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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.

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.

In the next two decades the aging baby boomers in Germany will gradually be leaving the work force. They are being followed by the much less numerous, "baby bust" generation who now need to finance and staff healthcare for the growing number of old people in society. In order to care for more needy persons with a smaller working population, the healthcare system must be restructured; however, despite these worrisome prospects, the awareness of the problem is still low in many areas. Here we focus on the area in the healthcare system that is growing particularly rapidly and additionally has the greatest need of personnel per patient: the care of the critically ill and functionally impaired patients. The lack of coordination of hospitals, rehabilitation centers and nursing institution is historical in origin. It promotes the tendency to discharge functionally impaired patients to nursing facilities without giving them a chance for recovery of functional autonomy. As the demographic change progresses, this tendency threatens to increase. In a first of two parts, we attempt to describe the present situation.In 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.

BACKGROUND For future development of machine learning tools for gait impairment assessment after stroke, simple observational whole-body clinical scales are required. Current observational scales regard either only leg movement or discrete overall parameters, neglecting dysfunctions in the trunk and arms. The purpose of this study was to introduce a new multiple-cue observational scale, called the stroke mobility score (SMS). MATERIAL AND METHODS In a group of 131 patients, we developed a 1-page manual involving 6 subscores by Delphi method using the video-based SMS: trunk posture, leg movement of the most affected side, arm movement of the most affected side, walking speed, gait fluency and stability/risk of falling. Six medical raters then validated the SMS on a sample of 60 additional stroke patients. Conventional scales (NIHSS, Timed-Up-And-Go-Test, 10-Meter-Walk-Test, Berg Balance Scale, FIM-Item L, Barthel Index) were also applied. RESULTS (1) High consistency and excellent inter-rater reliability of the SMS were verified (Cronbach's alpha >0.9). (2) The SMS subscores are non-redundant and reveal much more nuanced whole-body dysfunction details than conventional scores, although evident correlations as e.g. between 10-Meter-Walk-Test and subscore "gait speed" are verified. (3) The analysis of cross-correlations between SMS subscores unveils new functional interrelationships for stroke profiling. CONCLUSIONS The SMS proves to be an easy-to-use, tele-applicable, robust, consistent, reliable, and nuanced functional scale of gait impairments after stroke. Due to its sensitivity to whole-body motion criteria, it is ideally suited for machine learning algorithms and for development of new therapy strategies based on instrumented gait analysis. CA Raab

In the present study extinction and renewal of cognitive associations were assessed in two experiments in participants with focal and degenerative cerebellar disease. Using a predictive learning task, participants had to learn by trial and error the relationships between food items and the occurrence of stomach trouble in a hypothetical patient. In the first experiment, focus was on renewal effects. Participants with chronic cerebellar stroke (n = 14; mean age 50.9 ± 12 years), participants with degenerative cerebellar disease (n = 16; mean age 58 ± 12 years), age-, sex-, and education matched controls (n = 20; mean age 53.7 ± 10.8 years) and young controls (n = 19; mean age 23.2 ± 2.7 years) were tested. Acquisition and extinction of food-stomach trouble associations took part in two different contexts (represented by restaurants). In a subsequent test phase, food stimuli were presented in both contexts and no feedback was given. This allowed testing for renewal of the initially acquired associations in the acquisition context. Acquisition and extinction learning were not significantly different between groups. Significant renewal effects were present in young controls only. In the second experiment, focus was on extinction. To control for age effects, 19 young participants with chronic surgical lesions of the cerebellum (mean age 25.6 ± 6.1 years), and 24 age-, sex- and education-matched healthy controls were tested. Acquisition and extinction of food-stomach trouble associations took part in the same context. In the extinction phase, the relationship with stomach trouble was reversed in some of the food items. Acquisition and extinction learning were not significantly different between groups. The main finding of the present study was preserved extinction of learned cognitive associations in participants with chronic cerebellar disease. Findings agree with previous observations in the literature that cognitive abnormalities are frequently absent or weak in adults with cerebellar disease. This does not exclude a contribution of the cerebellum to extinction of learned associations. For example, findings may be different in more challenging cognitive tasks, and in participants with acute cerebellar disease with no time for compensation.

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.

Die Digitalisierung der Medizin hat zur Beschleunigung der Ablaufe und nahezu universellen Verfugbarkeit von Informationen gefuhrt. Verkurzte stationare Verweildauern erfordern nun auch intelligente und praxistaugliche Systeme in der Rehabilitation und Pravention. Hierzu gehoren u. a. die Optimierung von Bewegungsanalysen durch innovative Techniken, z. B. Detektoren mit Druckmessfolien, portable Monitorsysteme, robotergestutzte Assistenzsysteme sowie professionelle Praventionsprogramme, die auf reliablen Daten beruhen. Nicht zuletzt bedarf es allerdings auch klinischer Strukturen, um die Moglichkeiten kunstlicher Intelligenz (AI) und maschinellen Lernens in der Rehabilitation optimal zu nutzen. Einen Beitrag hierzu konnen inter- und transdisziplinare Behandlungsteams wie z. B. das RehaBoard liefern. Durch die zunehmende Einfuhrung von AI in der rehabilitativen Orthopadie und Unfallchirurgie mit der Unterstutzung sektorenubergreifender Behandlungspfade hat diese im Gegensatz zu anderen kostenintensiven Bereichen wie beispielsweise der Onkologie, sehr gute Chancen, bei einem Wettbewerb um den grosten Patientennutzen („value-based competition“) vergleichsweise gut abzuschneiden.

Poster-Abstract

Die Wiedergewinnung und der Erhalt der Mobilitat stellen aufgrund der demografischen Entwicklung eine wachsende medizinische und soziale Problematik dar, deren Meisterung neue, moderne Losungsstrategien aus der interdisziplinaren Zusammenarbeit zwischen Arzten, Therapeuten und Ingenieurwissenschaftlern erfordert. Wahrend bei der Therapieauswahl zur Behandlung von Gangstorungen, insbesondere bei neurologischen Erkrankungen, bisher hauptsachlich semiquantitative und teils „intuitive“ Diagnosemethoden von Arzten und Therapeuten zum Tragen kommen, bieten moderne Methoden der Bewegungssimulation neue Ansatze, die eine evidenzbasierte Therapieplanung ermoglichen. In dem Forschungsprojekt ReHabX wurde die Technologie der Bewegungssimulation genutzt, um innovative Methoden fur die personalisierte Therapiesteuerung in der Schlaganfallrehabilitation zu entwickeln. Dies umfasste (1) die Formulierung von klinischen Kenngrosen, welche eine reproduzierbare Bestimmung der funktionell erforderlichen Rehabilitationsmasnahmen unterstutzen, (2) eine Methodik, um die Masnahmenempfehlungen von klinischen Experten zu objektivieren, und (3) ein Softwaretool, das es Arzten und Therapeuten ermoglicht, aufgrund objektivierter Kriterien unterschiedliche Masnahmen fur die Rehabilitation der Gangfahigkeit nach einem Schlaganfall zu vergleichen und eine Empfehlung fur die Behandlung zu erhalten. Durch die Weiterentwicklung der Methoden konnten innovative, auf den Patienten zugeschnittene „Multi“-Therapien personalisiert gestaltet werden und aus den daraus resultierenden Therapieerfolgen konnte die Teilhabe der Patienten am gesellschaftlichen Leben deutlich verbessert werden.

Die Komorbiditat von kardiologischen und neurologischen Erkrankungen betrifft vorwiegend vaskulare Prozesse mit Endorganischamien und erfordert spezialisierte Akuttherapien. Die Sekundarpravention der Arteriosklerose ist in beiden Disziplinen ahnlich, wahrend die Antikoagulation auf einer neurologischen Indikation bei VHF und anderen kardialen Thrombenrisiken beruht. Sehr haufig sind erworbene QTc-Verlangerungen durch Pharmakointeraktionen neurologischer und kardiologischer Medikamente. Nach kardiologischen Erkrankungen (CPR, multiple Insulte) sind neuropsychologische Defizite oft unterdiagnostiziert und untertherapiert.

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.

University-based study of medicine continues to be in great demand in Germany, although many medical students seem to be preparing themselves for going abroad. University hospitals experience an increasing pressure to perform highly specialized tasks requiring more qualified personnel while at the same time facing, and also trying to manage to comply competitively with, the framework of Diagnostis Related Groups (DRG). Since a larger number of patients are “going through the mill”, the specialist doctor is now chiefly compelled to ensure efficient quality control of the treatment. At the same time, however, there must be enough time for combined ward rounds in the “long-standing” subjects for the adequate training of assistant doctors. Since the previously existing designation Doctor in the practising stage (AiP) has been abandoned in Germany, these “beginners” are made fully responsible straightaway. There has also been a dramatic change for doctors-in-chief and their working conditions. Clinical directors of privately financed German hospitals are now exclusively business executives. Many a doctor-in-chief spends sleepless nights when he realizes that his ideally first-class medical quality hospital has been “downgraded” due to only conditionally first-class doctors. Medical training is the key for the professional standard and medical qualification of a doctor and should revive and realize his image.

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.

Objective We hypothesized that a subgroup of patients with frank stroke due to sudden occlusion of the internal carotid artery could safely undergo surgery to restore carotid patency and to rescue brain tissue not yet irreversibly damaged if current stroke diagnostic methods were applied. Methods From November 1997 to March 2007, 1810 patients underwent carotid endarterectomy of the internal carotid artery for occlusive disease at our department. Within the same period, 5369 patients were examined at our stroke unit, and 502 from this cohort underwent internal carotid artery reconstruction. A subgroup of 35 patients (28 men, 7 women; mean age, 61 ± 10 years) underwent urgent surgical revascularization due to an acute internal carotid artery occlusion ≤72 hours (mean 25 ± 17 hours) after the onset of stroke symptoms and ≤36 hours (mean 16 ± 10 hours) after admission to our stroke unit. Our diagnostic workup consisted of extracranial intracranial duplex sonography, cerebral computed tomography, digital subtraction angiography, magnetic resonance imaging, and angiography, including diffusion- and perfusion-weighted imaging, to discriminate between viable and irreversibly damaged brain tissue. The study excluded patients who presented an impaired level of consciousness, occlusion of the intracranial internal carotid artery, occlusion of the ipsilateral middle cerebral artery, or infarction more than one-third of the territory perfused by the middle cerebral artery. Imaging showed signs of recent ischemic infarction in all 35 cases. On admission, eight patients (23%) scored 0 to 2 points and 27 (77%) scored 3 to 5 points in Rankin scale. Results Confirmed by postoperative Doppler and duplex sonography at discharge, internal carotid artery patency could be achieved in 30 of 35 cases (86%). Intracranial hemorrhage occurred in two patients (6%) and reinfarction in another two (6%). Two patients died during their hospital stay (30-day mortality, 6%). Compared with the preoperative neurologic status, rates of clinical improvement (≥1 point in Rankin scale), stability, and deterioration were 57%, 31%, and 6%, respectively. Conclusions Restoration of blood flow in an acutely occluded internal carotid artery can only be achieved in the acute stage. Our pilot study demonstrated that a thorough diagnostic workup allows selection of patients who may benefit from urgent revascularization of acute internal carotid artery occlusion in the stage of an acute stroke. A prospective randomized multicenter trial comparing surgery with conservative medical treatment is needed.

The Striatum is involved in the regulation of movements and motor skills. We have shown previously, that the osmolyte and neuromodulator taurine plays a role in striatal plasticity. We demonstrate now that hereditary taurine deficiency in taurine-transporter knock-out (TAUT KO) mice results in disinhibition of striatal network activity, which can be corrected by taurine supplementation. Modification of GABAA but not glycine receptors (taurine is a ligand for both receptor types) underlies this disinhibition. Whole-cell recordings from acutely isolated as well as cultured striatal neurons revealed a decreased agonist sensitivity of the GABAA receptor in TAUT KO neurons in the absence of changes in the maximal GABA-evoked current amplitude. The striatal GABA level in TAUT KO mice was unchanged. The amplitude enhancement of spontaneous IPSCs by zolpidem was stronger in TAUT KO than in wild-type (WT) animals. Tonic inhibition was absent in striatal neurons under control conditions but was detected after incubation with the GABA-transaminase inhibitor vigabatrin: bicuculline induced a larger shift of baseline current in WT as compared to TAUT KO neurons. Lack of taurine leads to reduced sensitivity of synaptic and extrasynaptic GABAA receptors and consequently to disinhibition. These findings help in understanding neuropathologies accompanied by the loss of endogenous taurine, for instance in hepatic encephalopathy.

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.

Untersucht wurde der gegenwartige Stellenwert der Revaskularisation eines akuten Karotisverschluss im akuten Insult. Von 1997–2006 wurden innerhalb einer kontinuierlichen Serie 34 Patienten mit einem akuten Karotisverschluss prospektiv erfasst, die wir innerhalb von 72 h (Durchschnitt 25 h) nach Symptombeginn und innerhalb von 36 h (Durchschnitt 16 h) nach stationarer Aufnahme notfallmasig revaskularisiert haben. Einschlusskriterium war der frische extrakraniellen A.-carotis-interna (ACI)-Verschluss im akuten ischamischen Insult. Ausschlusskriterien waren ein Verschluss der intrakraniellen ACI oder der A. cerebri media, ein Insult von mehr als einem Drittel des Mediastromgebietes oder eine eingeschrankte Bewusstseinslage. Alle Patienten erhielten praoperativ ein Doppler-/Duplexuntersuchung und eine Angiographie, ein zerebrales Computer- und/oder ein Magnetresonanztomogramm. Die Bifurkationsgefase wurden thrombendarteriektomiert und die distal davon gelegene Thrombose entfernt. Zwei Patienten (6%) erlitten eine intrakranielle Blutung und ein Patient (3%) einen Reinfarkt. Zum Zeitpunkt der Entlassung waren 30 (88%) der 34 Karotisverschlusse erfolgreich revaskularisiert, 59% der Patienten (n=20) hatten sich neurologisch verbessert, 29% (n=10) waren stabil, 6% (n=2) hatten sich verschlechtert. Die 30-Tage-Letalitat betrug 6% (n=2). Nach sorgfaltiger praoperativer Abklarung ist es moglich, einen akuten Karotisverschluss im ischamischen Insult mit relativ geringer Morbiditat und Mortalitat zu rekanalisieren.

Embryonic stem cells can be differentiated into neurons of diverse neurotransmitter-specific phenotypes. While the time course of functional progression of ES cell-derived neural precursors towards mature neurons has been described in detail on single-cell level, the temporal development and pharmacological modulation of ES cell-derived neuronal network activity have not been explored yet. Neuronal network activity can be assessed by the microelectrode array (MEA) technology that allows simultaneous monitoring of the electrical activity exhibited by entire populations of neurons over several weeks or months in vitro. We demonstrate here that ES cell-derived neural precursors cultured on MEAs for 5 to 6 weeks develop neuronal networks with oscillating and synchronous spike patterns via distinct states of activity and change electrophysiological characteristics even after 5 to 6 weeks in culture pointing towards late maturational processes. These processes were accompanied by an increasing density of presynaptic vesicles. Furthermore, we demonstrated that ES cell-derived network activity was sensitive to synaptically acting drugs indicating that pharmacologically susceptible neuronal networks were generated. Thus, the MEA technology represents a powerful tool to describe the temporal progression of stem cell-derived neural populations towards mature, functioning neuronal networks that can be applied to investigate pharmacologically active compounds.

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.

Purpose To investigate the evolution of the perfusion deficit area following systemic thrombolysis with recombinant tissue plasminogen activator (rtPA) in a clinical study on acute cerebral ischemia. Materials and Methods We performed volumetric measurements of the acute ischemic lesions in MR images of perfusion (TTP, MTT, and rCBV) and in diffusion-weighted (DW) images, as well as the manifest stroke lesions in T2-weighted MR images on day 8. We compared the data of 29 patients who were subjected to systemic thrombolysis with those of 18 patients who were not eligible for thrombolysis. Results In the treated patients there were prominent MTT/DWI and TTP/DWI mismatches (P < 0.0006). The acute TTP volumes were smaller than the acute MTT volumes, but as large as the T2 lesions on day 8. The MTT/T2 lesion volume reduction was significant (P < 0.03) in patients who received the GPIIb/IIIa receptor antagonist tirofiban (N = 13) in addition to the low-dose rtPA. This corresponded to a greater neurological improvement compared to patients who received rtPA alone (P < 0.05). In contrast, in the nontreated patients the initial MTT and TTP lesion volumes were of similar magnitude and predicted the T2 lesions on day 8. In the treated and nontreated patients the TTP lesion signified the viability threshold of acute ischemia, which corresponded to a rCBF of 25 ± 11 mL/100 g/min. Conclusion The perfusion deficit area comprises the ischemic core that is destined to undergo necrosis, and an ischemic rim that is salvageable by systemic thrombolysis. J. Magn. Reson. Imaging 2005;22:199–205. © 2005 Wiley-Liss, Inc.

Purpose To investigate the development of ischemic brain lesions, as present in the acute stroke phase, by diffusion-weighted magnetic resonance imaging (DWI), and in the subacute and chronic phases until up to four months after stroke, in fluid-attenuated inversion recovery (FLAIR)- and T2-weighted (T2W) magnetic resonance (MR) images. Materials and Methods Twelve consecutive patients with their first middle cerebral artery (MCA) infarction were included. Lesion volumes were assessed on T2W images recorded with a turbo spin echo (TSE) and on images recorded with the FLAIR sequence on average on day 8 and after about four months. They were compared with acute lesion volumes in perfusion and DWI images taken within 24 hours of stroke onset. Results On day 8, lesion volumes in images obtained with FLAIR exceeded the acute infarct volumes in DWI. The chronic lesion volumes were almost identical in T2W and FLAIR images but significantly reduced compared with the acute DWI lesions. The lesion volumes assessed on DWI images correlated highly with the lesions in the images obtained with TSE or FLAIR, as did the lesions in the images obtained with FLAIR and TSE. The secondary lesion shrinkage was accompanied by ventricular enlargement and perilesional sulcal widening, as most clearly visible in the images obtained with FLAIR. Conclusion Our results show that the acute DWI lesions are highly predictive for the infarct lesion in the chronic stage after stroke despite a dynamic lesion evolution most evident in MR images obtained with FLAIR. J. Magn. Reson. Imaging 2004;20:201–207. © 2004 Wiley-Liss, Inc.

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.

Incubation of cultured cortical astrocytes with tumor necrosis factor alpha (TNF alpha) led to a marked reduction of membrane potential. Here we report that this depolarization depends on activation of protein kinase C (PKC), since it could be blocked by the PKC antagonists staurosporine and H7 and it could be mimicked by direct activation of PKC using the phorbol ester phorbol 12-myristate 13 acetate (PMA). Analyses of whole cell currents revealed a reduction of inwardly rectifying K+ currents whereas K+ outward currents were not affected. We conclude that TNF alpha induces changes of basic electrophysiological properties of astrocytes which are similar to those induced by proliferation or an in vitro model of traumatic injury.

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.

Studies of cerebellar patients employing modern lesion-symptom mapping techniques have provided valuable insights into the contribution of the cerebellum to motor adaptation. In patients with chronic focal lesions of the cerebellum, the process of adapting reaching movements to force field (FF) and visuomotor rotation (VM) perturbations relies on different anatomical structures located primarily within the territory of the superior hand area. By contrast, results within the territory of the inferior hand area are less consistent. Compensatory mechanisms may have masked the contribution of the inferior hand area. To test this hypothesis, reaching adaptation to FF and VM perturbations was investigated in 24 patients with acute and subacute lesions of the cerebellum. High-resolution magnetic resonance images were acquired to perform voxel-based lesion-symptom mapping (VLSM). VLSM confirmed that distinct and only partially overlapping areas located primarily within the territory of the superior hand area were crucial for adaptation to FF and VM. More specifically, current results add to previous findings that lobule V is of particular importance in FF adaptation, whereas lobule VI plays a more important role in VM adaptation. No clear evidence for a contribution of the inferior hand area to either task was found. Reach adaptation appears to depend primarily on the superior hand area within the cerebellum.

CNS involvement is one of the hallmarks underlying poor prognosis in SLE and for therapeutic strategies it is difficult to assess which patients are at risk. As detectability of cerebral microembolic signals (MES) using long-term transcranial Doppler ultrasonography (TCD) proved to be predictive of past and future thromboembolic events in patients with carotid artery stenosis, we investigated whether MES might be similarly useful in patients with antiphospholipid syndrome (APS). Our study population consisted of 46 SLE patients and five with primary APS (pAPS). Twelve of the 46 patients with SLE, 10 of them with secondary APS (sAPS), and four of five patients with pAPS had a history of cerebrovascular ischaemia (CVI). MES in the middle cerebral artery were detected in 14 of 16 patients with and in one of 35 without CVI ( P < 0.001). Antiphospholipid antibodies (aPL) were positive in 12 of 15 patients with and 18 of 36 without MES, and the rate of MES correlated to the titre of aPL. MES from APS patients resembled in their energy distribution those from patients with symptomatic carotid disease and were significantly different from those associated with artificial heart valves. In conclusion, cerebral MES are detectable in APS patients and correlate with a history of CVI. Whether this innovative method may provide individual risk assessment in APS patients has to be addressed in prospective studies.