Histopathologic Characterization and Neurodegenerative Markers in Patients With Limbic Encephalitis Undergoing Epilepsy Surgery.

Purpose: Limbic encephalitis is an increasingly recognized cause of medial temporal lobe epilepsy (mTLE) and associated cognitive deficits, potentially resulting in hippocampal sclerosis (HS). For several reasons, these patients usually do not undergo epilepsy surgery. Thus, histopathologic examinations in surgical specimens of clearly diagnosed limbic encephalitis are scarce. The purpose of this study was a detailed histopathologic analysis of surgical tissue alterations, including neurodegenerative markers, in patients with limbic encephalitis undergoing epilepsy surgery. Methods: We investigated the surgical specimens of six patients operated on with mTLE related to limbic encephalitis (among them four patients were with GAD65 and one with Ma1/2 antibodies), and compared the findings to a control group with six patients matched according to age at the time of surgery without limbic encephalitis and without early inciting events. Results: Histopathologic analysis in the group with limbic encephalitis revealed HS in four patients, while three of them also displayed signs of an active inflammatory reaction with lymphocytes. In one of the patients with GAD65-encephalitis who was suffering from a late-onset mTLE and a long disease course, neurodegenerative protein markers (ß-amyloid and hyperphosphorylated tau) were found coexisting with inflammatory reactions and HS. Investigations in the control group did not reveal any inflammatory reaction or neurodegenerative marker. Conclusion: Our findings suggest a possible link between long-lasting immune reactions in the medial temporal lobe, HS, and further toward the development of neurodegenerative diseases. Presently, however, a causal relationship between these entities cannot yet be established. Furthermore, our results suggest that an immunological etiology should always be considered in late onset (> 18 years) mTLE, also in cases of long disease duration and the presence of HS.

High Mobility Group Box 1 Protein in Cerebral Thromboemboli.

High-mobility group box 1 protein (HMGB1) is a damage-associated molecular pattern (DAMP) involved in neutrophil extracellular trap (NET) formation and thrombosis. NETs are regularly found in cerebral thromboemboli. We here analyzed associated HMGB1 expression in human thromboemboli retrieved via mechanical thrombectomy from 37 stroke patients with large vessel occlusion. HMGB1 was detected in all thromboemboli, accounting for 1.7% (IQR 0.6-6.2%) of the total thromboemboli area and was found to be colocalized with neutrophils and NETs and in spatial proximity to platelets. Correlation analysis revealed that the detection of HMGB1 was strongly related to the number of neutrophils (r = 0.58, p = 0.0002) and platelets (r = 0.51, p = 0.001). Our results demonstrate that HMGB1 is a substantial constituent of thromboemboli causing large vessel occlusion stroke.

Endovascular Treatment for Acute Stroke in Cerebral Amyloid Angiopathy.

Background and Purpose: We aimed to compare outcome of endovascular thrombectomy in acute ischemic stroke in patients with and without cerebral amyloid angiopathy (CAA). Methods: We included patients with and without possible or probable CAA based on the modified Boston criteria from an observational multicenter cohort of patients with acute ischemic stroke and endovascular thrombectomy, the German Stroke Registry Endovascular Treatment trial. We analyzed baseline characteristics, procedural parameters, and functional outcome after 90 days. Results: Twenty-eight (17.3%) of 162 acute ischemic stroke patients were diagnosed with CAA based on iron-sensitive magnetic resonance imaging performed before endovascular thrombectomy. CAA patients were less likely to have a good 90-day outcome (14.3 versus 37.8%). National Institutes of Health Stroke Scale score (adjusted odds ratio, 0.88; P<0.001), successful recanalization (adjusted odds ratio 6.82; P=0.005), and CAA (adjusted odds ratio 0.28; P=0.049) were independent outcome predictors. Intravenous thrombolysis was associated with an increased rate of good outcome (36.3% versus 0%, P=0.031) in CAA. Conclusions: Endovascular thrombectomy with or without thrombolysis appears beneficial in acute ischemic stroke patients with possible or probable CAA, but is associated with a worse functional outcome. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03356392.

MR-Imaging and Histopathological Diagnostic Work-Up of Patients with Spontaneous Lobar Intracerebral Hemorrhage: Results of an Institutional Prospective Registry Study.

Intracerebral hemorrhage (ICH) is a frequently disabling or fatal disease. The localization of ICH often allows an etiological association. However, in atypical/lobar ICH, the cause of bleeding is less obvious. Therefore, we present prospective histopathological and radiological studies which were conducted within the diagnostic workup to identify causes for lobar ICH other than hypertension. From 2016 to 2018, 198 patients with spontaneous, non-traumatic ICH requiring neurosurgical monitoring were enrolled in an institutional prospective patient registry. Patients with deep-seated ICH and/or hemorrhagically transformed cerebral infarcts were excluded from further analysis. Data to evaluate the source of bleeding based on histopathological and/or radiological workup were prospectively evaluated and analyzed. After applying the inclusion criteria and excluding patients with incomplete diagnostic workup, a total of 52 consecutive patients with lobar ICH were further analyzed. Macrovascular disease was detected in 14 patients with lobar ICH (27%). In 11 patients, diagnostic workup identified cerebral amyloid angiopathy-related ICH (21%). In addition, five patients with tumor-related ICH (10%) and six patients with ICH based on infectious pathologies (11%) were identified. In four patients, the cause of bleeding remained unknown despite extensive diagnostic workup (8%). The present prospective registry study demonstrates a higher probability to identify a cause of bleeding other than hypertension in patients with lobar ICH. Therefore, a thorough diagnostic work-up in patients with ICH is essential to accelerate treatment and further improve outcome or prevent rebleeding.

Temporal changes in total and hippocampal brain volume and cognitive function in patients with chronic heart failure-the COGNITION.MATTERS-HF cohort study.

AIMS: We quantified the concurring dynamics affecting total and hippocampal brain volume and cognitive function in patients with chronic heart failure (HF) over a period of three years. METHODS AND RESULTS: A total of 148 patients with mild stable HF entered this monocentric prospective cohort study: mean age 64.5 (10.8) years; 16.2% female; 77% in New York Heart Association functional classes I-II; 128 and 105 patients attended follow-up visits after 1 and 3 years, respectively. The assessment included cardiological, neurological, psychological work-up, and brain magnetic resonance imaging. Total and regional brain volumes were quantified using an operator-independent fully automated approach and reported normalized to the mean estimated intracranial volume. At baseline, the mean hippocampal volume was ∼13% lower than expected. However, the 3-year progressive hippocampal volume loss was small: -62 mm3 [95% confidence interval (CI) -81 to -42, P < 0.0001). This corresponded to a relative change of -1.8% (95% CI -2.3 to -1.2), which was similar in magnitude as observed with physiological aging. Moreover, the load of white matter hypointensities increased within the limits of normal aging. Cognitive function during the 3-year observation period remained stable, with 'intensity of attention' as the only domain declining (LSmean -1.82 points, 95% CI -3.05 to -0.58, P = 0.004). After 3 years, performance in all domains of cognition remained associated with hippocampal volume (r ≥ 0.29). CONCLUSION: In patients with predominantly mild HF, the markedly reduced hippocampal volume observed at baseline was associated with impaired cognitive function, but no accelerated deterioration in cognition and brain atrophy became evident over a mid-term period of three years.

From research to clinical practice: a European neuroradiological survey on quantitative advanced MRI implementation.

OBJECTIVE: Quantitative MRI (qMRI) methods provide versatile neuroradiological applications and are a hot topic in research. The degree of their clinical implementation is however barely known. This survey was created to illuminate which and how qMRI techniques are currently applied across Europe. METHODS: In total, 4753 neuroradiologists from 27 countries received an online questionnaire. Demographic and professional data, experience with qMRI techniques in the brain and head and neck, usage, reasons for/against application, and knowledge of the QIBA and EIBALL initiatives were assessed. RESULTS: Two hundred seventy-two responders in 23 countries used the following techniques clinically (mean values in %): DWI (82.0%, n = 223), DSC (67.3%, n = 183), MRS (64.3%, n = 175), DCE (43.4%, n = 118), BOLD-fMRI (42.6%, n = 116), ASL (37.5%, n = 102), fat quantification (25.0%, n = 68), T2 mapping (16.9%, n = 46), T1 mapping (15.1%, n = 41), PET-MRI (11.8%, n = 32), IVIM (5.5%, n = 15), APT-CEST (4.8%, n = 13), and DKI (3.3%, n = 9). The most frequent usage indications for any qMRI technique were tissue differentiation (82.4%, n = 224) and oncological monitoring (72.8%, n = 198). Usage differed between countries, e.g. ASL: Germany (n = 13/63; 20.6%) vs. France (n = 31/40; 77.5%). Neuroradiologists endorsed the use of qMRI because of an improved diagnostic accuracy (89.3%, n = 243), but 50.0% (n = 136) are in need of better technology, 34.9% (n = 95) wish for more communication, and 31.3% need help with result interpretation/generation (n = 85). QIBA and EIBALL were not well known (12.5%, n = 34, and 11.0%, n = 30). CONCLUSIONS: The clinical implementation of qMRI methods is highly variable. Beyond the aspect of readiness for clinical use, better availability of support and a wider dissemination of guidelines could catalyse a broader implementation. KEY POINTS: • Neuroradiologists endorse the use of qMRI techniques as they subjectively improve diagnostic accuracy. • Clinical implementation is highly variable between countries, techniques, and indications. • The use of advanced imaging could be promoted through an increase in technical support and training of both doctors and technicians.

Supratentorial ependymoma in childhood: more than just RELA or YAP.

Two distinct genetically defined entities of ependymoma arising in the supratentorial compartment are characterized by the presence of either a C11orf95-RELA or a YAP-MAMLD1 fusion, respectively. There is growing evidence that supratentorial ependymomas without these genetic features exist. In this study, we report on 18 pediatric non-RELA/non-YAP supratentorial ependymomas that were systematically characterized by means of their histology, immunophenotype, genetics, and epigenomics. Comprehensive molecular analyses included high-resolution copy number analysis, methylation profiling, analysis of fusion transcripts by Nanostring technology, and RNA sequencing. Based upon histological and immunohistochemical features two main patterns were identified-RELA-like (n = 9) and tanycytic ependymomas (n = 6). In the RELA-like group histologically assigned to WHO grade III and resembling RELA-fused ependymomas, tumors lacked nuclear expression of p65-RelA as a surrogate marker for a pathological activation of the NF-κB pathway. Three tumors showed alternative C11orf95 fusions to MAML2 or NCOA1. A methylation-based brain tumor classifier assigned two RELA-like tumors to the methylation class "EP, RELA-fusion"; the others demonstrated no significant similarity score. Of the tanycytic group, 5/6 tumors were assigned a WHO grade II. No gene fusions were detected. Methylation profiling did not show any association with an established methylation class. We additionally identified two astroblastoma-like tumors that both presented with chromothripsis of chromosome 22 but lacked MN1 breaks according to FISH analysis. They revealed novel fusion events involving genes in chromosome 22. One further tumor with polyploid cytogenetics was interpreted as PFB ependymoma by the brain tumor methylation classifier but had no relation to the posterior fossa. Clinical follow-up was available for 16/18 patients. Patients with tanycytic and astroblastoma-like tumors had no relapse, while 2 patients with RELA-like ependymomas died. Our data indicate that in addition to ependymomas discovered so far, at least two more supratentorial ependymoma types (RELA-like and tanycytic) exist.

Derivo embolization device in the treatment of unruptured intracranial aneurysms: a prospective multicenter study.

BACKGROUND: Flow diverters (FD) are used regularly for the endovascular treatment of unruptured intracranial aneurysms. We aimed to assess the safety and effectiveness of the Derivo embolization device (DED) with respect to long-term clinical and angiographic outcomes. METHODS: A prospective multicenter trial was conducted at 12 centers. Patients presenting with modified Rankin Score (mRS) of 0-1, treated for unruptured intracranial aneurysms with DED were eligible. Primary endpoint was the mRS assessed at 18 months with major morbidity defined as mRS 3-5. Satisfactory angiographic occlusion was defined as 3+4 on the Kamran scale. RESULTS: Between July 2014 and February 2018, 119 patients were enrolled. Twenty-three patients were excluded. Ninety-six patients, 71 (74%) female, mean age 54±12.0 years, were included in the analysis. Mean aneurysm size was 14.2±16.9 mm. The mean number of devices implanted per patient was 1.2 (range 1-3). Clinical follow-up at 18 months was available in 90 (94%) patients, resulting in a mean follow-up period of 14.8±5.2 months. At last available follow-up of 96 enrolled patients, 91 (95%) remained mRS 0-1. The major morbidity rate (mRS 3-5) was 3.1% (3/96), major stroke rate was 4.2% (4/96), and mortality was 0%. Follow-up angiographies were available in 89 (93%) patients at a median of 12.4±5.84 months with a core laboratory adjudicated satisfactory aneurysm occlusion in 89% (79/89). CONCLUSION: Our results suggest that DED is a safe and effective treatment for unruptured aneurysms with high rates of satisfactory occlusion and comparably low rates of permanent neurological morbidity and mortality. TRIAL REGISTRATION: DRKS00006103.

Resection of piriform cortex predicts seizure freedom in temporal lobe epilepsy.

OBJECTIVE: Transsylvian selective amygdalo-hippocampectomy (tsSAHE) represents a generally recognized surgical procedure for drug-resistant mesial temporal lobe epilepsy (mTLE). Although postoperative seizure freedom can be achieved in about 70% of tsSAHE, there is a considerable amount of patients with persisting postoperative seizures. This might partly be explained by differing extents of resection of various tsSAHE target volumes. In this study we analyzed the resected proportions of hippocampus, amygdala as well as piriform cortex in regard of postoperative seizure outcome. METHODS: Between 2012 and 2017, 82 of 103 patients with mTLE who underwent tsSAHE at the authors' institution were included in the analysis. Resected proportions of hippocampus, amygdala and temporal piriform cortex as target structures of tsSAHE were volumetrically assessed and stratified according to favorable (International League Against Epilepsy (ILAE) class 1) and unfavorable (ILAE class 2-6) seizure outcome. RESULTS: Patients with favorable seizure outcome revealed a significantly larger proportion of resected temporal piriform cortex volumes compared to patients with unfavorable seizure outcome (median resected proportional volumes were 51% (IQR 42-61) versus (vs.) 13 (IQR 11-18), P = 0.0001). Resected proportions of hippocampus and amygdala did not significantly differ for these groups (hippocampus: 81% (IQR 73-88) vs. 80% (IQR 74-92) (P = 0.7); amygdala: 100% (IQR 100-100) vs. 100% (IQR 100-100) (P = 0.7)). INTERPRETATION: These results strongly suggest temporal piriform cortex to constitute a key target resection volume to achieve seizure freedom following tsSAHE.

Immunohistological Analysis of Neutrophils and Neutrophil Extracellular Traps in Human Thrombemboli Causing Acute Ischemic Stroke.

Ischemic stroke caused by thromboembolic occlusion of large cerebral arteries, such as the internal carotid (ICA) and/or the middle cerebral artery (MCA), is treated by mechanical thrombectomy (MT). MT allows salvage of the vessel-occluding thrombemboli, which most frequently originate from the left atrium or the left ventricle of the heart or from sites of plaque rupture within large arteries above the heart. Clot composition may influence the efficacy of (intravenous) thrombolysis and MT, respectively. We analyzed 37 human thrombemboli obtained from acute ischemic stroke patients during MT with special emphasis on histological staining of neutrophils and neutrophil extracellular traps (NETs). We found neutrophils as the main cellular component of cerebral thrombemboli but encountered considerable morphological heterogeneity. Neutrophils accumulated in the border region of fibrin-rich structures indicating possible interaction of neutrophils with distinct structural thrombembolus components. Web-like NETs were found in 35 of 37 thrombemboli in varying amounts. NETs were almost exclusively found within fibrin-rich areas. Importantly, stroke etiology, age and present oral anticoagulation was associated with morphological patterns and the amount of neutrophils. Correlation of histological data and imaging data revealed that relative Hounsfield units of cerebral thrombemboli positively correlated with the amount of red blood cells. In summary, our results demonstrate that neutrophils and NETs are substantial constituents of cerebral thrombemboli and contribute to their structural complexity.

MRI follow-up after magnetic resonance-guided focused ultrasound for non-invasive thalamotomy: the neuroradiologist's perspective.

PURPOSE: Magnetic resonance-guided focused ultrasound (MRgFUS) systems are increasingly used to non-invasively treat tremor; consensus on imaging follow-up is poor in these patients. This study aims to elucidate how MRgFUS lesions evolve for a radiological readership with regard to clinical outcome. METHODS: MRgFUS-induced lesions and oedema were retrospectively evaluated based on DWI, SWI, T2-weighted and T1-weighted 3-T MRI data acquired 30 min and 3, 30 and 180 days after MRgFUS (n = 9 essential tremor, n = 1 Parkinson's patients). Lesions were assessed volumetrically, visually and by ADC measurements and compared with clinical effects using non-parametric testing. RESULTS: Thirty minutes after treatment, all lesions could be identified on T2-weighted images. Immediate oedema was rare (n = 1). Lesion volume as well as oedema reached a maximum on day 3 with a mean lesion size of 0.4 ± 0.2 cm3 and an oedema volume 3.7 ± 1.2 times the lesion volume. On day 3, a distinct diffusion-restricted rim was noted that corresponded well with SWI. Lesion shrinkage after day 3 was observed in all sequences. Lesions were no longer detectable on DWI in n = 7/10, on T2-weighted images in n = 4/10 and on T1-weighted images in n = 4/10 on day 180. No infarcts or haemorrhage were observed. There was no correlation between lesion size and initial motor skill improvement (p = 0.99). Tremor reduction dynamics correlated strongly with lesion shrinkage between days 3 and 180 (p = 0.01, R = 0.76). CONCLUSION: In conclusion, cerebral MRgFUS lesions variably shrink over months. SWI is the sequence of choice to identify lesions after 6 months. Lesion volume is arguably associated with intermediate-term outcome.

"Negative T2 shine through" in patients with hyperglycemia and seizures: a frequently overlooked MRI pattern.

Epileptic seizures associated with hyperglycemia have a rare but characteristic MR imaging pattern which however is frequently missed. It consists of a T2 hypointensity and an apparent diffusion coefficient (ADC) decrease of the white matter underlying the epileptic cortex; the cortex itself may be DWI hyperintense and show a blood-brain barrier disruption. Prompt diagnosis is relevant since treatment of the hyperglycemic state rather than treatment with anti-epileptic drugs frequently interrupts the seizures. Subcortical T2 hypointensity and ADC decrease may be completely reversible.

Functional Outcome Following Stroke Thrombectomy in Clinical Practice.

Background and Purpose- Endovascular treatment for large vessel occlusion in ischemic stroke has proven to be effective in large clinical trials. We aimed to provide real-world estimates of endovascular treatment reperfusion rates and functional outcome on a countrywide scale. Methods- Two thousand seven hundred ninety-four patients with large vessel occlusion were included into an investigator-initiated, industry-independent, prospective registry in 25 sites in Germany between June 2015 and April 2018. The primary outcome was the score on the modified Rankin Scale ranging from zero (no symptoms) to 6 (death) at 3 months. Secondary analyses included the prediction of a good outcome (modified Rankin Scale, 0-2). Dichotomized analyses of predictors were performed using logistic regression adjusted for potential confounders. Results- Median age was 75 years (interquartile range, 64-82); median National Institutes of Health Stroke Scale score was 15 (interquartile range, 10-19). Vessel occlusion was in the anterior circulation in 2265 patients (88%) and in the posterior circulation in 303 patients (12%). Intravenous alteplase before endovascular treatment was given in 1457 patients (56%). Successful reperfusion was achieved in 2143 subjects (83%). At 3 months, 854 patients (37%) showed a good outcome; mortality was 29%. There was no difference between anterior and posterior circulation occlusions (P=0.27). Significant predictors for a good outcome were younger age (odds ratio [OR], 1.06; 95% CI, 1.05-1.07), no interhospital transfer (OR, 1.39; 95% CI, 1.03-1.88), lower stroke severity (OR, 1.10; 95% CI, 1.08-1.13), smaller infarct size (OR, 1.26; 95% CI, 1.15-1.39), alteplase use (OR, 1.49; 95% CI, 1.08-2.06), and reperfusion success (OR, 1.69; 95% CI, 1.45-1.96). Conclusions- High rates of favorable outcome can be achieved on a countrywide scale by endovascular treatment. Mortality appears to be greater in the daily routine than otherwise reported by authors of large randomized trials. There were no outcome differences between the anterior and posterior circulation. Clinical Trial Registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT03356392.

Cognitive Deficits and Related Brain Lesions in Patients With Chronic Heart Failure.

OBJECTIVES: This study sought to determine the spectrum of brain lesions seen in heart failure (HF) patients and the extent to which lesion type contributes to cognitive impairment. BACKGROUND: Cognitive deficits have been reported in patients with HF. METHODS: A total of 148 systolic and diastolic HF patients (mean age 64 ± 11 years; 16% female; mean left ventricular ejection fraction 43 ± 8%) were extensively evaluated within 2 days by cardiological, neurological, and neuropsychological testing and brain magnetic resonance imaging (MRI). A total of 288 healthy, sex- and age-matched subjects sampled from the Austrian Stroke Prevention Study served as MRI controls. RESULTS: Deficits in reaction times were apparent in 41% of patients and deficits in verbal memory in 46%. On brain MRI, patients showed more advanced medial temporal lobe atrophy (MTA) (Scheltens score) compared to controls (2.1 ± 0.9 vs. 1.0 ± 0.6; p < 0.001). The degree of MTA was strongly associated with the severity of cognitive impairment, whereas the extent of white matter hyperintensities was similar in patients and controls. Moreover, patients had a 2.7-fold increased risk for presence of clinically silent lacunes. CONCLUSIONS: HF patients exhibit cognitive deficits in the domains of attention and memory. MTA but not white matter lesion load seems to be related to cognitive impairment.