Patent foramen ovale closure versus medical therapy in cases with cryptogenic stroke,meta-analysis of randomized controlled trials

Background

PFO is more common in cases with cryptogenic stroke compared to cases with no stroke or stroke of identified etiology. Several randomized controlled trials (RCTs) comparing PFO closure with medical therapy have been published with controversial findings.

Methods

PubMed, Embase and Cochrane library databases were searched for RCT comparing PFO closure with medical therapy including antiplatelet therapy (aspirin or clopidogrel or combination) or anticoagulation. We identified 5 trials, including 3627 cases. The mean duration of follow-up was 4 years. Relative risk (RR) and 95% confidence intervals (CI) were calculated using fixed and random-effects models.

Results

There was a significant reduction in the incidence of stroke among the PFO closure group compared to medical therapy group, 2.0 versus 4.2%, RR 0.48; 95% CI (0.3, 0.7), p < 0.001. The incidence of AF was higher in the PFO closure group compared to medical therapy group, 4.2 versus 0.7%, respectively, RR 5.9, 95% CI (3, 11), p < 0.001. After exclusion of oral anticoagulants cases (19%), analysis showed a lower incidence of stroke in the PFO closure group (2%) compared to antiplatelet therapy (5.2%), RR 0.4; 95% CI (0.3, 0.6), p < 0.001. There was no significant difference between both groups in the incidence of transient ischemic attacks or all-cause deaths.

Conclusion

PFO closure results in a significant reduction in the recurrence of ischemic stroke compared to medical therapy alone, primarily antiplatelet, among cases with PFO and cryptogenic stroke.

     

Closure of patent foramen ovale for cryptogenic stroke patients: an updated systematic review and meta-analysis of randomized trials

Objective

This systematic review and meta-analysis was performed to investigate the efficacy and safety of transcatheter device closure (TDC) plus anti-thrombotic drugs over medical management alone for patients with cryptogenic stroke and patent foramen oval.

Methods

PubMed, Embase and Cochrane Library database were searched for randomized controlled clinical trials (RCTs). The primary endpoint is the composite of stroke and transient ischemic attack. The secondary endpoints are all-cause mortality, total serious adverse events, atrial fibrillation and bleeding.

Results

Five RCTs with a total of 3440 participants were included. TDC significantly decreased the risk of primary endpoint when compared to medical therapy alone (RR 0.54, 95% CI 0.43–0.69). Further subgroup analyses showed that patients with male gender and with substantial shunt size of foramen ovale significantly benefited from TDC as compared to those with female gender and with no substantial shunt size of foramen oval separately. Moreover, TDC was superior to medical therapy with anti-platelet drug alone (not with anti-coagulation). On the other hand, the incidence of atrial fibrillation was higher in TDC group (RR 4.49, 95% CI 2.02–9.97), with the risk of other adverse events equivalent between the two groups.

Conclusions

TDC plus anti-thrombotic drugs is superior than medical therapy alone for secondary prevention of stroke, especially for those with male gender and with substantial shunt size of foramen ovale. Though it may increase the risk of postoperative atrial fibrillation, it would not bring higher risk of all-cause mortality, total adverse events and bleeding.

     

Guideline for Reversal of Antithrombotics in Intracranial Hemorrhage

Background

The use of antithrombotic agents, including anticoagulants, antiplatelet agents, and thrombolytics has increased over the last decade and is expected to continue to rise. Although antithrombotic-associated intracranial hemorrhage can be devastating, rapid reversal of coagulopathy may help limit hematoma expansion and improve outcomes.

Methods

The Neurocritical Care Society, in conjunction with the Society of Critical Care Medicine, organized an international, multi-institutional committee with expertise in neurocritical care, neurology, neurosurgery, stroke, hematology, hemato-pathology, emergency medicine, pharmacy, nursing, and guideline development to evaluate the literature and develop an evidence-based practice guideline. Formalized literature searches were conducted, and studies meeting the criteria established by the committee were evaluated.

Results

Utilizing the GRADE methodology, the committee developed recommendations for reversal of vitamin K antagonists, direct factor Xa antagonists, direct thrombin inhibitors, unfractionated heparin, low-molecular weight heparin, heparinoids, pentasaccharides, thrombolytics, and antiplatelet agents in the setting of intracranial hemorrhage.

Conclusions

This guideline provides timely, evidence-based reversal strategies to assist practitioners in the care of patients with antithrombotic-associated intracranial hemorrhage.

     

Detection of Atrial Fibrillation in Cryptogenic Stroke

Purpose of Review

To summarize the literature on the detection of atrial fibrillation (AF) in patients with “cryptogenic” stroke, a cohort including about 25% of all ischemic stroke patients and patients with embolic stroke of undetermined source (ESUS).

Recent Findings

A first episode of AF is detected in up to one third of cryptogenic stroke and in up to one fourth of ESUS patients during long-term monitoring. AF prevalence correlates to patient selection, duration, and quality of ECG monitoring. Higher rates of AF were reported in stroke patients with left atrial pathology, specific ECG alterations, or increased natriuretic peptides. While AF detection impacts on medical stroke prevention in the vast majority of patients, patient selection for prolonged monitoring is largely left at the physician’s discretion.

Summary

AF detection after cryptogenic stroke or ESUS is a frequent, potentially causal condition. Whether subsequent oral anticoagulation may improve outcome remains open.

     

Acute Treatment of Stroke (Except Thrombectomy)

Purpose of Review

The management of patients with acute stroke has been revolutionized in recent years with the advent of new effective treatments. In this rapidly evolving field, we provide an update on the management of acute stroke excluding thrombectomy, looking to recent, ongoing, and future trials.

Recent Findings

Large definitive trials have provided insight into acute stroke care including broadening the therapeutic window for thrombolysis, alternatives to standard dose alteplase, the use of dual antiplatelet therapy early after minor ischemic stroke, and treating elevated blood pressure in intracerebral hemorrhage. Further ongoing and future trials are eagerly awaited in this ever-expanding area.

Summary

Although definitive trials have led to improvements in acute stroke care, there remains a need for further research to improve our understanding of pathophysiological mechanisms underlying different stroke types with the potential for treatments to be tailored to the individual.

     

Secondary Stroke Prevention in Cryptogenic Stroke and Embolic Stroke of Undetermined Source (ESUS)

Purpose of the Review

The purpose of the study was to review the literature on cryptogenic stroke and embolic stroke of undetermined stroke (ESUS). Cryptogenic stroke according to TOAST criteria is a stroke which is not due to cardiogenic embolism, small vessel disease with lacunes or large vessel disease of brain supplying arteries. In the context of secondary stroke prevention studies, cryptogenic stroke is not operationally defined.

Recent Findings

The new concept of “embolic stroke of undetermined source” (ESUS) provides an operational definition. ESUS is diagnosed as a non-lacunar stroke on cerebral imaging and exclusion of large vessel atherosclerosis by CTA, MRA or ultrasound. Cardiogenic embolism is made less likely by ECG monitoring and echocardiography. At present, aspirin is used for secondary stroke prevention in patients with cryptogenic stroke.

Summary

Based on the construct that ESUS might be caused by undetected atrial fibrillation or other embolic mechanisms, ongoing randomised secondary stroke prevention trials are comparing non-vitamin K oral anticoagulants (NOACs) with aspirin.

     

Closure versus Medical Therapy for Patent Foramen Ovale in Patients with Cryptogenic Stroke: An Updated Meta-Analysis of Randomized Controlled Trials

Background

Debate continues about whether percutaneous closure of patent foramen ovale (PFO) is a better strategy for the treatment of patients with cryptogenic stroke in comparison with medical therapy alone. We performed an updated meta-analysis of 6 randomized controlled trials (RCTs) to assess the effectiveness and safety of percutaneous closure of PFO as secondary prevention for patients with previous cryptogenic stroke compared to medical therapy.

Thrombectomy for Acute Ischemic Stroke: Recent Insights and Future Directions

Purpose of Review

Mechanical thrombectomy has become the standard of care for acute ischemic stroke with proximal large vessel occlusions (LVO). This article reviews recent research relating to thrombectomy.

Recent Findings

Thrombectomy for anterior circulation stroke with proximal LVO was first shown to be highly efficacious within 6 h of stroke onset, but “late-window” trials have further demonstrated efficacy until 24-h postonset in select patients with salvageable tissue. However, the concept of “time is brain” remains critical. Thrombectomy trials have further stimulated worldwide efforts to develop systems of care for rapid treatment of eligible patients. Thrombectomy is cost-effective and likely to have long-term efficacy for both disability and mortality outcomes.

Summary

Thrombectomy is a highly efficacious acute stroke therapy. Enduring uncertainties include efficacy in patients with premorbid disability, posterior circulation, or more distal occlusions; use of bridging thrombolysis; and optimal techniques to achieve consistent revascularization and address tandem occlusions or stenoses.

     

Carotid Artery Stenosis: Medical Therapy,Surgery, and Stenting

Purpose of Review

The purpose of the study was to update the recent information pertaining to carotid artery stenosis risk stratification and treatment.

Recent Findings

Current decision-making related to carotid artery stenosis is based on clinical trials that are outdated. Medical therapy has improved considerably in the past two decades, and this has reduced the stroke rate for both symptomatic and asymptomatic carotid stenoses. In recent community-based studies, the stroke risk with asymptomatic stenosis has been < 1% per year. For asymptomatic carotid stenosis, new trials such as CREST 2 and ECST 2 will determine whether revascularization has any benefit beyond aggressive medical management. For symptomatic patients, carotid endarterectomy is associated with a lower periprocedural stroke rate compared to carotid stenting. Age greater than 70 years is also associated with an increased risk for carotid stenting patients.

Summary

Clinicians should consider a variety of clinical and radiologic variables in reaching treatment decisions for patients with carotid stenosis. Both symptomatic and asymptomatic patients should receive optimal medical therapy.

     

Serotonin Selective Reuptake Inhibitors (SSRIs) and Stroke

Purpose of Review

The interest in SSRIs after stroke has increased in the past few years, with better knowledge of post-stroke depression and with the demonstrated capacity of some SSRIs to act on the functional recovery of non-depressed subjects.

Recent Findings

Arguments for the action of SSRIs in favour of post-stroke neurological function recovery have improved through new elements: basic science and preclinical data, positive clinical trials and repeated series of stroke patient meta-analysis, and confirmation of favourable safety conditions in post-stroke patients.

Summary

Global coherence is appearing, showing that SSRIs improve stroke recovery in non-depressed patients when given for 3 months after the stroke, with highly favourable safety conditions and a favourable benefit/risk ratio. Large series are still needed.

     

Is CT perfusion helpful in the treatment allocation of patients with acute ischemic stroke? An expert-opinion analysis

Background

Intravenous tPA is the standard treatment for acute ischemic stroke within 4.5 hours of symptom onset. Neuroradiological selection is currently based upon non-contrast- brain CT scan (NCCT).

Aims

To verify, in an “expert-opinion setting”, the possible usefulness of CT perfusion (CTP) in decision-making toward i.v. thrombolysis.

Patients and method

One hundred and three consecutive patients with acute ischemic stroke who underwent NCCT and CTP were re-evaluated by an expert in cerebrovascular disease, to verify if adding CTP information would have changed expert’s opinion.

Results

After CTP, a definitive decision was made for 20 more patients, changing the proportion of patients candidate to i.v. tPA from 44% to 51%, and reducing uncertainty from 29% to 10%. CTP results were useful inmilder stroke (p = 0.01).

Conclusions

In a “real world” setting, CT perfusion could be useful for clinical decision, in particular for milder stroke.

     

Wake-up stroke and CT perfusion: effectiveness and safety of reperfusion therapy

Objective

Ischemic stroke is a neuroemergency condition highly treatable with thrombolysis and thrombectomy. Recently, observational studies have brought insights into clinical and imaging characteristics of wake-up stroke, which interested up to 25% of ischemic stroke patients. In clinical practice, wake-up strokes are usually not considered for reperfusion therapy. The aim of this study was to investigate the use CT perfusion imaging in patients with wake-up stroke and to assess the effect of neuroimaging information provided by CT perfusion maps on the efficacy and safety of thrombolysis and thrombectomy.

Patients and method

We studied 22 wake-up stroke (WUS) patients (13F/9M mean age) who underwent reperfusion therapy after the eligibility assessed by the CT perfusion imaging (<?50% core-to-penumbra ratio and negative CT perfusion).

Results

Mean National Institutes of Health Stroke Scale (NIHSS) was 8.1?±?4.9 at admission while 3.3?±?5.1 at discharge, significantly different from admission (p?<?0.001). As many as ten patients had mRS lower than 3 at discharge. Intracranial hemorrhage occurred in five patients and caused symptoms worsening only in two patients (decrease of NIHSS score of 4 points) of which one patient died.

Conclusion

The main finding of this study is that wake-up stroke with adequate selection by CT perfusion may benefit reperfusion treatment.

     

Mindfulness Meditation for Chronic Pain: Systematic Review and Meta-analysis

Background

Chronic pain patients increasingly seek treatment through mindfulness meditation.

Purpose

This study aims to synthesize evidence on efficacy and safety of mindfulness meditation interventions for the treatment of chronic pain in adults.

Method

We conducted a systematic review on randomized controlled trials (RCTs) with meta-analyses using the Hartung-Knapp-Sidik-Jonkman method for random-effects models. Quality of evidence was assessed using the GRADE approach. Outcomes included pain, depression, quality of life, and analgesic use.

Results

Thirty-eight RCTs met inclusion criteria; seven reported on safety. We found low-quality evidence that mindfulness meditation is associated with a small decrease in pain compared with all types of controls in 30 RCTs. Statistically significant effects were also found for depression symptoms and quality of life.

Conclusions

While mindfulness meditation improves pain and depression symptoms and quality of life, additional well-designed, rigorous, and large-scale RCTs are needed to decisively provide estimates of the efficacy of mindfulness meditation for chronic pain.

     

Facilitating triple rhomboid flaps for meningomyelocele defect closure using a honeycomb structure as a template

Purpose

Various reconstruction options are available for the soft-tissue coverage of meningomyelocele defects. For small defects, primary closure or local single flaps may be sufficient, while large defects require more complex reconstructive techniques. This study suggests an easy way for surgeons to close large meningomyelocele defects using triple rhomboid flaps.

Methods

The hexagonal structure of a honeycomb was considered when planning for the coverage of large meningomyelocele defects. The intact skin around the defect was imagined as multiple hexagons, which allowed us to plan triple rhomboid flaps correctly and more easily. This technique was used in seven patients with defects ranging from 7?×?5 to 12?×?8 cm in size.

Results

No major postoperative complications were seen. Minimal dehiscence was observed in two patients and healed secondarily.

Conclusions

The honeycomb modification for planning triple rhomboid flaps is an easy, practical, and memorable approach for surgeons reconstructing large meningomyelocele defects.

     

Dissection of Cervical and Cerebral Arteries

Purpose of Review

We aimed to summarize recent findings in cervical (CeAD) and intracranial artery dissection (IAD) research.

Recent Findings

Considered a disease of the young- and middle-aged, an analysis on the largest CeAD-population to date (n = 2391) revealed that about 1 of 14 CeAD-patients was aged ≥60 years. Distinct genetic variants were associated with CeAD. However, in clinical practice, genetic investigations are not helpful due to the small effect size. Despite the paucity of data from randomized-controlled trials in CeAD-stroke patients, both intravenous thrombolysis and endovascular treatment should be considered as acute treatment in such patients. Future research is needed to clarify which patients benefit most from each treatment modality. Whether to use antiplatelets or anticoagulants in stroke prevention in CeAD-patients is still a matter of debate. One randomized-controlled feasibility trial has been published, and another trial designed to show non-inferiority of aspirin to vitamin-K-antagonists is underway and will be terminated in late 2018. Non-vitamin-K-oral anticoagulants should not be used in CeAD outside a properly designed trial, as experience with these drugs in CeAD-patients is limited. With many IAD patients developing intracranial hemorrhage, antithrombotic therapy should be used with caution.

Summary

Knowledge about CeAD and IAD has advanced substantially. Nevertheless, further research is mandatory, in particular regarding pathophysiology, acute treatment, and stroke-preventive therapy, as well as long-term outcome and prognosis.

     

Sleep Apnea Is a Risk Factor for Stroke and Vascular Dementia

Purpose of Review

In this article, we review the cerebrovascular complications of sleep apnea (SA). SA is the major sleep disorder associated with stroke and vascular dementia.

Recent Findings

Sleep apnea syndrome of moderate to severe intensity affects 17% of 50–70-year-old men and 9% of 50–70-year-old women, making SA a notorious and prevalent disorder. SA increases the risk of hypertension, stroke, myocardial infarction, and atrial fibrillation (AF) and is closely linked to vascular dementia. In addition, SA may worsen the neurologic outcome in acute stroke patients and interferes with rehabilitation after stroke.

Summary

Proper management of SA may decrease the clinical impact of stroke risk factors, improve neurologic outcome after stroke, and lessen the progression of subcortical ischemic vascular disease. In this article, we will cover the most salient pathologies that associate SA and cerebrovascular pathology.

     

Albumin-Induced Neuroprotection in Focal Cerebral Ischemia in the ALIAS Trial: Does Severity,Mechanism, and Time of Infusion Matter?

Objective

To determine whether there is any differential benefit of albumin administration within 2 h of onset of ischemia and in settings (severe ischemia with reperfusion in cardioembolic strokes with National Institutes of Health Stroke Scale [NIHSS] ≥15), most representative of experimental models of cerebral ischemia in which albumin was effective in reducing neurological injury.

Background

High-dose intravenous (IV) albumin treatment for acute ischemic stroke (ALIAS) trial did not show overall clinical benefit in ischemic stroke patients in contrast to preclinical studies; however, models of preclinical studies were not completely followed.

Methods

A total of 1275 patients combined from ALIAS trials I and II were included in our analysis. We analyzed preclinical studies and selected patients with large ischemic stroke (NIHSS ≥15) related to cardioembolic etiology (n = 189). Outcomes were then studied including time from onset to IV albumin administration.

Results

The odds of excellent outcome (mRS 0–1) at 3 months was not different with high-dose IV albumin infusion (n = 100) compared with placebo (n = 89) ((odds ratio [OR]) 1.632 [0.719–3.708], p value 0.2419). When we further classified these subjects according to time of IV albumin administration, we observed significantly higher odds of excellent outcome at 3 months when patients received IV albumin within 2 h, OR 9.369 (CI 1.040–84.405), p value 0.0461, after adjusting for age, gender, baseline NIHSS score, and any therapeutic procedure.

Conclusion

A trend for benefit is noted in ischemic stroke patients with large cardioembolic stroke (NIHSS ≥15) when high-dose albumin was initiated within 2 h, suggesting that certain ischemic stroke subgroups of patients most representative of preclinical settings may benefit from such a treatment. Additional clinical trials maybe needed to stratify subjects and treatment assignments according to NIHSS severity and timely randomization to evaluate this concept further.

     

Management of Spontaneous Intracerebral Hemorrhage

Purpose of Review

We review the current evidence for medical and surgical treatments of spontaneous intracerebral hemorrhage (ICH).

Recent Findings

Therapy with hemostatic agents (e.g. factor VIIa and tranexamic acid) if started early after bleeding onset may reduce hematoma expansion, but their clinical effectiveness has not been shown. Rapid anticoagulation reversal with prothrombin concentrates (PCC) plus vitamin K is the first choice in vitamin K antagonist-related ICH. In ICH related to dabigatran, anticoagulation can be rapidly reversed with idarucizumab. PCC are recommended for ICH related to FXa inhibitors, whereas specific reversal agents are not yet approved. While awaiting ongoing trials studying minimally invasive approaches or hemicraniectomy, the role of surgery in ICH remains to be defined. Therapies targeting downstream molecular cascades in order to prevent secondary neuronal damage are promising, but the complexity and multi-phased nature of ICH pathophysiology is challenging. Finally, in addition to blood pressure control, antithrombotic prevention after ICH has to consider the risk of recurrent bleeding as well as the risk of ischemic events.

Summary

Treatment of acute ICH remains challenging, and many promising interventions for acute ICH await further evidence from trials.

     

Management of Brain Metastases in the New Era of Checkpoint Inhibition

Purpose of the Review

Brain metastasis is a common complication of advanced malignancies, especially, lung cancer, breast cancer, renal cell carcinoma, and melanoma. Traditionally surgery, when indicated, and radiation therapy, either as whole-brain radiation therapy or stereotactic radiosurgery, constituted the major treatment options for brain metastases. Until recently, most of the systemic chemotherapy agents had limited activity for brain metastases. However, with the advent of small molecule tyrosine kinase inhibitors and immunotherapy agents, there has been renewed interest in using these agents in the management of brain metastases.

Recent Findings

Immune checkpoint inhibitors have revolutionized the treatment of metastatic melanoma, lung cancer, kidney cancer, and bladder cancer among others. They modulate the immune system to recognize tumor antigens as “non-self” antigens and mount an immune response against them.

Summary

Initial studies of using immune checkpoint inhibitors in brain metastases have shown promising activity, and several clinical trials are currently underway. Studies are also assessing the combination of radiation therapy and immunotherapy in brain metastases. The results of these ongoing clinical trials have the potential to change the therapeutic paradigm in patients with brain metastases.

     

„Mission (im)possible“

Background

Specialized neurological treatment decreases the mortality and morbidity of stroke patients. In many regions of the world an extensive coverage is not available. The cooperation between the Krankenhaus Nordwest (KHNW, Frankfurt, Germany) and the Government of Brunei Darussalam describes the set-up process of a specialized neurological center, including stroke unit, science and rehabilitation center.

Aim

The aim of this project called to teach to treat – to treat to teach was to set up a center of excellence in neurology in Brunei Darussalam over a distance of 12,000?km. Treatment options were elucidated by teaching and taught by case examples.

Material and methods

The construction of the Brunei Neuroscience Stroke and Rehabilitation Center (BNSRC) began in July 2010. To overcome the large distance between the department of neurology and neuroradiology at the KHNW and the BNSRC, a telemedical network was established. We provided daily teleteaching for all professions involved in patient care as well as 24/7 availability of teleneurological services from Germany to support the local team on site.

Results

In the BNSRC unit over 1000 patients with ischemic and hemorrhagic stroke and all the various acute neurological conditions were treated from July 2010 until July 2016 as inpatients and over 5000 were treated as outpatients. Since 2010, a total of 52 patients with stroke were treated by thrombolysis within the thrombolytic window and 81 hemicraniectomies were performed.

Conclusion

The project has shown that it is possible to convey specialized neurological knowledge over large distances to provide significant benefits for patients and caregivers.