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

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

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

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

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

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

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

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

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

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

Towards a multimodal treatment of depression: a minireview on the potential role of antibiotics.

In regard of increasing rates of post-stroke mood disorders and evidences of a neuroprotective effect of antbiotics after cerebral ischemia we have reviewed the clinical relevance of the neuroprotective and mood stabilizing effects of antibiotics in the light of the basic pathophysiology of depression.

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

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

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

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

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

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

Effects of monocyte chemoattractant protein 1 on blood-borne cell recruitment after transient focal cerebral ischemia in mice.

Monocyte chemoattractant protein 1 (MCP-1) plays an important role in inflammatory reactions following cerebral ischemia. It is known that MCP-1 overexpression leads to increased infarct volume and elevated hematogenous cell recruitment, while MCP-1-deficient mice develop smaller infarcts. It was supposed that MCP-1 dependent macrophage recruitment might be the underlying mechanism of ischemic brain damage but a precise distinction of local microglia and invading macrophages was not performed. In this study we investigated the differential role of MCP-1 on inflammatory cells in MCP-1-deficient mice, using green fluorescent protein (GFP) transgenic bone marrow chimeras. After 30-min of focal cerebral ischemia microglia was rapidly activated and was not different between MCP-1-deficient mice and wild type controls. Activated microglia outnumbered GFP-positive macrophages over the study period. Furthermore, macrophage infiltration was significantly reduced at day 7 in MCP-1-deficient animals (31.2+/-20.1 cells/mm(2)) compared to MCP-1 wild type mice (131.5+/-66.7 cells/mm(2), P<0.001). Neutrophils were also significantly reduced in MCP-1-deficient mice (62% on day 4% and 87% on day 7; P<0.001). This is the first investigation in cerebral ischemia showing that MCP-1 is necessary for recruiting blood-borne cells to the injury site whereas it does not affect the microglia activation and migration. However, the remarkable predominance of activated microglia and the additional attenuation of invading macrophages suggest that different mechanisms than macrophage recruitment are responsible for the MCP-1-mediated neuroprotective effects after experimental stroke.

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

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

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

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

Interferon-beta stabilizes barrier characteristics of the blood-brain barrier in four different species in vitro.

BACKGROUND: Blood-brain barrier (BBB) breakdown is an early event in the pathogenesis of multiple sclerosis (MS). In a previous study we have found a direct stabilization of barrier characteristics after treatment of bovine brain capillary endothelial cells (BCECs) with human recombinant interferon-beta-1a (IFN-beta-1a) in an in vitro BBB model. In the present study we examined the effect of human recombinant IFN-beta-1a on the barrier properties of BCECs derived from four different species including humans to predict treatment efficacy of IFN-beta-1a in MS patients. METHODS: We used primary bovine and porcine BCECs, as well as human and murine BCEC cell lines. We investigated the influence of human recombinant IFN-beta-1a on the paracellular permeability for 3H-inulin and 14C-sucrose across monolayers of bovine, human, and murine BCECs. In addition, the transendothelial electrical resistance (TEER) was determined in in vitro systems applying porcine and murine BCECS. RESULTS: We found a stabilizing effect on the barrier characteristics of BCECs after pretreatment with IFN-beta-1a in all applied in vitro models: addition of IFN-beta-1a resulted in a significant decrease of the paracellular permeability across monolayers of human, bovine, and murine BCECs. Furthermore, the TEER was significantly increased after pretreatment of porcine and murine BCECs with IFN-beta-1a. CONCLUSION: Our data suggest that BBB stabilization by IFN-beta-1a may contribute to its beneficial effects in the treatment of MS. A human in vitro BBB model might be useful as bioassay for testing the treatment efficacy of drugs in MS.

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

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

[Development of new stroke therapies: outlook for neuroprotective drugs]. / Entwicklungen neuer Therapiemöglichkeiten des Schlaganfalls : Perspektiven für Neuroprotektiva?

Stroke remains one of the most urgent medical problems of our times. The failure of most neuroprotective drugs in clinical trials led to the initiation of the Stroke Therapy Academic Industry Roundtable guidelines. Due to this improvement, the positive clinical trial results with the free radical scavenger NXY-059 (SAINT I) was encouraging. However, the subsequent SAINT II trial did not confirm these results. In this article we critically review the history of preclinical and clinical trials based on experience of NXY-059 development and present recommendations for potential future preclinical and clinical development of neuroprotective stroke therapy.

[Treatment strategies for tetanus]. / Behandlungsstrategien des Tetanus.

As a result of active immunisation, tetanus has become a rare but still severe neurological disease in the developed world. Despite modern intensive care management, mortality ranges between 20 and 50%. Introduction of mechanical ventilation dramatically reduced mortality; the life-threatening vegetative dysfunctions with cardiovascular instability are now the main reasons for the remaining poor prognosis. This report provides information about clinical features, diagnosis and prophylaxis of the disease and gives an overview of the therapeutic principles of generalized tetanus, focusing on the management of autonomic instability.

Perspectives on neuroprotective stroke therapy.

After years of setbacks, the perspective of neuroprotective stroke therapy has revived in light of recent study results. We outline in this review how a neuroprotective candidate drug should be developed, beginning with a thorough preclinical evaluation according to the STAIR (Stroke Therapy Academic Industry Roundtable) criteria. Assessing the safety of the candidate drug in the relatively straightforward Phase IIA would be the first step into clinical development. While advancing into Phase IIB, the implementation of a responder analysis, the use of a surrogate biomarker as well as the use of Bayesian methodology should be considered to increase the likelihood of seeing any therapeutic sign. Clinical development in Phase III should consider that previously used dichotomized endpoints appropriate for evaluation of thrombolytic drugs are likely to be insufficient for assessing efficacy of neuroprotective drugs. Detection of a clinically relevant shift in the outcome measure appears to be a more relevant approach for the type of drug that achieves a reduction and not a reverse of the ischaemic lesion.