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Recurrent ischemic strokes (IS) in patients treated with direct oral anticoagulant agents (DOACs) are rare. Knowledge regarding the type of recurrent IS and predisposing factors is insufficient. We analyzed a cohort of 1001 patients (77.6 ± 9.2 years; females: 57.1%) with non-valvular atrial fibrillation (AF) treated with DOACs as part of secondary prevention after initial IS or transient ischemic attack. Cardiovascular risk factors, stroke etiology, and Fazekas score based on computed tomography images at the time of the initial IS were assessed. Low Fazekas scores were defined as 0 or 1 and high scores were 2 or 3. Recurrent IS occurred in 46 patients (4.6%, annual rate 1.6%) during the observation period (2.8 ± 1.8 years). Stroke was cardioembolic in 20 patients (43.5%), lacunar in 19 patients (37.5%) and large artery stroke in 6 patients (19.2%). Non-cardioembolic stroke was more common (75.0 vs 26.7%; P = .002) in patients with high Fazekas scores. Arterial hypertension was more frequent ( P = .027) in patients with high (93.3%) vs low (68.8%) Fazekas scores. Recurrent IS was predominantly non-cardioembolic with higher Fazekas score and arterial hypertension as predisposing factors. The reported hypothesis-generating results regarding the clinical relevance of the Fazekas score should be further evaluated.

In the absence of an automated software analysis, the role of computed tomography perfusion (CTP) in a real time clinical practice is not well established. We evaluated the clinical significance of a widely accessible and simple visual grading scale of CTP in the anterior circulation of acute ischemic stroke (AIS) patients treated with mechanical thrombectomy (MT).The single center consecutive CT investigations of AIS patients treated with MT in the anterior circulation have been evaluated retrospectively. ASPECT score and collateral circulation evaluation based on the Maas score were determined. Time to peak parametric maps, derived from CTP, were graded into four categories, from least to most favorable. The primary endpoint was functional outcome evaluated as modified Rankin Scale (mRS) ≤ 2 at 90 days after MT.We included 318 patients in the analysis; 142 (45%) patients had mRS ≤ 2 after 90 days, mortality rate was 24%. Higher CTP and Maas score were significantly correlated with better clinical outcome (Pearson χWe demonstrated that both visually graded CTP and collateral circulation grade strongly correlated with the clinical outcome of MT in the anterior circulation of AIS patients. Importantly, CTP correlated with the clinical outcome independent of the collateral circulation.

Odprto ovalno okno (OOO) je ostanek razvojne povezave med preddvoroma, ki se ob rojstvu običajno spontano zapre, pri približno 25 % populacije pa ostane odprto vse življenje. V redkih primerih je OOO zaradi desno-levega spoja lahko vpleteno v nastanek kriptogene ishemične možganske kapi, sistemske embolizacije, migrene in dekompresijske bolezni. Perkutano zapiranje OOO je preizkušen, razmeroma enostaven in varen poseg, ki pa prihaja v poštev le pri izbranih bolnikih. Študije namreč kažejo, da je smiseln predvsem pri mlajših bolnikih z embolično ishemično možgansko kapjo, ki tudi po natančnem stopenjskem diagnosticiranju in izključitvi ostalih alternativnih vzrokov ostaja nepojasnjena. Ne glede na opravljeno zapiranje OOO morajo bolniki s kriptogeno ishemično možgansko kapjo doživljenjsko prejemati tudi sekundarno medikamentno zaščito. Glede na doslej opravljene študije zaenkrat velja, da perkutano zapiranje OOO ni učinkovit način zdravljenja migrene, prihaja pa v poštev pri aktivnih potapljačih po preboleli dekompresijski bolezni in pri poklicnih potapljačih. Svetujemo, da se bolniki z indikacijo za zapiranje OOO napotijo na konzilij za OOO.

Prescribing anticoagulation therapy in very old (≥ 80-years) patients with atrial fibrillation (AF) is an emerging clinical issue, but current knowledge and recommendations are insufficient. We aimed to determine the efficacy and safety of direct oral anticoagulants (DOACs) in secondary stroke prevention in very old patients and to explore the related geriatric functional status of these patients. Three hundred fifty-three consecutive ≥ 80-year-old patients treated for transient ischemic attack (TIA) or ischemic stroke (IS) at the neurological clinic at UMC Ljubljana, who were prescribed DOACs for AF between December 2012 and May 2020, were included. Data regarding recurrent TIA/IS, major bleeds, intracranial hemorrhage (ICH) and death were collected. Data were descriptively compared with data from RCTs- including younger patients. Patients prescribed DOACs between January 2018 and May 2020 were contacted in December 2020, and their functional status was assessed using the Barthel index (BI). The efficacy of secondary stroke prevention with DOACs was comparable to RCTs for significantly younger patients. Major bleeds occurred more often, but most incidences were gastrointestinal, and the rate of ICH was comparable. Importantly, most patients were highly independent determined by BI. Overall, our real world results suggest that DOACs are as effective at preventing IS in secondary prevention in very old patients than in younger patients and that geriatric functional assessment could be a useful tool in the decision-making process.

Central nervous system (CNS) hemorrhage is a serious complication related to direct oral anticoagulant (DOAC) therapy. Current recommendations about re-initiation of anticoagulation treatment are limited to expert opinions. For this purpose, we analyzed the data of all consecutive DOAC patients with CNS hemorrhage, in whom DOACs were reinitiated. Over a 6-year period (2012–2018), all consecutive patients with CNS hemorrhage (subdural, subarachnoid, intracerebral, spinal), while receiving DOACs, were included in this observational single-center cohort study. DOAC therapy was reinitiated only in patients with well-controlled arterial hypertension and diabetes, as well as exclusion of vascular malformations and cerebral amyloid angiopathy. The composite primary endpoint comprised of recurrent CNS hemorrhage, ischemic stroke, and mortality; secondary endpoints were separate aforementioned outcomes. Of the 54 patients included, 18 died within a month of CNS hemorrhage. The average observational time was 590 days. DOACs were reinitiated in 13/36 patients (36%); of these patients, three died: none due to ischemic stroke or recurrent CNS bleeding. In 23 patients, anticoagulation was not reinitiated; of these patients, 10 died: three from recurrent CNS hemorrhage, one due to ischemic stroke, and six from causes unrelated to stroke. In carefully selected patients, re-initiation of DOAC therapy did not increase the rate of both endpoints. Recommendations for DOAC re-initiation, which include hypertension and diabetes control, as well as treated vascular malformations, and excluded cerebral amyloid angiopathy, appear to be valid in clinical practice.

The results of randomised clinical trials (RCTs) on direct oral anticoagulants (DOACs) for stroke prevention in patients with nonvalvular atrial fibrillation (NVAF) can mostly be applied to primary prevention in relatively young patients, since only a minority of patients included in these trials were receiving DOACs for secondary prevention. The real-life secondary prevention subgroup, comprising mostly elderly and high-risk patients, remains a point of interest where further exploration is needed. Our objective was to explore the effectiveness and safety of DOACs for secondary prevention in the real-life conditions. In a six-year (2012–2018) period all consecutive patients with a history of transient ischaemic attack (TIA) or stroke, recorded NVAF and prescription of DOAC, were included in this single-centre registry. Choice of the DOAC and dose was based on the discretion of the attending clinician. Data regarding recurrent stroke/TIA or other embolic events, intracranial haemorrhage, other major bleeding, adherence and potential changes of therapy were collected and analysed. During the study period, 566 patients were prescribed a DOAC for secondary stroke prevention, and follow-up data were available for 510 patients, with an average observational time of 2.6 years. The mean age of patients was 77.9 ± 8.7 years. The mean CHA2DS2-VASc and HAS-BLED scores were 5.1 ± 1.2 and 2.4 ± 0.6, respectively. Dabigatran was prescribed in 66%, apixaban in 21% and rivaroxaban in 13% of patients; 58% of patients were prescribed the reduced dose of DOAC. The overall yearly incidence of recurrent stroke, major bleeding and intracranial bleeding was 1.7%, 1.6% and 0.2%, respectively. Thus, we found similar effectiveness and safety of both standard and reduced dose of DOACs for secondary stroke prevention, compared to the RCT and large registries. Our real-life data study suggests that secondary stroke prevention with DOACs is as effective and safe as primary prevention, both in standard and reduced doses, in a typical group of patients who are older than patients included in RCTs.

Successful revascularization therapy is of paramount importance in patients suffering acute ischemic stroke (AIS). However, there is currently only limited evidence on revascularization outcomes for patients suffering AIS while treated with direct oral anticoagulants (DOACs). The aim of our study was to determine the efficacy and safety of intravenous thrombolysis (IVT) and mechanical reperfusion (MeR) in AIS patients taking DOACs, and compare them to randomized clinical trials (RCTs), which included patients without DOAC treatment. In an observational cohort study, we analyzed clinical and radiological outcomes following AIS for all consecutive patients on DOAC therapy treated by IVT or MeR, between 2013 and 2019, at the University Medical Center Ljubljana. Patients in the IVT group were on dabigatran treatment and have received idarucizumab as a reversal agent prior to IVT. Patients in the MeR group had a large vessel occlusion. The primary outcome of the study was efficiency, defined as significant improvement after recanalization (National Institutes of Health Stroke Scale (NIHSS) score improvement of ≥8 points after 24 h and modified Rankin Scale (mRS) ≤2 after 3 months) and safety, defined as occurrence of symptomatic intracerebral hemorrhage (SICH) and mortality. Fifty-one DOAC-treated patients with AIS were included. Nineteen dabigatran-treated patients received IVT after reversal by idarucizumab. Thirty-two patients with a large vessel occlusion (12 on dabigatran, 12 on rivaroxaban, and 8 on apixaban) received MeR. Median NIHSS at admission was 9 in the IVT group and 17 in the MeR group. A significant clinical improvement, 24 h after revascularization (median improvement of NIHSS ≥8), occurred in 84% of patients treated with IVT and 25% of patients treated with MeR. A favorable functional outcome after 3 months (modified Rankin Scale (mRS) ≤2) occurred in 84 % of patients treated with IVT and 44% of patients treated with MeR. SICH occurred in one patient (5%) in the IVT group, and in two patients (6%) in the MeR group. In summary, in our observational study of DOAC-treated AIS patients, the level of IVT efficiency was substantially better than in the RCTs. At the same time, the results of MeR treatment were on the same level as in non-DOAC AIS patients included in the RCTs. The observed safety of IVT and MeR treatment was similar to the RCTs. We propose that thrombi in patients on dabigatran may have increased susceptibility to IVT, thereby allowing for better clinical results.

Background Acute bilateral internal carotid artery (ICA) and/or middle cerebral artery (MCA) occlusion is extremely rare and associated with poor clinical outcomes. There are only a few reports in the literature about mechanical thrombectomy being performed for acute bilateral occlusions. The treatment strategies and prognoses (clinical outcomes) are therefore unclear. Methods A systematic review of the literature was performed through several electronic databases with the following search terms: acute bilateral stroke, mechanical recanalization and thrombectomy. Results In the literature, we identified five reports of six patients with bilateral ICA and/or MCA occlusion treated with mechanical recanalization. Additionally, we report our experience with a subsequent contralateral large brain artery occlusion during intravenous thrombolytic therapy, where the outcome after mechanical thrombectomy was not dependent on the time from stroke onset but rather on the capacity of collateral circulation exclusively. Conclusions Acute bilateral cerebral (ICA and/or MCA) occlusion leads to sudden severe neurological deficits (comas) with unpredicted prognoses, even when mechanical recanalization is available. As the collateral capacity seems to be more important than the absolute time to flow restoration in determining the outcomes, simultaneous thrombectomy by itself probably does not lead to improved functional outcomes.

Background: Intracranial hemorrhage is a severe and possibly fatal consequence of anticoagulation therapy. Idarucizumab is used in dabigatran-treated patients suffering from intracranial hemorrhage (ICH) to reverse the anticoagulant effect of dabigatran. Systematic review of real-life mortality in these patients is missing.Objectives: A review of all published dabigatran-related ICH cases treated with idarucizumab was performed. We aimed to estimate in-hospital mortality rate in these patients.Method: We searched PubMed and Scopus for all published cases of ICH in idarucizumab/dabigatran-treated patients until May 15, 2021. The assessed outcome was in-hospital mortality.Results: We identified six eligible studies (case series) with 386 patients and 54 single case reports. In-hospital mortality rate was 11.4% in the case series and 9.7% in the case reports.Conclusions: Our analysis provides clinically relevant quantitative data regarding in-hospital mortality in idarucizumab/dabigatran-treated patients with ICH, which is estimated to be 9.7–11.4%.

CAA is a heterogeneous group of diseases caused by Aβ deposition in the vascular walls, often leading to lobar ICH and cognitive impairment. Although CAA is rare in younger patients, it has been associated with specific mutations as well as with other causes.We present four cases of patients with CAA and recurrent ICH who have a history of severe TBI in childhood.Our cases as well as review of the literature suggest that a history of TBI in patients with genetic predispositions such as male sex may be associated with CAA in young persons.

Idarucizumab reverses the anticoagulant dabigatran; it is recommended during intravenous thrombolysis treatment of dabigatran-treated patients with acute ischemic stroke (AIS) and in dabigatran-treated patients with intracranial hemorrhage (ICH). Outcomes of consecutive idarucizumab/dabigatran-treated patients with intravenous thrombolysis-treated AIS (n = 22) were compared with consecutive similar intravenous thrombolysis-treated patients with AIS who were not anticoagulated (n = 182) [primary aim]; idarucizumab/dabigatran-treated patients with ICH (n = 13) were compared with patients with ICH who received the anticoagulants rivaroxaban or apixaban (n = 24) [secondary aim]. Efficacy was estimated by National Institutes of Health Stroke Scale score changes between admission and discharge and by the modified Rankin score after 3 months; safety was assessed by symptomatic ICH and mortality. Basal neurological impairment was similar in both idarucizumab/dabigatran-treated and control groups of patients with AIS and ICH. The idarucizumab/dabigatran-treated patients with AIS with subsequent intravenous thrombolysis showed a mean National Institutes of Health Stroke Scale improvement of 84% vs 68% in the control group (p < 0.05). A favorable outcome (modified Rankin score ≤ 2 after 3 months) was achieved significantly more frequently than in the control group (86% vs 57%; p < 0.05). The complication rate was similar in both groups. In patients with ICH, a positive functional outcome (modified Rankin score ≤ 3 after 3 months) was achieved more often in the idarucizumab/dabigatran-treated group than in the control group (70% vs 42%; p = 0.109). The complication rate was similar. Idarucizumab use in dabigatran-treated patients with AIS resulted in significantly more efficacious intravenous thrombolysis treatment and a non-significantly better outcome in dabigatran-treated patients with ICH compared with controls. There was no difference regarding complications.

Idarucizumab reverses the anticoagulant dabigatran; it is recommended during intravenous thrombolysis treatment of dabigatran-treated patients with acute ischemic stroke (AIS) and in dabigatran-treated patients with intracranial hemorrhage (ICH).Outcomes of consecutive idarucizumab/dabigatran-treated patients with intravenous thrombolysis-treated AIS (n = 22) were compared with consecutive similar intravenous thrombolysis-treated patients with AIS who were not anticoagulated (n = 182) [primary aim]; idarucizumab/dabigatran-treated patients with ICH (n = 13) were compared with patients with ICH who received the anticoagulants rivaroxaban or apixaban (n = 24) [secondary aim]. Efficacy was estimated by National Institutes of Health Stroke Scale score changes between admission and discharge and by the modified Rankin score after 3 months; safety was assessed by symptomatic ICH and mortality.Basal neurological impairment was similar in both idarucizumab/dabigatran-treated and control groups of patients with AIS and ICH. The idarucizumab/dabigatran-treated patients with AIS with subsequent intravenous thrombolysis showed a mean National Institutes of Health Stroke Scale improvement of 84% vs 68% in the control group (p0.05). A favorable outcome (modified Rankin score ≤ 2 after 3 months) was achieved significantly more frequently than in the control group (86% vs 57%; p0.05). The complication rate was similar in both groups. In patients with ICH, a positive functional outcome (modified Rankin score ≤ 3 after 3 months) was achieved more often in the idarucizumab/dabigatran-treated group than in the control group (70% vs 42%; p = 0.109). The complication rate was similar.Idarucizumab use in dabigatran-treated patients with AIS resulted in significantly more efficacious intravenous thrombolysis treatment and a non-significantly better outcome in dabigatran-treated patients with ICH compared with controls. There was no difference regarding complications.

The results of randomised clinical trials (RCTs) on direct oral anticoagulants (DOACs) for stroke prevention in patients with nonvalvular atrial fibrillation (NVAF) can mostly be applied to primary prevention in relatively young patients, since only a minority of patients included in these trials were receiving DOACs for secondary prevention. The real-life secondary prevention subgroup, comprising mostly elderly and high-risk patients, remains a point of interest where further exploration is needed. Our objective was to explore the effectiveness and safety of DOACs for secondary prevention in the real-life conditions.In a six-year (2012-2018) period all consecutive patients with a history of transient ischaemic attack (TIA) or stroke, recorded NVAF and prescription of DOAC, were included in this single-centre registry. Choice of the DOAC and dose was based on the discretion of the attending clinician. Data regarding recurrent stroke/TIA or other embolic events, intracranial haemorrhage, other major bleeding, adherence and potential changes of therapy were collected and analysed.During the study period, 566 patients were prescribed a DOAC for secondary stroke prevention, and follow-up data were available for 510 patients, with an average observational time of 2.6 years. The mean age of patients was 77.9 ± 8.7 years. The mean CHAOur real-life data study suggests that secondary stroke prevention with DOACs is as effective and safe as primary prevention, both in standard and reduced doses, in a typical group of patients who are older than patients included in RCTs.

Our aim was to perform an exploratory study of various irregular breathing patterns (IBPs) across different sleep stages in patients with acute unilateral lateral medullary infarction (ULMI) and compare them to apparently healthy individuals. Polysomnography (PSG) was analyzed for IBPs, such as periodic breathing, ataxic breathing and tachypnea. IBPs were found in 52 % of healthy and 90 % of ULMI subjects (p = 0.001) and occurred in long (≥ 10 min) episodes in 8% of healthy and 68 % of ULMI (p 0.001). In healthy subjects, short (10 min) episodes of mild to moderate ataxic breathing were observed in wakefulness and light sleep and short episodes of periodic breathing upon sleep onset. In ULMI, the most common IBPs were ataxic and periodic breathing (80 % of patients), followed by shallow tachypnea (28 %). Ataxic breathing predominated in wakefulness, ataxic or periodic breathing in light sleep, while breathing tended to normalize in deep and REM sleep. Considering the IBPs occurring in the healthy group as physiological, probably pathological breathing patterns (tachypnea, long episodes of moderate/severe ataxic or long episodes of periodic breathing) occurred in 67 % of ULMI patients. Our findings suggest that ULMI might exacerbate physiological sleep-stage-dependent breathing pattern irregularities, such as ataxic and periodic breathing, in terms of intensity and duration or might even induce non-physiological IBP, such as shallow tachypnea with sustained hypoxia.

Central nervous system (CNS) hemorrhage is a serious complication related to direct oral anticoagulant (DOAC) therapy. Current recommendations about re-initiation of anticoagulation treatment are limited to expert opinions. For this purpose, we analyzed the data of all consecutive DOAC patients with CNS hemorrhage, in whom DOACs were reinitiated.Over a 6-year period (2012-2018), all consecutive patients with CNS hemorrhage (subdural, subarachnoid, intracerebral, spinal), while receiving DOACs, were included in this observational single-center cohort study. DOAC therapy was reinitiated only in patients with well-controlled arterial hypertension and diabetes, as well as exclusion of vascular malformations and cerebral amyloid angiopathy. The composite primary endpoint comprised of recurrent CNS hemorrhage, ischemic stroke, and mortality; secondary endpoints were separate aforementioned outcomes.Of the 54 patients included, 18 died within a month of CNS hemorrhage. The average observational time was 590 days. DOACs were reinitiated in 13/36 patients (36%); of these patients, three died: none due to ischemic stroke or recurrent CNS bleeding. In 23 patients, anticoagulation was not reinitiated; of these patients, 10 died: three from recurrent CNS hemorrhage, one due to ischemic stroke, and six from causes unrelated to stroke.In carefully selected patients, re-initiation of DOAC therapy did not increase the rate of both endpoints. Recommendations for DOAC re-initiation, which include hypertension and diabetes control, as well as treated vascular malformations, and excluded cerebral amyloid angiopathy, appear to be valid in clinical practice.

The prognosis for unilateral lateral medullary infarction (ULMI) is generally good but may be aggravated by respiratory failure with fatal outcome. Respiratory failure has been reported in patients with severe bulbar dysfunction and large rostral medullary lesions, but its associated factors have not been systematically studied. We aimed to assess clinical and radiological characteristics associated with respiratory failure in patients with pure acute ULMI.Seventy-one patients (median age 55 years, 59 males) with MRI-confirmed acute pure ULMI were studied retrospectively. Clinical characteristics were assessed and bulbar symptoms were scored using a scale developed for this study. MRI lesions were classified into 4 groups based on their vertical extent (localized/extensive) and the involvement of the open and/or closed medulla. Clinical characteristics, bulbar scores and MRI lesion characteristics were compared between patients with and without respiratory failure.Respiratory failure occurred in 8(11%) patients. All patients with respiratory failure were male (p = 0.336), had extensive lesions involving the open medulla (p = 0.061), progression of bulbar symptoms (p=0.002) and aspiration pneumonia (p 0.001). Peak bulbar score (OR, 7.9 [95% CI, 2.3-160.0]; p 0.001) and older age (OR, 1.2 [95%CI, 1.0-1.6]; p=0.006) were independently associated with respiratory failure.Extensive damage involving the open/rostral medulla, clinically presenting with severe bulbar dysfunction, in conjunction with factors such as aspiration pneumonia and older age appears to be crucial for the development of respiratory failure in pure ULMI. Further prospective studies are needed to identify other potential risk factors, pathophysiology, and effective preventive measures for respiratory failure in these patients.

Acute unilateral lateral medullary infarction (ULMI) is complicated by respiratory failure in 2–6% of patients. However, studies investigating milder respiratory disorders not leading to overt respiratory failure, i.e., sleep-disordered breathing (SDB) and its outcome, are lacking. The aim of our study was to identify and prospectively follow SDB in acute ULMI. We prospectively followed 28 patients with MRI-confirmed acute ULMI. Polysomnography (PSG) was performed 1–3 times in the acute phase (at 1–4, 5–10, and 14–21 days after onset of symptoms) and after 3–6 months. PSG recordings in the acute phase were analyzed and compared to the follow-up. Apnea-hypopnea index (AHI) ≥ 5/h, AHI ≥ 15/h, and AHI ≥ 30/h in the acute phase were observed in 22 (79%), 19 (68%), and 10 (36%) patients, respectively. CSA, OSA, mixed CSA/OSA, or multiple interchanging SDB types were observed in the acute phase in 12 (43%), 2 (7%), 2 (7%), and 6 (21%) patients, respectively. Peak AHI varied in individual patients (median at 7 (3–14) days after onset). At follow-up, AHI and central AHI tended to decrease (p = 0.007, p = 0.003, respectively), obstructive AHI did not change (p = 0.396). Sleep architecture partially improved with significantly higher percentage of N2 and lower percentage of wakefulness after sleep onset (p = 0.007, p = 0.012, respectively). Our data show that SDB, particularly CSA, is common in the acute phase of ULMI and that the frequency of central events decreases in the subacute phase. Further studies are needed to clarify the clinical significance and possible treatment options of SDB in these patients.

Due to the diversity of underlying factors and the absence of a uniform treatment approach, diagnosis and management of patients with cerebral venous sinus thrombosis (CVST) remain a challenging task.1 CVST represents 0.5% to 1% of all strokes and affects approximately 5 patients per million every year, but has a higher frequency among younger patients. Typical acquired risk factors include recent surgery, trauma, pregnancy, postpartum state, antiphospholipid syndrome, cancer and use of oral contraceptives. Cases of inherited thrombophilia include Antithrombin III, Protein C and Protein S deficiency, factor V Leiden positivity, prothrombin gene mutation and hyperhomocisteinemia. Infection of parameningeal spaces (ears, paranasal sinuses, oral cavity, face and neck) is common cause of CVST in pediatric population but rare in adults. The symptoms of CVST are not specific. The most common complaint is headache which occurs in up to 90% of patients. Additionally, abnormal vision, any of the symptoms of stroke and seizures have been described. In the past D-dimer levels appeared to be of value as an initial screening test. A study in 2004 evaluated the sensitivity of D-dimer to be 97.1% and specificity 99.1%.8 However, later studies showed that up to 10% of patients with CVST have a normal D-dimer. As it is fast, affordable and widely available, non-contrast computed tomography (NCCT) is the most frequently performed imaging study for evaluation of patients with new headache, focal neurological abnormalities, seizure, or change in mental status. A typical imaging finding in patients with CVST is direct visualization of a hyperattenuating thrombus in the occluded sinus (dense sinus sign). Occasionally, NCCT may only show indirect signs of thrombosis, including diffuse brain edema and parenchymal hemorrhage. Sensitivity of NCCT in the diagnosis of CVST was previously considered rather poor. However, using modern multidetector row CT scanners, recent studies report higher sensitivity and specificity values. In addition, Buyck et al. suggest measurement of the venous sinus attenuation to increase the diagnostic yield of the examination. Therefore, the goal of the present study was to evaluate the diagnostic accuracy of NCCT in the diagnosis of CVST in the emergency setting

We recently reported a novel neurological syndrome characterized by a unique NREM and REM parasomnia with sleep apnea and stridor, accompanied by bulbar dysfunction and specific association with antibodies against the neuronal cell-adhesion protein IgLON5. All patients had the HLA-DRB1*1001 and HLA-DQB1*0501 alleles. Neuropathological findings in two patients revealed a novel tauopathy restricted to neurons and predominantly involving the hypothalamus and tegmentum of the brainstem. The aim of the current study is to describe the neuropathological features of the anti-IgLON5 syndrome and to provide diagnostic levels of certainty based on the presence of associated clinical and immunological data. The brains of six patients were examined and the features required for the neuropathological diagnosis were established by consensus. Additional clinical and immunological criteria were used to define “definite”, “probable” and “possible” diagnostic categories. The brains of all patients showed remarkably similar features consistent with a neurodegenerative disease with neuronal loss and gliosis and absence of inflammatory infiltrates. The most relevant finding was the neuronal accumulation of hyperphosphorylated tau composed of both three-repeat (3R) and four-repeat (4R) tau isoforms, preferentially involving the hypothalamus, and more severely the tegmental nuclei of the brainstem with a cranio-caudal gradient of severity until the upper cervical cord. A “definite” diagnosis of anti-IgLON5-related tauopathy is established when these neuropathological features are present along with the detection of serum or CSF IgLON5 antibodies. When the antibody status is unknown, a “probable” diagnosis requires neuropathological findings along with a compatible clinical history or confirmation of possession of HLA-DRB1*1001 and HLA-DQB1*0501 alleles. A “possible” diagnosis should be considered in cases with compatible neuropathology but without information about a relevant clinical presentation and immunological status. These criteria should help to identify undiagnosed cases among archival tissue, and will assist future clinicopathological studies of this novel disorder. Electronic supplementary material The online version of this article (doi:10.1007/s00401-016-1591-8) contains supplementary material, which is available to authorized users.

Background: Rapid inactivation of dabigatran by its specific inhibitor idarucizamab allows intravenous thrombolysis (IVT) in patients suffering ischemic stroke while being treated with dabigatran. Only limited data of this approach is available and numerous questions regarding efficacy/safety remain to be answered. Herein, we present the findings from the Slovenian national cohort study. Methods: Retrospective analysis of all stroke patients treated with idarucizumab and IVT (n = 11) in the period from July 2016 to February 2018 from Slovenian region were analyzed. Results: The indication for dabigatran treatment in all 11 cases was nonvalvular atrial fibrillation. Importantly, 6 out of 11 cases were classified as severe ischemic strokes (National Institutes of Health Stroke Scale; NIHSS ≥ 10) with a median NIHSS 13. At admission, prolonged activated partial thromboplastin time was present in 9 patients indicating therapeutic anticoagulation activity. The average door-to-needle time was 156 minutes. After 3 months, 9 patients had a modified Rankin Score of less than or equal to 2 and 7 patients had mRS less than 1 whereas, 2 patients died due to symptomatic intracranial hemorrhage (sICH); 1 due to spontaneous sICH, and the other due to a large ischemic stroke with hemorrhagic transformation. No thrombotic complications were observed. Conclusions: Our data show that IVT after idarucizumab administration is a safe and effective method of treatment in ischemic stroke patients on dabigatran. We recorded a higher proportion of patients with favorable outcome as well as with sICH compared to the randomized controlled studies which could suggest a higher sensitivity of thrombi to IVT in dabigatran treated patients.

Background: Leukoaraiosis (ILA) is believed to be ischaemic in origin due to its similar location as that of lacunar infarctions and its association with cerebrovascular risk factors. However, its pathophysiology is not well understood. The ischaemic injuries may be a result of increased pulsatility or cerebral hypo-perfusion. We used carotid duplex ultrasound to prove that the underlying mechanism is hypo-perfusion. Methods: We compared 55 ILA patients to 44 risk factor-matched controls with normal magnetic resonance imaging (MRI) of the head. ILA diagnosis was based on MRI and was further categorised according to the Fazekas scale. We measured carotid artery blood flow velocity and diameter and calculated carotid blood flow and resistance indexes. Results: Blood flow velocities and blood flows were significantly lower in the ILA group, including diastolic, systolic and mean pressures (p ≤ 0.05). The resistance indices were higher in the ILA group, but the differences were not statistically significant. All the velocities and blood flows showed a decreasing trend with higher Fazekas score, whereas resistance indexes showed an increasing trend. Conclusions: Lower blood flow and higher resistance of carotid arteries are consistent with the hypo-perfusion theory of ILA. Carotid ultrasound could have a diagnostic and prognostic role in ILA patients.

Background Acute unilateral dorsolateral medullary infarction (aUMI) is related to respiratory failure in 2−5% of patients. However, sleep disordered breathing (SDB) in these patients has not yet been systematically studied. Aims and objectives To identify and characterize SDB in patients with aUMI. Methods We prospectively followed 13 (9 male) patients (median age 53 years, range (49−66)) with aUMI. Polysomnography (PSG) was performed 1−3 times during hospitalization and at 3 months after the event. In patients that underwent more than one PSG recording the highest apnea-hypopnea index (AHI) was analysed. Data are presented as median (25th−75th percentile). Results During hospitalization, AHI≥10/h was detected at least once in 8 patients (62%) with highest AHI of 17 (7−19)/h, central AHI (CAHI) 17(7−18)/h and obstructive AHI (OAHI) 0.0(0−0.5)/h. Periodic breathing (PB) was recorded at least once in 12 (92%) patients, and 6 (46%) patients had PB ≥5% per total recording time. Intra-patient SDB severity varied between timely separated PSG recordings and its peak was at various times during hospitalization. At follow up, AHI and CAHI decreased to 6 (4−8)/h and 6 (3−8)/h (p=0.04 for each value), respectively, the changes in OAHI were not statistically significant (p=0.46), however. Conclusions Our preliminary results indicate high transient predisposition of patients with aUMI to central sleep apneas. Due to the risk of respiratory failure or even sudden death, PSG is warranted in all patients with aUMI early after the event. Since the time peak of SDB is variable it is reasonable to perform PSG repeatedly.

BACKGROUND: The vascular contributions to neurodegeneration and neuroinflammation may be assessed by magnetic resonance imaging (MRI) and ultrasonography (US). This review summarises the methodology for these widely available, safe and relatively low cost tools and analyses recent work highlighting their potential utility as biomarkers for differentiating subtypes of cognitive impairment and dementia, tracking disease progression and evaluating response to treatment in various neurocognitive disorders. ----- METHODS: At the 9th International Congress on Vascular Dementia (Ljubljana, Slovenia, October 2015) a writing group of experts was formed to review the evidence on the utility of US and arterial spin labelling (ASL) as neurophysiological markers of normal ageing, vascular cognitive impairment (VCI) and Alzheimer's disease (AD). Original articles, systematic literature reviews, guidelines and expert opinions published until September 2016 were critically analysed to summarise existing evidence, indicate gaps in current knowledge and, when appropriate, suggest standards of use for the most widely used US and ASL applications. ----- RESULTS: Cerebral hypoperfusion has been linked to cognitive decline either as a risk or an aggravating factor. Hypoperfusion as a consequence of microangiopathy, macroangiopathy or cardiac dysfunction can promote or accelerate neurodegeneration, blood-brain barrier disruption and neuroinflammation. US can evaluate the cerebrovascular tree for pathological structure and functional changes contributing to cerebral hypoperfusion. Microvascular pathology and hypoperfusion at the level of capillaries and small arterioles can also be assessed by ASL, an MRI signal. Despite increasing evidence supporting the utility of these methods in detection of microvascular pathology, cerebral hypoperfusion, neurovascular unit dysfunction and, most importantly, disease progression, incomplete standardisation and missing validated cut-off values limit their use in daily routine. ----- CONCLUSIONS: US and ASL are promising tools with excellent temporal resolution, which will have a significant impact on our understanding of the vascular contributions to VCI and AD and may also be relevant for assessing future prevention and therapeutic strategies for these conditions. Our work provides recommendations regarding the use of non-invasive imaging techniques to investigate the functional consequences of vascular burden in dementia.

Summary It seems that migraine patients might suffer from localized and not systemic endothelial dysfunction. However, the probability whether impaired endothelial function in the posterior cerebral circulation, and intact endothelial function elsewhere is associated with migraine is not known. This is a post hoc study based on two of our previous published studies that evaluated cerebral and systemic endothelial function in 40 migraine patients (20 with (MwA) and 20 without aura (MwoA)) without comorbidities, and 20 healthy subjects. Cerebrovascular reactivity (CVR) to l -arginine in the middle (MCA) and posterior (PCA) cerebral artery as well as flow mediated vasodilatation (FMD) were used for this purpose. The logistic regression analysis was used to evaluate the association between CVR to l -arginine, FMD and migraine. We found a significant association between CVR to l -arginine in the PCA and migraine (OR: 0.38; CI 95%: 0.19–0.79; p = 0.01), but not between CVR to l -arginine in the MCA and migraine (OR: 0.74; CI 95%: 0.34–1.59; p = 0.44). Similar results were obtained in MwA and MwoA. We did not find any significant association between FMD and migraine (OR: 0.99; CI 95%: 0.83–1.19; p = 0.96). The same conclusion was reached in both migraine groups (MwA OR: 1.0; CI 95%: 0.83–1.19; p = 0.99, MwoA OR: 0.99; CI 95%: 0.81–1.21; p = 0.99). We could conclude that impaired endothelial function in the posterior cerebral circulation is associated with migraine, both MwA and MwoA, while intact endothelial function in the anterior cerebral and systemic circulation is not associated only with migraine.

Background: Endothelial dysfunction could be involved in the pathophysiology of migraine. The results obtained from a few studies on endothelial dysfunction in migraine are controversial. We investigated brachial flow-mediated dilatation (FMD), which reflects systemic endothelial dysfunction, in migraine patients without comorbidities. By employing strict inclusion criteria we avoided the possible changes to FMD from confounding factors. Methods. Forty migraine patients without comorbidities (20 with and 20 without aura) and 20 healthy subjects were included. FMD of brachial arteries and carotid intima-media thickness were measured by using standard procedures. Results. We did not find any difference in FMD between migraine patients and healthy subjects ( p = .96). Also, no differences were found among healthy subjects, migraine patients with aura and without aura ( p = .99). Conclusion. Our study showed that systemic endothelial function is not impaired in migraine patients without comorbidities, neither in those with or without aura. Considering these findings, the investigation of cerebral endothelial function would be useful in a further investigation of the role of endothelial (dys)function in migraine pathophysiology.

Perko D, Pretnar-Oblak J, Sabovic M, Žvan B, Zaletel M. Cerebrovascular reactivity to l-arginine in the anterior and posterior cerebral circulation in migraine patients. Acta Neurol Scand: 2011: 124: 269–274. © 2011 John Wiley & Sons A/S. Objective – Cerebral infarction preferentially affects the posterior cerebral artery distribution in migraine patients. The results obtained from the few known studies that have compared the anterior and posterior cerebral endothelial function are contradictory. To the best of our knowledge, cerebrovascular reactivity to L-arginine (CVR), measured by transcranial Doppler sonography (TCD), has not been previously used to determine the posterior cerebral endothelial function in migraine patients with (MwA) and without aura (MwoA). Materials and methods – Forty migraine patients without comorbidities (20 MwA, 20 MwoA) and 20 healthy subjects were included. By employing strict inclusion criteria, we avoided the possible vascular risk factors. Mean arterial velocity in the middle cerebral artery (MCA) and the posterior cerebral artery (PCA) was measured by TCD before and after infusion of L-arginine, and CVR to L-arginine was then calculated. Results – All migraine patients had lower CVR to L-arginine in PCA (P = 0.002) and similar in MCA (P = 0.29) compared to healthy subjects. This difference was also present in MwA and MwoA compared to healthy subjects (P = 0.003). Conclusions – Lower CVR to L-arginine in PCA in migraine patients could associate migraine and cerebral infarcts that are more common in the posterior cerebral artery distribution.

Background: Cerebral endothelial function might be different in distinct cerebrovascular territory, thereby making these areas more susceptible to ischemia and stroke. Higher incidence and prevalence of stroke in males suggest that gender could have a strong influence on this difference. In order to evaluate cerebral endothelial function, we compared cerebrovascular reactivity (CVR) to L-arginine in the anterior and posterior cerebral circulation in healthy young males and females. Methods: Thirty healthy subjects, 15 females (32.1 ± 7.1 years) and 15 males (32.2 ± 6.3 years), were included. The mean arterial velocity in the middle cerebral artery (MCA) and the posterior cerebral artery (PCA) was measured by transcranial Doppler sonography before and after intravenous infusion of L-arginine, and CVR to L-arginine was then calculated. Results: CVR to L-arginine was significantly higher in PCA than in MCA in all subjects (19.2 ± 8.2 vs. 13.6 ± 7.1%, p ≤ 0.01). In addition, CVR to L-arginine was significantly more pronounced in females compared to males in PCA (22.7 ± 8.3 vs. 15.8 ± 6.7%, p ≤ 0.01) and MCA (16.8 ± 6.4 vs. 10.4 ± 6.4%, p < 0.05). Conclusions: Lower CVR to L-arginine and therefore lower cerebral endothelial function in the anterior cerebral circulation and in males might be related to the higher incidence of ischemia and stroke in the anterior cerebral circulation, particularly in males.

BacKGroUnD The pleiotropic effects of statins on the endothelial function are well recognized. However, the effect of statins might not be equally pronounced in the cerebral and systemic circulation. We compared cerebral and systemic endothelial function by l-arginine cerebrovascular reactivity and flow-mediated dilatation (FMD), respectively, in patients with arterial hypertension (AH) and healthy controls before and after atorvastatin treatment. metHoDS l-arginine reactivity and FMD were measured in patients with AH (29 patients, aged 61.1 ± 6.2 years) and 21 healthy controls. The mean arterial velocity (v m ) in both middle cerebral arteries was measured by transcranial Doppler sonography before, during, and after a 30-min intravenous infusion of l-arginine. FMD of the brachial artery after hyperemia was determined. The measurements were repeated after 3 months of treatment with atorvastatin. reSUL t S l-arginine reactivity and FMD were decreased in patients with AH (12.5 ± 8.7%; 2.7 ± 5.0 %) compared with controls (21.3 ± 10.9%; 8.5 ± 5.9%) (P < 0.01). After atorvastatin treatment, l-arginine reactivity and FMD improved in patients with AH (19.5 ± 10.6%; 4.6 ± 4.1%) compared with the controls (20.2 ± 10.2%; 9.7 ± 3.9%). The use of statin restored the cerebral circulation reactivity, while there was little change in the systemic circulation measured by FMD. concLUSIon The decreased l-arginine reactivity and FMD were found to improve after atorvastatin treatment in patients with AH, but the results suggest that statin therapy improved cerebral more than systemic endothelial function.

Recently, L-arginine reactivity has been used for evaluation of cerebral endothelial impairment. However, the diagnostic potential of the method is still unknown. The aim of the study was to establish the sensitivity and specificity of L-arginine reactivity and compare this method with flow-mediated dilation (FMD) and intima-media thickness (IMT). L-arginine reactivity, FMD and IMT were determined in patients with arterial hypertension (AH) and presumed endothelial impairment (41 patients, aged 60.9 ± 7.4 y) and 21 age- and gender-matched healthy controls. The relative increase in the mean arterial velocity after a 30-min i.v. infusion of L-arginine (dv m(L-arg) ) was ascertained by TCD. FMD of the brachial artery after hyperaemia and IMT of the common carotid artery on both sides were determined. The diagnostic value of the methods was assessed using receiver-operating-characteristic (ROC) analysis. In patients with AH, dv m(L-arg) , FMD and IMT were diminished (11.5% ± 8.9%; 3.8% ± 4.8%; 0.82 ± 0.16 mm) compared with the healthy controls (20.5% ± 9.9%; 7.9% ± 6.0%;0.64 ± 0.15 mm) ( p ≤ 0.01). The optimal cut-point for L-arginine reactivity of 0.22 yielded a 40% sensitivity and 93% specificity, which was comparable to the other two methods. For all three methods, the area under the ROC curves differed significantly from 0.5 (0.694; p = 0.013 for dv m(L-arg) , 0.784; p ≤ 0.01 for FMD, 0.827; p ≤ 0.01 for IMT). Cerebrovascular reactivity to L-arginine is a valuable method for determination of cerebral endothelial function. The diagnostic value of the three methods is comparable. (E-mail: janja.pretnar@kclj.si )

The relationships between cerebral and systemic endothelial (dys)function and between cerebral (dys)function and intima-media thickness (IMT) of carotid arteries in patients and healthy volunteers have not yet been clarified. In order to explore these issues, the authors performed a post hoc correlation analysis of cerebrovascular reactivity to L-arginine, a marker of cerebral endothelial function; flow-mediated dilatation (FMD), a marker of systemic endothelial function; and IMT of the carotid arteries, a marker of the extent of atherosclerosis. Correlations were analyzed in a heterogeneous group consisting of 20 patients with lacunar infarctions (LIs) and extensively impaired endothelial function, 21 patients with similar risk factors (SRs), but without LIs, and 21 healthy controls. Cerebrovascular reactivity to L-arginine was determined by the transcranial Doppler method (TCD), FMD by ultrasound measurements of the brachial artery after hyperemia, and IMT by measurement of the common carotid arteries. Analysis of correlations in the group of 62 subjects revealed that L-arginine reactivity, which was diminished in LI and SR patients, did not correlate with FMD, which was also diminished in both LI and SR patients (Rho = 0.10 with p = 0.458). On the contrary, a significant negative correlation was found between L-arginine reactivity and IMT (Rho = -0.30 with p = 0.015). In conclusion, our study investigating relations between cerebral and systemic endothelial dysfunction showed that cerebral endothelial function, determined by L-arginine reactivity, correlates well with the degree of atherosclerosis determined by IMT but does not correlate with FMD, suggesting that cerebral and systemic endothelial function may not be closely associated.

Background: It is well known that endothelial dysfunction plays an important role in the pathogenesis of many cardiovascular disorders. The aim of this study was to test the hypothesis that specific, marked endothelial dysfunction of cerebral arteries is present in patients with lacunar cerebral infarctions. Methods: Cerebrovascular reactivity to L-arginine, which reveals the function of the cerebral endothelium, was investigated in patients with lacunar infarctions (20 patients, 11 male and 9 female, aged 60.9 ± 7.3 years), 21 age- and gender-matched asymptomatic patients with similar cardiovascular risk factors (all patients had arterial hypertension) and 21 age- and gender-matched healthy controls. The mean arterial velocity (vm) in both middle cerebral arteries was measured by transcranial Doppler sonography during a 15-min baseline period, a 30-min intravenous infusion of L-arginine and a 15-min interval after L-arginine infusion. Arterial blood pressure, heart rate and CO2 were measured continuously. Results: The measured vm increase during L-arginine infusion in the patients with lacunar infarctions (13.4 ± 9.1%) was significantly lower compared to the healthy controls (20.5 ± 9.9%) but similar to that obtained in the patients with cardiovascular risk factors (11.5 ± 8.9%). Conclusions: Our results showed that cerebrovascular reactivity to L-arginine, which demonstrates cerebral endothelial function, is significantly impaired in patients with cardiovascular risk factors. Importantly, we found that patients with lacunar infarctions do not show any additional impairment of cerebral endothelial function.