Standard operating procedure for idarucizumab reversal of dabigatran anticoagulation in ischemic and hemorrhagic stroke.

BACKGROUND: Reversal of dabigatran anticoagulation activity using idarucizumab is indicated for individuals suffering from life-threatening or non-controlled bleeding and those in need of urgent operation or invasive intervention. Through idarucizumab application patients with acute ischemic stroke (AIS) may regain eligibility for intravenous thrombolysis (IVT) and patients with intracranial hemorrhage (ICH) may show less hematoma growth, thereby improving functional outcome in both groups. However, evidence is limited, and international guidelines contain heterogenous recommendations substantiating the need for the review of evidence and standard operating procedures (SOPs). MATERIALS AND METHODS: For our review, we searched PubMed for all published articles using idarucizumab and ischemic stroke/hemorrhagic stroke as keywords. Illustrating two clinical cases, we discuss the current literature and national guidelines. RESULTS: Our search retrieved 47 articles of which 8 case studies or series made public after 2020/2021, 28 reviews, 1 leading opinion article, 1 editorial and 10 guidelines. Summarizing the available evidence, idarucizumab application in stroke patients taking dabigatran results in decreased mortality rate and improved functional outcomes. Based on two clinical cases from our departments, we provide SOPs on how to deal with eligible patients in a time-efficient way, thereby reducing door-to-needle times in AIS and preventing early deterioration in ICH patients. CONCLUSION: Reversal of dabigatran with idarucizumab in stroke patients appears easy to manage, safe and beneficial. The SOPs aim to reassure stroke physicians to include dabigatran reversal into their daily clinical routine when dealing with patients presenting with ischemic or hemorrhagic stroke under dabigatran therapy.

Brain Natriuretic Peptide and Discovery of Atrial Fibrillation After Stroke: A Subanalysis of the Find-AFRANDOMISED Trial.

Background and Purpose- Diagnosing paroxysmal atrial fibrillation (pAF) can be challenging after acute ischemic stroke. Enhanced and prolonged Holter-ECG monitoring (EPM) improves the detection rate but is not feasible for all patients. We hypothesized that brain natriuretic peptide (BNP) may help to identify patients with stroke at high risk for pAF to select patients for EPM more effectively. Methods- Patients with acute cerebral ischemia ≥60 years presenting in sinus rhythm and without history of AF were included into a prospective, randomized multicenter study to receive either EPM (3× 10-day Holter-ECG) or usual stroke care diagnostic work-up. BNP plasma levels were measured on randomization and 3 months thereafter. Levels were compared between patients with and without pAF detected by means of EPM or usual care. Furthermore, the number needed to screen for EPM depending on BNP cut offs was calculated. Results- A total of 398 patients were analyzed. In 373 patients (93.7%), BNP was measured at baseline and in 275 patients (69.1%) after 3 months. pAF was found in 27 patients by means of EPM and in 9 patients by means of usual care (P=0.002). Median BNP was higher in patients with pAF as compared to patients without AF in both study arms at baseline (57.8 versus 28.3 pg/mL in the EPM arm, P=0.0003; 46.2 versus 27.7 pg/mL, P=0.28 in the control arm) and after 3 months (74.9 versus 31.3 pg/mL, P=0.012 in the EPM arm, 99.3 versus 26.3 pg/mL, P=0.02 in the control arm). Applying a cut off of 100 pg/mL, the number needed to screen was reduced from 18 by usual care to 3 by EPM. Conclusions- BNP measured early after ischemic stroke identifies a subgroup of patients with stroke at increased risk for AF, in whom EPM is particularly efficacious. Registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT01855035.

CDK5 protects from caspase-induced Ataxin-3 cleavage and neurodegeneration.

Spinocerebellar ataxia type 3 (SCA3) is one of at least nine inherited neurodegenerative diseases caused by an expansion of a polyglutamine tract within corresponding disease-specific proteins. In case of SCA3, mutation of Ataxin-3 results in aggregation of misfolded protein, formation of intranuclear as well as cytosolic inclusion bodies and cell death in distinct neuronal populations. Since cyclin-dependent kinase-5 (CDK5) has been shown to exert beneficial effects on aggregate formation and cell death in various polyglutamine diseases, we tested its therapeutic potential for SCA3. Our data show increased caspase-dependent Ataxin-3 cleavage, aggregation, and neurodegeneration in the absence of sufficient CDK5 activity. This disease-propagating effect could be reversed by mutation of the caspase cleavage site in Ataxin-3. Moreover, reduction of CDK5 expression levels by RNAi in vivo enhances SCA3 toxicity as assayed in a Drosophila model for SCA3. In summary, we present CDK5 as a potent neuroprotectant, regulating cleavage and thereby toxicity of Ataxin-3 and other polyglutamine proteins. We propose that increased caspase-dependent cleavage of mutated Ataxin-3, because of missing CDK5 shielding, leads to aggregation and cell death. Moreover, reduction of CDK5 expression levels by RNAi in vivo enhances SCA3 toxicity as assayed in a Drosophila model for SCA3. We think that CDK5 functions as a shield against cleavage-induced toxification and thereby is an interesting target for therapeutic intervention in polyQ disease in general.

Finding atrial fibrillation in stroke patients: Randomized evaluation of enhanced and prolonged Holter monitoring--Find-AF(RANDOMISED) --rationale and design.

BACKGROUND: Detecting paroxysmal atrial fibrillation (AF) in patients with ischemic strokes presenting in sinus rhythm is challenging because episodes are often short, occur randomly, and are frequently asymptomatic. If AF is detected, recurrent thromboembolism can be prevented efficiently by oral anticoagulation. Numerous uncontrolled studies using various electrocardiogram (ECG) devices have established that prolonged ECG monitoring increases the yield of AF detection, but most established procedures are time-consuming and costly. The few randomized trials are mostly limited to cryptogenic strokes. The optimal method, duration, and patient selection remain unclear. Repeated prolonged continuous Holter ECG monitoring to detect paroxysmal AF within an unspecific stroke population may prove to be a widely applicable, effective secondary prevention strategy. STUDY DESIGN: Find-AFRANDOMISED is a randomized and controlled prospective multicenter trial. Four hundred patients 60 years or older with manifest (symptoms ≥24 hours or acute computed tomography/magnetic resonance imaging lesion) and acute (symptoms ≤7 days) ischemic strokes will be included at 4 certified stroke centers in Germany. Those with previously diagnosed AF/flutter, indications/contraindications for oral anticoagulation, or obvious causative blood vessel pathologies will be excluded. Patients will be randomized 1:1 to either enhanced and prolonged Holter ECG monitoring (10 days at baseline and after 3 and 6 months) or standard of care (≥24-hour continuous ECG monitoring, according to current stroke guidelines). All patients will be followed up for at least 12 months. OUTCOMES: The primary end point is newly detected AF (≥30 seconds) after 6 months, confirmed by an independent adjudication committee. We plan to complete recruitment in autumn 2014. First results can be expected by spring 2016.

Andexanet Alfa: What We Have Learned from Clinical Trials and Real-World Data.

Andexanet alfa is a specific reversal agent for factor Xa inhibitors with immediate reversal of their anticoagulant effect. Andexanet alfa is currently approved for use in patients treated with rivaroxaban and apixaban who have life-threatening or uncontrolled bleeding. New data from both controlled clinical trials and real-world experience are continuously being published, providing greater insight into the clinical characteristics of the drug, such as efficacy and safety. It is worth considering that andexanet alfa could be of benefit in a variety of different clinical scenarios where patients receiving treatment with apixaban and rivaroxaban (and endoxaban) have life-threatening conditions. These different clinical scenarios, which range from pre-treatment of urgent surgery, especially neurosurgical interventions, and concomitant use of andexanet alfa and prothrombin complex concentrate to onset of bleeding more than 6 h prior to admission, should be clarified as well as the issue of "low/high" dose of andexanet alfa and the need for baseline anti-Xa inhibitor levels measured by point-of-care testing. Finally, management of patients at high risk of thrombosis or recent arterial/venous thrombotic events needs to be further explored. In this current opinion, we address these urgent questions in the light of recent literature and clinical trial data.

Idarucizumab in dabigatran-treated patients with acute stroke: a review and clinical update.

Idarucizumab is an antibody fragment specific for the immediate reversal of dabigatran anticoagulation effects. The use of idarucizumab is approved for dabigatran-treated patients suffering from life-threatening or uncontrolled bleeding and those in need of urgent surgery or invasive procedures. Data from randomized controlled clinical trials and real-world experience provide reassuring evidence about the efficacy and safety of idarucizmab use in patients with acute stroke. In this narrative review, we summarize the available real-world evidence and discuss the relevance and importance of idarucizumab treatment in acute stroke patients in everyday clinical practice. In addition, we also discuss special issues like prothrombin complex concentrate application as an alternative to idarucizumab, its application before endovascular therapy, sensitivity of thrombi to lysis, and necessary laboratory examinations.

Acute adverse events of Sars-CoV2 vaccines: Experiences from a health care worker vaccination campaign in two municipal hospitals in northwest Germany.

Vaccination is considered the best measure to overcome the Sars-Cov2 pandemic. However, changing national recommendations on sequence and time frame necessitate the collection of real-word data on adverse events of Sars-CoV2 vaccination protocols outside of pivotal trials. We report results from a survey on the adverse events and the operational consequences of a Sars-CoV2 vaccination campaign with partly mixed vaccination protocol as well as booster vaccination. While the spectrum of adverse effects in our cohort appeared to be similar to pivotal studies, there were substantial differences in both frequency and distribution with only 3 out of 10 participants staying symptom-free. In over 26% of vaccinees symptoms were so severe, that they stayed at home with mean days on sick leave being 1.5 per person using mixed vaccination protocol. Being aware, that these results might partially be attributable to nocebo effects they are of importance for future vaccination campaigns.

Andexanet Alfa to Reverse the Effect of Factor Xa Inhibitors in Intracranial Hemorrhage.

Andexanet alfa (AA) is a recombinant factor Xa competing for binding with factor Xa inhibitors, thereby reversing their anticoagulation effects. Since 2019, it has been approved for individuals under apixaban or rivaroxaban therapy suffering from life-threatening or uncontrolled bleeding. Apart from the pivotal trial, real-world data on the use of AA in daily clinics are scarce. We reviewed the current literature on patients with intracranial hemorrhage (ICH) and summarized the available evidence regarding several outcome parameters. On the basis of this evidence, we provide a standard operating procedure (SOP) for routine AA application. We searched PubMed and additional databases through 18 January 2023 for case reports, case series, studies, reviews, and guidelines. Data on hemostatic efficacy, in-hospital mortality, and thrombotic events were pooled and compared with the pivotal trial data. While hemostatic efficacy in world-wide clinical routine seems to be comparable to the pivotal trial, thrombotic events and in-hospital mortality appear to be substantially higher. Various confounding factors responsible for this finding such as exclusion and inclusion criteria resulting in a highly selected patient cohort within the controlled clinical trial have to be considered. The SOP provided should support physicians in patient selection for AA treatment as well as facilitate routine use and dosing. This review underlines the urgent need for more data from randomized trials to appreciate the benefit and safety profile of AA. Meanwhile, this SOP should help to improve frequency and quality of AA use in patients suffering from ICH while on apixaban or rivaroxaban treatment.

Treatment of Acute Ischaemic Stroke and Concomitant Multiple Arterial Splanchnic Thromboses in a Patient with Immune Thrombocytopenia on Thrombopoietin Agonist: A Case Report.

Immune thrombocytopenia (ITP) is an autoimmune blood disorder characterised by isolated severe thrombocytopenia. Arterial thrombotic events, such as acute ischaemic stroke (AIS), are rare complications. A 56-year-old woman with chronic ITP on eltrombopag and dexamethasone therapy presented to the emergency department due to AIS in the vertebrobasilar territory, and lower abdominal pain. The computed tomography (CT) scan of the head was unremarkable, whereas CT angiography revealed left vertebral artery occlusion. As the platelet count was sufficient, intravenous thrombolysis (IVT) was initiated. However, after 15 min, an anaphylactic reaction occurred, which was appropriately solved. Although the IVT was prematurely stopped, the NIHSS score improved from 7 to 2, and the follow-up head CT scan remained unremarkable. CT angiography of the thoracoabdominal aorta revealed multiple thrombi in the infrarenal aorta, inferior mesenteric artery (IMA), and left renal artery. The abdominal pain subsided after IVT, but recurred within 24 h. Repeated CT angiography showed ischaemia of the descending colon, with persistent IMA occlusion. After the hemicolectomy condition stabilised. Discrete left-sided ataxia and impaired sensation were the only neurological sequelae. We found two articles reporting only three patients with ITP who suffered AIS and were treated with IVT. A favourable outcome was observed in two cases, while one patient suffered an intracranial haemorrhage (ICH) and died. A review of AIS cases with undefined thrombocytopenia treated with IVT reported ICH in up to 6.8% of patients. Our case suggests that IVT for AIS may be effective in patients with ITP. Further data are needed to better clarify this issue.

Intravenous Thrombolysis in Patients With Ischemic Stroke and Recent Ingestion of Direct Oral Anticoagulants.

Importance: International guidelines recommend avoiding intravenous thrombolysis (IVT) in patients with ischemic stroke who have a recent intake of a direct oral anticoagulant (DOAC). Objective: To determine the risk of symptomatic intracranial hemorrhage (sICH) associated with use of IVT in patients with recent DOAC ingestion. Design, Setting, and Participants: This international, multicenter, retrospective cohort study included 64 primary and comprehensive stroke centers across Europe, Asia, Australia, and New Zealand. Consecutive adult patients with ischemic stroke who received IVT (both with and without thrombectomy) were included. Patients whose last known DOAC ingestion was more than 48 hours before stroke onset were excluded. A total of 832 patients with recent DOAC use were compared with 32 375 controls without recent DOAC use. Data were collected from January 2008 to December 2021. Exposures: Prior DOAC therapy (confirmed last ingestion within 48 hours prior to IVT) compared with no prior oral anticoagulation. Main Outcomes and Measures: The main outcome was sICH within 36 hours after IVT, defined as worsening of at least 4 points on the National Institutes of Health Stroke Scale and attributed to radiologically evident intracranial hemorrhage. Outcomes were compared according to different selection strategies (DOAC-level measurements, DOAC reversal treatment, IVT with neither DOAC-level measurement nor idarucizumab). The association of sICH with DOAC plasma levels and very recent ingestions was explored in sensitivity analyses. Results: Of 33 207 included patients, 14 458 (43.5%) were female, and the median (IQR) age was 73 (62-80) years. The median (IQR) National Institutes of Health Stroke Scale score was 9 (5-16). Of the 832 patients taking DOAC, 252 (30.3%) received DOAC reversal before IVT (all idarucizumab), 225 (27.0%) had DOAC-level measurements, and 355 (42.7%) received IVT without measuring DOAC plasma levels or reversal treatment. The unadjusted rate of sICH was 2.5% (95% CI, 1.6-3.8) in patients taking DOACs compared with 4.1% (95% CI, 3.9-4.4) in control patients using no anticoagulants. Recent DOAC ingestion was associated with lower odds of sICH after IVT compared with no anticoagulation (adjusted odds ratio, 0.57; 95% CI, 0.36-0.92). This finding was consistent among the different selection strategies and in sensitivity analyses of patients with detectable plasma levels or very recent ingestion. Conclusions and Relevance: In this study, there was insufficient evidence of excess harm associated with off-label IVT in selected patients after ischemic stroke with recent DOAC ingestion.

A30P α-synuclein impairs dopaminergic fiber regeneration and interacts with L-DOPA replacement in MPTP-treated mice.

Parkinson's disease (PD) is the most common neurodegenerative movement disorder and is characterized by the loss of dopaminergic neurons from the substantia nigra pars compacta (SNpc). α-synuclein (αsyn) has been linked to the pathophysiology of PD, because of its mutations causing familial PD and its accumulation in brains of patients with familial and sporadic PD. Dopamine (DA) replacement is the most effective therapy for ameliorating the motor symptoms of PD; however, it remains controversial whether DA-replacement boosts regeneration in the dopaminergic system or accelerates disease progression and enhances neuronal loss. Here, we studied the effect of chronic L-DOPA treatment on dopaminergic neurons in wild-type (WT) and A30P αsyn transgenic mice after MPTP treatment. Acute MPTP intoxication induced degeneration of dopaminergic neurons in both WT and A30P αsyn transgenic mice. A strong regeneration of dopaminergic fibers at 90 days after MPTP was observed in WT mice. In contrast, regeneration was less pronounced in A30P αsyn mice. Chronic L-DOPA treatment after MPTP intoxication did not only reduce the regeneration of nigrostriatal fibers but also led to an increased apoptotic gene-expression profile in the SNpc and to a decline of TH-positive neurons in A30P αsyn. Our findings reveal that the presence of A30P αsyn inhibits the regeneration of nigrostriatal dopaminergic fibers, and that L-DOPA treatment might interact with the pathogenesis in PD.

SOP: thrombolysis in ischemic stroke under oral anticoagulation therapy.

INTRODUCTION: Based on demographical trends and the expected worldwide increase in the number of individuals with atrial fibrillation, the rate of patients who are on oral anticoagulation therapy for secondary prevention of stroke rises continuously. Despite correct drug intake and good adherence to the respective medication, recurrent ischemic stroke still occurs in ~ 3% of patients. The question how to deal with such patients with regard to intravenous thrombolysis with rt-PA within the 4.5 h time window is of great relevance for daily clinical routine. However, international guidelines can be considered heterogenous or do even lack recommendations on this topic especially in light of available reversal agents. Therefore, we provide this SOP. COMMENTS: Beyond the identification of acute stroke patients on oral anticoagulation therapy, the type of medication, time since last intake, renal function and laboratory exams as well as the availability of reversal agents have to be considered before rt-PA application and potential endovascular therapy. Treatment on a Stroke Unit or Neuro-ICU is certainly recommended in any of those patients. CONCLUSIONS: This standardized operating procedure was designed to guide stroke physicians through questions on eligibility for rt-PA treatment in patients with acute ischemic stroke who are on approved oral anticoagulation therapy thereby increasing the number of patients benefitting from thrombolysis and minimizing door-to-needle times.

Belly Dancer's Dyskinesia: 3 Cases of a Rare Entity.

Involuntary, undulating, or circular movements of abdominal wall muscles are a rare condition descriptively termed belly dancer syndrome or belly dancer's dyskinesia. Differential diagnoses range from cerebral, spinal, peripheral, hormonal/drug-induced effects to local or even unknown/idiopathic and functional/psychogenic causes. Thorough diagnostic work-up is mandatory and therapeutic options depend on etiology and include surgical approaches and symptomatic treatment. We present 3 cases of belly dancer's dyskinesia, in which differential diagnostic work-up did not uncover known etiologies for this movement disorder. Strikingly, 2 patients manifested vitamin B12 deficiency while 1 case showed values close to the lower limit of normal. While relevance of vitamin B12 levels remains elusive, all patients improved substantially following a combined therapeutic approach of clonazepam treatment and vitamin B12 supplementation.

Long-Term Follow-up of Enhanced Holter-Electrocardiography Monitoring in Acute Ischemic Stroke.

BACKGROUND AND PURPOSE: Prolonged electrocardiography (ECG)-monitoring in stroke patients improves the detection of paroxysmal atrial fibrillation (pAF). However, most randomized studies only had short follow-up. We aimed to provide 3-year follow-up data for AF detection and stroke recurrence risk. METHODS: We randomized 402 patients aged ≥60 years with acute ischemic strokes without AF to either enhanced and prolonged monitoring (EPM; 3×10-day Holter-ECG-monitoring) or standard-of-care (≥24 hours ECG-monitoring). The endpoint of the current analysis was AF within 36 months analyzed by intention to treat. Long-term follow-up was performed for 36 months. RESULTS: Two hundred and seventy-four patients (80%) participated in the extended follow-up (median duration of follow-up was 36 months [interquartile range, 12 to 36]). During the first 6 months, more AF was documented in the EPM arm compared to the control arm (13.5% vs. 5.1%; 95% confidence interval, 2.9% to 14.4%; P=0.004). During months 6 to 36, AF was less detected in the EPM intervention arm than in the control arm (2.0% vs. 7.3%; 95% confidence interval, 0.7% to 9.9%; P=0.028). Overall, the detection rate of AF within 36 months was numerically higher within the EPM group (15.0% vs. 11.1%, P=0.30). Numerically less patients in the EPM arm had recurrent ischemic strokes (5.5% vs. 9.1%, P=0.18), transient ischemic attacks (3.0% vs. 4.5%, P=0.44) or died (4.5% vs. 6.6%, P=0.37). CONCLUSIONS: Enhanced and prolonged ECG monitoring increased AF detection during the first six months, but there was significantly more clinical AF during months 6 to 36 observed in the usual-care arm. This suggests that EPM leads to an earlier detection of clinically relevant AF.

Transthoracic echocardiography to rule out paroxysmal atrial fibrillation as a cause of stroke or transient ischemic attack.

BACKGROUND AND PURPOSE: We assessed whether echocardiography can predict paroxysmal atrial fibrillation (PAF) in patients with cerebral ischemia presenting in sinus rhythm. METHODS: Within the prospective Find-AF cohort, 193 consecutive patients with cerebral ischemia and sinus rhythm on presentation had evaluation of echocardiographic parameters of left atrial size and function. PAF was diagnosed by 7-day Holter monitoring. RESULTS: In 26 patients with PAF, late diastolic Doppler (A) and tissue Doppler (a') velocities were lower whereas left atrial diameter, left atrial volume index (LAVI), LAVI/A, and LAVI/a' were larger (P<0.05 for all) than they were in 167 patients without PAF. In multivariate models A, a', LAVI/A, and LAVI/a' predicted the presence of PAF. Area under the receiver operating characteristic curve to diagnose PAF was highest for LAVI/a' (0.813 [0.738; 0.889]). A previously suggested cut-off of LAVI/a'<2.3 had 92% sensitivity, 55.8% specificity, and 98% negative predictive value for PAF. CONCLUSIONS: LAVI/a'<2.3 can effectively rule out PAF in patients with cerebral ischemia.

Health-related quality of life, anxiety and depression up to 12 months post-stroke: Influence of sex, age, stroke severity and atrial fibrillation - A longitudinal subanalysis of the Find-AFRANDOMISED trial.

BACKGROUND: Stroke can negatively impact the health-related quality of life (HRQoL). Anxiety or depression after stroke have been associated with poorer HRQoL, higher mortality and greater dependence in activities of daily living. We aimed to analyze HRQoL, anxiety and depressive symptoms in patients with and without atrial fibrillation (AF) up to 12 months post-stroke. METHODS: Find-AFRANDOMISED was a prospective, randomized multicenter study, which included 398 patients ≥60 years with acute cerebral ischemia. HRQoL data were collected using the 3-level EuroQol-5D (EQ-5D-3L) and Stroke Impact Scale (SIS-16). Anxiety and depressive symptoms were measured using the Hospital Anxiety and Depression Scale (HADS). The severity of stroke was measured using the modified Rankin Scale (mRS). RESULTS: In this study (mean age 72.7 ± 7.5 years, 40.2% females), there was a significant improvement in HRQoL using EQ-5D-3L after 3 months (ß = 0.37, p < .01), 6 months (ß = 0.43, p < .01) and 12 months (ß = 0.44, p < .01) post-stroke compared to baseline. HADS anxiety scores after 3 months (ß = -0.22, p < .01) and 12 months (ß = -0.28, p < .01) were significantly reduced. Older patients reported reduced HRQoL and more depressive symptoms. Females indicated lower HRQoL and more anxiety. mRS score at baseline was an independent predictor for HRQoL. There was a significant but small effect of AF on EQ-5D-3L and on HADS anxiety. CONCLUSIONS: Patients showed significant improvement in HRQoL and reduced anxiety after 3 and 12 months after stroke. We could demonstrate that the severity of stroke as well as sex and age impact long-term post-stroke HRQoL. CLINICAL TRIAL REGISTRATION: Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01855035.

Autoantibodies Against the Purkinje Cell Protein RGS8 in Paraneoplastic Cerebellar Syndrome.

OBJECTIVE: To describe the identification of regulator of G-protein signaling 8 (RGS8) as an autoantibody target in patients with cerebellar syndrome associated with lymphoma. METHODS: Sera of 4 patients with a very similar unclassified reactivity against cerebellar Purkinje cells were used in antigen identification experiments. Immunoprecipitations with cerebellar lysates followed by mass spectrometry identified the autoantigen, which was verified by recombinant immunofluorescence assay, immunoblot, and ELISA with the recombinant protein. RESULTS: The sera and CSF of 4 patients stained the Purkinje cells and molecular layer of the cerebellum. RGS8 was identified as the target antigen in all 4 sera. In a neutralization experiment, recombinant human RGS8 was able to neutralize the autoantibodies' tissue reaction. Patient sera and CSF showed a specific reactivity against recombinant RGS8 in ELISA and immunoblot, whereas no such reactivity was detectable in the controls. Clinical data were available for 2 of the 4 patients, remarkably both presented with cerebellar syndrome accompanied by B-cell lymphoma of the stomach (patient 1, 53 years) or Hodgkin lymphoma (patient 2, 74 years). CONCLUSION: Our results indicate that autoantibodies against the intracellular Purkinje cell protein RGS8 represent new markers for paraneoplastic cerebellar syndrome associated with lymphoma. CLASSIFICATION OF EVIDENCE: This study provided Class IV evidence that autoantibodies against the intracellular Purkinje cell protein RGS8 are associated with paraneoplastic cerebellar syndrome in lymphoma.

Enhanced detection of paroxysmal atrial fibrillation by early and prolonged continuous holter monitoring in patients with cerebral ischemia presenting in sinus rhythm.

BACKGROUND AND PURPOSE: Diagnosis of paroxysmal atrial fibrillation is difficult but highly relevant in patients presenting with cerebral ischemia yet free from atrial fibrillation on admission. Early initiation and prolongation of continuous Holter monitoring may improve diagnostic yield compared with the standard of care including a 24-hour Holter recording. METHODS: In the observational Find-AF trial (ISRCTN 46104198), consecutive patients presenting with symptoms of cerebral ischemia were included. Patients free from atrial fibrillation at presentation received 7-day Holter monitoring. RESULTS: Two hundred eighty-one patients were prospectively included. Forty-four (15.7%) had atrial fibrillation documented by routine electrocardiogram on admission. All remaining patients received Holter monitors at a median of 5.5 hours after presentation. In those 224 patients who received Holter monitors but had no previously known paroxysmal atrial fibrillation, the detection rate with early and prolonged (7 days) Holter monitoring (12.5%) was significantly higher than for any 24-hour (mean of 7 intervals: 4.8%, P = 0.015) or any 48-hour monitoring interval (mean of 6 intervals: 6.4%, P = 0.023). Of those 28 patients with new atrial fibrillation on Holter monitoring, 15 (6.7%) had been discharged without therapeutic anticoagulation after routine clinical care (ie, with data from 24-hour Holter monitoring only). Detection rates were 43.8% or 6.3% for short supraventricular runs of ≥ 10 beats or prolonged episodes (> 5 hours) of atrial fibrillation, respectively. Diagnostic yield appeared to be only slightly and not significantly increased during the first 3 days after the index event. CONCLUSIONS: Prolongation of Holter monitoring in patients with symptoms of cerebral ischemic events increases the rate of detection of paroxysmal atrial fibrillation up to Day 7, leading to a relevant change in therapy in a substantial number of patients. Early initiation of monitoring does not appear to be crucial. Hence, prolonged Holter monitoring (≥ 7 days) should be considered for all patients with unexplained cerebral ischemia.

Global Use of Idarucizumab in Clinical Practice: Outcomes of the RE-VECTO Surveillance Program.

Idarucizumab was approved for the reversal of dabigatran in 2015. We investigated whether postapproval usage patterns of idarucizumab in a real-world setting reflect those observed in the pivotal trials. No safety or efficacy data were collected in this medical record-based observational study. RE-VECTO, a global postapproval, international, surveillance program, involved hospital pharmacies in countries where idarucizumab was licensed and dispensed (August 2016-June 2018). Characteristics of sites prescribing idarucizumab and of eligible patients (≥ 18 years old and receiving idarucizumab regardless of prior oral anticoagulant use), as well as idarucizumab utilization data, were collected and analyzed descriptively. Sixty-one sites enrolled 359 patients. Most pharmacies (85.2%) were centralized, and the median idarucizumab units stocked per hospital was 2.0 (interquartile range, 1.0-3.0). Almost three-quarters of patients were elderly (74.9% aged > 70 years), and only four (1.1%) had received idarucizumab before. Nearly all patients were treated with dabigatran (97.5%). There was a low frequency of unapproved dabigatran dosage regimens (3.3%). Life-threatening or uncontrolled bleeding was the most frequent indication for idarucizumab (57.7%), followed by emergency surgery/urgent procedure (35.9%). Of the life-threatening bleeding events, the most frequent were gastrointestinal tract (44.4%) and intracranial (38.6%). Most patients (95.0%) were given the full dose of two vials (2 × 2.5 g) of idarucizumab initially, and very few (1.7%) received a second dose. Of those patients requiring emergency or scheduled/planned surgery/procedures, 25.5% underwent gastrointestinal and/or abdominal surgery/procedures. Real-world usage patterns of idarucizumab provide valuable insights into emergency reversal strategies. Off-label use was minimal.

Longitudinal optic neuritis-unrelated visual evoked potential changes in NMO spectrum disorders.

OBJECTIVE: To investigate if patients with neuromyelitis optica spectrum disorder (NMOSD) develop subclinical visual pathway impairment independent of acute attacks. METHODS: A total of 548 longitudinally assessed full-field visual evoked potentials (VEP) of 167 patients with NMOSD from 16 centers were retrospectively evaluated for changes of P100 latencies and P100-N140 amplitudes. Rates of change in latencies (RCL) and amplitudes (RCA) over time were analyzed for each individual eye using linear regression and compared using generalized estimating equation models. RESULTS: The rates of change in the absence of optic neuritis (ON) for minimal VEP intervals of ≥3 months between baseline and last follow-up were +1.951 ms/y (n = 101 eyes; SD = 6.274; p = 0.012) for the P100 latencies and -2.149 µV/y (n = 64 eyes; SD = 5.013; p = 0.005) for the P100-N140 amplitudes. For minimal VEP intervals of ≥12 months, the RCL was +1.768 ms/y (n = 59 eyes; SD = 4.558; p = 0.024) and the RCA was -0.527 µV/y (n = 44 eyes; SD = 2.123; p = 0.111). The history of a previous ON >6 months before baseline VEP had no influence on RCL and RCA. ONs during the observational period led to mean RCL and RCA of +11.689 ms/y (n = 16 eyes; SD = 17.593; p = 0.003) and -1.238 µV/y (n = 11 eyes; SD = 3.708; p = 0.308), respectively. CONCLUSION: This first longitudinal VEP study of patients with NMOSD provides evidence of progressive VEP latency delay occurring independently of acute ON. Prospective longitudinal studies are needed to corroborate these findings and help to interpret the clinical relevance.