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Background and Purpose: Clinical trials on stroke prevention in patients with atrial fibrillation have consistently shown clinical benefit from either warfarin or non–vitamin K antagonist oral anticoagulants (NOACs). NOAC-treated patients have consistently reported to be at lower risk for intracerebral hemorrhage (ICH) than warfarin-treated patients. The aims of this prospective, multicenter, multinational, unmatched, case-control study were (1) to investigate for risk factors that could predict ICH occurring in patients with atrial fibrillation during NOAC treatment and (2) to evaluate the role of CHA 2 DS 2 -VASc and HAS-BLED scores in the same setting. Methods: Cases were consecutive patients with atrial fibrillation who had ICH during NOAC treatment. Controls were consecutive patients with atrial fibrillation who did not have ICH during NOAC treatment. As within the CHA 2 DS 2 -VASc and HAS-BLED scores there are some risk factors in common, several multivariable logistic regression models were performed to identify independent prespecified predictors for ICH events. Results: Four hundred nineteen cases (mean age, 78.8±8.1 years) and 1526 controls (mean age, 76.0±10.3 years) were included in the study. From the different models performed, independent predictors of ICH were increasing age, concomitant use of antiplatelet agents, active malignancy, high risk of fall, hyperlipidemia, low clearance of creatinine, peripheral artery disease, and white matter changes. Low doses of NOACs (given according to label or not) and congestive heart failure were inversely associated with the risk of ICH. HAS-BLED and CHA 2 DS 2 -VASc scores performed poorly in predicting ICH with areas under the curves of 0.496 (95% CI, 0.468–0.525) and 0.530 (95% CI, 0.500–0.560), respectively. Conclusions: Several risk factors were associated to ICH in patients treated with NOACs for stroke prevention but not HAS-BLED and CHA 2 DS 2 -VASc scores.

Introduction The aim of this study in patients with acute posterior ischaemic stroke (PS) and atrial fibrillation (AF) was to evaluate (1) the risks of recurrent ischaemic event and severe bleeding and (2) these risks in relation with oral anticoagulant therapy (OAT) and its timing. Materials and Methods Patients with PS were prospectively included; the outcome events of these patients were compared with those of patients with anterior stroke (AS) which were taken from previous registries. The primary outcome was the composite of stroke recurrence, transient ischaemic attack, symptomatic systemic embolism, symptomatic cerebral bleeding and major extracranial bleeding occurring within 90 days from acute stroke. Results A total of 2470 patients were available for the analysis: 473 (19.1%) with PS and 1997 (80.9%) with AS. Over 90 days, 213 (8.6%) primary outcome events were recorded: 175 (8.7%) in patients with AS and 38 (8.0%) in those with PS. In patients who initiated OAT within 2 days, the primary outcome occurred in 5 out of 95 patients (5.3%) with PS compared to 21 out of 373 patients (4.3%) with AS (OR 1.07; 95% CI 0.39–2.94). In patients who initiated OAT between days 3 and 7, the primary outcome occurred in 3 out of 103 patients (2.9%) with PS compared to 26 out of 490 patients (5.3%) with AS (OR 0.54; 95% CI 0.16–1.80). Discussion our findings suggest that, when deciding the time to initiate oral anticoagulation, the location of stroke, either anterior or posterior, does not predict the risk of outcome events. Conclusions Patients with PS or AS and AF appear to have similar risks of ischaemic or haemorrhagic events at 90 days with no difference concerning the timing of initiation of OAT.

Background and Purpose— Despite treatment with oral anticoagulants, patients with nonvalvular atrial fibrillation (AF) may experience ischemic cerebrovascular events. The aims of this case-control study in patients with AF were to identify the pathogenesis of and the risk factors for cerebrovascular ischemic events occurring during non–vitamin K antagonist oral anticoagulants (NOACs) therapy for stroke prevention. Methods— Cases were consecutive patients with AF who had acute cerebrovascular ischemic events during NOAC treatment. Controls were consecutive patients with AF who did not have cerebrovascular events during NOACs treatment. Results— Overall, 713 cases (641 ischemic strokes and 72 transient ischemic attacks; median age, 80.0 years; interquartile range, 12; median National Institutes of Health Stroke Scale on admission, 6.0; interquartile range, 10) and 700 controls (median age, 72.0 years; interquartile range, 8) were included in the study. Recurrent stroke was classified as cardioembolic in 455 cases (63.9%) according to the A-S-C-O-D (A, atherosclerosis; S, small vessel disease; C, cardiac pathology; O, other causes; D, dissection) classification. On multivariable analysis, off-label low dose of NOACs (odds ratio [OR], 3.18; 95% CI, 1.95–5.85), atrial enlargement (OR, 6.64; 95% CI, 4.63–9.52), hyperlipidemia (OR, 2.40; 95% CI, 1.83–3.16), and CHA 2 DS 2 -VASc score (OR, 1.72 for each point increase; 95% CI, 1.58–1.88) were associated with ischemic events. Among the CHA 2 DS 2 -VASc components, age was older and presence of diabetes mellitus, congestive heart failure, and history of stroke or transient ischemic attack more common in patients who had acute cerebrovascular ischemic events. Paroxysmal AF was inversely associated with ischemic events (OR, 0.45; 95% CI, 0.33–0.61). Conclusions— In patients with AF treated with NOACs who had a cerebrovascular event, mostly but not exclusively of cardioembolic pathogenesis, off-label low dose, atrial enlargement, hyperlipidemia, and high CHA 2 DS 2 -VASc score were associated with increased risk of cerebrovascular events.

Background and Purpose— Bridging therapy with low-molecular-weight heparin reportedly leads to a worse outcome for acute cardioembolic stroke patients because of a higher incidence of intracerebral bleeding. However, this practice is common in clinical settings. This observational study aimed to compare (1) the clinical profiles of patients receiving and not receiving bridging therapy, (2) overall group outcomes, and (3) outcomes according to the type of anticoagulant prescribed. Methods— We analyzed data of patients from the prospective RAF and RAF-NOACs studies. The primary outcome was defined as the composite of ischemic stroke, transient ischemic attack, systemic embolism, symptomatic cerebral bleeding, and major extracerebral bleeding observed at 90 days after the acute stroke. Results— Of 1810 patients who initiated oral anticoagulant therapy, 371 (20%) underwent bridging therapy with full-dose low-molecular-weight heparin. Older age and the presence of leukoaraiosis were inversely correlated with the use of bridging therapy. Forty-two bridged patients (11.3%) reached the combined outcome versus 72 (5.0%) of the nonbridged patients ( P =0.0001). At multivariable analysis, bridging therapy was associated with the composite end point (odds ratio, 2.3; 95% CI, 1.4–3.7; P P =0.005) and hemorrhagic (odds ratio, 2.4; 95% CI, 1.2–4.9; P =0.01) end points separately. Conclusions— Our findings suggest that patients receiving low-molecular-weight heparin have a higher risk of early ischemic recurrence and hemorrhagic transformation compared with nonbridged patients.

Background and Purpose— We aimed to assess if renal function can aid in risk stratification for ischemic stroke or transient ischemic attack (TIA) recurrence and death in patients with embolic stroke of undetermined source (ESUS). Methods— We pooled 12 ESUS datasets from Europe and America. Renal function was evaluated using the estimated glomerular filtration rate (eGFR) and analyzed in continuous, binary, and categorical way. Cox-regression analyses assessed if renal function was independently associated with the risk for ischemic stroke/TIA recurrence and death. The Kaplan-Meier product limit method estimated the cumulative probability of ischemic stroke/TIA recurrence and death. Results— In 1530 patients with ESUS followed for 3260 patient-years, there were 237 recurrences (15.9%) and 201 deaths (13.4%), corresponding to 7.3 ischemic stroke/TIA recurrences and 5.6 deaths per 100 patient-years, respectively. Renal function was not associated with the risk for ischemic stroke/TIA recurrence when forced into the final multivariate model, regardless if it was analyzed as continuous (hazard ratio, 1.00; 95% CI, 0.99–1.00 for every 1 mL/min), binary (hazard ratio, 1.27; 95% CI, 0.87–1.73) or categorical covariate (likelihood-ratio test 2.59, P =0.63 for stroke recurrence). The probability of ischemic stroke/TIA recurrence across stages of renal function was 11.9% for eGFR ≥90, 16.6% for eGFR 60–89, 21.7% for eGFR 45–59, 19.2% for eGFR 30–44, and 24.9% for eGFR P =0.63). The results were similar for the outcome of death. Conclusions— The present study is the largest pooled individual patient-level ESUS dataset, and does not provide evidence that renal function can be used to stratify the risk of ischemic stroke/TIA recurrence or death in patients with ESUS.

Visuospatial neglect (VN) frequently occurs in Posterior Cortical Atrophy (PCA) and requires specific rehabilitation. In this single-case study, we investigated the efficacy of a computer-assisted cognitive training (CCT) alone or coupled with multiple sessions of anodal transcranial direct-current stimulation (A-tDCS) over the right posterior parietal cortex in improving left VN symptoms in a patient with PCA. The digital ReMoVES platform was used for both VN assessment and training. We found a significant improvement after CCT combined with A-tDCS within the limits of a single-case, our results suggest, for the first time, the usefulness of this combined approach in a neurodegenerative disorder.

Supplemental Digital Content is available in the text., Recent case-series of small size implied a pathophysiological association between coronavirus disease 2019 (COVID-19) and severe large-vessel acute ischemic stroke. Given that severe strokes are typically associated with poor prognosis and can be very efficiently treated with recanalization techniques, confirmation of this putative association is urgently warranted in a large representative patient cohort to alert stroke clinicians, and inform pre- and in-hospital acute stroke patient pathways. We pooled all consecutive patients hospitalized with laboratory-confirmed COVID-19 and acute ischemic stroke in 28 sites from 16 countries. To assess whether stroke severity and outcomes (assessed at discharge or at the latest assessment for those patients still hospitalized) in patients with acute ischemic stroke are different between patients with COVID-19 and non-COVID-19, we performed 1:1 propensity score matching analyses of our COVID-19 patients with non-COVID-19 patients registered in the Acute Stroke Registry and Analysis of Lausanne Registry between 2003 and 2019. Between January 27, 2020, and May 19, 2020, 174 patients (median age 71.2 years; 37.9% females) with COVID-19 and acute ischemic stroke were hospitalized (median of 12 patients per site). The median National Institute of Health Stroke Scale was 10 (interquartile range [IQR], 4–18). In the 1:1 matched sample of 336 patients with COVID-19 and non-COVID-19, the median National Institute of Health Stroke Scale was higher in patients with COVID-19 (10 [IQR, 4–18] versus 6 [IQR, 3–14]), P=0.03; (odds ratio, 1.69 [95% CI, 1.08–2.65] for higher National Institute of Health Stroke Scale score). There were 48 (27.6%) deaths, of which 22 were attributed to COVID-19 and 26 to stroke. Among 96 survivors with available information about disability status, 49 (51%) had severe disability at discharge. In the propensity score-matched population (n=330), patients with COVID-19 had higher risk for severe disability (median mRS 4 [IQR, 2–6] versus 2 [IQR, 1–4], P

Background and Purpose: The optimal timing for starting oral anticoagulant after an ischemic stroke related to atrial fibrillation remains a challenge, mainly in patients treated with systemic thrombolysis or mechanical thrombectomy. We aimed at assessing the incidence of early recurrence and major bleeding in patients with acute ischemic stroke and atrial fibrillation treated with thrombolytic therapy and/or thrombectomy, who then received oral anticoagulants for secondary prevention. Methods: We combined the dataset of the RAF and the RAF-NOACs (Early Recurrence and Major Bleeding in Patients With Acute Ischemic Stroke and Atrial Fibrillation Treated With Non–Vitamin K Oral Anticoagulants) studies, which were prospective observational studies carried out from January 2012 to March 2014 and April 2014 to June 2016, respectively. We included consecutive patients with acute ischemic stroke and atrial fibrillation treated with either vitamin K antagonists or nonvitamin K oral anticoagulants. Primary outcome was the composite of stroke, transient ischemic attack, symptomatic systemic embolism, symptomatic cerebral bleeding, and major extracerebral bleeding within 90 days from the inclusion. Treated-patients were propensity matched to untreated-patients in a 1:1 ratio after stratification by baseline clinical features. Results: A total of 2159 patients were included, 564 (26%) patients received acute reperfusion therapies. After the index event, 505 (90%) patients treated with acute reperfusion therapies and 1287 of 1595 (81%) patients untreated started oral anticoagulation. Timing of starting oral anticoagulant was similar in reperfusion-treated and untreated patients (median 7.5 versus 7.0 days, respectively). At 90 days, the primary study outcome occurred in 37 (7%) patients treated with reperfusion and in 146 (9%) untreated patients (odds ratio, 0.74 [95% CI, 0.50–1.07]). After propensity score matching, risk of primary outcome was comparable between the 2 groups (odds ratio, 1.06 [95% CI, 0.53–2.02]). Conclusions: Acute reperfusion treatment did not influence the risk of early recurrence and major bleeding in patients with atrial fibrillation–related acute ischemic stroke, who started on oral anticoagulant.

Objective:\ud It is not known whether patients with atrial fibrillation (AF) with ischemic stroke despite oral anticoagulant therapy are at increased risk for further recurrent strokes or how ongoing secondary prevention should be managed.\ud \ud Methods:\ud We conducted an individual patient data pooled analysis of 7 prospective cohort studies that recruited patients with AF and recent cerebral ischemia. We compared patients taking oral anticoagulants (vitamin K antagonists [VKA] or direct oral anticoagulants [DOAC]) prior to index event (OACprior ) with those without prior oral anticoagulation (OACnaive ). We further compared those who changed the type (ie, from VKA or DOAC, vice versa, or DOAC to DOAC) of anticoagulation (OACchanged ) with those who continued the same anticoagulation as secondary prevention (OACunchanged ). Time to recurrent acute ischemic stroke (AIS) was analyzed using multivariate competing risk Fine-Gray models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs).\ud \ud Results:\ud We included 5,413 patients (median age = 78 years [interquartile range (IQR) = 71-84 years]; 5,136 [96.7%] had ischemic stroke as the index event, median National Institutes of Health Stroke Scale on admission = 6 [IQR = 2-12]). The median CHA2 DS2 -Vasc score (congestive heart failure, hypertension, age≥ 75 years, diabetes mellitus, stroke/transient ischemic attack, vascular disease, age 65-74 years, sex category) was 5 (IQR = 4-6) and was similar for OACprior (n = 1,195) and OACnaive (n = 4,119, p = 0.103). During 6,128 patient-years of follow-up, 289 patients had AIS (4.7% per year, 95% CI = 4.2-5.3%). OACprior was associated with an increased risk of AIS (HR = 1.6, 95% CI = 1.2-2.3, p = 0.005). OACchanged (n = 307) was not associated with decreased risk of AIS (HR = 1.2, 95% CI = 0.7-2.1, p = 0.415) compared with OACunchanged (n = 585).\ud \ud Interpretation:\ud Patients with AF who have an ischemic stroke despite previous oral anticoagulation are at a higher risk for recurrent ischemic stroke despite a CHA2 DS2 -Vasc score similar to those without prior oral anticoagulation. Better prevention strategies are needed for this high-risk patient group.

Background The relationship between different patterns of atrial fibrillation and early recurrence after an acute ischaemic stroke is unclear. Purpose In a prospective cohort study, we evaluated the rates of early ischaemic recurrence after an acute ischaemic stroke in patients with paroxysmal atrial fibrillation or sustained atrial fibrillation which included persistent and permanent atrial fibrillation. Methods In patients with acute ischaemic stroke, atrial fibrillation was categorised as paroxysmal atrial fibrillation or sustained atrial fibrillation. Ischaemic recurrences were the composite of ischaemic stroke, transient ischaemic attack and symptomatic systemic embolism occurring within 90 days from acute index stroke. Results A total of 2150 patients (1155 females, 53.7%) were enrolled: 930 (43.3%) had paroxysmal atrial fibrillation and 1220 (56.7%) sustained atrial fibrillation. During the 90-day follow-up, 111 ischaemic recurrences were observed in 107 patients: 31 in patients with paroxysmal atrial fibrillation (3.3%) and 76 with sustained atrial fibrillation (6.2%) (hazard ratio (HR) 1.86 (95% CI 1.24–2.81)). Patients with sustained atrial fibrillation were on average older, more likely to have diabetes mellitus, hypertension, history of stroke/ transient ischaemic attack, congestive heart failure, atrial enlargement, high baseline NIHSS-score and implanted pacemaker. After adjustment by Cox proportional hazard model, sustained atrial fibrillation was not associated with early ischaemic recurrences (adjusted HR 1.23 (95% CI 0.74–2.04)). Conclusions After acute ischaemic stroke, patients with sustained atrial fibrillation had a higher rate of early ischaemic recurrence than patients with paroxysmal atrial fibrillation. After adjustment for relevant risk factors, sustained atrial fibrillation was not associated with a significantly higher risk of recurrence, thus suggesting that the risk profile associated with atrial fibrillation, rather than its pattern, is determinant for recurrence.

The aim of this observational study was to assess the efficacy of a tetrahydrocannabinol-cannabidiol (THC : CBD) oromucosal spray on spasticity using the stretch reflex in patients with multiple sclerosis (MS). Numeric rating scale (NRS) for spasticity, modified Ashworth scale (MAS), and the stretch reflex were assessed before and during treatment in 57 MS patients with spasticity eligible for THC : CBD treatment. A significant reduction in stretch reflex amplitude as well as significant reductions of NRS and MAS scores were observed. There was a low concordance between the three measures (stretch reflex, NRS, and MAS), likely related to the different aspects of muscle hypertonia assessed. Stretch reflex responders were taking a significantly higher number of puffs, whereas no differences were found in the responders by the other scales, suggesting that a higher dosage would add benefit if tolerated. The present study confirms the efficacy of cannabinoids in reducing spasticity in patients with MS, suggesting a higher sensitivity and specificity of the stretch reflex compared with other measures. As an objective and quantitative measure of spasticity, the stretch reflex is particularly useful to assess the effects of cannabinoids on spinal excitability and may play a role in future pharmacological studies.

Recently, during the pandemic infection of the novel SARS-CoV-2, some cases of Guillan-Barré Syndrome (GBS) have been reported. The aim of this work is to report the natural history of patients with GBS, both COVID and not-COVID related, hospitalized in Liguria region, during lock down period, in order to assess clinical features of both groups and possible managements pitfalls due to pandemic emergency. Fifteen GBS patients were admitted to the Hospitals of Liguria, from February 15th to May 3rd 2020, six with SARS-CoV-2 infection and nine without infection. In COVID-19 related GBS five patients presented with classical GBS and one with variant. Two patients presented neurologic symptoms during or shortly after the viral syndrome, suggesting the pattern of a para-infectious profile. Multi-organ involvement, delay in the diagnosis, incomplete work up and start of therapy, were registered in 50% of cases with a GBS-Disability scale ≥4 at follow-up evaluation. In not-COVID-19 related GBS, main problem was diagnostic delay. In three patients the first neurological observation took place after a mean of 33,6 days. Moreover, five patients went to emergency room after an average of 30 days since the onset of neurological symptoms because of fear of contagion. In conclusion, not only SARS-CoV-2 infection can cause GBS, but it can also, due to effects of pandemic on the health organization, affect the outcome of patients with not COVID-19 related GBS., Highlights • Covid-19 and GBS. • Diagnostic and therapeutic delay. • Management pitfalls.

Moderate to severe spasticity is commonly reported in Multiple Sclerosis (MS) and its management is still a challenge. Cannabinoids were recently suggested as add-on therapy for the treatment of spasticity and chronic pain in MS but there is no conclusive scientific evidence on their safety, especially on cognition and over long periods. The aim of this prospective pilot study was to assess the long-term effects of a tetrahydrocannabinol-cannabidiol (THC/CBD) oromucosal spray (Sativex®) on cognition, mood and anxiety.An extensive and specific battery of neuropsychological tests (Symbol Digit Modalities Test-SDMT, California Verbal Learning Test-CVLT, Brief Visuospatial Memory Test-BVMT; PASAT-3 and 2; Free and Cued Selective Remind Test-FCSRT, Index of Sensitivity of Cueing-ISC) was applied to longitudinally investigate different domains of cognition in 20 consecutive MS patients receiving Sativex for spasticity. The primary endpoint was to assess any variation in cognitive performance. Secondary outcomes regarding mood and anxiety were investigated by means of Beck Depression Inventory (BDI) and Hamilton Anxiety Rating Scale (HAM-A). Any change in patients' spasticity was evaluated using the 0-10 Numerical Rating Scale (NRS).Twenty per protocol patients were followed up and evaluated at baseline, 6 and 12 months. Domains involving processing speed and auditory verbal memory significantly improved within the first 6 months of therapy (SDMT: p 0.001; CVLT: p = 0.0001). Mood and anxiety did not show any significant variation. Additionally, the NRS score significantly improved since the beginning (p 0.0001).These results are encouraging in supporting possible long-term benefits of Sativex on cognition and a wider role than symptom alleviator. Further studies on larger groups of patients would be necessary in order to test this intriguing possibility.

We present the neuropathological description of an autoptic case of fatal rebound of disease activity after fingolimod discontinuation in a multiple sclerosis patient. MRI prior to the fatal outcome showed several large tumefactive demyelinating lesions. These lesions were characterized by prominent astrocytic gliosis, with a remarkable preponderance of large hypertrophic reactive astrocytes showing intense expression of sphingosine-1-phosphate receptor 1. Prominent astrocytic gliosis was also diffusely observed in the normal-appearing white matter. Dysregulated sphingosine-1-phosphate signaling on astrocytes following fingolimod withdrawal might represent a possible contributing mechanism to disease rebound and might account for the unusual radiological and neuropathological features observed in the present case.

Background Spasticity and spastic dystonia are two separate phenomena of the upper motor neuron syndrome. Spasticity is clinically defined by velocity-dependent hypertonia and tendon jerk hyperreflexia due to the hyper-excitability of the stretch reflex. Spastic dystonia is the inability to relax a muscle leading to a spontaneous tonic contraction. Both spasticity and spastic dystonia are present in patients who are at rest; however, only patients with spasticity are actually able to kept their muscles relaxed prior to muscle stretch. The idea that has inspired the present work is that also in patients with spastic dystonia the stretch reflex is likely to be hyper-excitable. Therefore, velocity-dependent hypertonia could be mediated not only by spasticity, but also by spastic dystonia. Methods Tonic stretch reflexes in the rectus femoris muscle were evoked in 30 patients with multiple sclerosis showing velocity-dependent hypertonia of leg extensors and the habituation of the reflex was studied. Moreover, the capability of relax the muscle prior to muscle stretch (spastic dystonia) was also investigated. Results A tonic stretch reflex was evoked in all the enrolled patients. 73% of the patients were able to relax their rectus femoris muscle prior to stretch (spasticity). In the overwhelming majority of these patients, the tonic stretch reflex decreased during repeated stretches. In the remaining 27% of the subjects, the muscle was tonically activated prior to muscle stretch (spastic dystonia). In the patients in whom spastic dystonia progressively increased over the subsequent stretches (50% of the subjects with spastic dystonia), the habituation of the reflex was replaced by a progressive reflex facilitation. Discussion This study shows for the first time that velocity-dependent hypertonia can be caused by two distinct phenomena: spasticity and spastic dystonia. The habituation of the tonic stretch reflex, which is a typical feature of spasticity, is replaced by a reflex facilitation in the half of the subject with spastic dystonia. These preliminary findings suggest that differentiating the two types of velocity-dependent muscle hypertonia (spasticity and spastic dystonia) could be clinically relevant.

Objective:To investigate whether the correlation of age and sex with the risk of recurrence and death seen in patients with previous ischemic stroke is also evident in patients with embolic stroke of undetermined source (ESUS).Methods:We pooled datasets of 11 stroke registries from Europe and America. ESUS was defined according to the Cryptogenic Stroke/ESUS International Working Group. We performed Cox regression and Kaplan-Meier product limit analyses to investigate whether age (80 years) and sex were independently associated with the risk for ischemic stroke/TIA recurrence or death.Results:Ischemic stroke/TIA recurrences and deaths per 100 patient-years were 2.46 and 1.01 in patients 80 years old, 3.53 and 3.48 in women, and 4.49 and 3.98 in men, respectively. Female sex was not associated with increased risk for recurrent ischemic stroke/TIA (hazard ratio [HR] 1.15, 95% confidence interval [CI] 0.84–1.58) or death (HR 1.35, 95% CI 0.97–1.86). Compared with the group 80-year groups had higher 10-year cumulative probability of recurrent ischemic stroke/TIA (14.0%, 47.9%, and 37.0%, respectively, p < 0.001) and death (6.4%, 40.6%, and 100%, respectively, p < 0.001) and higher risk for recurrent ischemic stroke/TIA (HR 1.90, 95% CI 1.21–2.98 and HR 2.71, 95% CI 1.57–4.70, respectively) and death (HR 4.43, 95% CI 2.32–8.44 and HR 8.01, 95% CI 3.98–16.10, respectively).Conclusions:Age, but not sex, is a strong predictor of stroke recurrence and death in ESUS. The risk is ≈3- and 8-fold higher in patients >80 years compared with those

Background The optimal timing to administer non–vitamin K oral anticoagulants ( NOAC s) in patients with acute ischemic stroke and atrial fibrillation is unclear. This prospective observational multicenter study evaluated the rates of early recurrence and major bleeding (within 90 days) and their timing in patients with acute ischemic stroke and atrial fibrillation who received NOAC s for secondary prevention. Methods and Results Recurrence was defined as the composite of ischemic stroke, transient ischemic attack, and symptomatic systemic embolism, and major bleeding was defined as symptomatic cerebral and major extracranial bleeding. For the analysis, 1127 patients were eligible: 381 (33.8%) were treated with dabigatran, 366 (32.5%) with rivaroxaban, and 380 (33.7%) with apixaban. Patients who received dabigatran were younger and had lower admission National Institutes of Health Stroke Scale score and less commonly had a CHA 2 DS 2 ‐ VAS c score >4 and less reduced renal function. Thirty‐two patients (2.8%) had early recurrence, and 27 (2.4%) had major bleeding. The rates of early recurrence and major bleeding were, respectively, 1.8% and 0.5% in patients receiving dabigatran, 1.6% and 2.5% in those receiving rivaroxaban, and 4.0% and 2.9% in those receiving apixaban. Patients who initiated NOAC s within 2 days after acute stroke had a composite rate of recurrence and major bleeding of 12.4%; composite rates were 2.1% for those who initiated NOACs between 3 and 14 days and 9.1% for those who initiated >14 days after acute stroke. Conclusions In patients with acute ischemic stroke and atrial fibrillation, treatment with NOAC s was associated with a combined 5% rate of ischemic embolic recurrence and severe bleeding within 90 days.

Background and Purposes— This study was designed to derive and validate a score to predict early ischemic events and major bleedings after an acute ischemic stroke in patients with atrial fibrillation. Methods— The derivation cohort consisted of 854 patients with acute ischemic stroke and atrial fibrillation included in prospective series between January 2012 and March 2014. Older age (hazard ratio 1.06 for each additional year; 95% confidence interval, 1.00–1.11) and severe atrial enlargement (hazard ratio, 2.05; 95% confidence interval, 1.08–2.87) were predictors for ischemic outcome events (stroke, transient ischemic attack, and systemic embolism) at 90 days from acute stroke. Small lesions (≤1.5 cm) were inversely correlated with both major bleeding (hazard ratio, 0.39; P =0.03) and ischemic outcome events (hazard ratio, 0.55; 95% confidence interval, 0.30–1.00). We assigned to age ≥80 years 2 points and between 70 and 79 years 1 point; ischemic index lesion >1.5 cm, 1 point; severe atrial enlargement, 1 point (ALESSA score). A logistic regression with the receiver-operating characteristic graph procedure (C statistic) showed an area under the curve of 0.697 (0.632–0.763; P =0.0001) for ischemic outcome events and 0.585 (0.493–0.678; P =0.10) for major bleedings. Results— The validation cohort consisted of 994 patients included in prospective series between April 2014 and June 2016. Logistic regression with the receiver-operating characteristic graph procedure showed an area under the curve of 0.646 (0.529–0.763; P =0.009) for ischemic outcome events and 0.407 (0.275–0.540; P =0.14) for hemorrhagic outcome events. Conclusions— In acute stroke patients with atrial fibrillation, high ALESSA scores were associated with a high risk of ischemic events but not of major bleedings.

Background and Purpose— The risk of stroke recurrence in patients with Embolic Stroke of Undetermined Source (ESUS) is high, and the optimal antithrombotic strategy for secondary prevention is unclear. We investigated whether congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, and stroke or transient ischemic attack (TIA; CHADS 2 ) and CHA 2 DS 2 -VASc scores can stratify the long-term risk of ischemic stroke/TIA recurrence and death in ESUS. Methods— We pooled data sets of 11 stroke registries from Europe and America. ESUS was defined according to the Cryptogenic Stroke/ESUS International Working Group. Cox regression analyses were performed to investigate if prestroke CHADS 2 and congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, stroke or TIA, vascular disease, age 65–74 years, sex category (CHA 2 DS 2 -VASc) scores were independently associated with the risk of ischemic stroke/TIA recurrence or death. The Kaplan–Meier product limit method was used to estimate the cumulative probability of ischemic stroke/TIA recurrence and death in different strata of the CHADS 2 and CHA 2 DS 2 -VASc scores. Results— One hundred fifty-nine (5.6% per year) ischemic stroke/TIA recurrences and 148 (5.2% per year) deaths occurred in 1095 patients (median age, 68 years) followed-up for a median of 31 months. Compared with CHADS 2 score 0, patients with CHADS 2 score 1 and CHADS 2 score >1 had higher risk of ischemic stroke/TIA recurrence (hazard ratio [HR], 2.38; 95% confidence interval [CI], 1.41–4.00 and HR, 2.72; 95% CI, 1.68–4.40, respectively) and death (HR, 3.58; 95% CI, 1.80–7.12, and HR, 5.45; 95% CI, 2.86–10.40, respectively). Compared with low-risk CHA 2 DS 2 -VASc score, patients with high-risk CHA 2 DS 2 -VASc score had higher risk of ischemic stroke/TIA recurrence (HR, 3.35; 95% CI, 1.94–5.80) and death (HR, 13.0; 95% CI, 4.7–35.4). Conclusions— The risk of recurrent ischemic stroke/TIA and death in ESUS is reliably stratified by CHADS 2 and CHA 2 DS 2 -VASc scores. Compared with the low-risk group, patients in the high-risk CHA 2 DS 2 -VASc group have much higher risk of ischemic stroke recurrence/TIA and death, approximately 3-fold and 13-fold, respectively.

Background The monoclonal antibody natalizumab (NTZ) is a highly effective treatment for patients with multiple sclerosis (MS). However, this drug is associated with increased risk of developing Progressive Multifocal Leukoencephalopathy (PML), an opportunistic infection of central nervous system (CNS) caused by the John Cunningham polyomavirus (JCV). Objective To describe the 12-month clinical course of 39 patients with MS (28 women, 11 men) who developed NTZ-related PML after a mean exposure of 39 infusions. Methods An Italian independent collaborative repository initiative collected and analyzed socio-demographic, clinical, magnetic resonance imaging (MRI) data and number of JCV-DNA copies detected on cerebrospinal fluid (CSF) samples of patients diagnosed as affected by NTZ-related PML. The evolution of disability, measured by the Expanded Disability Status Scale, was assessed at NTZ start, at PML diagnosis and after 2, 6 and 12 months from PML diagnosis. The effect of clinical and paraclinical characteristics at PML diagnosis on the final outcome was also investigated. Results Ten patients (25.6%) were diagnosed before 24 NTZ infusions. In six cases (15.4%) the PML suspect was made on the basis of highly suggestive MRI findings in absence of any detectable change of clinical conditions (asymptomatic PML). In patients with symptomatic PML, the diagnosis was quicker for those who presented with cognitive symptoms (n = 12) rather than for those with other neurological pictures (n = 21) (p = 0.003). Three patients (7.7%) died during the 12-month observation period, resulting in a survival rate of 92.3%. Asymptomatic PML, more localized brain involvement and gadolinium-enhancement detected at MRI, as well as lower viral load were associated with a better disability outcome (p-values

[This corrects the article on p. e377 in vol. 4, PMID: 28804745.].

To verify whether scanning laser polarimeter with the new variable corneal compensation algorithm (GDx VCC) and scanning laser ophthalmoscopy (Heidelberg Retina Tomograph (HRT)) allow measuring retinal ganglion cell loss in patients with multiple sclerosis (MS).We enrolled 23 MS patients with a history of previous demyelinating monocular optic neuritis. Examination included visual evoked potentials (VEPs), scanning laser ophthalmoscopy, and scanning laser polarimeter. HRT was performed to assess optic nerve head (ONH) shape, while GDx VCC was used to evaluate the retinal nerve fibre layer thickness (RNFLt) around the ONH. Statistical analysis was performed comparing results obtained for each eye with the available normative database and with the unaffected fellow eye.When the affected eye group was compared to the fellow-eye group, a significant (P0.05) difference was found for few GDx VCC parameters. In contrast, no significant correlation was observed between clinical assessment and imaging techniques when the normal database of HRT and GDx VCC was used. A significant association was observed between VEP latency and some GDx VCC parameters.Our results suggested that scanning laser polarimetry could detect loss of ganglion cells following demyelinating optic neuritis, but further studies are needed.

Background: Many international guidelines address appropriateness, prescribing variability and drug-related expenditure in primary dyspepsia management. Aims: To evaluate the impact on general practitioner (GP) practice and healthcare costs of a participatory intervention to modify primary dyspepsia and Helicobacter pylori (Hp) infection management, by standardised implementation of an international guideline in the local setting, through a prospective, controlled before-and-after study. Methods: Primary dyspepsia management was monitored in the Local Health District of Padua; 63 of all 354 local GPs (total patient population: 82,284) took part in a primary-care improvement programme. Measured variables were: mean prescribed gastroscopies/1,000 registered patients, mean expenditure/1,000 registered patients for antisecretories (H2 blockers) and proton pump inhibitors (PPIs), inter-GP prescribing variability and adherence to guidelines, analysed through prospectively filled-out reports on GP consultations for dyspepsia. A 3-month pre-survey period was compared with a 6-month intervention period following implementation of an agreed guideline. Results: Compared to non-participating GPs, intervention yielded a 30 and 26.4% reduction in H2-blocker and PPI expenditure, respectively. Application of the guideline led to an upward trend in endoscopy prescriptions, coupled with a 7% increase in appropriate referrals. Intra-group variability marginally decreased; guideline compliance rose slightly. Conclusions: Participatory intervention can reduce prescribing variability among GPs and inappropriate esophagogastroduodenoscopies, lowering related costs. Results may not have been spectacular, but in view of the number of patients involved, they may have an important impact on Local Health District expenditure.

Michele Fornaro,1 Fabio Bandini,2 Luca Cestari,3 Christian Cordano,4 Carla Ogliastro,4 Claudio Albano,4 Domenico De Berardis,5 Matteo Martino,6 Andrea Escelsior,6 Giulio Rocchi,6 Pantaleo Fornaro,6 Concetta De Pasquale11Department of Educative Science, University of Catania, Catania, Italy; 2Department of Neurology, San Paolo Hospital, Savona, Italy; 3Department of Ophthalmology, University of Pisa, Pisa, Italy; 4Department of Neurosciences, Ophthalmology and Genetics – Section of Neurology, University of Genoa, Genoa, Italy; 5National Health Service, Department of Mental Health, Psychiatric Service of Diagnosis and Treatment, Hospital G. Mazzini, ASL 4, Teramo, Italy; 6Department of Neurosciences, Ophthalmology and Genetics – Section of Psychiatry, University of Genoa, Genoa, ItalyBackground: Agomelatine, the first melatonergic antidepressant, has been postulated to enhance the dopaminergic activity at the central nervous system by 5-hydroxytryptamine receptor type 2C (5-HT2C) antagonism, yet the impact of melatonergic agonism on this pathway is unclear. Previous studies employing simplified, yet reliable, proxy (retinal) measures of the central nervous system dopaminergic activity, namely the standard electroretinogram (ERG) technique, suggested a reduction of the dopaminergic activity of the main ERG parameter, the b-wave, by pure melatonin, notably a hormone devoid of any antidepressant activity. Therefore, the antidepressant effects of the melatonergic antidepressant drug agomelatine should be reflected by a differential b-wave trend at ERG versus the effect exerted by pure melatonin, which was eventually found to be due to a contrasting effect on central dopaminergic transmission between the two drugs.Objective and methods: The aim of the present preliminary ERG study carried out on healthy volunteers (n=23) receiving agomelatine was to explore the impact of this antidepressant drug on b-wave amplitude and latency of cones in daylight conditions using standard ERG.Results: As postulated, agomelatine induced an enhancement of retinal dopaminergic activity, in contrast to what has been previously documented for melatonin.Conclusion: Given the limits of this explorative study, especially the lack of a control group and that of a luminance response function to measure retinal sensitivity, further studies in clinical samples are recommended to allow more tenable conclusions about the potential role of ERG in discriminating between5-HT antagonism and melatonergic (MT) agonism in relationship to the claimed antidepressant effect of agomelatine.Keywords: electroretinogram, ERG, dopamine,5-HT2C

The previously unrecognised association of myoclonus in two patients with LHON with the 11778/ND4 pathogenic mutation is described. EEG failed to disclose epileptic figures, and a back averaging study suggested that myoclonus was cortical in origin in both patients.

The aim of this observational study was to assess the efficacy of tetrahydrocannabinol-cannabidiol oromucosal spray (THC:CBD, Sativex) on spasticity using the stretch reflex in subjects with multiple sclerosis (MS). Numeric rating scale (NRS) for spasticity, modified Ashworth scale (MAS) and the stretch reflex were assessed before and during treatment in 57 MS patients with spasticity eligible for THC:CBD treatment. A significant reduction of stretch reflex amplitude, as well as significant reductions of NRS and MAS scores were observed. There was a low concordance between the three measures (stretch reflex, NRS and MAS), likely related to the different aspects of muscle hypertonia assessed. Stretch reflex responders were taking a significantly higher number of puffs, while no differences were found in the responders by the other scales, suggesting that higher dosage would add benefit if tolerated. The present study confirms the efficacy of cannabinoids in reducing spasticity in patients with MS, suggesting a higher sensitivity and specificity of the stretch reflex compared to other measures. As an objective and quantitative measure of spasticity, the stretch reflex is particularly useful to assess the effects of cannabinoids on spinal excitability and may have a role in future pharmacological studies.

The risk of progressive multifocal leukoencephalopathy (PML) in patients treated with natalizumab for multiple sclerosis (MS) is a serious concern. The presence of anti-JC virus antibodies is a risk factor for PML development, but 2.5 % of the patients result falsely-negative, while the prognostic relevance of testing JCV-DNA in biological fluids of treated patients is debated. Aim of this work was to evaluate the utility of testing JCV-DNA, together with anti-JCV antibodies, in biological samples of treated patients as a tool for PML risk stratification. 126 subjects from 5 MS Centers in Italy were included in the study. We performed a cross-sectional study in 63 patients testing JCV-DNA in blood, peripheral blood cells and urine. We longitudinally assessed the presence of JCV-DNA in a cohort of 33 subjects, one of which developed PML. We could test retrospectively serum samples from another PML case occurred during natalizumab therapy. Anti-JCV antibodies and urinary JCV-DNA were both tested in 73 patients. No changes in JCV-DNA status occurred during natalizumab treatment. The subject who developed PML in the longitudinal cohort had detectable JCV-DNA in urine at all time-points while serum or blood from both PML patients were always negative before the onset of disease and, in one case, after. Four subjects with JCV-DNA in urine and undetectable anti-JCV antibodies were retested for anti-JCV antibodies and three out of four resulted positive. In conclusion, testing JCV-DNA in urine is complementary to testing anti-JCV antibodies in identifying patients at risk of PML.

Neurosyphilis is still a significant medical problem in developing countries and syphilitic ocular manifestations are often not diagnosed due to the lack of typical characteristics. We describe the case of a 59-year-old homosexual man with a 1-month history of decreased vision acuity in his left eye who was diagnosed with neurosyphilis and received treatment with intravenous penicillin G (16 million units in divided daily doses), with great improvement of visual acuity and CSF examination findings. The interest of this case is not only represented by the unusually early ocular involvement, but also by the rapid evolution of the disease into the secondary stage in a man who had had one at-risk homosexual relationship only 3 months before the onset symptoms. We also support the view that the presence of ocular involvement in syphilitic patients is suggestive of involvement of the CNS and should be considered synonymous with neurosyphilis.

Continuous recording of Visual Evoked Potentials (VEPs) and functional Magnetic Resonance Imaging (fMRI) exploits the VEPs high temporal resolution and the fMRI high spatial resolution. In this work, we present a new method of continuous VEPs/fMRI recording to study visual function in seven normal subjects. Our real-time artifact filtering is characterized by a procedure based on an analytical study of echo-planar imaging (EPI) sequence parameters related electro-encephalogram (EEG)-artifact shapes. The magnetic field artifacts were minimized by using a dedicated amagnetic device and by a subtraction algorithm that takes into account the EPI sequence parameters. No significant decrease in signal-to-noise ratio was observed in case of EEG recording simultaneously with MR acquisition; similarly, transient and steady-state VEPs parameters were comparable during fMRI acquisition and in the off-phase of fMRI recording. We also applied this method to one patient with optic neuritis, and, compared with controls, found different results. We suggest that our technique can be reliably used to investigate the function of human visual cortex and properly correlate the electrophysiological and functional neuroimaging related changes.

We describe two patients with Parkinson's disease (PD) who developed clinical criteria of pathological gambling addiction in the setting of increased dopamine replacement therapy (levodopa and dopamine agonist medications). The second patient showed also signs of dopamine dysregulation syndrome, with an addiction to dopaminergic medication. Neither patients responded to the standard therapy for gambling behavior, but dramatically improved after bilateral subthalamic nucleus (STN) deep brain stimulation (DBS) and early postoperative withdrawal of dopaminergic therapy. The possible therapeutic role of subthalamic nucleus deep brain stimulation (STN-DBS) on such a disabling behavior needs to be investigated prospectively.

Acquired nystagmus occurs frequently in patients with multiple sclerosis and is often the cause of illusory motion of the environment (oscillopsia), and blurring of vision. Based primarily on the beneficial effect of gabapentin on acquired pendular nystagmus (APN), a GABAergic mechanism in controlling nystagmus has been hypothesised. If increasing GABA concentrations in the CNS are critical for the treatment of nystagmus, then a selective GABAergic drug should be highly successful. However, as gabapentin is not a selective GABAergic agent, vigabatrin, a "pure" GABAergic medication, and gabapentin, were compared in a single blind cross over trial in eight patients with definite multiple sclerosis. Patients were randomly assigned to begin with gabapentin (1200 mg daily) or vigabatrin (2000 mg daily). Neuro-ophthalmological and electro-oculographic (EOG) evaluations were performed four and three times, respectively. Treatment efficacy was based on improving visual acuity and EOG indices (amplitude or frequency of nystagmus, or both) by at least 50% of pretreatment values. Three out of eight patients dropped out due to adverse effects. In the remaining five patients gabapentin improved symptomatic pendular or gaze evoked jerk nystagmus in four. Three patients decided to continue gabapentin therapy. Importantly, vigabatrin proved useful in only one out of five patients, suggesting that gabapentin effectiveness may be related to additional non-GABAergic mechanisms of action. Interaction with cerebral glutamate transmission by inhibition of NMDA receptor might be an alternative hypothesis for the therapeutic action of gabapentin.

Hemifacial spasm, a life-long condition characterized by involuntary unilateral contractions of the facial muscles, is a disabling disorder often resulting in patient irritation and social embarassment. Its probable etiology is neurovascular compression of the facial nerve at its root exit zone. The current medical treatment consists of either baclofen or anticonvulsant drugs, with limitation due to side effects or low efficacy. In recent years botulinum toxin injection and microvascular decompression of the facial nerve have been shown to be highly successful. However, both procedures share some complications and require special techniques. We present 5 patients affected by hemifacial spasm who responded well to the novel anticonvulsant drug gabapentin. Gabapentin was administered at a dose ranging from 900 to 1,600 mg daily, with rapid and clear improvement of spasms and absence of any remarkable adverse effects. Our findings suggest that gabapentin may be an effective treatment for patients with hemifacial spasm with a very good ratio of therapeutic effects to side effects when compared with other drugs currently used.

A 52-year-old patient developed an eye movement disorder first resembling a left internuclear ophthalmoplegia and subsequently a "one-and-a-half syndrome" as the presenting symptoms of ocular myasthenia gravis. No accompanying myasthenic features were present except for the fluctuation in the amplitude of dissociated nystagmus. This patient shows that an oculomotor disorder considered a typical pontine lesion may instead be caused by myasthenia gravis, even in the absence of other clinical and electrophysiologic features of neuromuscular deficit.