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Background: This study investigates the impact of general anesthesia (GA) versus conscious sedation/local anesthesia (CS/LA) on the outcome of patients with minor stroke and isolated M2 occlusion undergoing immediate mechanical thrombectomy (iMT)., Methods: The databases of 16 comprehensive stroke centers were retrospectively screened for consecutive patients with isolated M2 occlusion and a baseline National Institutes of Health Stroke Scale score ≤5 who received iMT. Propensity score matching was used to estimate the effect of GA versus CS/LA on clinical outcomes and procedure-related adverse events. The primary outcome measure was a 90-day modified Rankin Scale (mRS) score of 0-1. Secondary outcome measures were a 90-day mRS score of 0-2 and all-cause mortality, successful reperfusion, procedural-related symptomatic subarachnoid hemorrhage, intraprocedural dissections, and new territory embolism., Results: Of the 172 patients who were selected, 55 received GA and 117 CS/LA. After propensity score matching, 47 pairs of patients were available for analysis. We found no significant differences in clinical outcome, rates of efficient reperfusion, and procedural-related complications between patients receiving GA or LA/CS (mRS score 0-1, P = 0.815; mRS score 0-2, P = 0.401; all-cause mortality, P = 0.408; modified Treatment in Cerebral Infarction score 2b-3, P = 0.374; symptomatic subarachnoid hemorrhage, P = 0.082; intraprocedural dissection, P = 0.408; new territory embolism, P = 0.462)., Conclusions: In patients with minor stroke and isolated M2 occlusion undergoing iMT, the type of anesthesia does not affect clinical outcome or the rate of procedural-related complications. Our results agree with recent data showing no benefit of one specific anesthesiologic procedure over the other and confirm their generalizability also to patients with minor baseline symptoms., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Patients with minor stroke and M2 occlusion undergoing best medical management (BMM) may face early neurological deterioration (END) that can lead to poor long-term outcome. In case of END, rescue mechanical thrombectomy (rMT) seems beneficial. Our study aimed to define factors relevant to clinical outcome in patients undergoing BMM with the possibility of rMT on END, and find predictors of END., Methods: Patients with M2 occlusion and a baseline National Institutes of Health Stroke Scale (NIHSS) score≤5 that received either BMM only or rMT on END after BMM were extracted from the databases of 16 comprehensive stroke centers. Clinical outcome measures were a 90-day modified Rankin Scale (mRS) score of 0-1 or 0-2, and occurrence of END., Results: Among 10 169 consecutive patients with large vessel occlusion admitted between 2016 and 2021, 208 patients were available for analysis. END was reported in 87 patients that were therefore all subjected to rMT. In a logistic regression model, END (OR 3.386, 95% CI 1.428 to 8.032), baseline NIHSS score (OR 1.362, 95% CI 1.004 to 1.848) and a pre-event mRS score=1 (OR 3.226, 95% CI 1.229 to 8.465) were associated with unfavorable outcome. In patients with END, successful rMT was associated with favorable outcome (OR 4.549, 95% CI 1.098 to 18.851). Among baseline clinical and neuroradiological features, presence of atrial fibrillation was a predictor of END (OR 3.547, 95% CI 1.014 to 12.406)., Conclusion: Patients with minor stroke due to M2 occlusion and atrial fibrillation should be closely monitored for possible worsening during BMM and, in this case, promptly considered for rMT., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Staphylococcus aureus modulates the host immune response directly by interacting with the immune cells or indirectly by secreting molecules (secretome). Relevant differences in virulence mechanisms have been reported for the secretome produced by different S. aureus strains. The present study investigated the S. aureus secretome impact on peripheral bovine mononuclear cells (PBMCs) by comparing two S. aureus strains with opposite epidemiological behavior, the genotype B (GTB)/sequence type (ST) 8, associated with a high within-herd prevalence, and GTS/ST398, associated with a low within-herd prevalence. PBMCs were incubated with different concentrations (0%, 0.5%, 1%, and 2.5%) of GTB/ST8 and GTS/ST398 secretome for 18 and 48 h, and the viability was assessed. The mRNA levels of pro- (IL1-β and STAT1) and anti-inflammatory (IL-10, STAT6, and TGF-β) genes, and the amount of pro- (miR-155-5p and miR-125b-5p) and anti-inflammatory (miR-146a and miR-145) miRNAs were quantified by RT-qPCR. Results showed that incubation with 2.5% of GTB/ST8 secretome increased the viability of cells. In contrast, incubation with the GTS/ST398 secretome strongly decreased cell viability, preventing any further assays. The GTB/ST8 secretome promoted PBMC polarization towards the pro-inflammatory phenotype inducing the overexpression of IL1-β, STAT1 and miR-155-5p, while the expression of genes involved in the anti-inflammatory response was not affected. In conclusion, the challenge of PBMC to the GTS/ST398 secretome strongly impaired cell viability, while exposure to the GTB/ST8 secretome increased cell viability and enhanced a pro-inflammatory response, further highlighting the different effects exerted on host cells by S. aureus strains with epidemiologically divergent behaviors., (© 2023. The Author(s).)

Background: The purpose of this study was to evaluate the effectiveness of mechanical thrombectomy (MT) in patients with isolated M2 occlusion and minor symptoms and identify possible baseline predictors of clinical outcome., Methods: The databases of 16 high-volume stroke centers were retrospectively screened for consecutive patients with isolated M2 occlusion and a baseline National Institutes of Health Stroke Scale (NIHSS) score ≤5 who received either early MT (eMT) or best medical management (BMM) with the possibility of rescue MT (rMT) on early neurological worsening. Because our patients were not randomized, we used propensity score matching (PSM) to estimate the treatment effect of eMT compared with the BMM/rMT. The primary clinical outcome measure was a 90-day modified Rankin Scale score of 0-1., Results: 388 patients were initially selected and, after PSM, 100 pairs of patients receiving eMT or BMM/rMT were available for analysis. We found no significant differences in clinical outcome and in safety measures between patients receiving eMT or BMM/rMT. Similar results were also observed after comparison between eMT and rMT. Concerning baseline predicting factors of outcome, the involvement of the M2 inferior branch was associated with a favorable outcome., Conclusion: Our multicenter retrospective analysis has shown no benefit of eMT in minor stroke patients with isolated M2 occlusion over a more conservative therapeutic approach. Although our results must be viewed with caution, in these patients it appears reasonable to consider BMM as the first option and rMT in the presence of early neurological deterioration., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Aging accounts for increased risk and dismal outcome of ischemic stroke. Here, we investigated the impact of age-related changes in the immune system on stroke. Upon experimental stroke, compared with young mice, aged mice had increased neutrophil clogging of the ischemic brain microcirculation, leading to worse no-reflow and outcomes. Aged mice showed an enhanced granulopoietic response to stroke that led to the accumulation of CD101 + CD62L lo mature and CD177 hi CD101 lo CD62L lo and CD177 lo CD101 lo CD62L hi immature atypical neutrophils in the blood, endowed with increased oxidative stress, phagocytosis and procoagulant features. Production of CXCL3 by CD62L lo neutrophils of the aged had a key role in the development and pathogenicity of aging-associated neutrophils. Hematopoietic stem cell rejuvenation reverted aging-associated neutropoiesis and improved stroke outcome. In elderly patients with ischemic stroke, single-cell proteome profile of blood leukocytes identified CD62L lo neutrophil subsets associated with worse reperfusion and outcome. Our results unveil how stroke in aging leads to a dysregulated emergency granulopoiesis impacting neurological outcome., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Objectives: To investigate the clinical meaning of brain parenchymal computed-tomography hyperdensities (CTHD) in patients treated of anterior circulation acute stroke with reperfusion therapy., Methods: Patients were retrospectively enrolled from three different hospitals. Brain CT scans were assessed at four time points: We recorded ASPECT scores of pre-treatment CTs, assessed ASPECT scores and the presence of CTHD on post-treatment CTs acquired within 24-30 h and 24-72 h, and examined a one-month CTs follow-up to determine the ischemic evolution of CTHD. We correlated the presence of CTHD with clinical and radiological data to define its predictive and prognostic factors., Results: In total, 165 patients were evaluated. At post-treatment CTs acquired within 24-30 h, 68 (41%) patients showed the presence of CTHD. On post-treatment CTs acquired within 24-72 h, 43 (63%) of the CTHD showed hemorrhagic transformation. Sixty-five (95%) out of the 68 CTHD evolved in a final ischemic brain area. Multivariate statistical analysis identified puncture to recanalization time to be the only independent factors predicting the presence of CTHD (p = 0.045). The presence of CTHD at the first post-treatment CTs was an independent factor for clinical outcome determined with mRS scores at 3-month follow-up (p = 0.05). Outcomes were worse for hemorrhagic transformation at follow-up CTs compared to the ischemic evolution of the CTHD (p = 0.01)., Conclusions: The presence of CTHD at CTs imaging acquired within 24-30 h after reperfusion therapy is an independent prognostic factor of a worse clinical outcome, regardless of its ASPECT score at baseline CTs and of its hemorrhagic evolution., (© 2022. Italian Society of Medical Radiology.)

Background and Objectives: To explore cognitive, EEG, and MRI features in COVID-19 survivors up to 10 months after hospital discharge., Methods: Adult patients with a recent diagnosis of COVID-19 and reporting subsequent cognitive complaints underwent neuropsychological assessment and 19-channel-EEG within 2 months (baseline, N = 49) and 10 months (follow-up, N = 33) after hospital discharge. A brain MRI was obtained for 36 patients at baseline. Matched healthy controls were included. Using eLORETA, EEG regional current densities and linear lagged connectivity values were estimated. Total brain and white matter hyperintensities (WMH) volumes were measured. Clinical and instrumental data were evaluated between patients and controls at baseline, and within patient whole group and with/without dysgeusia/hyposmia subgroups over time. Correlations among findings at each timepoint were computed., Results: At baseline, 53% and 28% of patients showed cognitive and psychopathological disturbances, respectively, with executive dysfunctions correlating with acute-phase respiratory distress. Compared to healthy controls, patients also showed higher regional current density and connectivity at delta band, correlating with executive performances, and greater WMH load, correlating with verbal memory deficits. A reduction of cognitive impairment and delta band EEG connectivity were observed over time, while psychopathological symptoms persisted. Patients with acute dysgeusia/hyposmia showed lower improvement at memory tests than those without. Lower EEG delta band at baseline predicted worse cognitive functioning at follow-up., Discussion: COVID-19 patients showed interrelated cognitive, EEG, and MRI abnormalities 2 months after hospital discharge. Cognitive and EEG findings improved at 10 months. Dysgeusia and hyposmia during acute COVID-19 were related with increased vulnerability in memory functions over time., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Coronavirus disease 2019 (COVID-19) is associated with an increased risk of thrombotic events. Ischemic stroke in COVID-19 patients entails high severity and mortality rates. Here we aimed to analyze cerebral thrombi of COVID-19 patients with large vessel occlusion (LVO) acute ischemic stroke to expose molecular evidence for SARS-CoV-2 in the thrombus and to unravel any peculiar immune-thrombotic features. We conducted a systematic pathological analysis of cerebral thrombi retrieved by endovascular thrombectomy in patients with LVO stroke infected with COVID-19 (n = 7 patients) and non-covid LVO controls (n = 23). In thrombi of COVID-19 patients, the SARS-CoV-2 docking receptor ACE2 was mainly expressed in monocytes/macrophages and showed higher expression levels compared to controls. Using polymerase chain reaction and sequencing, we detected SARS-CoV-2 Clade20A, in the thrombus of one COVID-19 patient. Comparing thrombus composition of COVID-19 and control patients, we noted no overt differences in terms of red blood cells, fibrin, neutrophil extracellular traps (NETs), von Willebrand Factor (vWF), platelets and complement complex C5b-9. However, thrombi of COVID-19 patients showed increased neutrophil density (MPO + cells) and a three-fold higher Neutrophil-to-Lymphocyte Ratio (tNLR). In the ROC analysis both neutrophils and tNLR had a good discriminative ability to differentiate thrombi of COVID-19 patients from controls. In summary, cerebral thrombi of COVID-19 patients can harbor SARS-CoV2 and are characterized by an increased neutrophil number and tNLR and higher ACE2 expression. These findings suggest neutrophils as the possible culprit in COVID-19-related thrombosis., (© 2022. The Author(s).)

Background: Contrast-enhanced magnetic resonance angiography (CE-MRA) has become a very popular imaging technique in the evaluation of the extracranial vessels pathology, while it is not commonly used to rule out intracranial vascular pathology. On the contrary, 3D time of flight MRA (TOF-MRA) has a solid role in the study of intracranial arterial vessels disease., Materials and Methods: One hundred and eight patients were consecutively included in the study. All patients were submitted to a 3 Tesla 3D CE-MRA imaging to rule out extracranial vessels pathology. A comparison was made with a 3D-TOF sequence acquired at the same time in the assessment of intracranial vessels diseases such as steno-occlusion, dissection, and aneurysms., Results: With regard to steno-occlusive disease, Spearman's rank correlation coefficient was of 0.56 for stenosis detection and of 0.57 for occlusive disease detection. The two techniques shared similar results in the evaluation of anterior circulation, while 3D-TOF found higher grades of stenosis for posterior circulation. With regard to dissection, Spearman's rank correlation coefficient was of 0.7. 3D-TOF depicted more intramural hematoma (Spearman's rank = 0.46), while CE-MRA showed more pseudo-aneurysms (Spearman's rank = 0.56). Both the technique equally evaluated the presence of intracranial aneurysms (Spearman's rank = 1)., Conclusion: CE-MRA can be considered a reliable tool to rule out intracranial pathology associated to supraortic steno-occlusive disease, also allowing time reduction. In the suspicion of dissection a T1-weighted sequence has to be added to detect the presence of a subacute vessel wall hematoma., (© 2021. Fondazione Società Italiana di Neurologia.)

Background: Inflammation is emerging as an essential trigger for thrombosis. In the interplay between innate immunity and coagulation cascade, neutrophils and neutrophil extracellular traps (NETs) can promote thrombus formation and stabilization. In ischemic stroke, it is uncertain whether the involvement of the inflammatory component may differ in thrombi of diverse etiology. We here aimed to evaluate the presence of neutrophils and NETs in cerebral thrombi of diverse etiology retrieved by endovascular thrombectomy (EVT)., Methods: We performed a systematic histological analysis on 80 human cerebral thrombi retrieved through EVT in acute ischemic stroke patients. Thrombus composition was investigated in terms of neutrophils (MPO + cells) and NET content (citH3 + area), employing specific immunostainings. NET plasma content was determined and compared to NET density in the thrombus., Results: Neutrophils and NETs were heterogeneously represented within all cerebral thrombi. Thrombi of diverse etiology did not display a statistically significant difference in the number of neutrophils (p = 0.51). However, NET content was significantly increased in cardioembolic compared to large artery atherosclerosis thrombi (p = 0.04), and the association between NET content and stroke etiology remained significant after adjusted analysis (beta coefficient = -6.19, 95%CI = -11.69 to -1.34, p = 0.01). Moreover, NET content in the thrombus was found to correlate with NET content in the plasma (p ≤ 0.001, r = 0.62)., Conclusion: Our study highlights how the analysis of the immune component within the cerebral thrombus, and specifically the NET burden, might provide additional insight for differentiating stroke from diverse etiologies., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background & Aims: Coronavirus disease 2019 (COVID-19) may associate with clinical manifestations, ranging from alterations in smell and taste to severe respiratory distress requiring intensive care, that might associate with weight loss and malnutrition. We aimed to assess the incidence of unintentional weight loss and malnutrition in COVID-19 survivors., Methods: In this post-hoc analysis of a prospective observational cohort study, we enrolled all adult (age ≥18 years) patients with a confirmed diagnosis of COVID-19 who had been discharged home from either a medical ward or the Emergency Department of San Raffaele University Hospital, and were re-evaluated after remission at the Outpatient COVID-19 Follow-Up Clinic of the same Institution from April 7, 2020, to May 11, 2020. Demographic, anthropometric, clinical and biochemical parameters upon admission were prospectively collected. At follow-up, anthropometrics, the mini nutritional assessment screening and a visual analogue scale for appetite were assessed., Results: A total of 213 patients were included in the analysis (33% females, median age 59.0 [49.5-67.9] years, 70% overweight/obese upon initial assessment, 73% hospitalised). Sixty-one patients (29% of the total, and 31% of hospitalised patients vs. 21% of patients managed at home, p = 0.14) had lost >5% of initial body weight (median weight loss 6.5 [5.0-9.0] kg, or 8.1 [6.1-10.9]%). Patients who lost weight had greater systemic inflammation (C-reactive protein 62.9 [29.0-129.5] vs.48.7 [16.1-96.3] mg/dL; p = 0.02), impaired renal function (23.7% vs. 8.7% of patients; p = 0.003) and longer disease duration (32 [27-41] vs. 24 [21-30] days; p = 0.047) as compared with those who did not lose weight. At multivariate logistic regression analysis, only disease duration independently predicted weight loss (OR 1.05 [1.01-1.10] p = 0.022)., Conclusions: COVID-19 might negatively impact body weight and nutritional status. In COVID-19 patients, nutritional evaluation, counselling and treatment should be implemented at initial assessment, throughout the course of disease, and after clinical remission. CLINICALTRIALS., Gov Registration: NCT04318366., Competing Interests: Conflict of interest The authors have no competing interests to declare., (Copyright © 2020 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Data on residual clinical damage after Coronavirus disease-2019 (COVID-19) are lacking. The aims of this study were to investigate whether COVID-19 leaves behind residual dysfunction, and identify patients who might benefit from post-discharge monitoring. All patients aged ≥18 years admitted to the Emergency Department (ED) for COVID-19, and evaluated at post-discharge follow-up between 7 April and 7 May, 2020, were enrolled. Primary outcome was need of follow-up, defined as the presence at follow-up of at least one among: respiratory rate (RR) >20 breaths/min, uncontrolled blood pressure (BP) requiring therapeutic change, moderate to very severe dyspnoea, malnutrition, or new-onset cognitive impairment, according to validated scores. Post-traumatic stress disorder (PTSD) served as secondary outcome. 185 patients were included. Median [interquartile range] time from hospital discharge to follow-up was 23 [20-29] days. 109 (58.9%) patients needed follow-up. At follow-up evaluation, 58 (31.3%) patients were dyspnoeic, 41 (22.2%) tachypnoeic, 10 (5.4%) malnourished, 106 (57.3%) at risk for malnutrition. Forty (21.6%) patients had uncontrolled BP requiring therapeutic change, and 47 (25.4%) new-onset cognitive impairment. PTSD was observed in 41 (22.2%) patients. At regression tree analysis, the ratio of arterial oxygen partial pressure to fractional inspired oxygen (PaO2/FiO2) and body mass index (BMI) at ED presentation, and age emerged as independent predictors of the need of follow-up. Patients with PaO2/FiO2 <324 and BMI ≥33 Kg/m2 had the highest odds to require follow-up. Among hospitalised patients, age ≥63 years, or age <63 plus non-invasive ventilation or diabetes identified those with the highest probability to need follow-up. PTSD was independently predicted by female gender and hospitalisation, the latter being protective (odds ratio, OR, 4.03, 95% confidence interval, CI, 1.76 to 9.47, p 0.0011; OR 0.37, 95% CI 0.14 to 0.92, p 0.033, respectively). COVID-19 leaves behind physical and psychological dysfunctions. Follow-up programmes should be implemented for selected patients., Competing Interests: The authors have declared that no competing interests exist.

Background: Ischemic stroke patients show alterations in peripheral leukocyte counts that may result from the sterile inflammation response as well as the occurrence of early infections. We here aimed to determine whether alterations of circulating leukocytes in acute ischemic stroke are associated with long-term functional outcome and hemorrhagic complications, independently of the occurrence of infections. Methods: Blood laboratory values of patients with acute ischemic stroke, presenting within 4.5 h from symptom onset, were collected. Leukocyte subsets were analyzed in relation to 3-month functional outcome, mortality, and parenchymal hemorrhagic transformation (PH). A multivariable logistic regression analysis, considering the occurrence of early post-stroke infections, was performed for each outcome measure. Results: Five-hundred-ten patients were included in the study. Independently of infections, good functional outcome was associated with a lower neutrophil to lymphocyte ratio (NL-R, OR 0.906 [95% CI 0.822-0.998]), a higher lymphocyte count (OR 1.547 [95% CI 1.051-2.277]), a higher eosinophil count (OR 1.027 [95% CI 1.007-1.048]), and a higher eosinophil to leukocyte ratio (EoLeu-R, OR 1.240 [95% CI 1.071-1.436]) at admission. Death within 3 months was associated with higher NL-R (OR 1.103 [95% CI 1.032-1.179]) as well as with lower eosinophil counts (OR 0.909 [95% CI 0.827-0.999]). Patients developing parenchymal hemorrhagic transformation had higher neutrophil counts (OR 1.420 [95% CI 1.197-1.684]) as well as a higher NL-R (OR 1.192 [95% IC 1.088-1.305]). Conclusion: Leukocyte subtype profiles in the acute phase of ischemic stroke represent a predictor of outcome independently of infections. Stroke-evoked sterile inflammation is a pathophysiological relevant mechanism that deserves further investigation., (Copyright © 2020 Semerano, Strambo, Martino, Comi, Filippi, Roveri and Bacigaluppi.)

Large vessel occlusion (LVO) stroke might cause different degrees of hemodynamic impairment that affects microcirculation and contributes to metabolic derangement. Time-domain near-infrared spectroscopy (TD-NIRS) estimates the oxygenation of microcirculation of cerebral outer layers. We measure hemoglobin species and tissue oxygen saturation ( StO 2 ) of anterior circulation stroke patients, classified as LVO or lacunar, and assess the differences compared with controls and according to LVO recanalization status. Fiducial markers categorize the brain region below each TD-NIRS probe as ischemic or nonstroke areas. The study includes 47 consecutive acute ischemic stroke patients and 35 controls. The ischemic area has significantly higher deoxy-hemoglobin (HbR) and total hemoglobin (HbT) compared with controls in both recanalized and nonrecanalized patients but lower StO 2 only in recanalized patients. Recanalized patients have significantly lower mean StO 2 in the ipsilateral hemisphere compared with nonrecanalized patients. This is the first study to report TD-NIRS measurements in acute ischemic stroke patients. TD-NIRS is able to detect significant differences in hemoglobin species in LVO stroke compared with controls and according to recanalization status. This preliminary data might suggest that StO 2 can serve as a surrogate functional marker of the metabolic activity of rescued brain tissue.

The reproducibility of cerebral time-domain near-infrared spectroscopy (TD-NIRS) has not been investigated so far. Besides, reference intervals of cerebral optical properties, of absolute concentrations of deoxygenated-hemoglobin (HbR), oxygenated-hemoglobin (HbO), total hemoglobin (HbT) and tissue oxygen saturation (StO 2 ) and their variability have not been reported. We have addressed these issues on a sample of 88 adult healthy subjects. TD-NIRS measurements at 690, 785, 830 nm were fitted with the diffusion model for semi-infinite homogenous media. Reproducibility, performed on 3 measurements at 5 minutes intervals, ranges from 1.8 to 6.9% for each of the hemoglobin species. The mean ± SD global values of HbR, HbO, HbT, StO 2 are respectively 24 ± 7 μM, 33.3 ± 9.5 μM, 57.4 ± 15.8 μM, 58 ± 4.2%. StO 2 displays the narrowest range of variability across brain regions.

Objectives: To describe the clinical features, treatment response, and follow-up of a large cohort of Italian patients with immunoglobulin (Ig)G4-related disease (IgG4-RD) referred to a single tertiary care centre., Method: Clinical, laboratory, histological, and imaging features were retrospectively reviewed. IgG4-RD was classified as 'definite' or 'possible' according to international consensus guidelines and comprehensive diagnostic criteria for IgG4-RD. Disease activity was assessed by means of the IgG4-RD Responder Index (IgG4-RD RI)., Results: Forty-one patients (15 females, 26 males) were included in this study: 26 with 'definite' IgG4-RD and 15 with 'possible' IgG4-RD. The median age at diagnosis was 62 years. The median follow-up was 36 months (IQR 24-51). A history of atopy was present in 30% of patients. The pancreas, retroperitoneum, and major salivary glands were the most frequently involved organs. Serum IgG4 levels were elevated in 68% of cases. Thirty-six patients were initially treated with glucocorticoids (GCs) to induce remission. IgG4-RD RI decreased from a median of 7.8 at baseline to 2.9 after 1 month of therapy. Relapse occurred in 19/41 patients (46%) and required additional immunosuppressive drugs to maintain long-term remission. Multiple flares occurred in a minority of patients. A single case of orbital pseudotumour did not respond to medical therapy and underwent surgical debulking., Conclusions: IgG4-RD is an elusive inflammatory disease to be considered in the differential diagnosis of isolated or multiple tumefactive lesions. Long-term disease control can be achieved with corticosteroids and immunosuppressive drugs in the majority of cases.

Background: Thrombolysis is often withheld from acute ischemic stroke patients presenting with mild symptoms; however, up to 40% of these patients end up with a poor outcome when left untreated. Since there is lack of consensus on the definition of minor symptoms, we aimed at addressing this issue by looking for features that would better predict functional outcomes at 3 months., Methods: Among all acute ischemic stroke patients admitted to our Stroke Unit (n = 1,229), we selected a cohort of patients who arrived within 24 hours from symptoms onset, with baseline NIHSS ≤6, not treated with thrombolysis (n = 304). Epidemiological data, comorbidities, radiological features and clinical presentation (NIHSS items) were collected to identify predictors of outcome. Our cohort was tested against minor stroke definitions selected from the literature and a newly proposed one., Results: Three months after stroke onset, 97 patients (31.9%) had mRS ≥ 2. Independent predictors of poor outcome were age (OR 0.97 [95% CI 0.95-9.99]) and baseline NIHSS score (OR 0.79 [95% CI 0.67-0.94]), while cardioembolic aetiology was negatively associated (OR 3.29 [95% CI 1.51-7.14]). Items of NIHSS associated with poor outcome were impairment of right motor arm (OR 0.49 [95% CI 0.27-0.91]) or the involvement of any of the motor items (OR 0.69 [95% CI 0.48-0.99]). The definition of minor stroke as NIHSS ≤3 and the new proposed definition had the highest sensitivity and accuracy and were independent predictors of outcome., Conclusions: Our study confirmed that in spite of a low NIHSS score, one third of patients had poor outcome. As already described, age and NIHSS score remained independent predictors of poor outcome even in mild stroke. Also, motor impairment appeared a major determinant of poor outcome. The new proposed definition of minor stroke featured the NIHSS score and the NIHSS items that better predicted functional outcome. Awareness that even minor stroke can yield to poor outcome should sensitize patients to arrive early to the ED and neurologists to administer rt-PA., (© 2015 S. Karger AG, Basel.)

Diagnosis of IgG4-Related Hypertrophic Pachymeningitis (IgG4-HP) relies on meningeal biopsies, because cerebrospinal fluid (CSF) diagnostic biomarkers are lacking. Here, we determined whether IgG4 intrathecal production could distinguish IgG4-HP from other disorders presenting with HP (OHP). In patients with IgG4-HP, the median CSF IgG4 concentration, IgG4 Index and IgG4Loc were significantly higher than in both controls and OHP. CSF IgG4 levels higher than 2.27mg/dL identified 100% of IgG4-HP and 5% of OHP. An IgG4Loc cut-off of 0.47 identified 100% of IgG4-HP and no cases of OHP. Our results support CSF IgG4 quantification and IgG4 Indices as alternatives to meningeal biopsy for the diagnosis of IgG4-HP when this procedure is contraindicated or uninformative., (© 2013.)

Background: Patients with wake-up stroke (WUS) are excluded from thrombolysis because of unknown time of symptom onset. Previous studies have reported similar stroke severity and early ischemic changes (EICs) in patients with WUS and stroke of known onset. These studies, however, included patients within a large timeframe to imaging or did not quantify EICs. The aim of our study was to quantify EICs of patients with WUS presenting within 3 hours of symptom recognition compared to standard 3-hours recombinant tissue plasminogen activator (rt-PA)-treated patients and assess the extent of ischemic lesion and functional independence at follow-up., Methods: Patients were selected from our prospectively collected stroke database. Baseline and follow-up computed tomographic scans were graded with Alberta Stroke Program Early Computed Tomography Score (ASPECTS). Clinical outcome measures were modified Rankin Scale score, mortality, and symptomatic intracerebral hemorrhage., Results: Demographic features, risk factors, stroke severity, and baseline ASPECTS were similar in both groups. WUS and rt-PA-treated patients had similar tissue outcome (median ASPECTS 7.0 vs 7.5; P = .202). Functional outcome was more favorable in rt-PA-treated patients (61.6% vs 43.1%; odds ratio [OR] 2.12; 95% confidence interval [CI] 1.05-4.28; P = .037). After adjusting for age, stroke severity, treatment, and EICs in less than one-third of middle cerebral artery territory, rt-PA and National Institutes of Health Stroke Scale scores remained the only significant predictors of outcome (OR 7.76; 95% CI 2.40-25.05; P = .001 and OR 0.74; 95% CI 0.67-0.82; P < .001, respectively)., Conclusions: Within 3 hours of symptom recognition, patients with WUS have EICs similar to rt-PA-treated patients. It is reasonable to expect that selected WUS patients might benefit from thrombolysis within 3 hours of symptom awareness., (Copyright © 2013 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

We have recently noted marked reductions in the electroretinographic (ERG) b-wave in HIBA transgenic mice expressing bcl-2 under control of the human IRBP promoter. These electrophysiological results are unexpected as this promoter has been shown to specifically target transgene expression to the rod and cone photoreceptors. Here, we have carried out a series of studies to better understand this result. ERGs were recorded from three lines of HIBA transgenic mice. Mice with higher levels of transgene expression developed progressive photoreceptor degeneration, and an associated reduction in the ERG a-wave. These higher-expressing lines also exhibited a severe reduction in the ERG b-wave that affected both rod- and cone-mediated responses. These mice were mated to L7 transgenic mice, which express beta-galactosidase in bipolar cells. In double transgenic mice, the ERG b-wave reduction was associated with a decrease in the number of bipolar cells in the inner retina. These results indicate that bcl-2, targeted to photoreceptors, can induce bipolar cell degeneration, and indicate that the potential benefit for bcl-2 in treating hereditary retinal disease appears limited.

This article reviews the efficacy and tolerability of intravenous immunoglobulins (IVIg) in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), including those forms associated with monoclonal gammopathy (paraproteinemic demyelinating neuropathy, PDN). Class I trials demonstrated that IVIg are effective in CIDP. About two-thirds of patients respond to initial treatment; however, most of them require repeated drug doses to maintain improvement. For PDN there are some evidences that IVIg are efficacious; however, it seems that less than 50% of the patients respond to this treatment and the persistence of the response over time has not been thoroughly investigated. The safety profile of immunoglobulins is generally good; however, the possibility of the occurrence of serious adverse effects should always be considered before starting treatment.

This multicentre randomised double blind crossover trial tested the short term efficacy of intravenous immunoglobulin (IVIg) 2.0 g/kg given over 24 or 48 hours in patients with paraproteinaemic demyelinating neuropathy (PDN). Twenty-two patients were randomised and completed the trial. After 2 weeks, the overall disability grade decreased during both IVIg treatment and placebo but neither change was significant nor was the mean difference between the treatment effects. After 4 weeks the overall disability decreased by a mean of 0.55 [0.67] grades during the IVIg period (p = 0.001) while it was substantially unmodified during the placebo period. The mean difference between the treatment effects was significant (p = 0.05). Overall during the IVIg period 10 patients improved and 11 were stable and one got worse. During the placebo period 4 patients improved, 4 deteriorated and 14 were stable. Many secondary outcome measures, including Rankin scale, time to walk 10 metres, grip strength, sensory symptoms score were significantly better during IVIg treatment. Two serious adverse events occurred during the trial, both during placebo treatment. In conclusion the trial showed some short-term benefit of IVIg in about half of the patients confirming previous observation.

Although transgenic expression of oncogenes typically leads to tumorigenesis, oncogene expression directed to the rod photoreceptors leads to cell death without tumor formation. To evaluate the cellular and functional changes induced in cone photoreceptors by an oncogene, the Mas1 protooncogene was targeted to the cones of transgenic mice by the human red/green opsin promoter. Mas1 was chosen because of its exclusive expression in the nervous system and its homology to opsin. The overall histologic appearance of the transgenic retina was normal and retinal tumors were never observed. While rod-mediated electroretinograms were normal in all respects, cone-mediated responses were diminished in direct relationship to the level of transgene expression as determined by Northern blot analysis. Responses of UV- and green-sensitive cones were reduced equivalently, and Northern analysis and immunocytochemistry indicated that cone photoreceptor densities were markedly diminished throughout transgenic retinas. These results indicate that oncogene expression in cones induces cell death without tumor formation and support the possibility that aberrant oncogene expression may underlie some forms of hereditary retinal diseases. The Mas1 transgenic mice may be useful in understanding the cone photoreceptor degeneration that occurs in cone dystrophies and age-related macular degeneration and in evaluating potential therapies for these disorders., (Copyright 2000 Academic Press.)

The management of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is the main topic of this review. A few comments will also be made about treatment of the demyelinating form of paraproteinaemic demyelinating polyneuropathy (PDN) and of multifocal motor neuropathy (MMN). The review briefly describes the main characteristics of these neuropathies, and examines case series and trials which evaluated the principal therapeutic strategies for CIDP, PDN and MMN, such as intravenous immunoglobulin (IVIg) therapy, steroid treatment, plasma exchange and immunosuppressor administration. Controlled trials demonstrated that IVIg, steroid treatment and plasma exchange are effective in CIDP. For PDN the therapeutic strategies are the same as for idiopathic CIDP, but usually the clinical response is poorer. For MMN, IVIg therapy is definitely the first choice treatment.

The electroencephalographic modifications that occur during the course of Alzheimer's disease are characterised by an increase in the potential of low frequency bands, a diminution in the potential of alpha activity, and a change in the topographical distribution of the potential of all band frequencies. In this study, the fast Fourier transform (FFT) approximation was used to characterise modifications in the electroencephalogram location or orientation of the source of the dipole equivalent of the delta, theta, alpha1, alpha2, beta1 and beta2 frequencies in 20 with patients with Alzheimer's disease and in a control group of 20 age-matched subjects. A statistical (t-test) comparison of the two groups revealed a significant change in the location of the dipolar source along the vertical axis in 18 (90%) of the patients; this change involved all the frequency bands. There was also a significant movement of the dipolar source of the alpha1 band towards the anterior regions. In addition, the control group showed that there was a significant correlation between age and a more surface expression of the source of the delta, theta, alpha1 and beta1 bands.

Visual function was evaluated in transgenic mice expressing the simian virus 40 early region under the control of the promoter for phenylethanolamine-N-methyltransferase. These transgenic mice undergo a degeneration of the retinal horizontal cells and the outer plexiform layer. Electroretinograms (ERGs) were recorded under stimulus conditions chosen to elicit both receptoral and postreceptoral responses. The dark-adapted a-waves obtained from transgenic mice were not different from control recordings, indicating that the degenerative process does not interfere with function of the rod photoreceptors. In comparison, the ERG b-wave was markedly reduced in transgenic mice under both dark- and light-adapted conditions. Reproducible visual evoked potentials (VEPs) were recorded from transgenic mice in response to both low luminance stimuli that isolate rod function, and to higher luminance stimuli, indicating that retinal activity is transmitted centrally to the visual cortex. However, VEPs were delayed at all stimulus luminances compared to controls. Analysis of luminance-response functions suggests that the VEP delays could reflect the combination of a decrease in synaptic efficacy and an overall loss in visual sensitivity. These functional abnormalities correlate well with the anatomical abnormalities that have been previously observed in the transgenic retina (Hammang et al., 1993), namely a reduced number of synapses between photoreceptors and second-order neurons.

Several animal studies have shown an anatomical and functional separation between the ON- and OFF-pathways in the retina and in the lateral geniculate nucleus. Psychophysical studies in humans have also documented separate pathways that process increments and decrements of light. However, at the level of the visual cortex, there is electrophysiological evidence of interactions between the ON- and OFF-pathways. In addition, psychophysical studies have shown that these pathways can exhibit differential sensitivity and be differentially adapted. These findings motivated an electrophysiological study to gather further evidence of processing within the ON- and OFF-pathways in the human visual system. Using sawtooth stimulus modulation, we measured the visual evoked potential (VEP) before and after adaptation to both rapid-on and rapid-off sawtooth stimuli. The effect of adaptation was determined by comparing the VEP response in three test conditions: without adaptation, after adaptation to the same sawtooth polarity, and after adaptation to the opposite sawtooth polarity. The results reveal a selective adaptation effect, which provides physiological evidence for separate processing of increments and decrements in the human visual system. We conclude that with appropriate stimulus parameters, the VEP can serve as an objective measure of processing within the ON- and OFF-pathways in humans.