Pilot study on the probability of drug-drug interactions among direct oral anticoagulants (DOACs) and antiseizure medications (ASMs): a clinical perspective.

BACKGROUND: There is little and controversial information about changes in plasma concentrations (PCs) or clinical events during coadministration of antiseizure medications (ASMs) and direct oral anticoagulants (DOACs). We aimed to explore possible determinants of dosage class among DOACs trough PCs when ASMs are co-administered and the relative risks. We also provided some clinical examples of patients' management. METHODS: Data on adult patients concomitantly treated with ASMs (grouped in enzyme-inducing [I-ASMs], non-inducing [nI-ASMs], and levetiracetam [LEV]) and DOACs with at least one measurement of DOACs' PC were retrospectively collected. The role of DOAC-ASM combinations in predicting PC class (ranging from I at ischemic/thromboembolic risk to IV at increased bleeding risk) was investigated by an ordered logit model, and the marginal probabilities of belonging to the four dosage classes were calculated. RESULTS: We collected 46 DOACs' PCs out of 31 patients. There were 5 (10.9%) determinations in class I (4 out of 5 with concomitant I-ASMs) and 5 (10.9%) in class IV. The rivaroxaban/I-ASM combination was associated with lower DOAC dosages than rivaroxaban/LEV (OR: 0.00; 95% CI: 0.00-0.62). Furthermore, patient's probability of being in class I was approximately 50% with the rivaroxaban/I-ASM combination, while apixaban, dabigatran, and edoxaban had the highest cumulative probability of being in class II or III despite the ASM used. CONCLUSION: These preliminary results confirm the reduction of DOAC's PC by I-ASMs and suggest a better manageability of apixaban, dabigatran, and edoxaban independently from the concomitant ASM, whereas rivaroxaban seems the most liable to PC alterations with I-ASMs.

Genome-wide mapping of signatures of selection using a high-density array identified candidate genes for growth traits and local adaptation in chickens.

BACKGROUND: Availability of single nucleotide polymorphism (SNP) genotyping arrays and progress in statistical analyses have allowed the identification of genomic regions and genes under selection in chicken. In this study, SNP data from the 600 K Affymetrix chicken array were used to detect signatures of selection in 23 local Italian chicken populations. The populations were categorized into four groups for comparative analysis based on live weight (heavy vs light) and geographical area (Northern vs Southern Italy). Putative signatures of selection were investigated by combining three extended haplotype homozygosity (EHH) statistical approaches to quantify excess of haplotype homozygosity within (iHS) and between (Rsb and XP-EHH) groups. Presence of runs of homozygosity (ROH) islands was also analysed for each group. RESULTS: After editing, 541 animals and 313,508 SNPs were available for statistical analyses. In total, 15 candidate genomic regions that are potentially under selection were detected among the four groups: eight within a group by iHS and seven by combining the results of Rsb and XP-EHH, which revealed divergent selection between the groups. The largest overlap between genomic regions identified to be under selection by the three approaches was on chicken chromosome 8. Twenty-one genomic regions were identified with the ROH approach but none of these overlapped with regions identified with the three EHH-derived statistics. Some of the identified regions under selection contained candidate genes with biological functions related to environmental stress, immune responses, and disease resistance, which indicate local adaptation of these chicken populations. CONCLUSIONS: Compared to commercial lines, local populations are predominantly reared as backyard chickens, and thus, may have developed stronger resistance to environmental challenges. Our results indicate that selection can play an important role in shaping signatures of selection in local chicken populations and can be a starting point to identify gene mutations that could have a useful role with respect to climate change.

RNAseq reveals modulation of genes involved in fatty acid biosynthesis in chicken liver according to genetic background, sex, and diet.

Increases in chicken production are mainly due to specialised breeds. However, local breeds are of increasing importance, known for ability to adapt to the environment and unique products. Conventional poultry products contain lower levels of n-3 fatty acids (FAs) compared to those obtained from local breeds, therefore the aim of this study was to evaluate the modulation of expression of genes involved in long-chain polyunsaturated FA (PUFA) biosynthesis pathways according to genetic background, diet conditions, and sex. Animals from two local breeds and a commercial line were fed different diets: control and experimental diet (10% linseed supplementation). For each breed and diet group, both sexes were reared. The RNA was extracted from 36 liver samples and sequenced by RNAseq method. Bioinformatic analysis was carried out to find differentially expressed genes from comparisons between experimental groups. Results showed low impact of diet on differentially expressed genes related to FA biosynthesis, but linseed diet increased percentage of n-3 FAs of liver. Sex and genetic background determined the differential expression of genes related to long-chain PUFA biosynthesis. Specifically, females of local breeds shared 23 up-regulated genes when compared to their respective commercial line groups. Some of the shared genes had a role in de novo triglyceride biosynthesis (MTTPL and GPAM), and in de novo FA biosynthesis (ACACA and SCD) was detected. In conclusion, local breeds are able to better adapt to a diet rich in PUFA, by triggering certain transcriptomic shifts in the liver that allow birds to process the high PUFA content provided by diet.

Monoclonal Antibodies Targeting CGRP: A Novel Treatment in Vestibular Migraine.

Background. Monoclonal antibodies (mAbs) directed against the calcitonin gene-related peptide (CGRP) or its receptor represented the first targeted and specialized approach to migraine prophylaxis. Nevertheless, they have been rarely considered in the treatment of vestibular migraine (VM). Our aim was to evaluate the effectiveness of anti-CGRP mAbs in VM patients who did not respond to conventional migraine treatments. Methods. Consecutive VM patients treated with erenumab were considered. As a comparison, we considered the same VM patients during conventional migraine treatments (i.e., propranolol, flunarizine, or valproic acid), which were tried before mAbs therapy. Videonystagmography, the Italian version of the Dizziness Handicap Inventory (DHI) questionnaire, and migraine days over the last 3 months were evaluated in all patients before and after treatments. Results. In the present retrospective study, we included 21 female and 2 male VM patients, mean age 45.2 years. All patients underwent contrast-enhanced magnetic resonance imaging that ruled out other causes of vertigo. The DHI questionnaire significantly improved after mAb therapy (p < 0.0001). Mean migraine days over the last 3 months were significantly reduced after treatment (p = 0.001). Videonystagmography was altered in 11 (48%) patients prior to monoclonal antibodies. We found vertical positional nystagmus in 9 patients and horizontal positional nystagmus in 2 patients. After the treatment, we found vertical positional nystagmus only in 1 patient (p = 0.002). When patients were treated with conventional therapies, there was no significant reduction in DHI, and instrumental vestibular examinations remained altered. Conclusions. VM patients using anti-CGRP mAbs experienced a reduction in the dizziness-derived handicap, as reported in the DHI questionnaire. Furthermore, these treatments were significantly associated with a normalization of vestibular instrumental analysis. These findings were not seen with conventional treatments. Treatment with anti-CGRP mAbs may be effective in VM patients who did not respond to conventional migraine treatments. These findings should be tested in large, randomized clinical trials.

Acute revascularization treatments for ischemic stroke in the Stroke Units of Triveneto, northeast Italy: time to treatment and functional outcomes.

It is not known whether the current territorial organization for acute revascularization treatments in ischemic stroke patients guarantees similar time to treatment and functional outcomes among different levels of institutional stroke care. We aimed to assess the impact of time to treatment on functional outcomes in ischemic stroke patients who received intravenous thrombolysis (IVT) alone, bridging (IVT plus thrombectomy), or primary thrombectomy in level 1 and level 2 Stroke Units (SUs) in Triveneto, a geographical macroarea in Northeast of Italy. We conducted an analysis of data prospectively collected from 512 consecutive ischemic stroke patients who received IVT and/or mechanical thrombectomy in 25 SUs from September 17th to December 9th 2018. The favorable outcome measures were mRS score 0-1 and 0-2 at 3 months. The unfavorable outcome measures were mRS score 3-5 and death at 3 months. We estimated separately the possible association of each variable for time to treatment (onset-to-door, door-to-needle, onset-to-needle, door-to-groin puncture, needle-to-groin puncture, and onset-to-groin puncture) with 3-month outcome measures by calculating the odds ratios (ORs) with two-sided 95% confidence intervals (CI) after adjustment for pre-defined variables and variables with a probability value ≤ 0.10 in the univariate analysis for each outcome measure. Distribution of acute revascularization treatments was different between level 1 and level 2 SUs (p < 0.001). Among 182 patients admitted to level 1 SUs (n = 16), treatments were IVT alone in 164 (90.1%), bridging in 12 (6.6%), and primary thrombectomy in 6 (3.3%) patients. Among 330 patients admitted to level 2 SUs (n = 9), treatments were IVT alone in 219 (66.4%), bridging in 74 (22.4%), and primary thrombectomy in 37 (11.2%) patients. Rates of excellent outcome (51.4% vs 45.9%), favorable outcome (60.1% vs 58.7%), unfavorable outcome (33.3% vs 33.8%), and death (9.8% vs 11.3%) at 3 months were similar between level 1 and 2 SUs. No significant association was found between time to IVT alone (onset-to-door, door-to-needle, and onset-to-needle) and functional outcomes. After adjustment, door-to-needle time ≤ 60 min (OR 4.005, 95% CI 1.232-13.016), shorter door-to-groin time (OR 0.991, 95% CI 0.983-0.999), shorter needle-to-groin time (OR 0.986, 95% CI 0.975-0.997), and shorter onset-to-groin time (OR 0.994, 95% CI 0.988-1.000) were associated with mRS 0-1. Shorter door-to-groin time (OR 0.991, 95% CI 0.984-0.998), door-to-groin time ≤ 90 min (OR 12.146, 95% CI 2.193-67.280), shorter needle-to-groin time (OR 0.983, 95% CI 0.972-0.995), and shorter onset-to-groin time (OR 0.993, 95% CI 0.987-0.999) were associated with mRS 0-2. Longer door-to-groin time (OR 1.007, 95% CI 1.001-1.014) and longer needle-to-groin time (OR 1.019, 95% CI 1.005-1.034) were associated with mRS 3-5, while door-to-groin time ≤ 90 min (OR 0.229, 95% CI 0.065-0.808) was inversely associated with mRS 3-5. Longer onset-to-needle time (OR 1.025, 95% CI 1.002-1.048) was associated with death. Times to treatment influenced the 3-month outcomes in patients treated with thrombectomy (bridging or primary). A revision of the current territorial organization for acute stroke treatments in Triveneto is needed to reduce transfer time and to increase the proportion of patients transferred from a level 1 SU to a level 2 SU to perform thrombectomy.

Network meta-analysis on patent foramen ovale: is a stroke or atrial fibrillation worse?

OBJECTIVE: Systematic reviews suggest that patent foramen ovale closure (PFOc) is performed percutaneously with low complication rates. We did a network meta-analysis (NMA) comparing devices for PFO closures, evaluating safety and efficacy of transcatheter PFOc in preventing neurological events in patients with stroke when compared with medical therapy (MT), and assessing risk of atrial fibrillation (AF). METHODS: We searched 3 databases (MEDLINE, EMBASE, CENTRAL/CCTR) identifying six randomized controlled trials from 2012 until December 2019. We performed a Bayesian NMA; number-needed-to-treat and number-needed-to-harm were derived by applying the estimated odds ratios (ORs). The likelihood of being helped or harmed (LHH) was evaluated to estimate the risk-effectiveness balance. RESULTS: The 3560 patients allocated to PFOc were less subject to a stroke than patients with MT. The overall ORs of PFOc versus MT were 0.41 with fixed-effects, and 0.22 with random-effects model. NMA proves that PFOc induces AF episodes significantly higher than MT, even when analysis is limited to only new episodes of "serious AF." LHH (0.68 fixed-effects, 0.79 random-effects) showed that strokes saved are less than cases of AFs added. By considering only serious AF, strokes saved are higher than serious AFs induced by the PFOc (LHH was 3.46 and 4.00 respectively). CONCLUSIONS: NMA supported PFOc in patients with cryptogenic stroke, confirming that devices are better than MT, but increase the risk of AF by over 2/4 times (serious or unserious AF). Considering serious AFs (real risky clinical condition), patients have more advantages in being treated, since LHH is ≥ 3-4.

Stroke management during the coronavirus disease 2019 (COVID-19) pandemic: experience from three regions of the north east of Italy (Veneto, Friuli-Venezia-Giulia, Trentino-Alto-Adige).

BACKGROUND: Efficiency of care chain response and hospital reactivity were and are challenged for stroke acute care management during the pandemic period of coronavirus disease 2019 (COVID-19) in North-Eastern Italy (Veneto, Friuli-Venezia-Giulia, Trentino-Alto-Adige), counting 7,193,880 inhabitants (ISTAT), with consequences in acute treatment for patients with ischemic stroke. METHODS: We conducted a retrospective data collection of patients admitted to stroke units eventually treated with thrombolysis and thrombectomy, ranging from January to May 2020 from the beginning to the end of the main first pandemic period of COVID-19 in Italy. The primary endpoint was the number of patients arriving to these stroke units, and secondary endpoints were the number of thrombolysis and/or thrombectomy. Chi-square analysis was used on all patients; furthermore, patients were divided into two cohorts (pre-lockdown and lockdown periods) and the Kruskal-Wallis test was used to test differences on admission and reperfusive therapies. RESULTS: In total, 2536 patients were included in 22 centers. There was a significant decrease of admissions in April compared to January. Furthermore, we observed a significant decrease of thrombectomy during the lockdown period, while thrombolysis rate was unaffected in the same interval across all centers. CONCLUSIONS: Our study confirmed a decrease in admission rate of stroke patients in a large area of northern Italy during the lockdown period, especially during the first dramatic phase. Overall, there was no decrease in thrombolysis rate, confirming an effect of emergency care system for stroke patients. Instead, the significant decrease in thrombectomy rate during lockdown addresses some considerations of local and regional stroke networks during COVID-19 pandemic evolution.

The Closure of Patent Foramen Ovale in Preventing Subsequent Neurological Events: A Bayesian Network Meta-Analysis to Identify the Best Device.

BACKGROUND: Randomized-controlled trials (RCTs) reported a finding on the safety and efficacy of percutaneous patent foramen ovale (PFO) closure to prevent stroke recurrence. It showed that the Amplatzer (AMP) device appears to be superior to medical therapy (MT) in preventing strokes and episodes of atrial fibrillation (AF), than other devices. We performed a network meta-analysis (NMA) to evaluate the closure of PFO in preventing subsequent neurological events while investigating the results obtained by specific devices. METHODS: We searched 3 databases (MEDLINE, EMBASE, CENTRAL/CCTR) and identified 6 RCTs until March 2019. We performed an NMA and used pooled ORs. Analyses were done in NetMetaXL1.6-WinBUGS1.4. RESULTS: Six RCTs with 3,560 patients (mean age 45.2-46.2 years) were included in the present NMA. Depending on the device, 4 groups of patients were compared with MT: 1,889 patients undergoing PFO closure were significantly less likely to experience a stroke than 1,671 patients treated with MT (ORs 0.41; 95% Cr.I. 0.27-0.60 with fixed-effects model and ORs 0.22; 95% Cr.I. 0.05-0.70 with random-effects model). The patients with AMP showed a similar risk than those treated with Helex/Cardioform (HLX/CF) or with a group of 11 multiple devices. This suggests the equality between the 2 most currently used devices. When assessing TIA and, for the safety analysis, major bleeding, both models confirm no significant difference between any devices and MT. PFO closure increased the risk of new-onset AF: MT induces AF significantly less than all the devices. In favor of the AMP, there is a reduced number of cases of AF versus MT; however, no device superiority has been established in comparing HLX/CF and other devices in a random effect model. CONCLUSIONS: Our NMA provides evidence in favor of PFO closure with all the devices currently in use. We can conclude that these devices are better than MT, but not that 1 device is better than the rest in reducing stroke recurrences and AF episodes in the follow-up.

Pathogenesis of Cluster Headache: From Episodic to Chronic Form, the Role of Neurotransmitters and Neuromodulators.

OBJECTIVE: To describe the role of biochemical anomalies of tyrosine (TYR), tryptophan (TRP), and arginine (ARG) metabolism in patients suffering from episodic and chronic cluster headache (CCH). BACKGROUND: The pathogenesis of cluster headache (CH) and the process that transforms the episodic into the chronic form are unknown. However, the accompanying symptoms suggest a dysfunction of the sympathetic system and hypothalamus along with anomalies of metabolism of catecholamines, elusive amines, and nitric oxide (NO) metabolism. METHODS: We describe the results obtained from the last papers published on this issue. The level of metabolites were analyzed by different high-performance liquid chromatography methods. RESULTS: In both episodic and CH patients, the levels of dopamine and elusive amines are very elevated. The only biochemical difference found in studies between episodic and chronic cluster was that norepinephrine levels were significantly lower in episodic cluster in comparison to control and chronic subjects. In addition, the levels of ARG, homoarginine, and citrulline, precursors of synthesis of NO, were significantly lower in chronic cluster. CONCLUSIONS: All these results suggest that TYR, TRP, and ARG metabolism is abnormal and may constitute a biochemical fingerprint of CH patients. The increased levels of norepinephrine in chronic cluster constitute a possible cause of chronicity of this primary headache. The high levels of tryptamine and its activity on the central serotoninergic system may explain why the length of CH is brief in comparison to migraine and tension-type headache. The low levels of ARG, homoarginine, and citrulline may be the consequence of high circulating levels of α1 -agonists, such as epinephrine and norepinephrine, and their biochemical interaction with endothelial trace amine-associated receptor 1 that induces activation of NO synthase, resulting in NO synthesis in the circulation, NO release, intense vasodilation, and as a result, the cluster attack.

Intravenous thrombolysis for ischemic stroke in the Veneto region: the gap between eligibility and reality.

Intravenous thrombolysis (IVT) is the treatment of choice for most patients with acute ischemic stroke. According to the recently updated guidelines, IVT should be administered in absence of absolute exclusion criteria. We aimed to assess the proportion of ischemic strokes potentially eligible and actually treated with IVT, and to explore the reasons for not administering IVT. We prospectively collected and analyzed data from 1184 consecutive ischemic stroke patients admitted to the 22 Stroke Units (SUs) of the Veneto region from September 18th to December 10th 2017. Patients were treated with IVT according to the current Italian guidelines. For untreated patients, the reasons for not administering IVT were reported by each center in a predefined model including absolute and/or relative exclusion criteria and other possible reasons. Out of 841 (71%) patients who presented within 4.5 h of stroke onset, 704 (59%) had no other absolute exclusion criteria and were therefore potentially eligible for IVT according to the current guidelines. However, only 323 (27%) patients were eventually treated with IVT. Among 861 (73%) untreated patients, 480 had at least one absolute exclusion criterion, 283 only relative exclusion criteria, 56 only other reasons, and 42 a combination of relative exclusion criteria and other reasons. Our study showed that only 46% (323/704) of the potentially eligible patients were actually treated with IVT in the SUs of the Veneto region. All healthcare professionals involved in the acute stroke pathway should make an effort to bridge this gap between eligibility and reality.

Ratio Aß1-42:p-Tau: a Possible Diagnostic Tool in Differentiating Dementias.

BACKGROUND: Patients with Alzheimer's disease (AD) present a typical biochemical profile of biomarkers: low concentration of ß amyloid 1-42 (Aß1-42), high concentration of total Tau (t-Tau) and phosphorylated Tau at threonine 181 (p-Tau). Several neurodegenerative diseases may overlap with AD, both in regards to clinical symptoms and neuropathology. Many data suggest that Alzheimer's disease (AD) pathophysiology can be identified using biomarkers. It has been hypothesized that subjects with dementia due to AD showed low levels of Aß1-42 combined with the highest levels of total Tau and phosphorylated Tau; moreover, it has been hypothesized that the ratio Aß1-42:p-Tau further help in discriminating Alzheimer's disease from other diagnoses. The aim of this work is to verify this hypothesis in our cohort of patients and to investigate if the same ratio could be a sensitive index able to discriminate MCI due to neurodegenerative factors (MCId) from MCI due to vascular factors (MCIv). METHODS: Two hundred sixty-two patients meeting the NIA-AA and NINDS-AIREN criteria were diagnosed as follow: AD in 120 patients [mean age 71.6 (42 - 87)], FTD in 23 patients [mean age 67.3 (46 - 78)], LBD in 17 patients [mean age 73.2 (58 - 83)], VAD in 9 patients [mean age 71.2 (60 - 81)]. According to the criteria proposed by Petersen RC, 24 patients had the diagnosis of MCId [mean age 71.8 (59 - 81)], 38 MCIv [mean age 69.3 (55-82). The comparison between the ratio of Aß1-42/p-Tau among the six groups was done using t-test for independent samples. A p-value < 0.05 was considered to represent statistical significance. The ROC (Receiver Operating Characteristic) curve analysis was made using R-studio software. RESULTS: The ratio Aß1-42:p-Tau was significantly lower in AD and MCId with respect to all the other groups and the difference was also statistically significant between MCId and MCIv. CONCLUSIONS: Aß1-42:p-Tau ratio has potential for being implemented in the clinical routine for differential diagnosis between AD and other dementias and to distinguish underling pathology such as neurodegenerative or vascular disease.

Management of antibody-mediated autoimmune encephalitis in adults and children: literature review and consensus-based practical recommendations.

Autoimmune encephalitis associated with antibodies against neuronal surface targets (NSAE) are rare but still underrecognized conditions that affect adult and pediatric patients. Clinical guidelines have recently been published with the aim of providing diagnostic clues regardless of antibody status. These syndromes are potentially treatable but the choice of treatment and its timing, as well as differential diagnoses, long-term management, and clinical and paraclinical follow-up, remain major challenges. In the absence of evidence-based guidelines, management of these conditions is commonly based on single-center expertise.Taking into account different published expert recommendations in addition to the multicenter experience of the Italian Working Group on Autoimmune Encephalitis, both widely accepted and critical aspects of diagnosis, management and particularly of immunotherapy for NSAE have been reviewed and are discussed.Finally, we provide consensus-based practical advice for managing hospitalization and follow-up of patients with NSAE.

A Liquid Chromatography-Mass Spectrometry Assay for Determination of Perampanel and Concomitant Antiepileptic Drugs in the Plasma of Patients With Epilepsy Compared With a Fluorescent HPLC Assay.

BACKGROUND: Perampanel is a novel noncompetitive selective antagonist at the postsynaptic ionotropic alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA) glutamate receptor, which is approved as an adjunctive agent for the treatment of partial-onset seizure with or without secondary generalization and for primary generalized tonic-clonic seizure in patients with epilepsy who are at least 12 years of age. Limited information is available about the clinical utility of therapeutic drug monitoring of perampanel and therapeutic ranges are so far not established. Therefore, perampanel titration should be performed especially in case of insufficient success of the drug. METHODS: The authors developed a selective and sensitive LC-MS/MS (liquid chromatography-mass spectrometry) assay to monitor perampanel concentrations in plasma, which was compared to a commercially available high-performance liquid chromatography kit with fluorescent detection. Perampanel and the internal standard were extracted from plasma samples by a simple protein precipitation. The method allows the simultaneous quantification of perampanel and several other antiepileptic drugs (AEDs). RESULTS: Data were evaluated according to EMA guidelines for bioanalytical method validation. Extraction recovery of perampanel from human plasma was consistently above 98%. No matrix effect was found. Analytical interferences by other AEDs were not observed. The method was linear in the range from 2.5 to 2800 ng/mL. Intra-assay and interassay reproducibility analyses demonstrated accuracy and precision within acceptance criteria. Data collected from 95 patients, given perampanel as their maintenance antiepileptic therapy, showed a very strong correlation between the 2 methods. CONCLUSIONS: The assay allows for highly sensitive and selective quantification of perampanel and concomitant AEDs in patient plasma samples and can be easily implemented in clinical settings. Our findings are in agreement with previously published data in patients comedicated with enzyme inducer AEDs, but seem to indicate a possible interaction in patients treated with the enzyme inhibitor drug valproic acid.

Reciprocal Interaction of 24-Hour Blood Pressure Variability and Systolic Blood Pressure on Outcome in Stroke Thrombolysis.

BACKGROUND AND PURPOSE: Significance and management of blood pressure (BP) changes in acute stroke care are unclear. Here, we aimed to investigate the impact of 24-hour BP variability (BPV) on outcome in patients with acute ischemic stroke treated with intravenous thrombolysis. METHODS: From the Safe Implementation of Treatment in Stroke International Stroke Thrombolysis registry, 28 976 patients with documented pre-treatment systolic BP at 2 and 24 hours were analyzed. The primary measure of BP variability was successive variability. Data were preprocessed using coarsened exact matching. We assessed early neurological improvement, symptomatic intracerebral hemorrhage (SICH), and long-term functional outcome (modified Rankin Scale [mRS] at 90 days) by binary and ordinal regression analyses. RESULTS: Attempts to explain successive variation for analysis of BPV with patients characteristics at admission found systolic BP (5.5% variance) to be most influential, yet 92% of BPV variance remained unexplained. Independently from systolic BP, successive variation for analysis of BPV was associated with poor functional outcome mRS score of 0 to 2 (odds ratio [OR], 0.94; 95% confidence interval [CI], 0.90-0.98), disadvantage across the shift of mRS (OR, 1.04; 95% CI, 1.01-1.08), mortality (OR, 1.10; 95% CI, 1.01-1.08), SICHSITS (OR, 1.14; 95% CI, 1.06-1.23), and SICHECASS (OR, 1.24; 95% CI, 1.10-1.40; ECASS [European Cooperative Acute Stroke Study 2]). Analyzing successive variation for analysis of BPV as a function of pre-treatment, systolic BP significantly improved the prediction of functional outcome (mRS score of 0-1, mRS score of 0-2, neurological improvement, mRS-shift: all Pinteraction<0.01). Excluding patients with atrial fibrillation in a sensitivity analysis gave consistent results overall. CONCLUSIONS: This study suggests the need for a more individual BP management accounting for pre-treatment BP and the acute BP course (ie, BPV) to achieve best possible outcome for the patient.

Abnormal tyrosine metabolism in chronic cluster headache.

Objective Episodic cluster headache is characterized by abnormalities in tyrosine metabolism (i.e. elevated levels of dopamine, tyramine, octopamine and synephrine and low levels of noradrenalin in plasma and platelets.) It is unknown, however, if such biochemical anomalies are present and/or constitute a predisposing factor in chronic cluster headache. To test this hypothesis, we measured the levels of dopamine and noradrenaline together with those of elusive amines, such as tyramine, octopamine and synephrine, in plasma of chronic cluster patients and control individuals. Methods Plasma levels of dopamine, noradrenaline and trace amines, including tyramine, octopamine and synephrine, were measured in a group of 23 chronic cluster headache patients (10 chronic cluster ab initio and 13 transformed from episodic cluster), and 16 control participants. Results The plasma levels of dopamine, noradrenaline and tyramine were several times higher in chronic cluster headache patients compared with controls. The levels of octopamine and synephrine were significantly lower in plasma of these patients with respect to control individuals. Conclusions These results suggest that anomalies in tyrosine metabolism play a role in the pathogenesis of chronic cluster headache and constitute a predisposing factor for the transformation of the episodic into a chronic form of this primary headache.

Diagnostics of the neuromyelitis optica spectrum disorders (NMOSD).

This document presents the guidelines for anti-aquaporin-4 (AQP4) antibody testing that has been developed following a consensus process built on questionnaire-based surveys, internet contacts, and discussions at workshops of the sponsoring Italian Association of Neuroimmunology (AINI) congresses. Essential clinical information on neuromyelitis optica spectrum disorders, indications and limits of anti-AQP4 antibody testing, instructions for result interpretation, and an agreed laboratory protocol (Appendix) are reported for the communicative community of neurologists and clinical pathologists.

Effects of Emotional Facial Expression on Time Perception in Patients with Parkinson's Disease.

Previous studies have demonstrated that emotional facial expressions alter temporal judgments. Moreover, while some studies conducted with Parkinson's disease (PD) patients suggest dysfunction in the recognition of emotional facial expression, others have shown a dysfunction in time perception. In the present study, we investigate the magnitude of temporal distortions caused by the presentation of emotional facial expressions (anger, shame, and neutral) in PD patients and controls. Twenty-five older adults with PD and 17 healthy older adults took part in the present study. PD patients were divided into two sub-groups, with and without mild cognitive impairment (MCI), based on their neuropsychological performance. Participants were tested with a time bisection task with standard intervals lasting 400 ms and 1600 ms. The effect of facial emotional stimuli on time perception was evident in all participants, yet the effect was greater for PD-MCI patients. Furthermore, PD-MCI patients were more likely to underestimate long and overestimate short temporal intervals than PD-non-MCI patients and controls. Temporal impairment in PD-MCI patients seem to be mainly caused by a memory dysfunction. (JINS, 2016, 22, 890-899).

Therapeutic drug monitoring of topiramate with a new HPLC method, SPE extraction and high sensitivity pre-column fluorescent derivatization.

BACKGROUND: Topiramate is a 2nd generation antiepileptic drug (AED) recently approved by the FDA for migraine prophylaxis. Its pharmacological activity already appears significant at low doses. Unfortunately, the difficulty in determining the drug in serum at low concentrations hampers the completion of accurate pharmacokinetic studies in humans. Only chromatographic methods allow reaching the necessary sensitivities. METHODS: Almost all of the HPLC methods proposed were based on the preliminary extraction of topiramate from the sample using organic solvents. In our study, the conditions for purifying topiramate through solid-liquid technique in disposable cartridges (SPE) packed with C18 reversed phase were examinated and optimised. After a pre-column derivatization step with 9-fluorenylmethyl chloroformate (FMOC-Cl) and internal standard addition, topiramate was analysed on a CN column with sodium phosphate buffer 50 mmol/L (pH 2.5) containing acetonitrile (60:40, v/v) as the mobile phase. The column effluent was monitored with a fluorescence detector (excitation and emission 1 260 and 315 nm, respectively). 122 samples from our routine laboratory work were analysed in order to confirm the existence of a relationship between topiramate dose and serum concentration and to evaluate the effect of concomitant therapies with enzyme-inducing AEDs. RESULTS: Sensitivity (2 ng/mL), precision (CV within assay of 3.8% and between assays of 6.6%), linearity and accuracy of the method were better than other analytical procedures previously reported. Serum topiramate levels in the group with enzyme-inducing AEDs showed a reduction with respect to the group with non-enzyme-inducing AEDs and the correlation between doses and mean serum concentration gives a linear trend (r2 = 0.916). CONCLUSIONS: The efficacy of SPE extraction together with the method's reliability proved very advantageous for pharmacokinetics studies and, in principle, for therapeutic drug monitoring and toxicological investigations.

Analysis of combined CSF biomarkers in AD diagnosis.

BACKGROUND: The new proposed diagnostic criteria for early diagnosis of Alzheimer's Disease (AD) underline the value of cerebrospinal fluid (CSF) biomarkers. The first aim of the study was to determine the diagnostic accuracy of CSF biomarker Abeta1-42, T-tau, and P-tau in differentiating AD patients in our cohort by means of "pure" biomarkers and in form of a combined analysis of these biomarkers. The second aim of the study was to determine the diagnostic accuracy of these markers for predicting incipient AD in patients with mild cognitive impairment (MCI). METHODS: We studied 102 CSF samples: 33 AD [mean age at baseline 71.2 (54-86)], 16 MCI [mean age at baseline 71.3 (57-78)], 24 non AD dementia, including 7 vascular dementia, 4 frontotemporal degeneration, 5 dementia with Lewy Body, and 8 with other dementia [mean age at baseline 72.7 (51-87)] and 32 non-demented neurological patients [mean age at baseline 71.3 (45-87) referred to as control (CO) later in the text]. A double sandwich ELISA (Innotest beta amyloid Abeta1-42, hTau and P-tau181 by Innogenetics, Gent, Belgium) was performed to quantify the concentration of the above biomarkers. The three biomarkers were then combined in the IATI index [(measured Ab1-42)/(240 + 1.18 *measured tau)], and in the ratios Abeta1-42/T-tau, Abeta1-42/P-tau, T-tau/Abeta1-42 and P-tau/Abeta1-42. RESULTS: Abeta1-42, T-tau and P-tau181 concentration showed statistically significant differences between AD and CO (327.2 pg/mL +/- 150.2 pg/mL and 659.4 pg/mL +/- 254.2 pg/mL; 508.2 pg/mL +/- 360.2 pg/mL and 305.3 pg/mL +/- 228.9 pg/mL; 82.2 pg/mL +/- 26.1 pg/mL and 45.3 pg/mL +/- 26.4 pg/mL, respectively, p < 0.05), while the difference between AD and MCI was statistically different only for Abeta1-42 (327.2 pg/mL +/- 150.2 pg/mL and 600.8 +/- 271.9 pg/mL, respectively, p < 0.05). The IATI index was 0.5 +/- 0.3 in AD, 0.9 +/- 0.6 in MCI, 1.37 +/- 0.9 in non AD dementia and 1.26 +/- 0.8 in non-demented neurological patients. With a cut-off fixed at 1 the sensitivity and specificity of the IATI index in discriminating AD from CO was 84% and 52%, respectively. CONCLUSIONS: This study confirms the great significance of CSF biomarker measurements in AD diagnosis in clinical routine. It is understood that a clinical diagnostic work-up is necessary in the process. Moreover, a biochemical profile of CSF biomarkers requires further investigations.