[Sumatriptan-naproxen sodium fix-dose combination for acute migraine treatment, a review]. / Szumatriptán­naproxén-nátrium fix dózisú kombinációja a migrén akut kezelésében ­ irodalmi áttekintés.

Migraine as a common primary headache disorder has a significant negative effect on quality of life of the patients. Its pharmacotreatment includes acute and preventative therapies. Based on the shared therapeutic guideline of the European Headache Federation and the European Academy of Neurology for acute migraine treatment a combination of triptans and non-steroidal anti-inflammatory drugs is recommended for acute migraine treatment in triptan-nonresponders. In this short review we summarized the results of the randomized controlled clinical trials evaluating the effectiveness and safety of sumatriptan (85 mg)/naproxen sodium (500 mg) fix-dose combination. It was revealed that the fix-dose combination was better than placebo for the primary outcomes of exemption of pain and headache relief at 2 hours. Furthermore the combination showed beneficial effect on accompanying symptoms of migraine attack (i.e. nausea, photo- and phonophobia). Adverse events were mild or moderate in severity and rarely led to withdrawal of the drug.
It can be concluded that sumatriptan (85 mg)/naproxen sodium (500 mg) fix-dose combination is effective, safe and well-tolerated in the acute treatment of migraine. 

Reduction of Viral Load in Patients with Acute Sore Throats: Results from an Observational Clinical Trial with Echinacea/Salvia Lozenges.

BACKGROUND: Acute tonsillopharyngitis or sore throat is an initial sign of viral respiratory tract infection (RTI) and an optimal indicator for early antiviral and anti-inflammatory intervention. Both of these actions have been attributed to Echinacea purpurea and Salvia officinalis. METHODS: 74 patients (age 13-69 years) with acute sore throat symptoms (<48 h) were treated with five Echinacea/Salvia lozenges per day (4,000 mg Echinacea purpurea extract [Echinaforce®] and 1,893 mg Salvia officinalis extract [A. Vogel AG, Switzerland] daily) for 4 days. Symptom intensities were recorded in a diary and oropharyngeal swab samples collected for virus detection and quantification via RT-qPCR. RESULTS: The treatment was exceptionally well tolerated, no complicated RTI developed, and no antibiotic treatment was required. A single lozenge reduced throat pain by 48% (p < 0.001) and tonsillopharyngitis symptoms by 34% (p < 0.001). Eighteen patients tested virus positive at inclusion. Viral loads in these patients was reduced by 62% (p < 0.03) after intake of a single lozenge and by 96% (p < 0.02) after 4 days of treatment compared to pre-treatment. CONCLUSIONS: Echinacea/Salvia lozenges represent a valuable and safe option for the early treatment of acute sore throats capable to alleviate symptoms and contribute to reducing viral loads in the throat.Akute Tonsillopharyngitis oder Halsschmerzen/entzündungen sind ein erstes Anzeichen einer viralen Atemwegsinfektion (vAWI) und ein optimaler Indikator für eine frühzeitige antivirale und entzündungshemmende Intervention. Beide Wirkungen werden Echinacea purpurea und Salvia officinalis zugeschrieben.74 Patienten (Alter 13­69 Jahre) mit akuten Halsschmerzen/entzündungen (<48 h) wurden mit fünf Echinacea/Salvia-Lutschtabletten pro Tag (Tagesdosis: 4'000 mg Echinacea purpurea-Extrakt [Echinaforce®] und 1'893 mg Salvia officinalis Extrakt [A. Vogel AG, Schweiz]) behandelt für 4 Tage. Die Symptomintensität wurde in einem Tagebuch aufgezeichnet und Rachenabstrichproben wurden zum Virusnachweis und zur Quantifizierung mittels RT-qPCR entnommen.Die Behandlung wurde außergewöhnlich gut vertragen, es entwickelte sich keine komplizierten AWI und es waren keine Antibiotikabehandlungen erforderlich. Eine einzelne Lutschtablette reduzierte die akuten Halsschmerzen um 48% (p < 0,001) und die allgemeinen Tonsillopharyngitis Symptome um 34% (p < 0,001). Achtzehn Patienten wurden bei der Aufnahme viruspositiv getestet. Die Viruslast wurde bei diesen Patienten nach Einnahme einer einzigen Lutschtablette um 62% (p < 0,03), und nach 4-tägiger Behandlung um 96% (p < 0,02) reduziert im Vergleich zu vor der Behandlung.Echinacea/Salvia-Lutschtabletten stellen eine sichere Option für die frühzeitige Behandlung akuter Halsschmerzen/entzündungen dar, die Symptome lindern, und zur Verringerung der Viruslast im Hals beitragen können.

Managing migraine on the frontline: Identifying disease, understanding burden, and incorporating CGRP pathway-targeting therapies in primary care.

Migraine is a common neurologic disorder with clinical phenotypes encompassing a variety of symptoms which all contribute to the burden felt by patients. In addition to negative impacts on a patient's quality of life, migraine has both direct medical costs and indirect costs related to missed work and decreased productivity that affect individuals as well as society at large. Unfortunately, migraine diagnoses are often missed, and many patients do not receive appropriate treatment. Primary care providers are in a key position to provide timely diagnosis and effectively manage migraine for many patients. This review aims to be a guide for improving migraine management in the primary care setting by providing strategies to overcome common challenges in migraine diagnosis; summarizing current knowledge on the mechanism of action, efficacy, and safety of calcitonin gene-related peptide (CGRP) pathway-targeting therapies; and reviewing approaches to incorporate traditional and emerging treatment options into a patient-centric migraine management strategy.

Pediatric Headache in Primary Care and Emergency Departments: Consensus with RAND/UCLA Method.

Headache is the most frequent neurological symptom in childhood and the main reason for admission to pediatric emergency departments. The aim of this consensus document is to define a shared clinical pathway between primary care pediatricians (PCP) and hospitals for the management of children presenting with headache. For the purposes of the study, a group of hospital pediatricians and a group of PCP from the Emilia Romagna's health districts were selected to achieve consensus using the RAND/UCLA appropriateness method. Thirty-nine clinical scenarios were developed: for each scenario, participants were asked to rank the appropriateness of each option from 1 to 9. Agreement was reached if ≥75% of participants ranked within the same range of appropriateness. The answers, results, and discussion helped to define the appropriateness of procedures with a low level of evidence regarding different steps of the diagnostic-therapeutic process: primary care evaluation, emergency department evaluation, hospital admission, acute therapy, prophylaxis, and follow-up. The RAND proved to be a valid method to value appropriateness of procedures and define a diagnostic-therapeutic pathway suitable to the local reality in the management of pediatric headache. From our results, some useful recommendations were developed for optimizing the healthcare professionals' network among primary care services and hospitals.

A rational approach to migraine diagnosis and management in primary care.

Migraine is a chronic neurologic disease estimated to affect approximately 50 million Americans. It is associated with a range of symptoms, which contribute to disability and substantial negative impacts on quality of life for many patients. Still, migraine continues to be underdiagnosed, undertreated, and optimising treatment for individual patients has proven difficult. As many migraine patients will be seen first in primary care settings, internists and other primary care providers are ideally positioned to improve diagnosis and migraine management for many patients. In this review, we discuss some of the challenges in diagnosing migraine and suggest strategies to overcome them, summarise the current understanding of migraine pathophysiology and clinical evidence on acute and preventive treatment options, and offer practical approaches to diagnosis and contemporary management of migraine in the primary care setting.Key messagesMigraine is a prevalent disease with substantial impact. Primary care providers are ideally positioned to improve care for migraine patients with streamlined approaches to diagnosis and management.A stepwise diagnostic approach to migraine involves taking a thorough headache history, excluding secondary headache, and identifying primary headache disorder using screening tools or ICHD-3 criteria.The FDA approved seven new migraine therapies from 2018 to 2020 (four monoclonal antibodies, two gepants, one ditan), expanding acute and preventive therapeutic options.

Mechanical thrombectomy in patients with cervical artery dissection and stroke in the anterior or posterior circulation - a multicenter analysis from the German Stroke Registry.

BACKGROUND: Cervical artery dissection (CAD) is a rare cause of acute ischemic stroke (AIS) with large vessel occlusion (LVO) and may constitute a challenge for mechanical thrombectomy (MT). We compared procedural characteristics, reperfusion rates, and clinical outcome in AIS patients undergoing MT with and without CAD. METHODS: We performed a pre-specified analysis of patients registered within the German Stroke Registry, a prospectively maintained multicenter registry of consecutive patients with AIS patients treated by MT. Procedural characteristics included time periods and additional application of medication. RESULTS: Of 2589 patients, 62 (2.4%) were diagnosed with CAD. CAD patients were younger, had lower rates of known vascular risk factors and larger baseline stroke volumes. MT in CAD patients took significantly longer (median [IQR] groin-puncture-to-flow restoration time: 98 [67-136] versus 70 [45-100] minutes; p < 0.001) and more often required use of intra-arterial medication (34.4% versus 15.6%; p < 0.001). Reperfusion success (modified Treatment in Cerebral Infarction score 2b-3: 85.2% versus 83.3%, p = 0.690) and favorable functional outcome after 3 months (modified Rankin Scale score ≤ 2: 70.9% versus 36.4%, adjusted p = 0.086) did not differ significantly between patients with and without CAD. The latter findings held true for both CAD in the anterior and posterior circulation. CONCLUSION: CAD in AIS requiring MT is rare. MT in patients with CAD constitutes a particular procedural challenge, but still achieves favorable radiological and functional outcomes in most patients. Our data provide indirect evidence that MT is of clinical benefit in patients with AIS due to LVO and CAD.

Autotitrating Bilevel Positive Airway Pressure in Large Vessel Steno-Occlusive Stroke Patients With Suspected Sleep Apnea: A Multicenter Randomized Controlled Study.

Background: We hypothesized that autotitrating bilevel positive airway pressure (auto-BPAP) favorably affects short-term clinical outcomes in hyperacute ischemic stroke. Methods: In a multicenter, randomized, controlled trial patients with large vessel steno-occlusive stroke and clinically suspected sleep apnea were allocated to auto-BPAP or standard stroke care alone. Auto-BPAP was initiated within 24 h from stroke onset and performed over 48 h during diurnal and nocturnal sleep. Sleep apnea was assessed using cardiorespiratory polygraphy. Primary endpoint was early neurological improvement on National Institutes of Health Stroke Scale (NIHSS) score at 72 h. Safety and tolerability of BPAP, functional independence [modified Rankin Scale (mRS) 0-2], stroke recurrence, and mortality at 90 days were assessed. Results: Due to low recruitment, the trial was prematurely stopped after 24 patients had been randomized (auto-BPAP, n = 14; control, n = 10): median baseline NIHSS 13 (5.5-18), 88% large vessel occlusion, and 12% large vessel stenosis. Polygraphy confirmed sleep apnea in 64% of auto-BPAP and 88% of control patients (p = 0.34). Adherence to auto-BPAP was achieved by 9 of the 14 (64%) patients. Between auto-BPAP and control patients, no differences were observed in early neurological improvement (median NIHSS change: -2.0, IQR = 7 points vs. -0.5, IQR = 3 points), 90 days functional independence (21 vs. 30%, p = 0.67), stroke recurrence (0 vs. 20%, p = 0.16), and death (14 vs. 20%, p = 1.0). No safety concerns were identified. Conclusions: In this prematurely terminated trial, auto-BPAP was safe but did not show an effect on short-term clinical outcomes in selected ischemic stroke patients. Its tolerability, however, may be limited in hyperacute stroke care and needs to be improved before larger trials are conducted. Clinical Trial Registration: ClinicalTrials.gov, identifier: NCT01812993.

Health technology assessment for the acute and preventive treatment of migraine: A position statement of the International Headache Society.

The Clinical Trials Subcommittee of the International Headache Society presents the first Health Technology Assessment for the Acute Treatment of Migraine Attacks and Prevention of Migraine. Health technology assessments are systematic evaluations of the properties, effects, and consequences of healthcare technologies; this position statement is designed to inform decision makers about access to and reimbursement for medications and devices for the acute and preventive treatment of migraine. This position statement extends beyond the already available guidelines on randomized controlled trials for migraine to incorporate real-world evidence and a synthetic approach for considering multiple data sources and modelling methods when assessing the value of migraine treatments.

Calcitonin gene-related peptide (CGRP)-targeted therapies as preventive and acute treatments for migraine-The monoclonal antibodies and gepants.

Calcitonin Gene-Related Peptide (CGRP) plays a pivotal role in migraine pathophysiology. Two types of CGRP function-blocking modalities, monoclonal antibodies, and small molecules (gepants), have been developed to target the CGRP ligands and CGRP receptors. Four CGRP monoclonal antibodies have received FDA approval for the prevention of migraine: erenumab, fremanezumab, galcanezumab, and eptinezumab. Two gepants have been approved by the FDA for the acute treatment of migraine: ubrogepant and rimegepant. Multiple clinical trials of the CGRP monoclonal antibodies and gepants, and now some open-label long-term extension data, established their efficacy, safety, and tolerability. In this chapter, we summarize the major clinical trials, pharmacokinetic insights, safety and tolerability profiles, and real-world data (if available) of the CGRP monoclonal antibodies and gepants.

Therapeutic effect of N-carbamylglutamate in CPS1 deficiency.

The detoxification of ammonia to urea requires a functional hepatic urea cycle, which consists of six enzymes and two mitochondrial membrane transporters. The initial step of the urea cycle is catalyzed by carbamyl phosphate synthetase 1 (CPS1). CPS1 deficiency (CPS1D) is a rare autosomal recessive disorder. N-Carbamylglutamate (NCG), a deacylase-resistant analogue of N-acetylglutamate, can activate CPS1. We describe the therapeutic course of a patient suffering from neonatal onset CPS1D with compound heterozygosity for the c.2359C > T (p.Arg787*) and c.3559G > T (p.Val1187Phe) variants in CPS1, treated with NCG. She presented with hyperammonemia, which reached 944 µmol/L at the age of 2 days. The ammonia concentration decreased after treatment with continuous hemodiafiltration, NCG, sodium benzoate, sodium phenylbutyrate, L-arginine, vitamin cocktail (vitamin B1, vitamin B12, vitamin C, vitamin E, biotin), l-carnitine, coenzyme Q10, and parenteral nutrition. Her ammonia and glutamine levels remained low; thus, protein intake was increased to 1.2 g/kg/day. Furthermore, the amount of sodium benzoate and sodium phenylbutyrate were reduced. She remained metabolically stable and experienced no metabolic crisis following treatment with oral NCG, sodium benzoate, sodium phenylbutyrate, citrulline, vitamin cocktail, l-carnitine, and coenzyme Q10 until she underwent liver transplantation at 207 days of age. She had no neurological complications at the age of 15 months. Ammonia and glutamine levels of the patient were successfully maintained at a low level via NCG treatment with increased protein intake, which led to normal neurological development. Thus, undiagnosed urea cycle disorders should be treated rapidly with acute therapy including NCG, which should be maintained until a genetic diagnosis is reached. It is essential to prevent metabolic crises in patients with CPS1D until liver transplantation to improve their prognoses.

[Modern migraine therapy-interdisciplinary long-term care]. / Moderne Migränetherapie ­ fachübergreifende Versorgung im Langzeitverlauf.

Migraine has a very high lifetime prevalence with a severe illness-related burden. As a result, extensive long-term and regular treatment is required, which cannot be covered solely by neurologists. This is particularly the case for the long-term monitoring of migraine, which often takes place over several decades. The diagnosis is made using the diagnostic criteria of the International Headache Society (ICHD-3) based on the clinical phenotype. Owing to often complex neurological symptoms, a detailed weighing up of the differential diagnoses is required, which calls for specialist neurological expertise. The same is true for follow-up appointments of more complex therapy issues. Acute therapy with antiemetics, analgesics, and triptans can, so long as it is effective and is administered not longer than 10 days per month, be carried out by the general practitioner or specialist in internal medicine. This is also true for medical prophylactic treatment with dietary supplements, antihypertensive drugs, and tricyclic antidepressants. If this therapy is unsuccessful, prophylactic substances must be used that require more specialized knowledge, which is also reflected in the formal prescription requirements. Neurologists and pain therapists should then be involved in the treatment. This is particularly true for the use of Onabotulinumtoxin A and monoclonal CGRP-(receptor)-antibodies.

Comprehensive Migraine Initiative in the Pediatric Emergency Department Improves Treatment Outcomes.

OBJECTIVE: To compare pediatric migraine treatment efficacy in the emergency department before and after the implementation of a comprehensive migraine initiative, consisting of a standardized treatment protocol, provider educational series and standardized physician documentation template. BACKGROUND: Pediatric migraine is common, accounting for 1% of pediatric emergency department visits. Yet there is large variability in treatment practices, with few studies looking into measures of both clinical effectiveness and timeliness of treatment following implementation of standardized protocols. METHODS: A single-center retrospective chart review of pediatric patients presenting to the emergency department with migraine before and after implementation of an institutional headache initiative designed to more effectively and efficiently deliver care to pediatric migraine patients. RESULTS: The study yielded 110 patients each in the intervention and preintervention groups. There were no significant differences in patient characteristics with respect to age, gender, or initial pain score. Compared with the preintervention group, the intervention group demonstrated a significant reduction in headache pain score prior to discharge (decrease of 5.9 vs 4.8 in preintervention group, P value .006) with a greater percentage of patients achieving ≥50% reduction in pain (82% vs 67% in preintervention group, P value .039). Additionally, we found a significantly decreased time to treatment in the intervention group compared with the preintervention group (1.8 vs 2.1 hours, P value .046). CONCLUSION: Through the use of a standardized treatment protocol, improved provider education, and ease of documentation, this comprehensive migraine initiative improved efficacy and efficiency of migraine treatment in the pediatric emergency department.

Lasmiditan for the acute treatment of migraine: Subgroup analyses by prior response to triptans.

BACKGROUND: Lasmiditan demonstrated superiority to placebo in the acute treatment of migraine in adults with moderate/severe migraine disability in two similarly designed Phase 3 trials, SAMURAI and SPARTAN. Post-hoc integrated analyses evaluated the efficacy of lasmiditan in patients who reported a good or insufficient response to triptans and in those who were triptan naïve. METHODS: Subgroups of patients reporting an overall response of "good" or "poor/none" to the most recent use of a triptan at baseline (defined as good or insufficient responders, respectively) and a triptan-naïve subpopulation were derived from combined study participants randomized to receive lasmiditan 50 mg (SPARTAN only), 100 mg or 200 mg, or placebo, as the first dose. Outcomes including headache pain-freedom, most bothersome symptom-freedom, and headache pain relief 2 hours post-first dose of lasmiditan were compared with placebo. Treatment-by-subgroup analyses additionally investigated whether therapeutic benefit varied according to prior triptan response (good or insufficient). RESULTS: Regardless of triptan response, lasmiditan showed higher efficacy than placebo (most comparisons were statistically significant). Treatment-by-subgroup analyses found that the benefit over placebo of lasmiditan did not vary significantly between patients with a good response and those with an insufficient response to triptans. Lasmiditan also showed higher efficacy than placebo in triptan-naïve patients. CONCLUSIONS: Lasmiditan demonstrated comparable efficacy in patients who reported a good or insufficient response to prior triptan use. Lasmiditan also showed efficacy in those who were triptan naïve. Lasmiditan may be a useful therapeutic option for patients with migraine. TRIAL REGISTRATION: SAMURAI (NCT02439320); SPARTAN (NCT02605174).

Current Smoking Does Not Modify the Treatment Effect of Intravenous Thrombolysis in Acute Ischemic Stroke Patients-A Post-hoc Analysis of the WAKE-UP Trial.

Background: The "smoking paradox" indicates that patients with acute ischemic stroke (AIS) who smoke at the time of their stroke may have a better prognosis after intravenous thrombolysis than non-smokers. However, findings are inconsistent and data analyzing the effect of smoking on treatment efficacy of intravenous thrombolysis are scarce. Methods: We performed a pre-specified post-hoc subgroup analysis of the Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke (WAKE-UP) trial that randomized AIS patients with unknown time of symptom onset who had diffusion-weighted imaging-fluid attenuation inversion recovery (DWI-FLAIR) mismatch to either alteplase or placebo. Patients were categorized as current smokers or non-smokers (including former smokers and never-smokers). Baseline demographic and clinical characteristics, as well as clinical and imaging follow-up data were analyzed according to smoking status. Results: Four hundred and eighty six patients were included in the analysis. Current smokers (133, 27.4%) were younger (60.1 ± 13.0 vs. 67.2 ± 10.3 years; p < 0.001) and less often had arterial hypertension (45.0% vs. 56.8%; p = 0.02) or atrial fibrillation (3.8% vs. 15.3%; p < 0.001). The acute stroke presentation was more often due to large vessel occlusion among current smokers (27.1 vs. 16.2%; p = 0.01), and smokers had a trend towards more severe strokes (National Institutes of Health Stroke Scale score>10 in 27.1% vs. 19.5%; p = 0.08). The treatment effect of alteplase, quantified as odds ratio for a favorable outcome (modified Rankin Scale [mRS] score at 90 days of 0 or 1), did not differ between current smokers and non-smokers (p-value for interaction: 0.59). After adjustment for age and stroke severity, neither the proportion of patients with favorable outcome, nor the median mRS score at 90 days differed between current smokers and non-smokers. When additional potential confounders were included in the model, the median mRS score was higher in current smokers than in non-smokers (cOR of better outcome for current smokers vs. non-smokers: 0.664 [0.451-0.978], p = 0.04). Conclusions: In patients with mild to moderate MRI-proven AIS and unknown time of symptom onset with DWI-FLAIR mismatch, current smokers had worse functional outcome as compared to non-smokers. Current smoking did not modify the treatment effect of alteplase. Clinical Trial registration: Main trial (WAKE-UP): ClinicalTrials.gov, NCT01525290; and EudraCT, 2011-005906-32. Registered 02 February 2012.

Targeting CGRP and 5-HT1F Receptors for the Acute Therapy of Migraine: A Literature Review.

OBJECTIVE: To review and highlight current literature on emerging acute migraine treatments, focusing on CGRP receptor antagonists, gepants, and 5-HT1F receptor agonists (ditans). BACKGROUND: Current acute migraine therapy consists of nonspecific analgesia and triptans. Limitations to these medicines, including lack of efficacy in many patients, side effects and the contraindication of triptans in patients with cardiovascular disease, suggest that there is an unmet need for new treatments. Studies of serotonin pharmacology led to the development of triptans, 5-HT1B/1D receptor agonists, some of which have actions at the 5-HT1F receptor. Exploration of the role of calcitonin gene-related peptide (CGRP) has resulted in the development of CGRP receptor antagonists. METHOD: The authors performed a literature search of Pubmed and Cochrane databases as well as reviewed abstracts presented at meetings: American Headache Society, American Academy of Neurology, European Headache Federation and the Migraine Trust International Symposium, as well as on-line sources. The authors briefly detail the relevant migraine pathophysiology pertaining to 5-HT1F receptor and the CGRP pathway relevant to acute therapies. Recent clinical trials of acute therapies in which 5-HT1F receptor agonists or CGRP receptor antagonists were studied are summarized. RESULTS: Two 5-HT1F receptor agonists have reached phase II clinical trials. One, lasmiditan, has completed 2 phase III clinical trials, demonstrating a significant effect for pain freedom and most bothersome symptom at 2 hours. Among the 6 gepants tested for the acute treatment of migraine to date, after issues for some of hepatic safety or efficacy, 2 CGRP receptor antagonists, rimegepant and ubrogepant, have completed phase III trials showing efficacy and safety. CONCLUSION: Current available therapies have either been nonspecific or had important limitations, including in patients with cardiovascular risk factors. Phase III clinical trials of lasmiditan, rimegepant and ubrogepant all met their primary endpoints, so the options for migraine-targeted acute therapy will likely soon increase.

[Therapeutic Effects of Intranasal Sumatriptan for Cluster Headache].

To clarify the associated factors for negative response to sumatriptan nasal spray in patients with cluster headache, we investigated the involvement of clinical information, such as the characteristics of headaches, before commencing sumatriptan nasal spray treatment. There were 18 male patients and 4 female patients. A total of 17 responders and 5 non-responders to sumatriptan nasal spray participated in the present study. Three factors for negative response to sumatriptan nasal spray, "young age of onset", "psychiatric disorder", and "the headache is not in the orbit," were found. Oxygen inhalation and/or subcutaneous injection were effective for nonresponsive cases. Therefore, these factors are considered to be useful for predicting therapy before applying sumatriptan nasal spray.

Outcome of intracerebral haemorrhage related to non-vitamin K antagonists oral anticoagulants versus vitamin K antagonists: a comprehensive systematic review and meta-analysis.

INTRODUCTION: The characteristics and natural history of acute non-vitamin K antagonists oral anticoagulants (NOAC)-associated intracerebral haemorrhage (ICH) are largely unknown. We performed a comprehensive systematic review and meta-analysis to compare baseline ICH volume, haematoma expansion and clinical outcomes between NOAC-ICH versus vitamin K antagonists-ICH (VKA-ICH). METHODS: We searched PubMed and conference abstracts for observational studies comparing baseline characteristics and outcomes in patients with NOAC-ICH versus VKA-ICH using an appropriate keyword/MeSH term search strategy. Data were extracted following PRISMA and MOOSE guidelines. The main outcome measures were mortality and unfavourable functional outcome (modified Rankin Score: 4-6) at discharge and at 3 months, as well as ICH volumes and haematoma expansion rates in the two groups. Random-effects models with DerSimonian-Laird weights were used for pooled estimates calculation. RESULTS: Twelve studies including 393 NOAC-ICH and 3482 VKA-ICH were pooled in meta-analysis. There was no difference in mean ICH-volume between the two groups (standard mean difference: -0.24; 95% CI -0.52 to 0.04, p=0.093). The rates of haematoma expansion were comparable in NOAC-ICH versus VKA-ICH (OR: 0.76; 95% CI 0.49 to 1.19, p=0.236). We did not find any difference between patients with NOAC-ICH versus VKA-ICH in all-cause mortality at discharge (OR: 0.66; 95% CI 0.42 to 1.05, p=0.077) and unfavourable functional outcome at discharge (OR: 0.77; 95% CI 0.41 to 1.44, p=0.413). The 3-month outcome was also comparable between the two ICH groups. Moderate-to-substantial statistical heterogeneity was noted. CONCLUSION: Our results confirm that ICH volume, haematoma expansion, mortality and functional outcome appear to be similar for NOAC-ICH versus VKA-ICH. Large prospective cohorts and updated meta-analyses are needed to provide more precise estimates.

Leukoaraiosis as an outcome predictor in the acute and subacute phases of stroke.

INTRODUCTION: Leukoaraiosis (LA) is one of the neuroimaging features of cerebral small vessel disease and is associated with poor long-term prognosis. Areas covered: This narrative review focuses on the predictive role of LA on the evolution of the ischemic brain damage and on the clinical outcome in the subacute phase of stroke and in the short-term period afterwards. Expert commentary: LA predicts poorer tissue outcome and clinical prognosis also in acute and subacute stroke. In acute stroke, LA is associated with a less favorable fate of brain infarct and is a marker of increased risk of thrombolysis-related hemorrhagic transformation. The impaired cerebral microcirculation in LA patients may sustain the progression of ischemic lesion and enhance the bleeding risk. The short-term worse clinical outcome in ischemic stroke and intracranial hemorrhage patients with LA might be attributable to a state of altered brain connectivity. Endothelial failure, reduced micro-vessels density, and deficient collateral flow together with reduced functional reserve are some of the involved mechanisms. Future studies should aim at bridging the gap between the knowledge about LA pathophysiology and the therapeutic improvement of brain tissue perfusion and at producing data on early rehabilitation of stroke patients with LA at high disability risk.

The second paradigm shift occurred on acute stroke therapy.

Outcome of acute stroke patients with embolic large vessel occlusion can be improved dramatically, if the effective and rapid reperfusion of the occluded vessel achieved. Since 2015, when the evidence of acute endovascular therapy established its efficacy, such scenario became no longer uncommon. Along with introduction of direct oral anticoagulant (DOAC), many options of antithrombotic therapy for acute ischemic stroke also became available. This review summarize the recent advances on acute ischemic stroke therapy.

Intensive blood pressure lowering in patients with acute intracerebral haemorrhage: clinical outcomes and haemorrhage expansion. Systematic review and meta-analysis of randomised trials.

INTRODUCTION: It is unclear whether intensive lowering of blood pressure (BP) at the acute phase of intracerebral haemorrhage (ICH) is beneficial. We performed a meta-analysis of randomised controlled trials (RCTs) to assess whether intensive BP lowering in patients with acute ICH is safe and effective in improving clinical outcomes. METHODS: We searched PubMed, EMBASE and the Cochrane databases for relevant RCTs and calculated pooled OR for 3-month mortality (safety outcome) and 3-month death or dependency (modified Rankin Scale (mRs) ≥3;efficacy outcome), in patients with acute ICH randomised to either intensive BP-lowering or standard BP-lowering treatment protocols. We also investigated the association between treatment arm and ICH expansion at 24 hours. Random effects models with DerSimonian-Laird weights were used. RESULTS: Five eligible studies including 4360 patients with acute ICH were pooled in meta-analysis. The risk of 3-month mortality was similar between patients randomised to intensive BP-lowering treatment and standard BP-lowering treatment (OR: 0.99; 95% CI: 0.82 to 1.20, p=0.909). Intensive BP-lowering treatment showed a (non-significant) trend for an association with lower 3-month death or dependency risk compared with standard treatment (OR: 0.91; 95% CI: 0.80 to 1.02), p=0.106). Intensive BP reduction was associated with a trend for lower risk of significant ICH expansion compared with standard treatment (OR: 0.82; 95% CI: 0.68 to 1.00, p=0.056), especially in larger RCTs. CONCLUSIONS: For patients with acute ICH similar to those included in RCTs and without contraindication to acute BP treatment, intensive acute BP lowering is safe, but does not seem to provide an incremental clinical benefit in terms of functional outcomes. The effect of intensive BP lowering on significant haematoma expansion at 24 hours warrants further investigation.