[Therapies for the Improvement of Stroke Recovery - Assessment of Clinical Trial Results]. / Therapien zur Verbesserung der Schlaganfall-Regeneration ­ Ergebnisse klinischer Studien im wissenschaftlichen Kontext.

Recovery processes after stroke include restoration or compensation of function initially lost or newly acquired after injury. Therapeutic interventions can either directly improve these processes and/or inhibit processes that impede regeneration. Numerous experimental studies suggested a great opportunity for such treatments, but the results from recent large clinical trials with neuromodulators such as dopamine and fluoxetine have been rather disappointing. The reasons for this are manifold and involve the extrapolation of results from animal models to humans. Given the differences between animals and humans in genetic and epigenetic background, brain size and anatomy, cerebral vascular anatomy, immune system, as well as clinical function, and behavior, direct extrapolation is unlikely to work. Backward blockades include the incompatible adaption of clinical trial objectives and outcomes in clinical trials with regard to previous preclinical findings. For example, the clinical recovery trial design widely varies and has been characterized by the selection of different clinical endpoints, the inclusion a wide spectrum of stroke subtypes and clinical syndromes, and different time windows for treatment initiation after onset of infarction. This review will discuss these aspects based on the results of the recent stroke recovery trials with the aim to contributing to the development of a therapy that improves the functional outcome of a chronic stroke patient.

Postvaccinal Encephalitis after ChAdOx1 nCov-19.

The global SARS-CoV-2 pandemic has contributed to more than 163 million confirmed infections and 3.3 million deaths worldwide. The severity of the pandemic has led to an unprecedented effort to develop multiple effective vaccines. Due to excellent safety and efficacy data from clinical trials, several vaccines were approved. We report a case series of postvaccinal encephalitis in temporal correlation to vaccination with ChAdOx1 nCov-19. The diagnostic criteria for possible autoimmune encephalitis were fulfilled. Our patients responded well to immunosuppressive therapy with corticosteroids. The incidence has been estimated to be approximately 8 per 10 million vaccine doses. Complication of postvaccinal encephalitis after ChAdOx1 nCoV-19 vaccination still appear to be very rare, but need to be diagnosed and treated adequately. Large pooled data from observational epidemiologic studies are necessary to verify causality. ANN NEUROL 2021;90:506-511.

Detection of Atrial Fibrillation on Stroke Units: Comparison of Manual versus Automatic Analysis of Continuous Telemetry.

BACKGROUND: Detection of atrial fibrillation (AF) is one of the primary diagnostic goals for patients on a stroke unit. Physician-based manual analysis of continuous ECG monitoring is regarded as the gold standard for AF detection but requires considerable resources. Recently, automated computer-based analysis of RR intervals was established to simplify AF detection. The present prospective study analyzes both methods head to head regarding AF detection specificity, sensitivity, and overall effectiveness. METHODS: Consecutive stroke patients without history of AF or proof of AF in the admission ECG were enrolled over the period of 7 months. All patients received continuous ECG telemetry during the complete stay on the stroke unit. All ECGs underwent automated analysis by a commercially available program. Blinded to these results, all ECG tracings were also assessed manually. Sensitivity, specificity, time consumption, costs per day, and cost-effectiveness were compared. RESULTS: 216 consecutive patients were enrolled (70.7 ± 14.1 years, 56% male) and 555 analysis days compared. AF was detected by manual ECG analysis on 37 days (6.7%) and automatically on 57 days (10.3%). Specificity of the automated algorithm was 94.6% and sensitivity 78.4% (28 [5.0%] false positive and 8 [1.4%] false negative). Patients with AF were older and had more often arterial hypertension, higher NIHSS at admission, more often left atrial dilatation, and a higher CHA2DS2-VASc score. Automation significantly reduced human resources but was more expensive compared to manual analysis alone. CONCLUSION: Automatic AF detection is highly specific, but sensitivity is relatively low. Results of this study suggest that automated computer-based AF detection should be rather complementary to manual ECG analysis than replacing it.

Cervical Artery Dissection Caused by Electrical Cupping Therapy with High-Negative Pressure - Case Report.

BACKGROUND: Cervical artery dissection is an important cause of stroke in the young. The etiology is still discussed controversial. The most obvious reason for a dissection of extracranial arteries is due to a trauma, eg. after car accidents or other high speed traumas such as high-velocity road traffic accidents. Besides these clear cases, chiropractic neck maneuvers represent potential reasons for vessel injuries. CASE PRESENTATION: We here report a rare case of secondary cervical artery dissection after so-called cupping therapy and a preventive treatment with a direct oral anticoagulant. CONCLUSIONS: Therapists using this technique should be aware of the potentially devastating side effects. The diagnosis of ICA dissection should be considered with any new onset of unknown neck pain or headache, specifically in combination with neurological deficits.

Creutzfeldt-Jakob disease mimicking autoimmune encephalitis with CASPR2 antibodies.

BACKGROUND: Differential diagnosis of severe progressive dementia includes a wide spectrum of inflammatory and neurodegenerative diseases. Particularly challenging is the differentiation of potentially treatable autoimmune encephalitis and Creutzfeldt-Jakob disease. Such a coincidence may indeed complicate the correct diagnosis and influence subsequent treatment. CASE PRESENTATION: A 75-year-old woman was admitted due to rapid progressive cognitive impairment. Her husband observed a temporal disorientation and confusion. The initial neurological examination and an extensive neuropsychological evaluation showed significant impairments in almost all tested cognitive domains. All other neurological functions including motor, sensory and coordinative function were intact. Initial diagnostics included EEG, MRI and lumbar puncture with unspecific results. Complementary blood testing revealed a positive result for antineural antibodies to Contactin-associated protein 2 (CASPR2) and the patient received treatment for CASPR2 autoimmune encephalitis. Further symptoms and results, including 14-3-3 proteins, led to suspected Creutzfeldt-Jakob disease. The postmortem examination supported the diagnosis of a definitive Creutzfeldt-Jakob disease. CONCLUSION: One could argue that global screening for antineural antibodies may lead to a false diagnosis triggering intense and potentially dangerous procedures. We believe, however, that potentially treatable causes of dementia should aggressively sought out and subsequently treated in an attempt to curtail the course of disease and ultimately reduce the rate of mortality.

Functional long-term outcome following endovascular thrombectomy in patients with acute ischemic stroke.

Endovascular thrombectomy (EVT) is the most effective treatment for acute ischemic stroke caused by large vessel occlusion (LVO). Yet, long-term outcome (LTO) and health-related quality of life (HRQoL) in these patients have rarely been addressed, as opposed to modified Rankin scale (mRS) recordings. We analysed demographic data, treatment and neuroimaging parameters in 694 consecutive stroke patients in a maximum care hospital. In 138 of these patients with respect on receipt of written informed consent, LTO and HRQoL were collected over a period of 48 months after EVT using a standardised telephone survey (median 2.1 years after EVT). Age < 70 years (OR 4.82), lower NIHSS on admission (OR 1.11), NIHSS ≤ 10 after 24 h (OR 11.23) and complete recanalisation (mTICI3) (OR 7.79) were identified as independent predictors of favourable LTO. Occurrence of an infection requiring treatment within the first 72 h was recognised as a negative predictor for good long-term outcome (OR 0.22). Patients with mRS > 2 according to the telephone survey more often had complaints regarding mobility, self-care, and usual activity domains of the HRQoL. Our results underline a sustainable positive effect of effective EVT on the quality of life in LVO stroke. Additionally, predictive parameters of outcome were identified, that may support clinical decision making in LVO stroke.

Long-term functional outcome and quality of life 2.5 years after thrombolysis in acute ischemic stroke.

BACKGROUND: Evaluation of outcome after stroke is largely based on assessment of gross function 3 months after stroke onset using scales such as mRS. Cognitive or social functions, level of symptom burden or emotional health are not usually assessed, nor are data available on long-term functional outcomes years after stroke. METHODS: Analysis of 1141 patients with AIS treated with IVT from two major German university hospitals between 2017 and 2020. Patient characteristics and short-term outcome were analysed from patient records. Long-term outcome of 228 patients with prior written informed consent was assessed via telephone survey using mRS and PROMs (EQ-5D-5L, EQ-VAS) 2.5 years after stroke. RESULTS: Predictors of excellent to good long-term outcome were younger age, event to door time ≤ 2 h, NIHSS ≤ 6 on admission and NIHSS ≤ 6 after IVT. Stroke recurrence was a negative predictor. Predictors of excellent quality of life at 2.5 years included age < 73 years, lower NIHSS after IVT, absence of hypertension. Quality of life was rated in all dimensions with a medium score of 1 and a medium EQ-VAS of 70, representing the good general health status of this stroke population. CONCLUSION: Main predictors of an excellent to good long-term outcome and excellent QoL 2.5 years after stroke are younger age, lower NIHSS, and event to door time ≤ 2 h. Research on long-term outcome after disease and treatment is of utmost importance, as it has the ability to reveal the patient true functional outcome and quality of life and to provide information on the status of independence and self-esteem.

Stroke recovery enhancing therapies: lessons from recent clinical trials.

Poststroke recovery processes include restoration or compensation of function, respectively functions initially lost or new functions acquired after an injury. Therapeutic interventions can enhance these processes and/or reduce processes impeding regeneration. Numerous experimental studies suggest great opportunities for such treatments, but the results from recent large clinical trials using neuromodulators such as dopamine and fluoxetine are disappointing. The reasons for this are manifold affecting forward translation of results from animals models into the human situation. This "translational road block" is defined by differences between animals and humans with regard to the genetic and epigenetic background, size and anatomy of the brain, cerebral vascular anatomy, immune system, as well as clinical function and behavior. Backward blockade includes the incompatible adaption of targets and outcomes in clinical trials with regard to prior preclinical findings. For example, the design of clinical recovery trials varies widely and was characterized by the selection of different clinical endpoints, the inclusion a broad spectrum of stroke subtypes and clinical syndromes as well as different time windows for treatment initiation after infarct onset. This review will discuss these aspects based on the results of the recent stroke recovery trials with the goal to contribute to the currently biggest unmet need in stroke research - the development of a recovery enhancing therapy that improves the functional outcome of a chronic stroke patient.

Transient Global Amnesia (TGA): Sex-Specific Differences in Blood Pressure and Cerebral Microangiopathy in Patients with TGA.

Transient global amnesia (TGA) is defined by an acute memory disturbance of unclear aetiology for a period of less than 24 h. Observed psychological, neuroanatomical and hormonal differences between the sexes in episodic memory suggest sex-specific differences in memory disorders such as TGA. The aim of this study was to determine sex-specific differences in cardiovascular risk profiles, recurrences and magnetic resonance imaging (MRI). In total, 372 hospitalised TGA patients between 01/2011 and 10/2021 were retrospectively analysed. Comparisons were made between female and male TGA patients and compared to 216 patients with acute stroke. In our sample, women were overrepresented (61.8%), especially compared to the general population in the 65−74 age category (χ2 = 10.6, p < 0.02). On admission, female TGA patients had significantly higher systolic blood pressure values and a higher degree of cerebral microangiopathy compared to male TGA patients, whereas acute stroke patients did not. No sex-specific differences were observed with respect to recurrences or hippocampal DWI lesions. Our data demonstrate sex-specific differences in TGA. The higher blood pressure on admission and different degree of cerebral microangiopathy in female TGA patients supports the theory of blood pressure dysregulation as a disease trigger. Distinct precipitating events in female and male patients could lead to differences in the severity and duration of blood pressure abnormalities, possibly explaining the higher incidence in female patients.

Severe drug-induced liver injury caused by levetiracetam - A case report and review of the literature.

Levetiracetam (LEV) is a broad-spectrum, second-generation anti-seizure medication, which has quickly become one of the most commonly prescribed drugs for people with epielpsy due to its good tolerability, rapid up-dosing capability, with both parenteral and enteral routes of administration. Considering the frequent prescriptions and predominant excretion by the kidney with minimal hepatic metabolism, severe liver injury is very rarely a complication associated with LEV. An analysis of this reported case and further published cases was performed with respect to indication, relevant previous liver diseases, concomitant medication, and both the dosage as well as the duration of LEV when drug-induced liver injury (DILI) was noted. DILI occurs after a few days to a maximum of five months after initiation of therapy with LEV and, in the worst case, may require liver transplantation or result in death. Monitoring of serum transaminase values may be helpful. Discontinuing LEV is the first therapeutic measure. In addition, immunosuppression with cortisone can be considered for serious cases.

[Embolic stroke of undetermined source (ESUS) - Classification of a new stroke entity]. / Embolischer Schlaganfall mit ungeklärter Emboliequelle (ESUS) ­ Klassifikation einer neuen Schlaganfallentität.

Embolic stroke of undetermined source (ESUS) represents a subpopulation of cryptogenic strokes defined by its embolic stroke pattern on imaging and if after a carefully performed diagnostic evaluation, a specific, well recognized cause of stroke has not been identified. This review article analyses the basics of the ESUS concept and provides an overview of the evidence from recent cohort studies. The definition, aetiology and diagnosis of ESUS are reassessed. Targeted diagnostics in ESUS patients can reduce the number of cryptogenic strokes by making a specific diagnosis.

Atrial Fibrillation in Patients with Embolic Stroke of Undetermined Source during 3 Years of Prolonged Monitoring with an Implantable Loop Recorder.

BACKGROUND: Undocumented atrial fibrillation (AF) is suspected as a main stroke cause in patients with embolic stroke of undetermined source (ESUS), but its prevalence is largely unknown. This prospective study therefore aimed at delineating the prevalence of AF in patients with ESUS using continuous cardiac monitoring by implantable loop recorder (ILR) with daily remote interrogation over a period of 3 years and its clinical consequences, including recurrent stroke. METHODS: In consecutive patients with an ESUS diagnosis after complete work-up, an ILR was implanted and followed by daily remote monitoring until AF was detected or a follow-up of at least 3 years was completed. Additionally, the ILR was interrogated in-hospital in 6-month intervals. RESULTS: A total of 123 patients (74 male, mean age 65 ± 9 years) were enrolled and completed the 3 years study period. AF was detected in 51 patients (41.4%). In 43 of the 51 AF positive patients (84%) oral anticoagulation was established. Recurrent strokes occurred in 18 patients (14.6%) of this ESUS population, 9 of these patients being AF positive (17.6% of the AF-positive patients) and 9 being AF negative (12.5% of AF-negative patients). Patients with AF were slightly older than patients without AF (63.1 ± 8.8 vs. 67.5 ± 9.6 years, p = 0.12). Other parameters such as CHA2DS2-VASc score, infarct localization, micro- and macroangiopathy, carotid or aortic plaques, or stroke recurrence were not significantly different between groups. CONCLUSION: In ESUS patients, early implantation of an ILR with cardiac monitoring and remote transmission over a 3-year period detected AF in 41.4% and resulted in oral anticoagulation in 84% of these patients.

Differentiating Progressive Supranuclear Palsy and Parkinson's Disease With Head-Mounted Displays.

Background: Progressive supranuclear palsy (PSP) is a neurodegenerative disorder that, especially in the early stages of the disease, is clinically difficult to distinguish from Parkinson's disease (PD). Objective: This study aimed at assessing the use of eye-tracking in head-mounted displays (HMDs) for differentiating PSP and PD. Methods: Saccadic eye movements of 13 patients with PSP, 15 patients with PD, and a group of 16 healthy controls (HCs) were measured. To improve applicability in an inpatient setting and standardize the diagnosis, all the tests were conducted in a HMD. In addition, patients underwent atlas-based volumetric analysis of various brain regions based on high-resolution MRI. Results: Patients with PSP displayed unique abnormalities in vertical saccade velocity and saccade gain, while horizontal saccades were less affected. A novel diagnostic index was derived, multiplying the ratios of vertical to horizontal gain and velocity, allowing segregation of PSP from PD with high sensitivity (10/13, 77%) and specificity (14/15, 93%). As expected, patients with PSP as compared with patients with PD showed regional atrophy in midbrain volume, the midbrain plane, and the midbrain tegmentum plane. In addition, we found for the first time that oculomotor measures (vertical gain, velocity, and the diagnostic index) were correlated significantly to midbrain volume in the PSP group. Conclusions: Assessing eye movements in a HMD provides an easy to apply and highly standardized tool to differentiate PSP of patients from PD and HCs, which will aid in the diagnosis of PSP.

Transient Global Amnesia (TGA): Influence of Acute Hypertension in Patients Not Adapted to Chronic Hypertension.

Objective: Transient global amnesia (TGA) is defined by an acute memory disturbance of unclear etiology for a period of <24 h. Several studies showed differences in vascular risk factors between TGA compared to transient ischemic attack (TIA) or healthy controls with varying results. This retrospective and cross-sectional study compares the cardiovascular risk profile of TGA patients with that of acute stroke patients. Methods: Cardiovascular risk profile and MR imaging of 277 TGA patients was retrospectively analyzed and compared to 216 acute ischemic stroke patients (26% TIA). Results: TGA patients were significantly younger and predominantly female compared to stroke patients. A total of 90.6% of TGA patients underwent MRI, and 53% of those showed hippocampal diffusion-weighted imaging (DWI) lesions. Scores for cerebral microangiopathy were lower in TGA patients compared to stroke patients. After statistical correction for age, TGA patients had higher systolic and diastolic blood pressure, higher cholesterol levels, lower HbA1c, as well as blood glucose levels, and lower CHA2DS2-VASc scores. Stroke patients initially displayed higher CRP levels than TIA and TGA patients. TGA patients without DWI lesions were older and showed higher CHA2DS2-VASc scores compared to TGA patients with DWI lesions. Conclusion: This study revealed significant differences between TGA and stroke patients in regard to the cardiovascular risk profile. Our main findings show a strong association between acute hypertensive peaks and TGA in patients not adapted to chronic hypertension, indicating a vascular cause of the disease.

Transient Global Amnesia (TGA): Younger Age and Absence of Cerebral Microangiopathy Are Potentially Predisposing Factors for TGA Recurrence.

Background: Transient global amnesia (TGA) is defined by an acute memory disturbance of unclear etiology for a period of less than 24 h. TGA occurs as a single event in most cases. Prevalence rates of recurrent TGA vary widely from 5.4 to 27.1%. This retrospective study aimed to determine predictors for TGA recurrence. Methods: Cardiovascular risk profile and magnetic resonance imaging (MRI) of 340 hospitalized TGA patients between 2011 and 2020 were retrospectively analyzed. The median follow-up period amounted to 4.5 ± 2.7 years. Comparisons were made between TGA patients with and without subsequent recurrence. Results: TGA patients with subsequent recurrence were significantly younger (recurrent vs. single episode, 63.6 ± 8.6 years vs. 67.3 ± 10.5 years, p = 0.032) and showed a lower degree of cerebral microangiopathy compared to TGA patients without recurrence. The mean latency to recurrence was 3.0 years ± 2.1 years after the first episode. In a subgroup analysis, patients with at least five years of follow-up (N = 160, median follow-up period 7.0 ± 1.4 years) had a recurrence rate of 11.3%. A 24.5% risk of subsequent TGA recurrence in the following five years was determined for TGA patients up to 70 years of age without microangiopathic changes on MRI (Fazekas' score 0). Conclusion: Younger TGA patients without significant microangiopathy do have an increased recurrence risk. In turn, pre-existing cerebrovascular pathology, in the form of chronic hypertension and cerebral microangiopathy, seems to counteract TGA recurrence.

Effects of granulocyte-colony stimulating factor after stroke in aged rats.

BACKGROUND AND PURPOSE: In aged humans, stroke is a major cause of disability for which no neuroprotective measures are available. Granulocyte-colony stimulating factor (G-CSF), a member of the cytokine family of growth factors, promotes brain neurogenesis and improves functional outcome after stroke in young animals. We tested the hypothesis that G-CSF provides a restorative therapeutic benefit in aged animals. METHODS: Focal cerebral ischemia was produced by reversible occlusion of the right middle cerebral artery in 19- to 20-month-old male Sprague-Dawley rats. One hour after reperfusion, the aged rats were treated daily with 15 microg/kg G-CSF and for 15 days total. Rats were behaviorally tested and the brains removed for analysis at 28 days poststroke. RESULTS: G-CSF treatment after stroke exerted a robust and sustained beneficial effect on survival rate and running function. Transient improvement after G-CSF treatment could be observed for coordinative motor function on the inclined plane test and for working memory in the radial-arm maze test. At the cellular level, G-CSF treatment increased the number of proliferating cells in the subventricular zone and dentate gyrus and also increased the number of newborn neurons in the subventricular zone ipsilateral to the lesion. CONCLUSIONS: These results suggest that G-CSF treatment in aged rats has a survival-enhancing capacity and a beneficial effect on functional outcome, most likely through supportive cellular processes such as neurogenesis.

Cognitive training in an everyday-like virtual reality enhances visual-spatial memory capacities in stroke survivors with visual field defects.

OBJECTIVES: Visual field defects due to hemi- or quadrantanopia after stroke represent an under-recognized neurological symptom with inefficient instruments for neurorehabilitation to date. We here examined the effects of training in a virtual reality (VR) supermarket on cognitive functions, depressive symptoms, and subjective cognitive complaints in patients with hemianopia/quadrantanopia and healthy controls. METHODS: During a 14-day rehabilitation program, 20 patients and 20 healthy controls accomplished a real-life-like shopping task in a VR supermarket. A comparison between pre- and post-training standard neuropsychological measures, depressive symptoms, and subjective memory complaints allowed us to assess a putative transfer of rehabilitation effects from the training tasks to specific cognitive functions. RESULTS: The results indicate that VR training may improve performance not only in the trained task but also in specific neuropsychological functions. After the training, both patients and controls showed improved performances in visual scanning, mental rotation, visuoconstruction, and cognitive flexibility. Moreover, depressive symptoms were attenuated in both groups. In the patient group compared to the control group, the training particularly resulted in improved visual memory retrieval and reduced memory complaints. CONCLUSIONS: The results of the current study suggest that VR training can improve particularly visual-spatial skills in patients with hemianopia or quadrantanopia. Our study thus introduces an interesting novel treatment approach to improve cognitive functions relevant to daily life in stroke patients with visual field defects.

The efficacy of erythropoietin and its analogues in animal stroke models: a meta-analysis.

BACKGROUND AND PURPOSE: Erythropoietin (EPO) was explored regarding its suitability as a candidate stroke drug in animal experimental studies. We performed a meta-analysis to obtain an overall impression of the efficacy of EPO in published animal experimental stroke studies and for potential guidance of future clinical studies. METHODS: By electronic and manual searches of the literature, we identified studies describing the efficacy of EPO in experimental focal cerebral ischemia. Data on study quality, EPO dose, time of administration, and outcome measured as infarct volume or functional deficit were extracted. Data from all studies were pooled by means of a meta-analysis. RESULTS: Sixteen studies were included in the meta-analysis. When administered after the onset of ischemia, EPO and its analogues reduced infarct size by 32% and improved neurobehavioral deficits significantly. A meta-regression suggests higher doses of EPO to be associated with smaller infarct volumes. When administered earlier than 6 hours EPO was more effective compared to a later treatment initiation. Both hematopoietic and nonhematopoietic EPO analogues showed efficacy in experimental stroke. CONCLUSIONS: In conclusion, this analysis further strengthens confidence in the efficacy of EPO and its analogues in stroke therapy. Nonhematopoietic EPO analogues which are known to have less systemic adverse effects compared to EPO are also promising candidate stroke drugs. Further experimental studies are required that evaluate the safety of a combination of EPO with thrombolysis and whether EPO is also effective in animals with comorbidity.