While the consensus on a healthy diet has generally been interpreted to mean limiting intake of sodium, red meat and saturated fat intake, several other dietary factors have been reported to reduce stroke risk, such as diets rich in magnesium, flavonoids, lycopenes, fruits and vegetables, and chocolate. Further, the Mediterranean diet was found to reduce cardiovascular risk in a randomized trial.Intensive exercise has been also reported to have a benefit in secondary stroke prevention.Thus, it is incumbent upon healthcare providers to emphasize lifestyle changes for stroke risk reduction. Pharmacological approaches to reduce stroke risk often include agents which prevent or reduce thrombus formation. Anti-platelet agents are used for secondary prevention in most non-cardiogenic IS patients to prevent worsening of atherosclerotic disease. The main mechanism of IS reduction are through blockade of platelet aggregation and activation through the suppression of thromboxane A2 via cyclooxygenase-1 blockade and upregulation of cAMP via phosphodiesterase 3 or P2Y12 receptor blockade. Aspirin, clopidgrel, dipyridamole, and cilostazol have all demonstrated efficacy for secondary prevention of IS through this anti-platelet effect. Prasugrel is newer antiplatelet agent, but has not been shown to be superior to conventional anti-platelet agents in recent study.Ticagrelor, a recently approved anti-platelet inhibitor of the P2Y12 ADP receptor in coronary disease, was shown to also have efficacy in primary and secondary IS prevention.Dual antiplatelet treatment typically consists of aspirin plus clopidogrel has met with conflicting results. Early studies suggested that such combination therapy led to unacceptably high risks of major cerebral and gastrointestinal bleeding and a recent metaanalysis indicated that such hemorrhage due to DAPT negated any antithrombotic benefit. It should be pointed out that these early studies used long term DAPT for months or even years. More recent studies of short term DAPT have now shown that this approach can further reduce stroke risk while not increasing the risk of significant hemorrhage .As such,grow racks indoor it is now common practice to prescribe DAPT for periods of 21 or 90 days after non-cardiogenic IS.
It should also be noted that DAPT may increase HTf when used with t-PA in experimental stroke models,In contrast, a recent study showed that combination therapy of aspirin or clopidogrel with cilostazol has been reported not to increase the incidence of HTf and to reduce relative risk of recurrent IS by 51% compared to single anti-platelet therapy.Cilostazol is also thought to have pleiotropic effects such as an improvement of endothelial function by inhibition of smooth muscle cell proliferation and reduction of inflammation.In a recent experimental study, cilostazol was also shown to have a neuroprotective effect via reduction of inflammatory molecules, stabilization of the blood-brain barrier, and prevented apoptosis.Significant extracranial carotid artery stenosis is detected about 15% of IS patients. Revascularization, either via endarterectomy or endovascular approaches, of symptomatic stenotic carotids has been shown to significantly reduce stroke risk, especially if carried out within two weeks of the index transient ischemic attack or stroke.While endarterectomy has long been the mainstay of revascularizing stenotic carotids, endovascular approaches include carotid artery angioplasty followed by stenting , which has the advantage of being less invasive and similarly efficacious.Less clear is the role of carotid revascularization on asymptomatic carotids.In patients with a cardiogenic cause of stroke, anti-thrombotic therapy to prevent thrombus formation has been shown in several studies to substantially reduce recurrent stroke, particularly for atrial fibrillation.The vitamin K antagonist warfarin has been the most widely studied and used, but recently, orally available direct thrombin and factor X inhibitors have been shown to be as effective and easier to manage than warfarin. Several clinical studies have shown that DOACs are noninferior to warfarin in the prevention of IS with a lower incidence of significant HTf. Further, the presence of cerebral microbleeds , which may be an indication of underlying cerebral amyloid angiopathy, increases the risk for cerebral hemorrhage in association with anti-thrombotic therapy. The incidence of intracranial hemorrhage in the presence of CMBs during DOAC treatment has been reported to be less than anti-platelet and warfarin therapy. This is thought to be due to the ability of DOACs to avoid inhibiting factor VII, although hemorrhage risk is still higher compared to that amongst patients without CMBs.
Thus, it is still not recommended to initiate DOAC or other anticoagulant treatment in this patient population.ESUS are now increasingly thought to be due to occult atrial fibrillation , in part, due to the availability of long term cardiac monitoring technology ; however, it is unclear whether these patients should be empirically anticoagulated.DOACs were considered for secondary prevention of ESUS; however, a few studies have failed to show that this approach is effective.Other embolic sources such as aortic plaque, patent foramen ovale, and neoplasm have been identified as the etiology of ESUS where anticoagulation is not always the indicated treatment. Hence, documentation of occult AF will be important prior to initiating anticoagulant therapy. Other beneficial effects of DOACs have been suggested in experimental studies. Dabigatran, a direct thrombin inhibitor, has been shown to inhibit microglial and astrocyte activation.Edoxaban, a factor X inhibitor, has also been shown to have anti-inflammatory effects via suppression of PAI-1, MCP-1, and TNF-α. Some ‘natural’ approaches have been studied in stroke prevention as well, but have not been routinely implemented at the clinical level. Polyphenol supplementation has been proposed as a preventive agent for IS. In a previous study, polyphenol intake was thought to act as an antioxidant, leading to reduction in atherosclerosis.It is also thought to have other beneficial properties such as regulating neurotrophin levels, especially nerve growth factor and brain-derived neurotrophic factor . Epigallocatechin gallate , which is a polyphenol found in green tea, has gained interest for its putative antioxidant and neuroprotective effects via prevention of NF-κB activation, inhibition on PI3K/Akt signaling, and improvement of mitochondrial dysfunction.EGCG also seems to the downregulate MMP-2 and MMP-9 and upregulate the endogenous t-PA inhibitor plasminogen activator inhibitor-1 . These latter observations suggest that EGCG may have a role as an adjunctive agent to t-PA by extending the therapeutic time-window for thrombolytic treatment while reducing other undesirable side effects of t-PA treatment such as severe HTf, brain edema and BBB disruption. Other polyphenols have demonstrated antioxidant effects, which have the potential to reduce stroke risk. Resveratol, a component of red wine, has been shown to inhibit phosphodiesterase and regulate cAMP, AMPK, and SIRT1 pathways during ischemic injury. Salvianolic acid has been shown to have neuroprotective effects dependent on mitochondrial connexin43 via PI3K/Akt pathway.
Flavonol rich diets has been reported for a 14% relative risk reduction of IS. Flavonoids is main sources of apple polyphenol, which has been reported to reverse oxidative stress via P38 mitogen-activated protein kinase signaling pathway.harmacological recanalization with t-PA has been the mainstay for acute IS treatment for several decades. t-PA therapy has been shown to improve neurological outcome provided it is initiated within 4.5 h from symptom onset. In addition to rt-PA therapy, recent randomized controlled trials have demonstrated the efficacy of mechanical thrombectomy in large vessel stroke.98) In several of these trials, pre-treatment with t-PA before MT intervention was superior to t-PA alone. A few studies also showed that MT could be extended to even 24h after stroke onset, provided imaging studies showed a large mismatch. The DAWN ,DEFUSE3 , and EXTEND studies all evaluated endovascular methods of thrombectomy to acutely revascularize occluded large cerebral vessels that cause stroke. These studies have not only shown that acute revascularization can improve stroke outcome from longer time windows,grow shelf rack but can also lengthen the therapeutic time windows for t-PA. These studies utilized imaging based criteria to identify appropriate candidates. In particular, those studies which showed longer time windows for thrombectomy used imaging to demonstrate a large, and thus salvageable ischemic penumbra in relation to the ischemic core . Further, imaging criteria have allowed for the use of t-PA therapy in so-called “wake-up stroke”, where the time of stroke onset is unclear because the patient reports waking up with a neurological deficit after being neurologically intact at the time of sleep. Such cases may be pre-selected by mismatch from diffusion weighted and FLAIR MRI.While the expansion of therapeutic time windows and improved outcomes have been shown in acute revascularization approaches, reperfusion injury has the potential to worsen outcome, compared to no revascularization. While this phenomenon is well established in experimental stroke models, its existence in clinical stroke has been debated. Nevertheless, some have reported a hyperintense acute reperfusion marker on MRI which is thought to predict HTf and clinical worsening in some IS patients, and this has been suggested R/I in humans.In experimental studies, R/I has been attributed to the introduction and generation of ROS when a previously occluded vessel is opened. This flood of ROS leads to inflammation. Inflammation then results in the generation of various damaging immune mediators, effector molecules and more ROS. ROS can also lead to apoptosis/necrosis via DNA/RNA damage, lipid peroxidation, and the reduction of ATP production. Further, t-PA treatment can promote extracellular matrix damage to lead to HTf. Hence, targeted R/I treatments in conjunction with t-PA and/or MT has the potential to further improve neurological outcomes.A few potential adjunctive agents have been explored at the clinical level.At the clinical level, edaravone contributes to improving neurological function and reducing adverse events. In the PROTECT 4.5 trial, the efficacy and safety of combination therapy with edaravone and t-PA in stroke patients suggested that combination therapy might increase the numbers of patients with better outcomes, accelerated recanalization and reduced HTf.
The YAMATO study showed that the timing of edaravone infusion did not affect the rate of early recanalization, symptomatic HTf, or favorable outcomes after t-PA therapy. However, early edaravone infusion in parallel with endovascular revascularization led to better functional outcomes at discharge, lower mortality, and lower incidence of HTf in a recent clinical trial. Edaravone has been already approved for the treatment of IS patients who present within 24 h of the onset of symptoms in Japan and other countries, but not the United States. Thus, the prospects of adding edaravone to t-PA and MT seem favorable. Therapeutic hypothermia has already been shown to improve neurological outcomes in comatose survivors of cardiac arrest and neonatal hypoxic encephalopathy. While it has yet to be shown whether it has any role in patients with IS, major mechanisms for its neuroprotective effect seems to be related to its effects on multiple cell death pathways including inflammation, apoptosis, excitotoxicity and preservation of metabolic stores.HT has also been shown to reduce BBB disruption and HTf in relation to t-PA use in experimental models.Combination therapy with HT and t-PA also reduced HTf and endogeneous tPA expression, and has the potential to extend the time window for other acute therapies. Few clinical studies have been carried out in IS. The ReCCLAIM and ICTuS studies assessed the combination therapy with rt-PA and HT in IS patients with large pretreatment infarcts, and both trials showed that this approach was safe and may even reduce reperfusion injury, as outcomes were improved compared to stroke patients who did not receive HT. The ICTuS2 study showed the safety and feasibility of both HT and HT with t-PA, although cooling increased the incidence of pneumonia. HT has been also combined with MT with selective brain cooling elicited by intra-arterial chilled saline infusion and was shown to be both safe and feasible.The RECCLAIM-Ⅱ also examined MT with HT; however, this trial was stopped early for lack of funding.A recent laboratory study also showed that the neuroprotective effect of HT differentially affects cells of neurovascular unit depending on the depth, duration and even timing of cooling.Yet, clinical studies used a single target temperature with fixed duration . Thus, it may be important to design future clinical trials with adjusted temperature and cooling duration depending on targeted cell type for neuroprotection versus vasculoprotection. Recent years have seen an advent in population-based studies that examine the prevalence, etiology, and developmental trajectories of diverse sub-clinical psychopathological symptoms that pose a risk for the later development of severe mental illnesses. It is increasingly recognized that most categorically defined psychiatric disorders occur on a spectrum or continuum that is not necessarily normally distributed , show high heterogeneity and symptom overlap, and share genetic and environmental risk factors . Therefore, population-based studies of psychopathology in youth assess a broad spectrum of symptoms as well as genetic risk, cognitive and general functioning, socioeconomic, and environmental factors to yield a more complete understanding of symptom etiology and development.