[Embolic stroke of undetermined source (ESUS) : How much monitoring is necessary?] / ESUS ("embolic stroke of undetermined source") : Wie viel Monitoring ist nötig?

The clinical construct of embolic stroke of unknown source (ESUS) was first described in 2014. It is defined as cryptogenic ischemic stroke after the exclusion of a lacunar infarct, a significant (≥50%) stenosis of extracranial or intracranial arteries and a cardiac source of embolism. Initially, there was hope that these patients would benefit from anticoagulation. This was based on the suspicion that imaging criteria of stroke mimic features of embolism from cardiac sources or the great arteries. In two large randomized trials with 12,600 patients neither rivaroxaban nor dabigatran could reduce the risk of recurrent stroke. Based on these results, current research is focused on paroxysmal atrial fibrillation as a potential cause of stroke in these patients. Several randomized trials could show that by prolongation of monitoring to 30 days atrial fibrillation can be detected in approximately 10% of the patients. Using continuous monitoring (e. g. by implantable loop recorders) atrial fibrillation can even be detected in one quarter of the patients. Not all stroke patients can receive such an intensive monitoring. Therefore, this article summarizes the evidence and presents the resulting recommendations for patient selection and staged rhythm diagnostics and discusses a recently presented algorithm of an expert group for use in daily clinical practice.

Anti-contactin-associated protein-2 encephalitis: relevance of antibody titres, presentation and outcome.

BACKGROUND AND PURPOSE: To clarify the relevance of titres of IgG antibodies against contactin-associated protein-2 (CASPR2) in diagnosing anti-CASPR2 encephalitis and to describe features and outcomes. METHODS: This was a retrospective analysis of 64 patients with CASPR2 antibodies, categorized independently as 'autoimmune encephalitis' or 'other disease'. Logistic regression methods were performed to identify potential predictors of 'autoimmune encephalitis' in addition to CASPR2 antibodies. RESULTS: An upfront CASPR2 antibody serum titre cut-off at ≥1:200 had a diagnostic sensitivity of 85% and a specificity of 81%. Logistic regression analyses indicated that, in addition to titre, encephalitic magnetic resonance imaging (MRI) was a significant predictor of 'autoimmune encephalitis' (Nagelkerke's R2 = 0.81, P < 0.001) with high sensitivity (84%) and very high specificity (100%). Patients with CASPR2 antibodies and an estimated probability of >70% of having anti-CASPR2 encephalitis (n = 22) had limbic encephalitis (n = 18, one patient plus ataxia), Morvan syndrome (n = 2) or a hyperkinetic movement disorder (n = 2). Median modified Rankin score (mRS) at diagnosis was 3 (range 1-4). Twenty patients were male; median age was 64 (range 54-75) years; 5/15 patients with cerebrospinal fluid data had intrathecal CASPR2 antibody synthesis, and 12/19 with follow-ups >3 months (median 12 months, range 4-43 months) improved by ≥1 mRS point resulting in a median mRS of 2 (range 0-6; one death; all but one having received immunotherapy); and 2/15 patients with follow-up MRI developed hippocampal atrophy. CONCLUSIONS: Only higher CASPR2 serum antibody titres indicate anti-CASPR2 encephalitis, and diagnostic accuracy increases if MRI findings are considered. Anti-CASPR2 encephalitis has characteristic features and a favourable outcome with immunotherapy.

Limbic encephalitis due to GABAB and AMPA receptor antibodies: a case series.

BACKGROUND: Two novel antibodies (abs) directed to γ-aminobutyric acid B receptor (GABA(B)R) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) in patients with limbic encephalitis (LE) were first described by the Philadelphia/Barcelona groups and confirmed by the Mayo group. We present a novel series for further clinical and paraclinical refinement. METHODS: Serum and cerebrospinal fluid samples from a diagnostic laboratory were selected if found to be positive for GABA(B)R or AMPAR abs within a broad antineuronal ab panel. Data were retrospectively compiled. RESULTS: In 10 patients, we detected abs to GABA(B)R. Median age was 70 years. Five of them were diagnosed with small cell lung cancer (SCLC). Intrathecal GABA(B)R ab synthesis was found in all six patients with sufficient data available (median ab-index: 76.8). On MRI, we found bilateral mediotemporal and in two cases cortical abnormalities. EEG revealed encephalopathy, partly with epileptiform discharges. Five patients received immunotherapy, two patients tumour treatment and three both therapies. Three patients died, in five patients cognitive functions declined, one patient improved slightly and one patient fully recovered. AMPAR abs were detected in three patients with mnestic disturbances. Median age was 60.7 years. The only female patient was diagnosed with ovarian cancer. None of the patients had intrathecal ab synthesis. MRI findings showed bilateral mediotemporal abnormalities. EEG was normal in all patients. Two of the three immunologically treated patients improved, one patient stabilised on a low level. DISCUSSION: GABA(B)R and AMPAR abs are well associated with LE. GABA(B)R abs lead to severe clinical, neuroradiological and EEG abnormalities with poorer outcome.

[FEES in the stroke unit: recommendations for implementation in the clinical routine]. / FEES auf der Stroke-Unit : Empfehlungen zur Umsetzung im klinischen Alltag.

Dysphagia occurs in about 50 % of patients with acute stroke, is strongly related to early complications, such as aspiration pneumonia and is a major cause of increased morbidity and mortality in acute stroke. Flexible endoscopic evaluation of swallowing (FEES) has proven to be an easy to use, non-invasive tool for assessment of dysphagia in acute stroke, significantly adding accuracy to the clinical evaluation of dysphagia. With respect to the growing use of FEES in German stroke units this article summarizes recommendations for implementation and execution.A 3-step process is recommended to acquire the relevant knowledge and skills for carrying out FEES. After a systematic training (first step), swallowing endoscopy should be done under close supervision (second step) which is then followed by independent practice coupled with indirect supervision (third step). In principle, FEES should adopt a team approach involving both neurologists and speech language pathologists (SLP) or alternatively speech therapists. The allocation of responsibilities between these two professions should be kept flexible and should be adjusted to the individual level of education. Reducing the role of the SLP to mere assistance work in particular should be avoided. To enhance interprofessional communication and to allow for a smooth and efficient workflow, endoscopic grading of stroke-related dysphagia should adopt a standardized score that also includes protective and rehabilitative measures as well as nutritional recommendations. A major task for the future is to develop an educational curriculum for FEES that takes the specific needs of stroke unit care into account and is applicable to both physicians and SLPs.

[Concept for allocation of acute stroke patients: evaluation of the quality of diagnosis reached by the emergency medical services of Münster]. / Zuweisungskonzept bei akutem Schlaganfall : Untersuchung der rettungsdienstlichen Diagnosequalität in der Stadt Münster.

BACKGROUND: Acute stroke is a time- and expertise-critical emergency. An immediate and correct diagnosis by emergency medical services (EMS) in the prehospital phase and patient transfer to the nearest adequate hospital with a stroke unit is required for early treatment of acute stroke. PATIENTS AND METHODS: We evaluated all patients who were admitted by the EMS of Münster to one of the two stroke units in the town between October 2008 and December 2010 with a diagnosis of acute stroke. Furthermore all patients were critically analyzed who were admitted without a diagnosis of acute stroke by the EMS but nonetheless had a stroke and the correct diagnosis was not found until examination in the neurological department. RESULTS: We analyzed 615 patients who were admitted to the stroke units with the diagnosis of acute stroke. In 561 cases (91%) this diagnosis could be confirmed, but in 54 patients (9%) the diagnosis by the EMS was incorrect. Epileptic seizure was the most frequent false-positive diagnosis in this group of patients (39%; n = 21). Although the acute symptoms were caused by a stroke, the correct diagnosis was not defined by the EMS in 127 patients. This accounted for 18% of all patients admitted to the emergency departments by the EMS where ultimately a stroke was diagnosed. In 24% of these cases (n = 30) the emergency doctor missed the correct diagnosis, which meant 4% of all patients admitted by the EMS, finally diagnosed with an acute stroke. In all other cases in the group with a false-negative diagnosis (76% or 97 patients) an emergency doctor was not involved in the referral by the EMS. CONCLUSION: Emergency medical services should be involved in the establishment of admission programs for acute stroke patients to provide the fastest means of transportation to a stroke unit. Coma, symptoms of posterior cerebral circulation and epileptic seizures cause difficulties in ensuring an immediate and correct diagnosis. Sending an emergency doctor to the scene increases diagnostic certainty which is essential to initiate early treatment.

[Treatment of neuro-AIDS on a neurological intensive care unit: epidemiology and predictors of outcome]. / Behandlung von Neuro-Aids auf der neurologischen Intensivstation : Epidemiologie, Outcome und Prädiktoren des Verlaufs.

BACKGROUND: Investigations concerning the outcome for patients suffering from neuro-AIDS treated on a neurological intensive care unit and specific predictors indicating "dead" were analyzed. MATERIAL AND METHODS: A total of 56 patients with a mean age of 39 ± 0.7 years, a mean CD4+ cell count of 130 ± 166 CD4+ cells/µl and viral load of 146,520 ± 198,059 copies/ml were treated on a neurological intensive care unit due to different forms of neuro-AIDS. RESULTS: Of the patients, 34% were immigrants of whom 74% came from sub-Saharan regions. In 57% of the patients the diagnosis of HIV infection was made during therapy on the neurological intensive care unit. The median for the time between diagnosis of HIV infection and the treatment on the neurological intensive care unit was 8 days for immigrants and 10 years for residents. The most common manifestations of neuro-AIDS were cerebral toxoplasmosis, cryptococcosis and progressive multifocal leukoencephalopathy (PML). Fifty per cent of the patients (n=28) died during treatment on the neurological intensive care unit. Negative predictors for the outcome "dead" were (a) artificial ventilation, (b) antiretroviral naïve immigrant, (c) primary cerebral lymphoma and (d) missing antiretroviral therapy as a result of admission to the intensive care unit. DISCUSSION: The rate of death during treatment of neuro-AIDS on a neurological intensive care unit is much higher than during treatment of internal medicine problems of HIV infection. Antiretroviral naïve immigrants show a much higher rate of death compared to residents in Germany. A lot of research and effort is necessary to improve the availability of the Highly Active Anti-Retroviral Therapy (HAART) worldwide in order to improve the outcome especially for immigrants with neuro-AIDS treated on a neurological intensive care unit.

[Clinical relevance of normal and enlarged Virchow-Robin spaces]. / Klinische Bedeutung normaler und erweiterter Virchow-Robin-Räume.

Virchow-Robin spaces ensheathe the penetrating vessels of the brain. They communicate with the subpial space, are filled with interstitial fluid and contain a specific population of macrophages.Virchow-Robin spaces are a common finding in both CT and MR imaging. Recent radiologic studies have led to a concise definition of Virchow-Robin spaces.Virchow-Robin spaces appear isointense to cerebrospinal fluid on all imaging sequences. They are typically localised in the basal ganglia, subcortically or in the midbrain and pons. Enlarged Virchow-Robin spaces may appear as a single or multiple lesion(s). They may cause hydrocephalus in rare cases. Some studies indicate that enlarged Virchow-Robin spaces occur more frequently in elderly patients, in patients with arterial hypertension or CADASIL.In this review we illustrate the diagnostic criteria of normal and enlarged Virchow-Robin spaces and discuss their clinical relevance. Furthermore, we present an overview of the current knowledge on the anatomy, physiology and pathology of Virchow-Robin spaces.

Intravenous levetiracetam: a new treatment alternative for refractory status epilepticus.

The purpose of this study was to investigate the safety and efficacy of intravenous levetiracetam (LEV-iv) in refractory status epilepticus (SE). A retrospective chart review was performed on patients who received LEV-iv for treatment of SE (n = 36) and had failed at least one other antiepileptic drug. LEV-iv (median 3000 mg/day; range 1000-9000) was administered as a bolus loading (500-2000 mg per 30-60 min, n = 30) or as a continuous pump infusion (n = 6). SE was terminated in 69% ("responders"); 31% ("non-responders") remained in SE. Factors associated with failure were: dose escalation over 3000 mg/day, lack of bolus loading, treatment latency over 48 h, age over 80 years, non-convulsive SE with coma ("subtle SE"), periodic lateralised epileptiform discharges (PLEDs) on EEG, acute cerebral lesion and intubation narcosis. SE was terminated in all eight patients without brain lesion (p = 0.033), and in all seven patients with complex partial SE (p = 0.051). Outcome was favourable (ambulatory patients) in 48% (responders) compared with 0% (non-responders), and "adverse" (death or continuing coma/stupor) in 24% (responders) compared with 100% (non-responders). Mortality was 17% (responders 4%, non-responders 45%). No patient had cardiocirculatory side effects or worsening of SE. Two patients experienced nausea and vomiting during LEV-iv loading, leading to aspiration pneumonia in one. This study suggests that LEV-iv may be a safe and efficacious treatment of SE. Prospective and controlled trials are imperative to confirm these preliminary findings.

[Acute polyneuritis and polyradiculoneuritis: uncommon causes and their pathomechanisms]. / Akute Polyneuritiden und Polyradikuloneuritiden: Ungewöhnliche Ursachen und deren Pathomechanismen.

Although the total incidence rate of acute inflammatory polyneuropathies is low, it is the most frequent cause of acute progressive, generalized paresis in developed countries (> 50 %). The most common form of the disease is the Guillain-Barré syndrome (GBS). Even though the clinical and pathologic spectrum of GBS has substantially grown over the last decade, about 15 % of cases of acute polyneuritis or polyradiculoneuritis do not fulfil the revised and extended diagnostic criteria and classification for GBS and its variants. The underlying pathogenesis still remains unclear. It is assumed that these "untypical" acute inflammatory polyneuropathies and cases fulfilling the GBS criteria are variants of the same underlying immune disorder, but that pathogenetic mechanisms produce different acute neurological syndromes. Thus, immunotherapy (which is not GBS-specific) is also effective for treating acute inflammatory polyneuropathies that do not fulfil the diagnostic criteria for GBS, and early diagnosis and treatment of these cases is essential. Since no reliable serological and electrodiagnostic markers of autoimmune neuropathies are currently available, the diagnosis is based on its clinical presentation. However, clinical symptoms are variable, and a rational diagnostic decision can be challenging. Thus, it is important to know that acute inflammatory polyneuropathies not fulfilling the diagnostic criteria of GBS are less often preceded by an infective condition but frequently associated with uncommon causes and triggers. This report presents our experiences with uncommon variants of inflammatory polyneuropathies and polyradiculoneuritides that do not fulfil the international diagnostic criteria for GBS. We provide a detailed review of the pertinent literature discussing possible pathomechanisms, its clinical associations and possible dispositions.

Old friends in new constellations--the hematopoetic growth factors G-CSF, GM-CSF, and EPO for the treatment of neurological diseases.

Currently, growth factors which have been identified in hematopoiesis and angiogenesis are re-considered as therapeutical agents in a number of neurological diseases, mainly neurodegenerative disorders like Parkinson's Disease, amyotrophic lateral sclerosis (ALS), or cerebrovascular events such as stroke. Among these growth factors, erythropoietin (EPO) and granulocyte colony-stimulating growth factor (G-CSF) are the most prominent. With regard to neurological disease, EPO has been tested in clinical trials for potential use in stroke, schizophrenia, and addiction, G-CSF is currently under clinical investigation for stroke treatment. The major advantage of these growth factors is their well-described pharmacological behavior and their clinical use over several years. A number of mechanisms of action in the CNS have been identified that are probably important for the beneficial action of these factors in animal models of disease, the most relevant relating to neuroprotection, neuroplasticity and stem cell growth and differentiation. In this review, we will discuss the current efforts and prerequisites of novel growth factor therapies for neurodegenerative diseases with regard to their possible mechanism of action on the molecular level and their effects on brain-derived stem cell populations. Additionally, we will describe the necessities for future research before such therapies can be envisioned.

Assessment of aspiration risk in acute ischaemic stroke--evaluation of the simple swallowing provocation test.

BACKGROUND: Aspiration is a common complication in acute stroke patients and is strongly associated with a poor outcome. Due to an insufficient sensitivity and specificity of clinical bedside tests, further refinements are needed to improve the accuracy of clinical aspiration screening in acute stroke. OBJECTIVE: To assess the ability of the simple 2-step swallowing provocation test (SPT) to detect aspiration risk in acute stroke patients. METHODS: 100 consecutive patients with first-ever stroke were examined by SPT and fiberoptic endoscopic evaluation of swallowing (FEES) within 72 hours of stroke onset. Using FEES as an objective instrumental technique to evaluate dysphagia, statistical measures representing the ability of SPT to detect aspiration risk were calculated. RESULTS: The incidence of endoscopically proven aspiration risk was 81%. The 1st-step SPT had a sensitivity of 74.1% and a specificity of 100%. Although the 2nd-step SPT showed the same 100% specificity, sensitivity was significantly lower. False-negative results of SPT appeared predominantly in subjects exhibiting leakage of liquids to pyriform sinus without a pronounced delay in swallow onset. CONCLUSIONS: In acute stroke patients with an impairment of the pharyngeal phase of swallowing, 1st-step SPT reliably detects aspiration risk. In patients with a sole or predominant impairment of the oral phase of swallowing and a relatively intact pharyngeal phase, SPT fails to detect aspiration risk sufficiently. In the latter group, FEES or additional clinical features more specifically indicating oral-phase pathology should be considered to accurately judge the patient's aspiration risk.

Intravenous brain-derived neurotrophic factor reduces infarct size and counterregulates Bax and Bcl-2 expression after temporary focal cerebral ischemia.

BACKGROUND AND PURPOSE: Pretreatment with intraventricular brain-derived neurotrophic factor (BDNF) reduces ischemic damage after focal cerebral ischemia. In this experiment we studied the effect of intravenous BDNF delivered after focal cerebral ischemia on neurological outcome, infarct size, and expression of proapoptotic and antiapoptotic proteins Bax and Bcl-2, respectively. METHODS: With the use of the suture occlusion technique, the right middle cerebral artery in rats was temporarily occluded for 2 hours. Thirty minutes after vessel occlusion, BDNF (300 microg/kg per hour in vehicle; n=12) or vehicle alone (n=13) was continuously infused intravenously for 3 hours. After 24 hours the animals were weighed and neurologically assessed on a 5-point scale. The animals were then killed, and brains underwent either 2,3,5-triphenyltetrazolium chloride staining for assessment of infarct volume or paraffin embedding for morphology and immunohistochemistry (Bax, Bcl-2). RESULTS: Physiological parameters (mean arterial blood pressure, PO(2), PCO(2), pH, body temperature, glucose) and weight revealed no difference between groups. Neurological deficit was improved in BDNF-treated animals versus controls (P:<0.05, unpaired, 2-tailed t test). Mean+/-SD infarct volume was 229.7+/-97.7 mm(3) in controls and 121.3+/-80.2 mm(3) in BDNF-treated animals (P:<0.05, unpaired, 2-tailed t test). Cortical infarct volume was 155.5+/-78.5 mm(3) in the placebo group and 69.9+/-50.2 mm(3) in the BDNF-treated group (P:<0.05, unpaired, 2-tailed t test). Subcortical infarct volume was 74.1+/-30.6 mm(3) in the placebo group and 51.1+/-26.8 mm(3) in the BDNF-treated group (P:=NS). Bax-positive neurons were significantly reduced in the ischemic penumbra in BDNF-treated animals (P:<0.05, unpaired, 2-tailed t test), whereas Bcl-2-positive neurons were significantly increased in this area (P:<0.001, unpaired, 2-tailed t test). CONCLUSIONS: This study demonstrates a neuroprotective effect of BDNF when delivered intravenously after onset of focal cerebral ischemia. As shown here, one possible mechanism of action of neuroprotection of BDNF after focal ischemia appears to be counterregulation of Bax/Bcl-2 proteins within the ischemic penumbra.

Delayed neuroprotective effect of insulin-like growth factor-i after experimental transient focal cerebral ischemia monitored with mri.

BACKGROUND AND PURPOSE: Insulin-like growth factor (IGF) treatment has been shown to have trophic and neuroprotective effects in vitro and in vivo in different lesion models. IGF-I has potent neuroprotective effects after hypoxic-ischemic injury and global ischemia. The role of IGF-I in focal cerebral ischemia is only partially understood. Therefore, in the present study, we evaluated, by applying MRI monitoring, whether a clinically relevant systemic administration of IGF-I can achieve a long-lasting neuroprotective effect. METHODS: Male Wistar rats underwent transient occlusion of the right middle cerebral artery for 1 hour by using the suture occlusion model. Animals then were intraventricularly treated with 33.33 microg IGF-I/d for 3 days (group A, the IGF-I group [n=13]; group B, the placebo group [n=14]) or subcutaneously treated with 200 microg IGF-I/d for 7 days (group D, the IGF-I group [n=10]; group E, the placebo group [n=10]). Groups C and F served as sham-operated controls (n=5 and n=3, respectively). Treatment was begun 30 minutes after occlusion of the middle cerebral artery. Subcutaneously treated animals underwent MRI studies (diffusion-weighted imaging, perfusion imaging, and T2-weighted imaging) beginning 60 minutes after vessel occlusion at 6 hours and at days 1, 2, 5, and 7 after ischemia. The animals were weighed and neurologically assessed daily (rating scale ranged from 0, indicating no deficit, to 5, indicating death). On the third day (intraventricular trial) and on the seventh day (subcutaneous trial), animals were euthanized, and brain sections were stained with triphenyltetrazolium chloride. RESULTS: The mean infarct volume was 52.9+/-25.2 mm(3) in intraventricularly treated animals versus 146.4+/-62.2 mm(3) in control animals (P<0.01) and 42.2+/-17.9 mm(3) in subcutaneously IGF-I-treated animals versus 73.1+/-38.1 mm(3) in control animals (P<0.05). Apparent diffusion coefficient-derived lesion volume at 60 minutes after occlusion was 40.4+/-23.7 mm(3) versus 38.3+/-19.3 mm(3) (P=NS), increased to 168.3+/-49.55 mm(3) versus 105.5+/-33.8 mm(3) (P<0.05) at 24 hours, and then decreased to 55.8+/-30.3 mm(3) versus 23.3+/-20.2 mm(3) (P<0.05) for control and IGF-I-treated animals, respectively. The T2-weighted-derived ischemic lesion volume at 24 hours after occlusion was 236+/-49.2 mm(3) versus 115.9+/-56.8 mm(3) (P<0.05) and decreased to 115.9+/-26.2 mm(3) versus 75.7+/-35.8 mm(3) (P<0.05) at day 7 for control and IGF-I-treated animals, respectively. The relative regional cerebral blood volume was reduced to 50% before reperfusion in all regions of interest except for region of interest 1 (vessel territory of anterior cerebral artery), recovered during reperfusion, but was not different between the control and the growth factor-treated group at any imaging time point. There was no significant difference in weight loss. There was less neurological deficit after ischemia in intraventricularly and subcutaneously IGF-I-treated animals compared with control animals (P<0.05). CONCLUSIONS: Continuous treatment with intraventricularly and subcutaneously administered IGF-I achieved a long-lasting neuroprotective effect as early as 24 hours after ischemia as measured by MRI. Therefore, IGF-I may represent a new approach to the treatment of focal cerebral ischemia.

Neuroprotective effect of delayed moderate hypothermia after focal cerebral ischemia: an MRI study.

BACKGROUND AND PURPOSE: In contrast to early hypothermia, the effects of delayed hypothermia in focal cerebral ischemia have not been widely addressed. We examined the influence of delayed hypothermia on secondary ischemic injury, MRI lesion size, and neurological outcome after transient focal cerebral ischemia in a rat model. METHODS: Rats (n=30) were subjected to transient middle cerebral artery occlusion (MCAO, 120 minutes) by use of the intraluminal filament model. Animals of the treatment group (n=12) were exposed to whole-body hypothermia of 33 degrees C for 5 hours starting 3 hours after MCAO, whereas the control group (n=18) was kept at 37 degrees C throughout the whole experiment. The normothermia- and hypothermia-treated animals were investigated daily by using the Menzies neurological score. Serial MRI was performed 1, 3, and 6 hours after MCAO and on days 1, 2, 3, and 5. After the final MRI scan, the rats were euthanized, and brain slices were stained by 2,3,5-triphenyltetrazolium chloride. RESULTS: Delayed hypothermia resulted in a significant increase of survival rate and a significant improvement of the Menzies score. Moreover, a significant decrease in the extent of hyperintense volumes in T2-weighted scans and a reduction of cerebral edema as calculated from T2-weighted scans throughout the examination period were obvious. The extent of cerebral infarct volume and cerebral brain edema examined by MRI was consistent with 2,3,5-triphenyltetrazolium chloride staining. CONCLUSIONS: Our results suggest that even delayed postischemic hypothermia can reduce the extent of infarct volume and brain edema after transient focal cerebral ischemia.

Neuroprotective effect of granulocyte colony-stimulating factor after focal cerebral ischemia.

BACKGROUND AND PURPOSE: The potential neuroprotective effect of the granulocyte colony-stimulating factor (G-CSF) after glutamate-induced excitotoxicity in cell culture and after focal cerebral ischemia in rats was studied. We hypothesized the existence of the G-CSF receptor (G-CSFR) as a main G-CSF effector on neurons, and immunohistochemistry, immunoblotting, and polymerase chain reaction were performed. The G-CSFR-mediated action was studied by activation of signal transducer(s) and activator(s) of transcription-3 (STAT3) in the periphery of the infarction. METHODS: Neuroprotection of various G-CSF concentrations on glutamate-induced excitotoxicity was studied in cell culture. In vivo, ischemia was induced by use of a suture occlusion model of the middle cerebral artery (90-minute occlusion) in the rat. Thirty minutes after the induction of ischemia, the animals (n=12 per group) received G-CSF at 60 microg/kg body wt IV for 90 minutes or vehicle (saline). Infarct volume was calculated on the basis of 2,3,5-triphenyltetrazolium chloride staining 24 hours after ischemia. Expression of the G-CSFR was studied by immunohistochemistry and verified by reverse transcription-polymerase chain reaction and immunoblotting. Expression of STAT3 was determined by immunohistochemistry. RESULTS: In cell culture, G-CSF exhibited a significant neuroprotective effect after glutamate-induced excitotoxicity (P<0.05). A G-CSF concentration of 10 ng/mL was maximally effective, resulting in a nearly complete protection. In vivo, G-CSF reduced infarct volume to 47% (132.0+/-112.7 mm3 versus 278.9+/-91.6 mm3 [P<0.05] in the control group). Immunohistochemistry, Western blotting, and reverse transcription-polymerase chain reaction revealed the existence of G-CSFRs in neurons and glial cells. Animals treated with G-CSF significantly upregulated STAT3 in the periphery of the infarction compared with control animals (P<0.05). CONCLUSIONS: G-CSF achieved a significant neuroprotective effect in cell culture and after intravenous administration after stroke. Increased STAT3 expression in the penumbra of G-CSF-treated rats suggests mediation by G-CSFR.

Effect of brain-derived neurotrophic factor treatment and forced arm use on functional motor recovery after small cortical ischemia.

BACKGROUND AND PURPOSE: Both the administration of growth factors and physical therapy such as forced arm use (FAU) are promising approaches to enhance recovery after stroke. We explored the effects of these therapies on behavioral recovery and molecular markers of regeneration after experimental ischemia. METHODS: Rats were subjected to photothrombotic ischemia: sham (no ischemia), control (ischemia), brain-derived neurotrophic factor (BDNF; ischemia plus BDNF, 20 microg), and FAU (ischemia plus FAU, 1-sleeve plaster cast ipsilateral limb). Animals survived 1 or 6 weeks and underwent behavioral testing (Rotarod, beam balance, adhesive removal, plantar test, neuroscore). After the rats were killed, brain sections were immunostained for semiquantitative analysis of MAP1B, MAP2, synaptophysin, GFAP expression, and quantification of infarct volumes. RESULTS: Infarct volumes were not different between the groups 1 or 6 weeks after ischemia. BDNF-treated animals had better functional motor recovery (Rotarod, beam balance, neuroscore) compared with all other groups (P<0.05). There was no significant adverse effect of early FAU treatment on motor recovery, although sensorimotor function (adhesive removal test) was impaired (P<0.05). There were no differences between groups as measured by nociception of the left and right forepaw (plantar test). BDNF treatment transiently induced MAP1B expression in the ischemic border zone and synaptophysin expression within the contralateral cortex 6 weeks after ischemia (P<0.05). Both BDNF and FAU reduced astrogliosis compared with controls (P<0.05). CONCLUSIONS: Postischemic intravenous BDNF treatment improves functional motor recovery after photothrombotic stroke and induces widespread neuronal remodeling. Early FAU treatment after stroke does not increase infarct size, impairs sensorimotor function, but leaves motor function unchanged. Postischemic astrogliosis was reduced by both treatments.

Hemorrhagic transformation of ischemic brain tissue: asymptomatic or symptomatic?

BACKGROUND AND PURPOSE: The term symptomatic hemorrhage secondary to ischemic stroke implies a clear causal relationship between clinical deterioration and hemorrhagic transformation (HT) regardless of the type of HT. The aim of this study was to assess which type of HT independently affects clinical outcome. METHODS: We used the data set of the European Cooperative Acute Stroke Study (ECASS) II for a post hoc analysis. All patients had a control CT scan after 24 to 96 hours or earlier in case of rapid and severe clinical deterioration. HT was categorized according to radiological criteria: hemorrhagic infarction type 1 and type 2 and parenchymal hematoma type 1 and type 2. The clinical course was prospectively documented with the National Institutes of Health Stroke Scale and the modified Rankin Scale: The independent risk of each type of HT was calculated for clinical deterioration at 24 hours and disability and death at 3 months after stroke onset and adjusted for possible confounding factors such as age, severity of stroke syndrome at baseline, and extent of the ischemic lesion on the initial CT. RESULTS: Compared with absence of HT, only parenchymal hematoma type 2 was associated with an increased risk for deterioration at 24 hours after stroke onset (adjusted odds ratio, 18; 95% CI, 6 to 56) and for death at 3 months (adjusted odds ratio, 11; 95% CI, 3.7 to 36). All other types of HT did not independently increase the risk of late deterioration. CONCLUSIONS: Only parenchymal hematoma type 2 independently causes clinical deterioration and impairs prognosis. It has a distinct radiological feature: it is a dense homogeneous hematoma >30% of the ischemic lesion volume with significant space-occupying effect.

Intraventricular brain-derived neurotrophic factor reduces infarct size after focal cerebral ischemia in rats.

Brain-derived neurotrophic factor (BDNF), acting through the high-affinity receptor tyrosine kinase (TrkB), is widely distributed throughout the central nervous system and displays in vitro trophic effects on a wide range of neuronal cells, including hippocampal, cerebellar, and cortical neurons. In vivo, BDNF rescues motorneurons, hippocampal, and substantia nigral dopaminergic cells from traumatic and toxic brain injury. After transient middle cerebral artery occlusion (MCAO), upregulation of BDNF-mRNA in cortical neurons suggests that BDNF potentially plays a neuroprotective role in focal cerebral ischemia. In the current study, BDNF (2.1 micrograms/d) in vehicle or vehicle alone (controls) was delivered intraventricularly for 8 days, beginning 24 hours before permanent middle cerebral artery occlusion by intraluminal suture in Wistar rats (n = 13 per group). There were no differences in physiological variables recorded during surgery for the two groups. Neurological deficit (0 to 4 scale), which was assessed on a daily basis, improved in BDNF-treated animals compared with controls (P < 0.05; analysis of variance and Scheffe's test). There were no significant differences in weight in BDNF-treated animals and controls during the experiment. After elective killing on day 7 after MCAO, brains underwent 2,3,5-triphenyltetrazolium chloride staining for calculation of the infarct volume and for histology (hematoxylin and eosin and glial fibrillary acid protein). The mean total infarct volume was 83.1 +/- 27.1 mm3 in BDNF-treated animals and 139.2 +/- 56.4 mm3 in controls (mean +/- SD; P < 0.01, unpaired, two-tailed t-test). The cortical infarct volume was 10.8 +/- 7.1 mm3 in BDNF-treated animals and 37.9 +/- 19.8 mm3 in controls (mean +/- SD; P < 0.05; unpaired, two-tailed t-test), whereas ischemic lesion volume in caudoputaminal infarction was not significantly different. These results show that pretreatment with intraventricular BDNF reduces infarct size after focal cerebral ischemia in rats and support the hypothesis of a neuroprotective role for BDNF in stoke.