Bernhard Schaller

Cerebral ischemia and reperfusion: The pathophysiologic concept as a basis for clinical therapy

The ischemic penumbra has been documented in the laboratory animal as severely hypoperfused, nonfunctional, but still viable brain tissue surrounding the irreversibly damaged ischemic core. Saving the penumbra is the main target of acute stroke therapy, and is the theoretical basis behind the reperfusion concept. In experimental focal ischemia, early reperfusion has been reported to both prevent infarct growth and aggravate edema formation and hemorrhage, depending on the severity and duration of prior ischemia and the efficiency of reperfusion, whereas neuronal damage with or without enlarged infarction also may result from reperfusion (so-called reperfusion injury). Activated neutrophils contribute to vascular reperfusion damage, yet posthypoxic cellular injury occurs in the absence of inflammatory species. Protein synthesis inhibition occurs in neurons during reperfusion after ischemia, underlying the role that these pathways play in prosurvival and proapoptotic processes that may be differentially expressed in vulnerable and resistant regions of the reperfused brain tissue. Ischemia-induced decreases in the mitochondrial capacity for respiratory activity probably contribute to the ongoing impairment of energy metabolism during reperfusion and possibly also the magnitude of changes seen during ischemia. From these experimental data, the concept of single-drug intervention cannot be effective. Further experimental research is needed, especially of the study of biochemical markers of the injury process to establish the role of several drugs.

Cerebral ischemic preconditioning. An experimental phenomenon or a clinical important entity of stroke prevention

Abstract. Neurons can be preconditioned by various procedures to resist ischemic events. The preconditioning mechanism induced is characterized by a brief episode of ischemia that renders the brain more resistant against subsequent longer ischemic events. This ischemic tolerance has been shown in numerous experimental models of cerebral ischemia. The basic molecular mechanisms of ischemic tolerance are largely unknown. During the induction phase N-methyl-O-aspartate and adenosine receptors and, possibly, oxygen free radicals and conservation of energy metabolism are required. Protein kinases, transcription factors, and immediate early genes appear to transduce the signal into a tolerant response. Although the mechanism of ischemic tolerance remains uncertain, its discovery provides the focus for further understanding of the mechanism of endogenous neuroprotection and the potential of novel therapeutic strategies for neuroprotection. Such neuroprotective strategies may extend beyond ischemic tolerance to include other brain injury states as well.

Brain tumor and seizures: Pathophysiology and its implications for treatment revisited

Summary:u2002 Seizures affect ∼50% of patients with primary and metastatic brain tumors. Partial seizures have the highest incidence, followed by secondarily generalized, depending on histologic subtype, location, and tumor extent. The underlying pathophysiologic mechanisms of tumor‐associated seizures are poorly understood and include theories of altered peritumoral amino acids, regional metabolism, pH, neuronal or glial enzyme and protein expression, as well as immunologic activity. An involvement of changed distribution and function of N‐methyl‐d‐aspartate subclass of glutamate receptors also has been suggested. The often unpredictable responses to seizures after surgical tumor removal add substantial evidence that multiple factors are involved. The therapy of tumor‐related seizures is far from perfect. Several factors contribute to these treatment difficulties, such as tumor growth and drug interactions; however, one of the main reasons for poor seizure control may result from the insufficient or even absent influence of the currently available antiepileptic drugs (AEDs) on most of the pathophysiologic mechanisms of tumor‐related seizures. Studies are needed to elucidate more clearly the pathophysiologic mechanisms of tumor‐related seizures and to identify and develop the optimal AEDs.

Cerebral Venous Infarction: The Pathophysiological Concept

Cerebral venous occlusion represents an often underdiagnosed cause for acute or slowly progressive neurological deterioration. The underlying pathophysiological basis is not well understood, but is different from those of arterial occlusion reflecting therefore different anatomical and physiological features of the cerebral venous system. Extensive collateral circulation within the cerebral venous system allows for a significant degree of compensation in the early stages of venous occlusion. Elevated cerebral venous pressure due to cerebral venous occlusion can result in a spectrum of phenomena including a dilated venous and capillary bed, development of interstitial edema, increased cerebrospinal fluid production, decreased cerebrospinal fluid absorption and rupture of venous structures (hematoma). All of these pathophysiological changes may explain the clinical observation that cerebral venous occlusion, if promptly diagnosed and adequately managed, contains reversible alterations and need not always lead to venous infarction. The present review outlines this different pathophysiological behavior of venous compared to arterial occlusion in the cerebral vasculature; special reference is given to the effect of these changes on the therapeutic impact.

PET-based molecular imaging in neuroscience

Positron emission tomography (PET) allows non-invasive assessment of physiological, metabolic and molecular processes in humans and animals in vivo. Advances in detector technology have led to a considerable improvement in the spatial resolution of PET (1–2xa0mm), enabling for the first time investigations in small experimental animals such as mice. With the developments in radiochemistry and tracer technology, a variety of endogenously expressed and exogenously introduced genes can be analysed by PET. This opens up the exciting and rapidly evolving field of molecular imaging, aiming at the non-invasive localisation of a biological process of interest in normal and diseased cells in animal models and humans in vivo. The main and most intriguing advantage of molecular imaging is the kinetic analysis of a given molecular event in the same experimental subject over time. This will allow non-invasive characterisation and phenotyping of animal models of human disease at various disease stages, under certain pathophysiological stimuli and after therapeutic intervention. The potential broad applications of imaging molecular events in vivo lie in the study of cell biology, biochemistry, gene/protein function and regulation, signal transduction, transcriptional regulation and characterisation of transgenic animals. Most importantly, molecular imaging will have great implications for the identification of potential molecular therapeutic targets, in the development of new treatment strategies, and in their successful implementation into clinical application. Here, the potential impact of molecular imaging by PET in applications in neuroscience research with a special focus on neurodegeneration and neuro-oncology is reviewed.

Hemodynamic and metabolic effects of decompressive hemicraniectomy in normal brain: An experimental PET-study in cats

Hemicraniectomy is increasingly used as treatment option in stroke and in head trauma, but little is known on the (patho)physiological regional effects of hemicraniectomy in the normal brain. A standard left-sided craniectomy was performed in three cats. Regional cerebral blood flow (CBF), cerebral metabolic rate of oxygen (CMRO(2)) and cerebral metabolic rate of glucose (CMR(glc)) were measured from the brain tissue underneath the craniectomy at 2, 20 and 28 h after hemicraniectomy. CBF significantly decreased (P<0.01) and oxygen extraction fraction (OEF) (P<0.05) significantly increased. CMRO(2) and CMR(glc) decreased only in regions with most severe CBF reduction. These effects remained for at least a day irrespective of corrective sustaining cranioplasty. The authors demonstrated for the first time that decompressive hemicraniectomy in the cat decreases CBF, and to a lesser extent CMR02 and CMR(glc) 2 h after hemicraniectomy in normal brain tissue that last for at least 1 day. Even though the underlying basis of these phenomena are not fully understood, this finding implies that persisting pathophysiological processes are induced by hemicraniectomy and should be taken into consideration for surgical indications.

Spinal meningioma: relationship between histological subtypes and surgical outcome?

SummaryIntraspinal meningiomas are slow growing benign tumors that produce indolent neurological deficits, which are often reversible following operation. It is unclear, if there is a correlation between postoperative neurological restoration and histopathological parameters. The aim of the present work was to seek for existence of such parameters. Retrospectively, we reviewed the charts of 33 patients with spinal meningiomas who were operated on from January 1980 through December 1995. Histological classification was performed according to WHO criteria. Laminoplasty or hemilaminoplasty was performed in 29 patients (88%) and suboccipital craniotomy with cervical laminoplasty in 4 patients (12%). Mean age of the 30 women (91%) and the 3 men (9%) was 63xa0±xa020xa0years (range 22–88). Spinal meningiomas were of high-cervical location in 9 (27%) and of low-cervico–thoracic location in 24 (73%) patients. Tumor position was laterally in 19 (58%), posteriorly in 8 (24%) and anteriorly in 6 (18%) patients. Histological classification was psammomatous in 22 (66%), fibroblastic in 7 (22%) and meningothelial in 4 (11%) patients. Following tumor resection, neurological deficits resolved in 26 of 33 patients (79%) and worsened in 7 of 33 patients (21%) all of the latter had meningiomas of the psammomatous type. Resection of psammomatous meningiomas of the spine is associated with a less favorable neurological outcome postoperatively than resection of spinal meningiomas of other pathological subtypes. Posterior or lateral tumor position in the spinal canal, location below C4, age less than 60xa0years, and duration of preoperative symptoms seem to be correlated with a good outcome.

Symptomatic granular cell tumor of the pituitary gland: case report and review of the literature.

OBJECTIVE AND IMPORTANCEnThe posterior pituitary lobe is rarely the site of symptomatic primary tumors. The most common lesions arising from the neurohypophysis and the pituitary stalk seem to be granular cell tumors (GCTs), of which only 42 symptomatic cases have been reported. Here we present an unusually well-documented case of a GCT, which has implications for the differential diagnosis of sellar masses.nnnCLINICAL PRESENTATIONnA 75-year-old woman presented with decreased visual acuity, visual field loss, and a 2-year history of progressive vertigo and headaches. Neuroradiological studies showed a supra- and intrasellar, 25 x 20-mm mass, containing calcifications, that compressed the optic chiasm and extended into the third ventricle.nnnINTERVENTIONnThe tumor was subtotally resected through a transsphenoidal approach. The tumor was tough and vascular and could not be suctioned. Histological examination revealed a typical GCT. The postoperative course was uneventful. Residual tumor was treated with fractionated radiation therapy. Ophthalmological testing 10 months after surgery showed a slight improvement in the visual symptoms.nnnCONCLUSIONnTumor calcifications in computed tomographic scans do not exclude a GCT. The diagnosis requires histological confirmation. Surgical removal by the transsphenoidal approach is the therapy of choice, as for other sellar tumors. Radiation therapy may be advisable after subtotal resection. Our literature review suggests the possibility of gender-related tumor biology in GCTs.

Pathophysiological Changes of the Gastrointestinal Tract in Ischemic Stroke

OBJECTIVE:Dysphagia is common after stroke and represents a marker of poor prognosis. After ischemic stroke, dysphagia represents only one part of the clinical spectrum of changes in the gastrointestinal (GI) tract and includes GI hemorrhage, delayed GI emptying, and colorectal dysfunction. State-of-the-art imaging techniques have started to revolutionize to study the cortical and brainstem control of these GI symptoms. It has become increasingly obvious that GI alterations after stroke are complex and its recovery following stroke is even more so.METHODS:In this review, an electronic database research was performed in MEDLINE, EMBASE, and the COCHRAINE database using the terms stroke, dysphagia, GI motility, or cortical reorganization; an extensive manual searching was additionally conducted.RESULTS:Cerebral ischemia may lead to an interruption of the axis between central nervous system and GI system. This altered interrelation between the central nervous system and the GI system may cause, among other things, mainly dysphagia, GI dysmotility, and GI hemorrhage. The consecutive clinical symptoms can often be directly attributed to specific cerebral ischemic lesions involving the brain stem as well as certain cortical and subcortical structures. However, in some cases the pathophysiological mechanisms leading to GI symptoms are incompletely understood. Recent improvement of imaging techniques, especially in functional imaging, has lead to new insights of the central control of the GI tract, suggesting that its cortical and medullar organization is multifocal, and bilateral with handness-independent hemispheric dominance.CONCLUSIONS:Following stroke, patients may have swallowing impairment and other changes of the GI tract that could affect nutritional and hydration status and that lead to aspiration pneumonia. Impaired nutritional status is associated with reduced functional improvement, increased complication rates, and prolonged hospital stays.

Focal Neurological Deficits following Spontaneous Thrombosis of Unruptured Giant Aneurysms

Background: Giant aneurysms (GAs) must be regarded as dynamic lesions with respect to their growth and intraluminal thrombus formation, occasionally giving rise to thromboembolic events. Little is known about spontaneous thrombosis of unruptured GAs leading to focal neurological deficits which can mimic arteriosclerotic, epileptic or neoplastic disease. Methods: Three patients (2 men, 27 and 68 years old, and 1 woman, 32 years old) presented with progressive neurological deficits. Neuroradiological studies showed unruptured GAs [two of the middle cerebral artery (MCA), one of the anterior communicating artery] displaying spontaneous near complete intraluminal thrombosis. In one of the cases with a giant MCA aneurysm, acute thrombosis was followed by infarction of the corresponding territory. Results: Partial excision of the intraluminal thrombus was performed in the anterior communicating artery lesion. Wrapping followed by an extracranial-intracranial bypass and stepwise trapping successfully excluded one MCA lesion from circulation. The other MCA aneurysm was treated conservatively. All three patients showed full recovery neurologically after treatment. Conclusion: The reported clinical history of three patients who developed rapid focal progressive neurological deterioration following acute spontaneous thrombosis can be attributed to the acute swelling of the aneurysmal mass. Their pattern of consecutive rapid clinical improvement represents a previously undescribed clinical course of unruptured GAs.