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ZusammenfassungIn seinem jetzigen Zustand wird das deutsche Gesundheitssystem nicht in der Lage sein, eine ansteigende Zahl alter Menschen in der Bevölkerung mit einer verminderten Zahl qualifizierter Erwerbspersonen zu versorgen. Diese Problematik betrifft besonders die postakute Versorgung von Schwerkranken, wie in einem ersten von zwei Beitragsteilen unter Situationsbeschreibung dargelegt wurde. Hier diskutieren wir Perspektiven und Handlungsmöglichkeiten. Eine führende Schlussfolgerung ist, dass akut- und rehabilitativmedizinische Maßnahmen deutlich wirksamer als bisher auf einander abgestimmt werden könnten und sollten.

IntroductionMalnutrition is prevalent after stroke, particularly if post-stroke oropharyngeal dysphagia (OD) reduces nutritional intake. To further understand stroke-related malnutrition, a thorough nutritional assessment was performed in ischemic stroke patients with or without OD during sub-acute inpatient rehabilitation.MethodsIn this exploratory, observational, cross-sectional, multi-center study in Germany (NTR6802), ischemic stroke patients with (N = 36) or without (N = 49) OD were age- and sex-matched to healthy reference subjects. Presence of (risk of) malnutrition (MNA-SF), blood concentration of stroke-relevant nutritional compounds and metabolites, nutritional intake, quality of life (EQ-5D-5L), and activities of daily living (Barthel index) were assessed.ResultsMore than half of the stroke patients displayed (risk of) malnutrition, with higher prevalence in patient with OD vs. without OD. Fasted blood concentrations of vitamins B1, B2, B6, A, D, and E, selenium, choline, coenzyme Q10, albumin, pre-albumin, transferrin, docosahexaenoic acid, and eicosapentaenoic acid were all lower in stroke patients compared to their matched healthy reference subjects, irrespective of OD status. Reported energy, macronutrient, and water intake were lower in stroke patients vs. healthy reference subjects. As expected, quality of life and activities of daily living scores were lower in stroke vs. healthy reference subjects, with OD scoring worse than non-OD patients.DiscussionThis study shows that malnutrition is highly prevalent in sub-acute stroke patients during rehabilitation. Even though patients with OD were more likely to be malnourished, blood levels of specific nutritional compounds were similarly lower in stroke patients with or without OD compared to healthy reference subjects. Furthermore, subgroup analysis showed similarly lower blood levels of specific nutritional compounds in patients that are normal nourished vs. patients with (risk of) malnutrition. This might imply disease-specific changes in blood levels on top of overall protein-energy malnutrition. The results of the current study underline that it is important to screen for nutritional impairments in every stroke patient, either with or without OD.

ZusammenfassungIn den nächsten zwei Jahrzehnten werden in Deutschland die Babyboomer aus dem Erwerbsleben ausscheiden. Erwerbsarbeit muss dann von der zahlenschwachen „Pillenknick“-Generation geleistet werden. Mehr ältere Personen in der Gesellschaft bedeuten trotz und teilweise wegen verbesserter medizinischer Möglichkeiten eine höhere Belastung durch Gesundheits- und Pflegeversorgung, die finanziert und personell getragen werden muss. Um mit weniger Erwerbstätigen mehr Bedürftige zu versorgen, muss das Gesundheitssystem umgebaut werden. Weil allerdings die Entwicklungen schleichend verlaufen, ist das Problembewusstsein vielerorts noch gering. Hier fokussieren wir auf den Bereich in unserem Gesundheitssystem, welcher mit am stärksten wächst und zusätzlich den größten Personalbedarf pro Betroffenem hat: die Versorgung schwerkranker und selbsthilfeeingeschränkter Menschen. Das Nebeneinander von Krankenhaus, Rehabilitationsklinik und Pflegeinstitution ist historisch bedingt und unzureichend koordiniert. Es fördert die Tendenz, selbsthilfeeingeschränkte Patient*innen in Pflegeeinrichtungen ohne Chance auf Wiederbefähigung zu entlassen, statt sie zu rehabilitieren. Mit dem weiteren demografischen Wandel droht sich diese Tendenz zu verstärken. Hier versuchen wir in einem ersten von zwei Teilen eine Beschreibung der aktuellen Situation.

During recent decades, many studies have yielded evidence for cerebellar involvement in cognitive, emotional and affective processes besides the well-known cerebellar contribution to motor performance and learning (Koziol et al., 2014; Marien et al., 2014; Van Overwalle et al., 2014; Strata, 2015; Adamaszek et al., 2017; Kansal et al., 2017; Guell et al., 2018; King et al., 2019). Cerebellar diseases can result in executive, linguistic and visuospatial dysfunctions as well as problems with the regulation of emotion and affect. This combination of non-motor symptoms has been named cerebellar cognitive affective/Schmahmann syndrome (CCAS) (Schmahmann and Sherman, 1998). For many years, diagnosis has relied on non-standardized bedside cognitive examination and, if available, detailed neuropsychological test batteries. A short and easily applicable bedside test (CCAS Scale), published by Hoche et al. (2018) in Brain, was developed to screen for CCAS and is already in widespread use. We therefore believe that it is important to share our recent findings that the reference values published by Hoche and colleagues may apply only within a limited age and education range, while their more universal application may lead to a substantial number of false-positive test results.

Extinction of conditioned aversive responses (CR) has been shown to be context-dependent. The hippocampus and prefrontal cortex are of particular importance. The cerebellum may contribute to context-related processes because of its known connections with the hippocampus and prefrontal cortex. Context dependency of extinction can be demonstrated by the renewal effect. When CR acquisition takes place in context A and is extinguished in context B, renewal refers to the recovery of the CR in context A (A-B-A paradigm). In the present study acquisition, extinction and renewal of classically conditioned eyeblink responses were tested in 18 patients with subacute focal cerebellar lesions and 18 age- and sex-matched healthy controls. Standard delay eyeblink conditioning was performed using an A-B-A paradigm. All cerebellar patients underwent a high-resolution T1-weighted brain MRI scan to perform lesion-symptom mapping. CR acquisition was not significantly different between cerebellar and control participants allowing to draw conclusions on extinction. CR extinction was significantly less in cerebellar patients. Reduction of CR extinction tended to be more likely in patients with lesions in the lateral parts of lobule VI and Crus I. A significant renewal effect was present in controls only. The present data provide further evidence that the cerebellum contributes to extinction of conditioned eyeblink responses. Because acquisition was preserved and extinction took place in another context than acquisition, more lateral parts of the cerebellar hemisphere may contribute to context-related processes. Furthermore, lack of renewal in cerebellar patients suggest a contribution of the cerebellum to context-related processes.

To systematically review the ultrasonographic criteria proposed for the diagnosis of chronic cerebrospinal venous insufficiency (CCSVI). The authors analyzed the five ultrasonographic criteria, four extracranial and one intracranial, suggested for the diagnosis of CCSVI in multiple sclerosis (MS), together with the references from which these criteria were derived and the main studies that explored the physiology of cerebrospinal drainage. The proposed CCSVI criteria are questionable due to both methodological and technical errors: criteria 1 and 3 are based on a scientifically incorrect application of data obtained in a different setting; criteria 2 and 4 have never been validated before; criterion 2 is technically incorrect; criteria 3 and 5 are susceptible to so many external factors that it is difficult to state whether the data collected are pathological or a variation from the normal. It is also unclear how it was decided that two or more of these five ultrasound criteria may be used to diagnose CCSVI, since no validation of these criteria was performed by different and independent observers nor were they blindly compared with a validated gold-standard investigation. The European Society of Neurosonology and Cerebral Hemodynamics (ESNCH) has considerable concerns regarding the accuracy of the proposed criteria for CCSVI in MS. Therefore, any potentially harmful interventional treatment such as transluminal angioplasty and/or stenting should be strongly discouraged.

For the past decades, new technical developments in brain imaging have greatly contributed to a better understanding of the pathophysiology of acute stroke und have paved the way for new possibilities in the diagnosis and treatment of acute stroke. Brain imaging provides indispensable information for a specific and effective management of acute stroke patients. Non-contrast CT is the most widely available technique and has its major impact in the diagnosis or exclusion of intracranial hemorrhage. In addition, early ischaemic signs can be identified on CT in a large number of patients already within the first hours of stroke. Non-contrast CT is the only imaging modality that is required prior to treatment with intravenous thrombolysis. Multiparametric stroke MRI including diffusion-weighted imaging, perfusion imaging, MR angiography and T2*-weighted imaging also detects intracranial haemorrhage with high sensitivity, and provides additional information on the extent of the ischaemic lesion, hypoperfused tissue and on the vessel status. Stroke MRI allows the identification of tissue at risk of infarction, which is the target for reperfusion therapies beyond the 3-hour time window. Multiparametric CT combining perfusion CT and CT angiography likely provides comparable information. Doppler and duplex sonography is a reliable method to screen for pathologies of the extracranial arteries. Transcranial sonography additionally enables one to assess large intracranial vessels in the majority of patients. For the future, multiparametric brain imaging with modern CT or MRI techniques is expected to play an increasing role in the management of acute stroke in the routine clinical setting, as well as in clinical trials.

Neurological diseases frequently induce pathological changes of cerebrospinal fluid (CSF) that might secondarily influence brain activity, as the CSF–brain barrier is partially permeable. However, functional effects of CSF on neuronal network activity have not been specified to date. Here, we report that CSF specimens from patients with reduced Glasgow Coma Scale values caused by severe traumatic brain injury suppress synchronous activity of in vitro-generated neuronal networks in comparison with controls. We present evidence that underlying mechanisms include increased N-methyl-D-aspartate receptor activity mediated by a CSF fraction containing elevated amino acid concentrations. These proof-of-principle data suggest that determining effects of CSF specimens on neuronal network activity might be of diagnostic value. Ann Neurol 2009;66:546–555

Soluble amyloid beta(1-42) (A beta(1-42)) peptide has recently been assigned a key role in early Alzheimer's disease (AD) pathophysiology accounting for synaptic dysfunction before amyloid plaque formation and neurodegeneration can occur. Following sublethal A beta(1-42) administration, we observed an acute but transient reduction of the spike and burst rate of spontaneously active cortical networks cultured on microelectrode arrays. This simple experimental system appears suitable for future long-term pharmacological and genetic studies of A beta(1-42) signaling, thus providing a valuable new tool in AD research.

Telemedicine is increasingly being utilised for the remote evaluation of stroke patients, particularly in neurologically underserved areas. It is usually based on video examination and teleradiological evaluations of brain scans. Scientific analyses have demonstrated the reliability of neurological scores assessed via videoconference. Teleradiology using electronically transmitted original imaging data is potentially equivalent to onsite assessment. Intravenous thrombolysis can be indicated with similar results as in experienced stroke centres if both technological and professional quality standards are applied. However, improved clinical outcomes of stroke patients have only been shown when telemedicine was combined with the Stroke Unit concept based on specialised stroke wards and organised stroke care. More scientific evaluation is needed in the fields of cost effectiveness, quality management and implementation of further technological innovations. There are still insufficient data about the use of telemedicine in prevention, rehabilitation and post-stroke care and a comprehensive scientific evaluation is still needed.

Background and Purpose— Inflammation contributes to brain damage caused by ischemic stroke. Ultrasmall superparamagnetic iron oxide (USPIO)-enhanced MRI allows noninvasive monitoring of macrophage recruitment into ischemic brain lesions. In this study, we determined the extent of USPIO enhancement during early stages of ischemic stroke. Methods— Twelve consecutive patients with typical clinical signs of stroke underwent multimodal stroke imaging at 1.5-T within 24 hours of symptom onset. They received intravenous USPIO (ferumoxtran) infusion at 26 to 96 hours (mean, 44 hours) after stroke. A total of four follow-up MRI scans were performed 24 to 36 hours, 48 to 72 hours, 7 to 8 days, and 10 to 11 days after USPIO infusion. Results— Nine patients were included in the final analysis. Parenchymal USPIO enhancement occurred in 3 of 9 analyzed patients and was mainly evident on T1-weighted spin-echo images. USPIO-dependent signal changes were spatially heterogeneous, reflecting the distinct patterns of hematogenous macrophage infiltration in different lesion types. Conclusions— Our findings suggest a variable extent and distribution of macrophage infiltration into early ischemic stroke lesions. USPIO-enhanced MRI may help to more specifically target antiinflammatory therapy in patients with stroke.

ZusammenfassungIm Subnetz „Klinische Studien“ des Kompetenznetzes Schlaganfall werden multizentrische klinische Studien zum akuten Schlaganfall koordiniert und durchgeführt. Studien über die Sicherheit und Effektivität der akuten Schlaganfallbehandlung mit dem Glykoprotein IIb/IIIa-Rezeptorantagonisten Tirofiban zeigen erfolgversprechende Ansätze zur verbesserten Akuttherapie und bilden die Basis für Zulassungsstudien. In einer großen multizentrischen Studie konnte gezeigt werden, dass die intravenöse Thrombolyse mit tPA im erweiterten Zeitfenster bis sechs Stunden nach Symptombeginn bei mittels MRT-Kriterien ausgewählten Patienten sicher und effektiv ist. In einer aktuellen Studie wird untersucht, ob die multimodale MRT-Bildgebung bereits in der Akutphase die zuverlässige Identifikation von Risikopatienten für die Entwicklung eines malignen Mediainfarktes ermöglicht. Erste Ergebnisse der noch laufenden COSBID-Studie haben gezeigt, dass Periinfarkt-Depolarisationen bei malignem Mediainfarkt, Subarachnoidalblutung und intrakranieller Blutung auftreten. Im weiteren Verlauf der Studie wird die klinische Relevanz dieser transienten Depolarisationen als wesentliches Merkmal der Sekundärschädigung bei den genannten Krankheitsbildern überprüft. Insgesamt hat die Kooperation mehrerer Schlaganfallzentren in einem multizentrischen Ansatz im Subnetz „Klinische Studien“ die Durchführung von Studien ermöglicht, welche in einzelnen Zentren in dieser Form nicht zu realisieren gewesen wären.

Background and Purpose— We investigated whether transient ischemic attacks (TIAs) before stroke can induce tolerance by raising the threshold of tissue vulnerability in the human brain. Methods— Sixty-five patients with first-ever ischemic territorial stroke received diffusion- and perfusion-weighted MRI within 12 hours of symptom onset. Epidemiological and clinical data, lesion volumes in T2, apparent diffusion coefficient (ADC) maps and perfusion maps, and cerebral blood flow and cerebral blood volume values were compared between patients with and without a prodromal TIA. Results— Despite similar size and severity of the perfusion deficit, initial diffusion lesions tended to be smaller and final infarct volumes were significantly reduced (final T2: 9.1 [interquartile range, 19.7] versus 36.5 [91.2] mL; P =0.014) in patients with a history of TIA (n=16). This was associated with milder clinical deficits. Conclusions— The beneficial effect of TIAs on lesion size in ADC and T2 suggests the existence of endogenous neuroprotection in the human brain.

Background and Purpose— Early reperfusion is one of the best predictors of good outcome after acute middle cerebral artery (MCA) occlusion. The purpose of this study was to analyze the frequency and relevance of incomplete recanalization for tissue and clinical outcome. Methods— From a larger acute stroke database (Kompetenznetzwerk Schlaganfall B5), all patients (n=82) with MCA main stem occlusion (excluding carotid T-occlusions) were selected. These patients had received a multiparametric stroke MRI protocol including diffusion- and perfusion-weighted imaging (DWI, PWI) and MR angiography (MRA) within 6 hours after symptom onset, at day 1 and after 1 week. Recanalization status was determined with MRA on day 1 (according to Thrombolysis In Myocardial Infarction flow grades) and used to group patients into those with persistent occlusion (0) or minimal (1), partial (2), or complete (3) recanalization. Results— Incomplete recanalization according to MRI criteria was found in 39 patients (grade 1: n=20; grade 2: n=19), complete recanalization in 10, and persistent occlusion in 33. There was no statistically significant difference in any of the clinical (National Institutes of Health Stroke Scale score) or MRI baseline parameters (DWI lesion, PWI deficit, mismatch volume, mismatch ratio). However, lesion growth was smaller in patients with recanalization (even in patients with only minimal recanalization) and outcome was related to the degree of recanalization (mean modified Rankin score at 90 days: 3.36, 2.70, 1.79, and 1.44 for the groups with no, minimal, partial, and complete recanalization, respectively). Both incomplete and complete recanalization was more frequent in patients receiving thrombolysis. Conclusions— Incomplete recanalization on day 1 is a frequent MR finding after MCA main stem occlusion, indicating a more favorable clinical course than persistent occlusion. MR indicators of early recanalization could be useful surrogates of efficacy in thrombolytic trials.

The concept of a mismatch between the lesion volume in diffusion- and perfusion-weighted magnetic resonance imaging (MRI) indicating ‘tissue at risk of infarction’ is based on the assumption that tissue with diffusion slowing in diffusion-weighted MRI (DWI) or decreased values of the apparent diffusion coefficient represents irreversibly damaged tissue. Recent experimental as well as clinical studies, however, have shown that tissue with diffusion slowing may well normalize if the hypoperfusion is moderate or transient. We will interpret these findings in the light of experimental data and suggest a way for the interpretation of different time courses of lesion development in DWI within a clinical MRI protocol. MR stroke imaging delivers important information in acute stroke, particularly in defining the ‘tissue at risk of infarction’.

Opsoclonus myoclonus syndrome (OMS) is a rare disease characterized by opsoclonus, an eye movement disorder causing involuntary, chaotic saccades in all directions, and arrhythmic action myoclonus often involving the trunk, limbs, and head. Cerebellar dysfunction with dysarthria and ataxia as well as encephalopathy and behavioral disturbances are also frequently found. OMS typically occurs along with infections or paraneoplastic mechanisms and is less frequently seen with other conditions, such as toxic, metabolic, or vascular disorders, among others. Tumors most commonly underlying paraneoplastic OMS are lung cancer or gynecologic malignancies, especially breast and ovarian cancers. Although paraor postinfectious OMS often improve with immunotherapy, paraneoplastic OMS is less responsive and prognosis normally depends on the treatment of the underlying neoplasm. In both types, an autoimmune pathophysiology is assumed. We report a 62-year-old female patient who developed a gastrointestinal infection after travelling to Russia and France. One week later, she developed a progressive, severe OMS. She was first admitted to a local neurologic hospital, where she was treated with intravenous immunoglobulin (IVIG) and acyclovir for 5 days, respectively. Because symptoms did not improve, she was transferred to our hospital approximately 1 month after symptom onset for further diagnostic workup and treatment. At admission, the patient presented with severe opsoclonus and generalized action myoclonus, with additional ataxia of the trunk, gait, and head, severe dysarthria, and severe encephalopathy with worsening of vigilance (see Video, Segment 1). Following blood tests were normal or negative: routine laboratory, thyroid-stimulating hormone, thyroid hormones, thyroid antibodies, antinuclear antibodies, gliadin antibodies, hepatitis A–C, human immunodeficiency virus, and Tropheryma whipplei polymerase chain reaction. Antibodies for herpes simplex virus, varicella zoster virus, and borrelia burgdorferi were negative. Tumor markers were normal, except CA-125, which was elevated twice that of normal. Cerebrospinal fluid (CSF) revealed a slight pleocytosis of 9 cells/lL and an elevated protein level of 71 mg/dL. Immunoglobulin G (IgG) quotient was 0.7, and oligoclonal bands were positive. Protein 14-3-3 was negative, and tau-protein, amyloid beta 140, amyloid beta 1-42, and amyloid beta ratios were normal. Malignant cells could not be detected in the CSF. Specific antibody index for herpes simplex virus and varicella zoster virus were negative. Antineuronal antibodies in the CSF and blood, including anti-Ri and anti-Hu, could not be detected. Cranial MRI, thoracoabdominal CT, esophagogastroduodenoscopy, and F18-FDG-onco-PET were inconspicuous. Gynecologic examination, including digital mammography, was also normal. We initiated immunosuppressive pulse therapy with methylprednisolone (1 g/day) for 5 days. Additionally, symptomatic antimyoclonic treatment with levetiracetam was started and rapidly titrated up to 2 g/day. Hereunder, opsoclonus and myoclonus significantly

Background and Purpose —The procoagulant protein tissue factor (TF) has been implicated in thromboembolic complications associated with advanced atherosclerosis. In this study, we investigated whether TF expression in high-grade stenoses of the internal carotid artery (ICA) is associated with clinical features of plaque destabilization and addressed the relationship between TF expression and plaque inflammation. Methods —In 36 consecutive patients undergoing surgery for high-grade ICA stenosis, clinical evidence of plaque instability was provided by the recent occurrence of ischemic symptoms attributable to the stenosis and the detection of cerebral microembolism by means of transcranial Doppler ultrasound monitoring of the ipsilateral middle cerebral artery. Endarterectomy specimens were stained immunocytochemically for TF expression as well as macrophage (CD68) and T cell (CD3) infiltration. Results —Morphologically, TF immunoreactivity was codistributed with plaque inflammation and predominantly localized to CD68+ macrophages. Accordingly, statistical analysis revealed a significant association of TF expression with plaque infiltration by macrophages ( P P =0.013). Plaques extensively stained for TF (median of TF+ total section area >40% in semiquantitative assessment) were more frequent in symptomatic (12/27) than in asymptomatic patients (1/9). Conversely, plaques exhibiting little TF expression (median of TF+ section area P =0.016). Likewise, we found a highly significant association of TF expression with the occurrence of cerebral microembolism ( P =0.008). Conclusions —Induction of TF at sites of plaque inflammation may play an important role in the destabilization of high-grade ICA stenosis.

Arterioarterial thromboembolism from extracranial internal carotid artery (ICA) stenosis is an important pathogenic mechanism of ischemic stroke. However, even a high-grade ICA stenosis carries a greatly variable annual risk of stroke, as high as 13% following a recent occurrence of transient or minor cerebral ischemia or as low as 1-2% in clinically asymptomatic patients. There is increasing evidence that inflammatory processes play a central role in atherosclerosis and particularly in plaque destabilization converting chronic atherosclerosis into an acute neurological disorder. In thromboendarterectomy specimens from patients with high-grade ICA stenoses, the extent of inflammatory infiltration and the expression of matrixmetalloproteinase-9 correlated to clinical and ultrasonic features of plaque destabilization such as cerebral microembolism. Inflammation might become a new therapeutic target in symptomatic carotid artery disease.

There is increasing evidence that inflammatory processes play a central role in atherosclerosis and in secondary infarct growth after focal cerebral ischaemia. Focal cerebral ischaemia is often the result of arterio-arterial thromboembolism arising from plaques in the internal carotid artery (ICA). In the ICA, the extent of inflammatory infiltration by T cells and macrophages, and the expression of matrix metalloproteinase-9 in high grade stenoses, correlate with clinical features of plaque destabilisation. Within the CNS, focal ischaemia induces a strong inflammatory response, with recruitment of granulocytes, T cells and macrophages which is facilitated by early upregulation of cell adhesion molecules. In experimental animals, anti-adhesion strategies have led to a dramatic reduction of stroke volumes; however, these strategies have failed to be effective in humans. ‘Immunological’ transcription factors and inducible nitric oxide synthase are upregulated in focal ischaemia and contribute to secondary infarct growth between 24 and 72 hours after the initial insult. The cytokines interleukin-1β and tumour necrosis factor-α are induced prior to inflammation. Functionally, these cytokines exert both neurotoxic and neuroprotective effects after cerebral ischaemia. At present, immunological strategies targeted at a single immunomodulator for the treatment of stroke are hampered by an incomplete understanding of the complex cellular and molecular interactions that lead to divergent functional effects of inflammatory cells and immunological mediators after focal ischaemia.

We report acute and follow-up diffusion- and perfusion-weighted MRI (DWI, PWI) findings in a patient with a prolonged reversible ischaemic neurological deficit. PWI 12 h after the patient was last seen to be without symptoms revealed a large perfusion deficit in the left posterior MCA territory with a relatively inconspicuous and much smaller abnormality on DWI. Follow-up showed resolution of abnormalities on both DWI and PWI, and conventional MRI was normal, apart from a very slight abnormality, visible only on FLAIR images, at the centre of the initially DWI-positive region. These findings demonstrate the utility of PWI when be used in combination with DWI to investigate the pathophysiology of transient ischemic syndromes.

Background and Purpose —Embolus detection using transcranial Doppler ultrasound is a useful method for the identification of active embolic sources in cerebrovascular diseases. Automated embolus detection systems have been developed to reduce the time of evaluation in long-term recordings and to provide more “objective” criteria. The purpose of this study was to evaluate the critical conditions of automated embolus detection by means of a trained neural network (EMBotec V5.1 One, STAC GmbH, Germany). Methods —In 11 normal volunteers and in 11 patients with arterial or cardiac embolic sources, we performed simultaneous recordings from both middle or both posterior cerebral arteries. In the normal subjects, we produced 1342 additional artifacts to use the latter as false-positives. Detection of microembolic signals (MES) was done offline from digital audiotapes (1) by an experienced blinded investigator used as a reference and (2) by a trained 3-layer–feed-forward neural network. Results —From the 1342 provoked artifacts the neural network labeled 216 events as microemboli, yielding an artifact rejection of 85%. In microembolus-positive patients the neural network detected 282 events as emboli, among these 122 signals originating from artifacts; 58 “real” events were not detected. This result revealed a sensitivity of 73.4% and a positive predictive value of 56.7. The spectral power of the detected artifact signals was 16.5±5 dB above background signal. MES from patients with artificial heart valves had a spectral power of 6.4±2.1 dB; however, in patients with other sources of emboli, MES had an averaged energy reflection of 2.7±0.9 dB. Conclusions —The neural network is a promising tool for automated embolus detection, the formal algorithm for signal identification is unknown. However, extreme signal qualities, eg, strong artifacts, lead to misdiagnosis. Similar to other automated embolus detection systems, good signal quality and verification of MES by an experienced investigator is still mandatory.

Background and Purpose —Inflammatory mechanisms have been implicated in the pathogenesis of atherosclerosis. In this study, we investigated whether the extent of inflammatory infiltration in high-grade stenoses of the internal carotid artery (ICA) correlates to clinical features of plaque destabilization. Methods —Endarterectomy specimens from 37 consecutive patients undergoing surgery for high-grade ICA stenosis were stained immunocytochemically for macrophages (CD68) and T cells (CD3). The staining was quantified by planimetry of immunostained areas (CD68) or counting individual cells (CD3). Clinical evidence of plaque instability was provided by the preoperative assessment of recent ischemic symptoms attributable to the stenosis and of the occurrence of cerebral microembolism in transcranial Doppler ultrasound monitoring of the ipsilateral middle cerebral artery. Results —The percentage of macrophage-rich areas and number of T cells per mm 2 section area were larger in recently symptomatic patients than in asymptomatic patients (macrophages: 18±10% versus 11±4%, P =0.005; T cells: 71.2±34.4 versus 40.5±31.4 mm 2 , P =0.005). The presence of microembolism was associated with an increase in macrophage-rich areas ( P =0.011). Macrophage (19±10% versus 9±3%, P =0.0009) and T cell (71.5±39.0 versus 46.4±22 mm 2 , P =0.045) infiltration were more pronounced in predominantly atheromatous than in fibrous plaques, but did not correlate significantly to the presence of surface ulceration or luminal thrombosis. Conclusions —Our data suggest a role of plaque-infiltrating macrophages and T cells in the clinical destabilization of high-grade ICA stenoses. Inflammatory mechanisms may be a therapeutic target in patients with symptomatic ICA disease.

Abstract —Transcranial Doppler ultrasound is capable of detecting microembolic material, both gaseous and solid, within the intracranial cerebral arteries. To avoid discrediting this promising and exciting new technique, experts in this field met in January 1997 in Frankfurt, Germany, to discuss the limitations and problems of embolus detection and to determine guidelines for its proper use in clinical practice, as well as in scientific investigations. In particular, the authors suggest that studies report the following parameters: (1) ultrasound device, (2) transducer type and size, (3) insonated artery, (4) insonation depth, (5) algorithms for signal intensity measurement, (6) scale settings, (7) detection threshold, (8) axial extension of sample volume, (9) fast Fourier transform (FFT) size (number of points used), (10) FFT length (time), (11) FFT overlap, (12) transmitted ultrasound frequency, (13) high-pass filter settings, and (14) recording time. There was agreement that no current system of automatic embolus detection has the required sensitivity and specificity for clinical use.

Background and Purpose Different frequencies of asymptomatic Doppler embolic signals have been reported in studies. There has been concern that different criteria for identification may account for some of this variation. A previous reproducibility study between two centers found good agreement, but no studies among large numbers of centers have been performed. We performed an international reproducibility study among nine centers, each of which had published recent studies of embolic signal detection in peer-reviewed journals. Methods Each center performed blinded analysis of a taped audio Doppler signal composed of transcranial Doppler middle cerebral artery recordings from 6 patients with symptomatic carotid artery stenosis. The exact time of any embolic signal was recorded. Six centers also measured the intensity increase of any embolic signals detected. Interobserver agreement was determined by a method based on the proportion of specific agreement. Results Seven centers reported between 39 and 55 signals, but one center reported 142 embolic signals. The probability of agreement between observers was .678, which rose to .791 when the data from the highest reporting center were excluded. Introducing a decibel threshold resulted in a significant increase in the probability of agreement; a decibel threshold of >7 dB resulted in a probability of agreement of .902. Intensity measurements made by different centers were usually highly correlated, but this was not always the case, and 3 of the 15 correlations were not significant. The absolute values of the intensities measured varied between centers by as much as 40%. Conclusions Although most centers report similar numbers of embolic signals, some use less specific criteria and report more events. The use of a decibel threshold improves reproducibility. However, intensity thresholds developed by one center cannot be directly transferred without validation to another center; differing methods of measurement are being used, and this results in different intensity values for the same embolic signals, even when the same equipment is used.

Background and Purpose There has been concern regarding the reproducibility of the detection of embolic signals, particularly in patients with carotid artery stenosis in whom the signals are of low intensity. No published studies have examined intercenter agreement in reporting specific embolic signals or the factors responsible for any lack of agreement. We examined reproducibility between two centers in which widely differing proportions of embolic signals have previously been reported in patients with carotid artery stenosis. Methods Recordings from the middle cerebral artery of eight patients with ipsilateral carotid artery stenosis in whom embolic signals had been detected during a previous study were independently examined by three experienced observers in one center and by one experienced observer in another center. We calculated agreement within and between centers by estimating the probability that one observer would identify a specific embolic signal if other observers had identified it (a probability of 1 indicates complete agreement). The influence of different characteristics of the embolic signal on the probability of its detection as an embolic signal was determined. Results A high level of agreement in the identification of specific embolic signals was found. This was similar between all observers (.90), between the three observers in one center (.89), and between observers in the two different centers (.94). The probability of detection was independently related to the relative intensity of the embolic signal ( P P =.02), with signals in systole being more reliably detected. There was no independent relationship between the probability of detection and either the duration of the embolic signal or the velocity at the maximum intensity increase. The use of threshold intensity as a criterion for embolic signal detection increased inter-observer agreement but reduced the sensitivity in detecting signals. Conclusions The high level of interobserver agreement suggests that the technique is sufficiently reproducible for clinical use.

Multiple sclerosis is a common inflammatory disease of the CNS. A great number of immunologically active molecules have been identified in the CSF of these patients (CSF-MS), but the role of these substances in neuronal dysfunction, especially in the origin of transient symptoms, is unclear. Therefore, we investigated the effect of CSF from 13 multiple sclerosis patients on membrane currents of cultured cortical neurons from embryonic rat and compared it with the effect of CSF from 12 patients with non-inflammatory neurological diseases. We found an increase in Na + current (I Na ) inactivation by a shift of the h oo curve to more hyperpolarizing potentials by 9.3 mV. This effect was reversible by washing and could be abolished by CSF-MS heat inactivation. The degree of the shift ranged from 4.3 mV to 17.6 mV and correlated with the IgG index, but not with the degree of pleocytosis, protein or albumin content. The maximal amplitude of I Na was unchanged. We concluded that diffusible factors are released into the CSF which reduce neuronal excitability and thereby disturb the function of the neuronal network. These factors may well contribute to transient neurological symptoms seen in patients with 'active' multiple sclerosis.

Extent of cerebellar involvement in cognition and emotion is still a topic of ongoing research. In particular, the cerebellar role in humor processing and control of laughter is not well known. A hypermetric dysregulation of affective behavior has been assumed in cerebellar damage. Thus, we aimed at investigating humor comprehension and appreciation as well as the expression of laughter in 21 patients in the acute or subacute state after stroke restricted to the cerebellum, and in the same number of matched healthy control subjects. Patients with acute and subacute cerebellar damage showed preserved comprehension and appreciation of humor using a validated humor test evaluating comprehension, funniness and aversiveness of cartoons ("3WD Humor Test"). Additionally, there was no difference when compared to healthy controls in the number and intensity of facial reactions and laughter while observing jokes, humorous cartoons, or video sketches measured by the Facial Action Coding System. However, as depression scores were significantly increased in patients with cerebellar stroke, a concealing effect of accompanying depression cannot be excluded. Current findings add to descriptions in the literature that cognitive or affective disorders in patients with lesions restricted to the cerebellum, even in the acute state after damage, are frequently mild and might only be present in more sensitive or specific tests.

Previous findings suggested that the human cerebellum is involved in the acquisition but not the long-term storage of motor associations. The finding of preserved retention in cerebellar patients was fundamentally different from animal studies which show that both acquisition and retention depends on the integrity of the cerebellum. The present study investigated whether retention had been preserved because critical regions of the cerebellum were spared. Visual threat eye-blink responses, that is, the anticipatory closure of the eyes to visual threats, have previously been found to be naturally acquired conditioned responses. Because acquisition is known to take place in very early childhood, visual threat eye-blink responses can be used to test retention in patients with adult onset cerebellar disease. Visual threat eye-blink responses were tested in 19 adult patients with cerebellar degeneration, 27 adult patients with focal cerebellar lesions due to stroke, 24 age-matched control subjects, and 31 younger control subjects. High-resolution structural magnetic resonance images were acquired in patients to perform lesion-symptom mapping. Voxel-based morphometry was performed in patients with cerebellar degeneration, and voxel-based lesion-symptom mapping in patients with focal disease. Visual threat eye-blink responses were found to be significantly reduced in patients with cerebellar degeneration. Visual threat eye-blink responses were also reduced in patients with focal disease, but to a lesser extent. Visual threat eye-blink responses declined with age. In patients with cerebellar degeneration the degree of cerebellar atrophy was positively correlated with the reduction of conditioned responses. Voxel-based morphometry showed that two main regions within the superior and inferior parts of the posterior cerebellar cortex contributed to expression of visual threat eye-blink responses bilaterally. Involvement of the more inferior parts of the posterior lobe was further supported by voxel-based lesion symptom mapping in focal cerebellar patients. The present findings show that the human cerebellar cortex is involved in long-term storage of learned responses. © 2013 The Author (2013).

Patients with the Bing Neel type of Waldenstrom's macroglobulinemia often present with global neurological symptoms. In this case report, we investigated the effects of cerebrospinal fluid (CSF) of a such a patient (CSF-WM), who presented with seizures and psychomotor slowing, on the electrophysiological properties of cultured rat neurons and astrocytes. Membrane potential and Na + and K + currents of neurons were unaffected. Astrocytes, however, were significantly depolarized from − 77.6 ± 8.2 mV to − 48.0 ± 7.6 mV (38%) by CSF-WM. The depolarization was markedly reduced after CSF-WM heat inactivation or after pre-incubation of astrocytes with dexamethasone (1 μM). Astrocytes are electrophysiologically active cells, which control local ionic micro-environment. Therefore, we conclude that global neurological symptoms in the Bing Neel type of Waldenstrom's macroglobulinemia like generalized seizures can result from an impairment of glial cells electrophysiological functions.

Background: The pathogenesis of Sneddon's syndrome is unclear. This study addresses the question whether cerebral thromboembolism may be involved in the pathogenesis of the neurologic complications of the disorder. The study consisted of 13 patients with Sneddon's syndrome defined by both generalized livedo reticularis and a history of one or more cerebrovascular ischemic events; none had clinical or Doppler ultrasonographic evidence of atherosclerosis. Methods: Transcranial Doppler microembolic monitoring of the middle cerebral artery; blood screening for antiphospholipid antibodies (lupus anticoagulant, anticardiolipin antibodies). Results: Five patients (38%) showed clinically silent microembolism at transcranial Doppler monitoring, with individual microembolic event rates of the middle cerebral artery between 2 per hour and 33 per hour. In this group, the time since the last ischemic symptom was significantly shorter than in the eight patients without microemboli. Antiphospholipid antibodies were detected in three patients (23%), all of whom belonged to the microemboli-positive group. Conclusions: These data suggest that the detectability of both clinically silent cerebral microembolism and antiphospholipid antibodies may provide paraclinical evidence of active disease in patients with Sneddon's syndrome. The results support the notion that an immune-mediated prothrombotic state facilitating the formation of arterial thrombi with subsequent cerebral embolization, and/or triggering in situ thrombosis of cerebral vessels, plays a pathogenetic role in the neurologic manifestations of this disorder.

Stroke patients can recover upon intravenous thrombolysis but remain impaired in lacking recanalization. We sought to investigate the clinical effect of systemic thrombolysis with an intravenous bolus of 20 mg recombinant tissue plasminogen activator (rtPA) and an infusion of body-weight adjusted tirofiban for 48 hours in acute stroke. This prospective, open label study, included 192 patients (68±13 years, 50% males) treated between 1 January 2005 and 31 December 2007. The neurological deficit was assessed with the National Institutes of Health stroke scale (NIHSS). Follow-up was performed using a telephone interview of modified Rankin Scale (mRS) and Barthel index. The site of cerebral artery occlusion was determined by computed tomography or magnetic resonance angiography. Data were analyzed by descriptive statistics and multiple regression analyses. Eighty-one percent of the patients had an infarct in the middle cerebral artery (MCA) territory and were severely affected with a median NIHSS of 10. During treatment on the Stroke Unit the patients improved (P

The endotoxins of bacteria are lipopolysaccharides which are released in the central nervous system during bacterial meningitis. Endotoxin titers in cerebrospinal fluid correspond to the appearance of severe neurological symptoms like seizures and coma. The pathogenic mechanism, however, by which endotoxins disturb neuronal function, is unclear. The functional deficit may originate either from direct alteration of neuronal excitability or from indirect effects mediated by glial cells. Therefore, we investigated the effects of lipopolysaccharides on electrophysiological properties of cortical neurons and astrocytes in separate cell cultures. Membrane potential, resistance and membrane currents of neurons were unaffected. By contrast, astrocytes depolarized markedly in a dose dependent manner (concentration range 1.0-10.0 micrograms/ml). The depolarization was Na+ dependent and amiloride sensitive (250 microM), both indicating an activation of an electrogenic sodium dependent transport system like the Na+/Ca2+ exchanger as a source of the depolarization. These results suggest that endotoxin induced neurological deficits are not caused by direct effects on neurons, but may result from an impaired glial cell function.

The remaining limitations of ultrasonographic imaging in accurately quantifying internal carotid stenosis or diagnosing internal carotid occlusion may be overcome by enhancing the echogenicity of flowing arterial blood with contrast agents. This study assessed the usefulness of the intravenous (transpulmonary) contrast medium SH U 508 A in improving the characterization and quantification of severe internal carotid stenosis. We examined 32 patients (30 had vessels with a stenosis of greater than 70% luminal narrowing and 2 had vessel occlusions) using a 7.5-MHz linear-array transducer for color Doppler-assisted duplex imaging before and after injection of the contrast medium. The SH U 508 A-induced increase in carotid blood echogenicity began 11 +/- 2 (mean +/- SD) seconds after the start of the bolus injection, peaked at 21 +/- 2 dB, and showed a half-life of 75 seconds. Quantitative vascular measurements (cross-sectional luminal area reduction and plaque length, respectively) obtained before and after contrast application were highly correlated (r > .90). Visualization of the entire length of the intrastenotic residual flow lumen, however, was significantly improved by contrast enhancement (52% versus 83%, P = .01). This pilot study on patients with extracranial carotid artery disease suggested that ultrasonic contrast media may be most useful in improving the ultrasonography-based diagnosis of internal carotid occlusion.

Background and Purpose— Tirofiban is a highly selective, fast-acting nonpeptide glycoprotein IIb/IIIa platelet receptor antagonist with a short half-life time. Glycoprotein IIb/IIIa antagonists are effective for the treatment of acute coronary syndromes proven in large clinical trials. Safety and efficacy in patients with ischemic stroke are uncertain. This was addressed in the Safety of Tirofiban in acute Ischemic Stroke (SaTIS) trial. Methods— Two hundred sixty patients with acute ischemic stroke were randomized in a placebo-controlled, prospective, open-label treatment, blinded outcome reading multicenter trial. Subjects with a National Institutes of Health Stroke Scale between 4 and 18 received intravenously either tirofiban or placebo within 3 to 22 hours after symptom onset for 48 hours. The primary end point was the rate of cerebral bleeding as measured in follow-up CT scans 2 to 7 days after inclusion. The secondary end point was clinical efficacy within 1 week (National Institutes of Health Stroke Scale, modified Rankin Scale) and after 5 months (Barthel Index, modified Rankin Scale). Results— The rate of cerebral hemorrhagic transformation (I/II) and parenchymal hemorrhage (I/II) did not differ between both groups (tirofiban 36 of 120; placebo 33 of 124: OR, 1.18; 95% CI, 0.66 to 2.06). Mortality after 5 months was significantly lower in patients treated with tirofiban (3 of 130 [2.3%] versus 11 of 126 [8.7%]; OR, 4.05; 95% CI, 1.1 to 14.9). No difference in neurological/functional outcome was found after 1 week and after 5 months. Conclusions— We conclude that tirofiban might be safe in acute moderate ischemic stroke even when administered within a large time window after symptom onset and might save lives in the late outcome. Clinical Trial Registration— URL: www.strokecenter.org/trials/ . Trial name: SaTIS. Enrollment began before July 1, 2005.

Fourteen symptomatic patients with severe extracranial internal carotid artery stenosis (> or = 70% of luminal narrowing) were monitored using long-term transcranial Doppler ultrasonography to determine the rate of clinically silent embolism of the ipsilateral middle cerebral artery. Before carotid endarterectomy (all patients being treated with intravenous heparin), 462 such events occurred during a total monitoring time of 45 h. Statistical analyses of the inter-event intervals and of the relationship between events and cardiac cycle revealed random occurrence. While the ipsilateral events were found in each subject, silent embolism of the contralateral middle cerebral artery occurred in only four patients each of whom had angiographically proven intracranial cross-flow from the symptomatic carotid territory (39 embolic events during 7 h monitoring time). The other 10 patients showed no contralateral embolism (10 h monitoring time). Five or more days (median 10 days) after surgery and cessation of intravenous anticoagulation the ipsilateral event rate had dropped to 13 in 33 h (P < 0.001) and the contralateral rate to zero. This suggests that the stenosed arterial segment is the main source of cerebral embolism detectable with ultrasound in symptomatic patients with high-grade internal carotid stenosis, and that carotid endarterectomy substantially reduces the rate of these events. Since reduction of ipsilateral stroke risk by successful endarterectomy is known to be of a similar degree in patients as those studied here, transcranially detected embolism may represent a new marker of disease activity of extracranial carotid artery stenosis.

Background: The clinical response to systemic thrombolysis with recombinant tissue plasminogen activator (rtPA) is thought to depend on an early recanalization. We sought to investigate the effect of early recanalization on stroke lesion development as assessed with magnetic resonance imaging (MRI). Methods: Thirty-seven consecutive stroke patients (66 ± 13 years) treated with systemic thrombolysis with rtPA and tirofiban were grouped according to successful or failed recanalization as assessed on angiographic imaging. Infarct lesions were determined volumetrically in MRI prior to treatment and after 4 days. Results: Patients were severely affected (median National Institutes of Health Stroke Scale 14) and had significantly larger perfusion (PWI) than diffusion weighted imaging (DWI) lesion volumes. Ten patients with failed recanalization of the internal carotid or the middle cerebral artery did not improve. Their PWI and DWI lesion volumes were larger and the apparent diffusion coefficient more depressed than in the 27 patients with significant improvement and successful recanalization (p < 0.001). The DWI lesion volumes increased profoundly in the patients with failed recanalization (p < 0.001) but only little in the patients with successful recanalization. Multivariate regression analysis showed a relation of the initial DWI lesion volumes to the DWI lesion volumes at follow-up and the neurological recovery. Conclusions: The ischemic brain damage was particularly severe in patients with no recanalization already before systemic thrombolysis and predicted further lesion growth and failed recovery.

Thrombolysis has been shown to improve neurological recovery in acute stroke. But the response to thrombolysis is variable across patients. We sought to investigate this variability by analyzing the lesion patterns following systemic thrombolysis with recombinant tissue plasminogen activator (rtPA) and tirofiban in middle cerebral artery (MCA) stroke. One hundred three consecutive stroke patients (67 ± 14 years) were grouped according to the site of MCA occlusion and successful or failed recanalization as assessed with magnetic resonance angiography. Infarct lesions were analyzed in T2-weighted magnetic resonance images after 10 days. Patients recovered markedly upon successful recanalization following thrombolysis (p

BACKGROUND Computed tomography (CT) and magnetic resonance imaging (MRI) are tools of investigation in acute stroke. We wondered if the additional information offered by MRI outweighs the disadvantage of its longer scanning duration for systemic thrombolysis. METHODS Two hundred ninety-four consecutive patients (66 ± 13 years) were subjected to thrombolyis between 1999 and 2004. Inclusion criteria were ischemic infarction, scoring at entry and discharge with the NIH stroke scale and modified Rankin scale, systemic thrombolysis within 3 hours after symptom onset, multimodal MRI or standard CT. Subgroup analysis of 42 patients compared standard CT with CT and CT angiography. RESULTS Patients were similarly affected on admission (P > .1). At discharge, 6 days after stroke onset, the patients investigated with MRI were less impaired than those investigated with standard CT (P < .05). Symptomatic hemorrhage was rare in both groups. Also, patients investigated with CT and CT angiography were less impaired at discharge than those with standard CT (P < .02). A multifactorial regression showed that systolic blood pressure, glucose level and initial neurological impairment determined the neurological outcome at discharge. CONCLUSIONS Systolic blood pressure, glucose level and neurological impairment but not the imaging modality determined the neurological outcome following systemic thrombolysis in the 3-hour window.

Background: Cerebral microembolic signals (MES) after carotid endarterectomy (CEA) are associated with an increased risk of postoperative stroke. We investigated the relationship of an intraoperatively recorded ultrasound turbulence index (TI) during CEA and the occurrence of MES. Methods: Short-time MES detection was performed on 164 patients (mean age 64 years, 140 males) in the ipsilateral middle cerebral artery within 2 h after CEA. A specialized continuous-wave ultrasound Doppler probe measured the TI within the reconstructed internal carotid artery during surgery. Results: The occurrence of postoperative MES increased significantly with the TI: a TI >26 predicted MES with a sensitivity of 72% and a specificity of 76%. The MES rate and TI were higher in patients operated with the eversion technique than in patients operated with the patch technique (p = 0.005). There was no relationship with preoperative MES, site of surgery or age of patients. Female patients had a higher risk of postoperative MES than males (p = 0.003). Conclusions: Simplified intraoperative Doppler sonography or short-time MES detection after CEA are feasible, and may be helpful for surgical quality control and decision making (e.g. treatment with platelet antagonists).

Background and Purpose— The CARESS (Clopidogrel and Aspirin for Reduction of Emboli in Symptomatic carotid Stenosis) trial proved the effectiveness of the combination of clopidogrel and aspirin compared with aspirin alone in reducing presence and number of microembolic signals (MES) in patients with recently symptomatic carotid stenosis. The present study aimed at installing primary and secondary quality control measures in CARESS because MES evaluation relies on subjective judgment by human experts. Methods— As primary quality control, centers participating in CARESS evaluated a reference digital audio tape (DAT) before the study containing both MES and artifacts. Interobserver agreement of classifying signals as MES was expressed as proportions of specific agreement of positive ratings (ps±values). For all DATs included in CARESS (n=300), online number of MES and off-line number of MES read by the central reader were compared using correlation coefficients. As secondary control, a sample of 16 of 300 DATs was cross-validated by another independent reader (post-trial validator). Results— For the reference tape, the cumulative ps±value was 0.894 based on 12 of 14 observers. Two observers with very different results improved after a training procedure. Agreement between post-trial validator and central reader was ps+=0.805, indicating very good agreement. Correlation between online evaluation and off-line evaluation of DATs was very good overall (cumulative ρ=0.84; P Conclusion— Multicenter studies using MES as outcome parameter are feasible. However, primary and secondary quality control procedures are important.

Background: A large number of patients experience ischemic stroke despite treatment with aspirin (acetylsalicylic acid, ASA). It is not clear whether all of these patients with ischemic stroke respond normally to ASA or are hyporesponsive as assessed by inhibition of aggregation and thromboxane (TX) synthesis. Methods: We studied the effect of ASA given orally and ASA in vitro on collagen- and arachidonic-acid-induced TX formation and aggregation in platelet-rich plasma of 90 patients with ischemic stroke and 25 healthy control subjects. Results: Thirty-seven patients were being treated with ASA at the time of stroke. Arachidonic-acid-induced TX formation was not depressed below a predefined threshold of 25 ng/ml in 9 patients. Eight of these however exhibited a normal platelet sensitivity to ASA in vitro, suggesting poor compliance or a pharmacokinetic mechanism of nonresponse. The addition of ASA in vitro did not inhibit arachidonic-acid-induced TX formation below the above threshold in 6 patients (11%) in the group of 53 stroke patients not receiving oral ASA, indicating an impaired response to ASA at the platelet level. Moreover, platelets from stroke patients showed an increased collagen-induced, TX-independent aggregation as compared with those of healthy individuals. Conclusion: Different categories of ASA nonresponders can be distinguished in patients with ischemic stroke. These include patients with poor bioavailability or noncompliance, an impaired platelet response to ASA in vitro and an increased, TX-independent hyperreactivity to collagen.

To determine the effect of systemic thrombolysis with low-dose recombinant tissue plasminogen activator (rtPA) and the body-weight adjusted platelet GPIIb/IIIa receptor antagonist tirofiban, the authors performed lesion volumetry on magnetic resonance perfusion and diffusion images recorded before thrombolysis and on T2-weighted magnetic resonance images on day 8. Treatment with rtPA and tirofiban (n = 13) resulted in a 50% lesion reduction (p < 0.03), while lesion reduction was less in rtPA treatment (n = 16) and absent in nontreated patients (n = 18).

Understanding the structural and functional development of neurons in networks has a high impact to estimate the potentials for restorative therapies. Neurons derived from the human NT2 cell line (hNT) formed networks with a clustered neuritic architecture in vitro, whereas primary dissociated embryonic rat cortical neurons (Cx) displayed a more homogenous cell assembly. Spontaneous spikes of both cell types were recorded on microelectrode arrays within 2 weeks after seeding, but hNT showed a mostly uncorrelated firing pattern in contrast to Cx with highly synchronized bursting. hNT neurons were less sensitive to TTX (IC50 = 5.7 +/- 0.1 nM vs. IC50 = 1.1 +/- 0.2 nM), magnesium (IC50 = 1.83 +/- 0.01 mM vs. IC50 = 0.161 +/- 0.023 mM), and APV (IC50100 microM vs. IC50 = 18 microM). We conclude that embryonic cortical neurons and hNT neurons have different network properties. This should be carefully considered before hNT neurons are used in therapeutic approaches, e g., central nervous system (CNS) grafting.