Stefan H. Kreisel

Inflammatory cytokines in subarachnoid haemorrhage: association with abnormal blood flow velocities in basal cerebral arteries

Subarachnoidal release of inflammatory cytokines (interleukin (IL)-1β, IL-6, and tumour necrosis factor (TNF)-α) was characterised in 35 patients with subarachnoid haemorrhage (SAH) and control subjects and compared with development of complicating haemodynamic abnormalities in basal cerebral arteries and clinical outcome. Serial analysis allowed the observation of a subacute response profile of these key mediators of inflammation in the subarachnoidal space. This compartmentalised inflammatory host response was closely associated in time and extent with development of increased blood flow velocities in the basal cerebral vessels as recorded by transcranial Doppler sonography. Moreover, intrathecal secretion of inflammatory cytokines was significantly increased in patients with poor clinical outcome. Together, these findings suggest a role of excessive compartmentalised inflammatory host response in pathogenesis of cerebrovascular complications after SAH.

Pathophysiology of Stroke Rehabilitation: The Natural Course of Clinical Recovery, Use-Dependent Plasticity and Rehabilitative Outcome

Even though the disruption of motor activity and function caused by stroke is at times severe, recovery is often highly dynamic. Recuperation reflects the ability of the neuronal network to adapt. Next to an unmasking of latent network representations, other adaptive processes, such as excitatory metabolic stress, an imbalance in activating and inhibiting transmission, leading to salient hyperexcitability, or the consolidation of novel connections, prime the plastic capabilities of the system. Rehabilitative interventions may modulate mechanisms of neurofunctional plasticity and influence the natural course after stroke, both positively, but potentially also acting detrimentally. Though routine rehabilitative procedures are an integral part of stroke care, evidence as to their effectiveness remains equivocal. The present review describes the natural course of motor recovery, focusing on ischemic stroke, and discusses use- and training-dependent adaptive effects. It complements a prior article which highlighted the pathophysiology of plasticity. Though the interaction between rehabilitation and plasticity remains elusive, an attempt is made to clarify how and to what extent rehabilitative therapy shapes motor recovery.

Pragmatic Management of Hyperglycaemia in Acute Ischaemic Stroke: Safety and Feasibility of Intensive Intravenous Insulin Treatment

Background: In patients with acute ischaemic stroke, hyperglycaemia has been retrospectively associated with negative outcome. There is an ongoing discussion as to which treatment algorithm, if any, provides the most effective prospective intervention. Here we test the safety and feasibility of an intravenous insulin-only infusion protocol designed for pragmatic routine clinical use. Methods: 40 ischaemic stroke patients with onset <24 h ago, admitted to our stroke unit, were randomized either to the study regimen (50 IU insulin in 50 ml 0.9% saline solution applied intravenously via a perfusor pump), with the aim of reaching and maintaining blood glucose levels between 4.44 mmol/l (80 mg/dl) and 6.11 mmol/l (110 mg/dl), or were treated with insulin subcutaneously if concentrations were above 11.10 mmol/l (200 mg/dl). Treatment was continued for 5 days. Primary outcome was the number of hypoglycaemic (<3.33 mmol/l; <60 mg/dl) and severe hyperglycaemic (>16.65 mmol/l; >300 mg/dl) events. Results: Hypoglycaemic events were significantly more common in patients treated intensively (total n = 25; incidence rate ratio, IRR = 5.3; 95% CI = 1.2–22.4; p < 0.05). Symptomatic events were rare (total n = 5). Severe hyperglycaemia was associated with conventional treatment (IRR = 4.9; 95% CI = 1.5–15.9; p < 0.05). Though those treated intensively attained near-normoglycaemic levels quicker and had significantly lower blood glucose levels over the study period (6.49 ± 2.19 mmol/l vs. 8.01 ± 3.06 mmol/l; 95% CI = –1.78 to –1.28, p < 0.0005), treatment imposes considerable strain on both patients and caregivers. Conclusions: The intensive intravenous insulin infusion protocol effectively lowers blood glucose levels with an increased risk of manageable hypoglycaemic events. However, a highly motivated and trained staff seems essential, limiting feasibility outside of specialty care settings.

Pathophysiology of Stroke Rehabilitation: Temporal Aspects of Neurofunctional Recovery

Stroke almost always causes an impairment of motor activity and function. Clinical recovery, though usually incomplete, is often highly dynamic and reflects the ability of the neuronal network to adapt. Mechanisms that underlie neurofunctional plasticity are now beginning to be understood. Albeit the enormous efforts undertaken to support the natural course of reconvalescence through rehabilitation, little has been done to relate possible effects of these therapeutic approaches to mechanisms of adaptive pathophysiology. The review presented here focuses on these mechanisms during the course of recovery poststroke. Next to an unmasking of latent network representations, other adaptive processes, such as excitatory metabolic stress, an imbalance in activating and inhibiting transmission, leading to salient hyperexcitability or mechanisms that consolidate novel connections prime the system’s plastic capabilities. These pathophysiological processes potentially interact with rehabilitative interventions. They therefore form the foundation of positive, but possibly also negative recuperation under therapy.

Effect of combined ultrasound and microbubbles treatment in an experimental model of cerebral ischemia.

Combined 2-MHz ultrasound (US) and second-generation, sulfur hexafluoride microbubbles (MB) treatment (US+MB) was performed in a permanent middle cerebral artery (MCA) occlusion model in rats to evaluate possible effects on the ischemic cascade. We used 16 Wistar rats and the MCA occlusion model for stroke induction. Glutamate, pyruvate, lactate and glycerol levels were measured by intracerebral microdialysis before and after stroke induction and after US+MB application (n = 8) for 20 h. After 24 h, brain infarct volume, apoptosis and IL-6 and TNF-alpha levels were evaluated. The infarct volume was significantly reduced (p < 0.05) in the US+MB-treated group compared with control animals. In additional, glutamate levels were significantly lower in US+MB-treated animals, and these animals showed a higher rate of apoptotic cell death in the infarcted area. The levels of IL-6 and TNF-alpha concentrations were not different in both groups, and there was no apoptotic cell death outside the infarction in animals treated with US+MB. The results demonstrate that US+MB with second generation microbubbles does not have a harmful effect on ischemic stroke in an MCA occlusion model of the rat.

Lipoaspirate-derived adult mesenchymal stem cells improve functional outcome during intracerebral hemorrhage by proliferation of endogenous progenitor cells stem cells in intracerebral hemorrhages.

Stem cell therapy seems promising in reducing deficits after focal cerebral ischemia. As stroke may result from intracerebral hemorrhage (ICH) in up to 20% we investigated whether human processed lipoaspirate mesenchymal stem cells (PLA-MSC) influence the functional outcome, migration behavior and the activation of endogenous progenitor cells. Experimental ICH was induced by stereotactic administration of collagenase in rats randomly assigned to the control or treatment group. The latter received 3 x 10(6) PLA-MSC by intravenous (i.v.) injection 24h after ICH induction. The outcome was continuously monitored using the RotaRod test over a period of 4 weeks. Morphometric analysis of ICH was performed consecutively by magnetic resonance imaging (MRI) studies and immunohistochemical analysis. The RotaRod test revealed a significant 1.5-fold improvement (p<0.005) in functional outcome for the PLA-MSC treated group after 4 weeks compared to controls. Histological and MRI assessment of lesion size showed no difference between the two groups. Although i.v. injected human cells could not be detected in the post mortem brain, evaluation of the number of endogenous progenitor cells revealed a twofold increase in the treated animals compared to controls. Treatment with PLA-MSC improved the functional outcome significantly in an experimental ICH model. This effect was achieved by stimulation of endogenous progenitor cells rather than integration and differentiation of the infused PLA-MSC.

Inflammatory Leukocyte Infiltration in Focal Cerebral Ischemia: Unrelated to Infarct Size

Objective: An inflammatory host response in the ischemically injured brain is well documented. However, its pathophysiological relevance is uncertain. We investigated whether inflammatory leukocyte response in the ischemic brain alters infarct size. Methods: The cellular inflammatory response to cerebral ischemia in Wistar-derived rats induced by the transient occlusion of the middle cerebral artery with a thread was pharmacologically upmodulated by lipopolysaccharide (LPS) or downmodulated by continuous infusion of carboxylated sialyl Lewisx (sLex). The effects of such experimental modulation of focal cerebral leukocyte recruitment on the extent of the resulting infarction were assessed. Results:Compared to control treatments, LPS strongly enhanced (540.5 ± 504.8 vs. 94.6 ± 60.6, p < 0.01) and sLex decreased (32.8 ± 29.1vs. 97.0 ± 49.7, p < 0.05) the numbers of neutrophils at the investigated sites in cerebral ischemia. Unexpectedly, despite such marked experimental modulation of leukocyte infiltration in the ischemic brain, the extent of the resulting cerebral infarction (percent of total hemisphere) remained unchanged under these different conditions (54.5 ± 10.8vs. 53.0 ± 19.1, n.s. and 50.3 ± 18.0 vs. 57.2 ± 10.0, n.s., respectively). Conclusions: The striking dissociation between the massively altered inflammatory leukocyte infiltration in the ischemic brain and the unchanged infarct outcome indicates that intracerebral inflammatory leukocyte recruitment is not a major pathogenic factor in the development of ischemic tissue damage.

Thrombolysis in very old people with stroke: stroke subtypes, patterns, complications, and clinical outcome.

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Sugar and NICE - aggressive hyperglycaemic control in ischaemic stroke and what can we learn from non-neurological intensive glucose control trials in the critically ill?

There are two lines of evidence that drove the evolution of these guidelines: (1) The weight of arguments that suggest an association between high glucose levels and detrimental outcome has substantially increased in the last few years. Observational studies, both naturalistic [8, 9] and trialassociated [10–12] , have reported higher morbidity and mortality in patients with initial hyperglycaemia. (Note that there is neither consensus as to what actually defines ‘initial’ – is it a 1-measurement baseline, continuously elevated levels within the first 24 h or other timelines? – nor is there a clear definition of when hyperglycaemia necessitates treatment [13] .) Moreover, experimental data have underlined the association. Early neuropathological animal studies provided evidence that hyperglycaemia augments morphological brain damage in acute stroke [14, 15] . Imaging studies in hyperglycaemic animals subjected to ischaemic stroke corroborated these findings: hyperglycaemia is associated with enhanced MRI diffusion-weighted imaging alterations [16] and reduced hemispheric cerebral blood volume [17] . Importantly, equivalent correlations have been established in MRI studies in human subjects. Acute hyperglycaemia is associated with reduced salvage of perfusion-impaired tissue and larger final infarct size [18, 19] . This is also true for patients treated with intravenous tissue plasminogen Hyperglycaemia is a common phenomenon after cerebral ischaemia (for that matter, after most acute medical or surgical conditions), and clinicians have certainly been itching to treat. But should we? The devil is in the details. Continuous assessment of blood glucose levels and qualified treatment are often noted to be core components of specialized stroke care [1] . Expert statements have taken a somewhat sinusoidal course when discussing the matter. In 1994, the Stroke Council of the American Heart Association said that it may be a good idea to treat hyperglycaemia in patients with stroke just as one would treat hyperglycaemia in ‘other persons with elevated blood glucose’ [2] . The guideline was substantiated in 2003, with treatment then being warranted should blood glucose levels exceed 16.6 mmol/l (300 mg/dl) [3] . Europeans were more stringent, finding that a cut-off of 10 mmol/l (180 mg/dl) would be optimal [4, 5] . The American Stroke Association followed this lead and in 2007 revised its suggestions and noted that treatment should begin above 11.1 mmol/l (200 mg/dl), possibly as low as 7.8 mmol/l (140 mg/dl) [6] . In 2008, instead of continuing on the downward track and effectively postulating fasting normoglycaemia below 5.5 mmol/l (99 mg/dl), the European Stroke Organization retained its previous recommendation of 10 mmol/l (180 mg/dl) [7] . Received: August 26, 2009 Accepted: August 26, 2009 Published online: March 30, 2010

MMP-2 concentrations in stroke according to etiology: Adjusting for enzyme degradation in stored deep-frozen serum and other methodological pitfalls

Matrix metalloproteinases (MMP) have a prominent role in the pathophysiology of stroke. We investigated potential differences in MMP-2 concentrations with respect to acute stroke etiology. For another MMP family member, MMP-9, significant degradation over time has been found even when stored at -80 °C, so we measured temporal degradation of MMP-2 and adjusted for this and other factors potentially affecting our results. For 264 patients with acute stroke at baseline and a control cohort of 120 subjects, MMP-2 concentrations were measured using commercially available enzyme-linked immunosorbent assay (ELISA) kits. For each stroke patient, stroke etiology was categorized as cardioembolic, large vessel or small vessel ischemic stroke, or primary hemorrhage. Stroke patients had significantly lower MMP-2 concentrations than controls (mean ± standard deviation: 175.6 ± 65.6 ng/mL versus 212.0 ± 54.8 ng/mL, p<0.001). However, sample degradation (average sample storage time: 240.0 ± 113.7 days) was considerable, amounting to approximately 15% per year. The full extent of differences in MMP-2 concentrations between stroke of different subtypes only became evident when results were adjusted for enzyme degradation during storage and other methodological pitfalls. Before adjustment, the only significant difference between etiologies was that the cardioembolic stroke group had a significantly higher concentration of MMP-2 than the hemorrhage group. After adjustment for time to analysis and ELISA plate clustering, patients with cardioembolic stroke had significantly higher MMP-2 concentrations in comparison to all other stroke subtypes.