Rolf W. Seiler

Dependency of Blood Flow Velocity in the Middle Cerebral Artery on End-Tidal Carbon Dioxide Partial Pressure—A Transcranial Ultrasound Doppler Study:

The end-tidal carbon dioxide partial pressure (PCO2) response curves for the flow velocity in the middle cerebral artery were studied in 31 normal subjects with transcranial Doppler techniques. An exponential curve with an exponent of 0.034 mm Hg−1 was found to be a good fit to the recorded data. By means of this relationship, recordings of flow velocity in cerebral arteries can be normalized to a standard value of PCO2. Physiological aspects of cerebrovascular reactivity to PCO2 and the clinical implications of the PCO2 response curve are discussed. The normal material provides a reference for assessing pathological responses.

Evaluation of posttraumatic cerebral blood flow velocities by transcranial Doppler ultrasonography.

Thirty-five patients were admitted to the hospital with Glasgow coma scale scores of 4 to 7 after severe, blunt head injury. Blood flow velocities of the middle cerebral artery (MCA) and the ipsilateral internal carotid artery (ICA), high in the neck, were recorded noninvasively by Doppler ultrasonography. Serial examinations were begun within 48 hours of trauma and continued until the patient either died or was discharged. Spasm of the MCA was assumed if the ratio of the velocity of blood flow in the MCA (VMCA) to the velocity of blood flow in the ICA (VICA) exceeded 3 (normal value, 1.7 +/- 0.4). In cases of severe MCA spasm, this ratio is higher because of increased flow velocity in the MCA and reduced flow in the ICA due to increased cerebrovascular resistance. Higher MCA velocities with VMCA/VICA above 3, consistent with MCA spasm, were found in 14 of the 35 patients (40%). The increase began as early as 48 hours after injury, reached a maximum between Days 5 and 7, and lasted until 2 weeks after injury. There was a significant correlation between the occurrence of vasospasm and the quantity of cisternal or intracerebral blood seen on a computed tomographic scan. No correlation was found with the age of the patients, the Glasgow coma scale score at admission, the intracranial pressure, or the functional outcome 6 months after injury. The occurrence of a secondary infarction in a patient with severe MCA spasm suggests that, at least in some cases, spasm may influence the prognosis.

Evaluation of cerebrovascular disease by combined extracranial and transcranial Doppler sonography. Experience in 1,039 patients.

Results from 1,039 combined cervical and transcranial Doppler examinations are reported. Satisfactory transcranial signals were not found in 2.7% of the cases. Compared with angiography, the accuracy of transcranial criteria in assessing collateral flow over the circle of Willis was 94 and 88% for anterior and posterior circulation, respectively. The method also appeared very promising for detection of lesions of the intracranial arteries although the number of such cases with angiographic verification was limited in the present series. Arterial narrowing due to cerebral vasospasm was diagnosed with a sensitivity of 80%. In patients with ruptured intracranial aneurysms, an incidence of 93% arterial narrowing in basal cerebral arteries was found. Patients with subarachnoid hemorrhage and no aneurysm on angiography also showed arterial narrowing with an incidence of 56%. It was possible to monitor the time course and severity of cerebral vasospasm. Arteriovenous malformations were characterized by Doppler findings of high velocities and low pulsatilities. These lesions were diagnosed with an accuracy of 95%.

Implants of Polymer-Encapsulated Genetically Modified Cells Releasing Glial Cell Line-Derived Neurotrophic Factor Improve Survival, Growth, and Function of Fetal Dopaminergic Grafts

Neural transplantation as an experimental therapy for Parkinsonian patients has been shown to be effective in several clinical trials. Further benefit, however, may be expected if the grafting is combined with a treatment of neurotrophic factors thus improving the survival and growth of grafted embryonic dopaminergic neurons. Continuous trophic support may be needed and therefore requires the long-term delivery of neurotrophic factors to the brain. We demonstrate here that the implantation of polymer-encapsulated cells genetically engineered to continuously secrete glial cell line-derived neurotrophic factor to the adult rat striatum improves dopaminergic graft survival and function. Near complete compensation of 6-hydroxydopamine-induced rotation was already achieved within 3 weeks postgrafting in rats that received glial cell line-derived neurotrophic factor-releasing capsules in addition to dopaminergic cell grafts of cultured tissue. Rats without trophic factor supply showed only little recovery at the same time point and sham grafted rats showed no recovery. The number of tyrosine hydroxylase-immunoreactive cells per graft was increased 2.6-fold in the presence of glial cell line-derived neurotrophic factor 6 weeks postgrafting. Similarly, tyrosine hydroxylase-immunoreactive fibers around the graft were increased by 53%. Moreover, these fibers showed a preferential growth towards the trophic factor-releasing capsule. Taken together, these results provide evidence that encapsulated genetically engineered cells are an effective means of long-term trophic factor supply into the adult rat brain and that the delivery of glial cell line-derived neurotrophic factor can sustain dopaminergic graft function and survival.

Outcome of aneurysmal subarachnoid hemorrhage in a hospital population: a prospective study including early operation, intravenous nimodipine, and transcranial Doppler ultrasound

A total of 153 consecutive patients with proven aneurysmal subarachnoid hemorrhages (SAHs) admitted immediately after diagnosis regardless of clinical condition were managed according to the same protocol. The initial evaluation included computed tomography (CT), transcranial Doppler ultrasound (TCD), angiography-CT, and/or angiography. Intravenous nimodipine (2 mg/hour) was started after confirmation of the diagnosis. The timing of operation was determined individually according to age, clinical course, and CT and TCD findings. Twenty-one Grade V patients treated with intensive care and ventriculostomy died or did not improve within 24 hours after SAH. Three patients with life-threatening intracerebral hematomas underwent emergency operation. Operation was early in 55 good risk patients and late in 57 patients because of poor initial grade, late admission, or logistic reasons. Seventeen patients had no operation because of old age, persistent poor clinical condition, medical complication, or lethal rebleeding before operation. In the total series, 90 patients (59%) made a full recovery, the overall morbidity rate was 14% (21 of 153 cases), and the mortality rate was 27% (42 of 153). Postoperative mortality including emergency evacuation of hematomas was 7.8% and mortality after elective operation was 6.2%. The causes of disability and death were the initial effect of the hemorrhage in 25 patients (16.3%), rebleeding in 15 (9.8%), delayed cerebral infarction in 8 (5.2%), surgical complications in 7 (4.5%), hydrocephalus in 4 (2.6%), and medical complications in 4 (2.6%).

Transcranial Doppler monitoring in head injury: relations between type of injury, flow velocities, vasoreactivity, and outcome.

Eighty-six patients with head injuries with an admission Glasgow Coma Scale score between 3 and 12 were studied sequentially by transcranial and cervical Doppler sonography. On a subset of 26 patients, sequential autoregulation and CO2 reactivity testing was also performed. Patient characteristics and hemodynamic data were correlated and analyzed with respect to the final outcome. The internal carotid artery (ICA) and middle cerebral artery flow velocities followed a typical pattern. Both were depressed during the first 3 days after the trauma and then increased to a maximum between Days 5 and 7. The increase of the middle cerebral artery flow velocities was more pronounced than the increase of the ICA flow velocities, thus indicating some degree of vasospasm. The amount of subarachnoid hemorrhage on the initial computed tomography correlated with the average middle cerebral artery/ICA flow velocity ratio (r = 0.5). Subarachnoid hemorrhages on computed tomography and, to a lesser degree, subdural and intracerebral hematomas were correlated with an unfavorable outcome. Vasospasm remained subcritical, and no negative relationship to outcome could be identified. Hyperperfusion, as based on ICA flow velocities, and vasospasm were correlated with diminished vasoreactivity. However, disturbed vasoreactivities, particularly during the first days, were common and did not necessarily predict an unfavorable outcome.

Effects of BDNF on dopaminergic, serotonergic, and GABAergic neurons in cultures of human fetal ventral mesencephalon

The neurotrophin brain-derived neurotrophic factor (BDNF) was tested for its ability to promote the survival and regulation of expression of phenotypic markers of dopaminergic, serotonergic, and GABAergic neurons in free-floating roller tube cultures of human fetal ventral mesencephalon. This culture system contains neurons of the anlage of the substantia nigra as well as that of the rostral raphe nucleus. Dopaminergic neuron number and tyrosine hydroxylase (TH) fiber density was monitored by TH immunocytochemistry. Measurement of dopamine (DA) content, TH enzymatic activity, serotonin (5-HT) content, and glutamic acid decarboxylase (GAD) activity were used as indices of their respective neurotransmitter function. The presence of GABAergic and serotonergic neurons in this culture system was confirmed by GABA and 5-HT immunocytochemistry. In cultures maintained in the presence of BDNF (10 ng/ml), the density of TH-positive cells was increased by 2.5-fold (P F 0.05), and the TH-positive fiber density was increased by 3.5-fold (P F 0.01), relative to control cultures. Similarly, the relative increases in DA content and TH activity were 2.6- and 2.3-fold, respectively, in the BDNF-treated cultures (P F 0.01 and P F 0.01). On a per neuron basis, DA content and TH activity were not markedly changed by BDNF treatment, suggesting that the increases in DA content and TH activity are due to more DA neurons surviving. Relative elevations were also observed in serotonin content (2.0-fold, P F 0.01) and GAD enzymatic activity (1.4-fold, P F 0.01). Future studies will need to determine whether these changes result from the direct action of BDNF on these neurons or through some indirect mechanism. The results demonstrate that BDNF has beneficial effects on cultured human fetal tissue, which may be relevant in optimizing neuronal transplantation techniques, and that multiple systems are simultaneously influenced by BDNF.

Comparison of the Effects of the Neurotrophins on the Morphological Structure of Dopaminergic Neurons in Cultures of Rat Substantia Nigra

The effect of the various neurotrophin family members on the morphological structure of dopaminergic neurons was compared in dissociated cultures of embryonic rat ventral mesencephalon. Cultures were maintained in vitro in the presence of brain‐derived neurotrophic factor (BDNF), neurotrophin‐3 (NT‐3), neurotrophin‐4/5 (NT‐4/5), nerve growth factor (NGF) or no added growth factors. Three‐dimensional reconstructions of 48 neurons were made in each of the experimental groups following immunocytochemical staining for tyrosine hydroxylase to detect dopaminergic neurons. In addition [3H]mazindol binding analyses were carried out in replicate cultures in order to quantify the effects of the neurotrophins on the number of dopamine uptake sites. Among the neurotrophins tested, NT‐4/5 influenced the proximal morphological parameters most, as determined by a 36% increase in the soma profile area and 35% in the number of stem neurites. Analysis of neuritic size and complexity in these cultures revealed that combined neuritic length and number of segments/cell were increased by 45 and 40% respectively. A change in neurite complexity in the NT‐4/5 treated cultures was further confirmed using Scholls concentric sphere analysis. In addition, relative to the control, NT‐4/5 increased the neuronal differentiation as evidenced by increases in varicosity density and [3H]mazindol binding by 114 and 101% respectively. BDNF and, to a lesser extent, NT‐3 also increased both proximal parameters and parameters of differentiation, but were without effect on parameters of neuritic size and Complexity. No effects on neuronal structure were observed in NGF treated cultures. These findings demonstrate that BDNF, NT‐3 and NT‐4/5 influence the morphological differentiation of dopaminergic neurons in vitro, suggesting they may play a role in the structural development and plasticity of these neurons in the mesencephalon.

Effects of cerebral perfusion pressure and increased fraction of inspired oxygen on brain tissue oxygen, lactate and glucose in patients with severe head injury

Summary¶Objective. The purpose of the study was to measure the effects of increased inspired oxygen on patients suffering severe head injury and consequent influences on the correlations between CPP and brain tissue oxygen (PtiO2) and the effects on brain microdialysate glucose and lactate. Methods. In a prospective, observational study 20 patients suffering severe head injury (GCS≤8) were studied between January 2000 and December 2001. Each patient received an intraparenchymal ICP device and an oxygen sensor and, in 17 patients brain microdialysis was performed at the cortical-subcortical junction. A 6 h 100% oxygen challenge (FIO2 1.0) (Period A) was performed as early as possible in the first 24 hours after injury and compared with a similar 6 hour period following the challenge (Period B). Statistics were performed using the linear correlation analysis, one sample t-test, as well as the Lorentzian peak correlation analysis. Results. FIO2 was positively correlated with PtiO2 (p<0.0001) over the whole study period. PtiO2 was significantly higher (p<0.001) during Period A compared to Period B. CPP was positively correlated with PtiO2 (p<0.001) during the whole study. PtiO2 peaked at a CPP value of 78 mmHg performing a Lorentzian peak correlation analysis of all patients over the whole study. During Period A the brain microdialysate lactate was significantly lower (p=0.015) compared with Period B. However the brain microdialysate glucose remained unchanged. Conclusion. PtiO2 is significantly positively correlated with FIO2, meaning that PtiO2 can be improved by the simple manipulation of increasing FIO2 and ABGAO2. PtiO2 is positively correlated with CPP, peaking at a CPP value of 78 mmHg. Brain microdialysate lactate can be lowered by increasing PtiO2 values, as observed during the oxygen challenge, whereas microdialysate glucose is unchanged during this procedure. Extension of the oxygen challenge time and measurement of the intermediate energy metabolite pyruvate may clarify the metabolic effects of the intervention. Prospective comparative studies, including analysis of outcome on a larger multicenter basis, are necessary to assess the long term clinical benefits of this procedure.

Chronic Subdural Hematomas: To Drain or Not to Drain?

A consecutive series of 21 adult patients with chronic subdural hematoma was studied in respect to postoperative resolution of subdural collections and clinical improvement after burr hole evacuation without subdural drainage. This series was compared to a previously studied series of patients with chronic subdural hematoma in whom postoperative closed system drainage had been installed. Using the identical protocol for treatment and postoperative follow-up, we obtained identical results with respect to time-related neurological improvement and persistence of subdural collections in the undrained and drained series, except that the steadily progressive clinical improvement during the early postoperative phase (24 hours) in all cases of the drained series was not universal in the undrained cases. Our study suggests that, to avoid the possibility of early postoperative clinical deterioration, burr hole craniostomy and closed system drainage is advisable. We think that subdural drainage is not necessary when the installation of the drainage system seems to be technically difficult, as it may be in cases with considerable perioperative cortical expansion.