicht mitgeteilt. In diesem sonst gesunden Patienten war kein Fokus gefunden worden.