© Springer International Publishing Switzerland 2015
Ajay Bhalla and Jonathan Birns (eds.)Management of Post-Stroke Complications10.1007/978-3-319-17855-4_1616. Future Developments
(1)
Department of Clinical Neurosciences, King’s College London, London, UK
Abstract
The past decade has witnessed major advances in stroke care, but stroke continues to remain a major cause of death and the most common cause of adult physical disability. This chapter presents an overview of selected future developments which will have an impact on reducing stroke-related complications. Foremost amongst these is the prevention of post-stroke pneumonia, and the chapter discusses the difficulties in diagnosing post-stroke pneumonia and various interventions to reduce its incidence. Brain injury is a major consequence of stroke; imaging methods that may provide insight into repair mechanisms and their modulation using physical therapy, pharmacological interventions, and stem cells are discussed. Motor impairment is a major complication after stroke, and a commentary on the role of bi-hemispheric interactions and interventions for modulating this interaction to reduce impairments is given. Monitoring of stroke-related complications and their consequences is also important for reducing their incidence and quality assurance, and this chapter highlights ongoing initiatives and the use of health information technology to meet some of the challenges in improving stroke care.
Keywords
Post-stroke pneumoniaBrain injuryMR imagingRegenerationStem cellsNon-invasive brain stimulationMonitoring and quality assuranceHealth information technologyIntroduction
The past decade has witnessed major advances in stroke care, notable amongst these being the advent of reperfusion treatments to reduce ischaemic damage to the brain, the widespread introduction of stroke units to prevent stroke-related complications and improve outcomes, and neurosurgical interventions to reduce mortality in patients with malignant infarcts or severe haemorrhagic strokes. Advances in vascular risk and carotid disease management, anti-thrombotic treatments, and anticoagulation in atrial fibrillation (to name a few) have also significantly decreased stroke incidence.
Developments in imaging, especially the wider availability of multimodal CT and MR scanning, have allowed targeted delivery of interventions for prevention and treatment of acute ischaemic stroke and reducing the risk of haemorrhagic stroke due to vascular pathology or the use of anti-thrombotic agents. Despite these advances, stroke continues to be a major cause of death and the most common cause of adult physical disability. Residual brain damage (even after successful reperfusion) remains a major cause of impairments, and debate and controversy continues to exist over the best interventions to manage these impairments. The ability to monitor quality of care in preventing post-stroke complications and improving outcomes also remains a major concern for policymakers and healthcare providers.
This chapter presents an expert view of selected areas of development which will have a major impact on mitigating the consequences of stroke in the future and will concentrate on
The definition and diagnosis of post-stroke pneumonias and their prevention
Imaging as a tool for understanding processes involved in recovering from brain injury
Current concepts in reducing the motor deficits after stroke that may have implications for other impairments
The use of health information technology to monitor complications and drive up the quality of stroke care
Post-Stroke Pneumonia
Diagnosis of Post-Stroke Pneumonia
Pneumonia frequently complicates stroke and has a major impact on outcome. However, diagnosis of pneumonia in stroke is difficult because presentation may be non-specific, blood results may reflect concomitant pathology, and routine radiological examination or microbiological sampling may not be possible or performed. It is not surprising that the incidence of post-stroke pneumonia ranges from 2 % to 57 % in different studies, with a median incidence rate of 10 % (IQR 6.4–16.2 %) [1]. Patients who develop post-stroke pneumonia have higher mortality, longer length of hospital stay, worse rehabilitation outcomes, and higher care needs after discharge [1, 2]. Whilst most of the information in meta-analyses comes from studies during the first weeks after stroke, mainly during inpatient stays, longer-term studies in stroke patients have shown even higher incidence in stroke survivors of up to 20 % in the first 6 months [3]. The wide variations in the incidence rates for post-stroke pneumonia reflect not only the diversity of settings and patient populations in which these studies were undertaken but also the diversity in the criteria used to diagnose post-stroke pneumonia. A recent systematic review of studies on the diagnosis of stroke-associated pneumonia undertaken by the international Pneumonia In Stroke ConsEnsuS (PISCES) group concluded that the diagnostic approaches to pneumonia in stroke vary considerably, with less than a third of the studies having used objective standardised criteria based on previously published criteria or guidelines and more than 60 % using ad hoc criteria, clinician-reported diagnosis, or initiation of antibiotics as evidence of infection [4]. Furthermore, biomarkers such as white cell counts and C-reactive protein have little more to add to the diagnostic conundrum, as stroke itself or other co-morbidities may be responsible for elevated levels. Hence, one of the first challenges for the future being addressed by the PISCES group is to agree to common terminology, diagnostic criteria, investigative approach, and guidelines to antibiotic initiation for this commonly encountered spectrum of lower respiratory tract infections complicating management of stroke patients.
Prevention of Post-Stroke Pneumonia
The most frequently reported risk factors for post-stroke pneumonia are older age, male sex, increasing stroke severity, reduced level of consciousness, the presence of swallowing difficulty, and the absence of cough [2]. The relation between dysphagia and cough in the incidence of post-stroke pneumonia is of particular interest. Dysphagia is associated with a 2- to 3-fold increase in risk of pneumonia after stroke, which increases further to 5- to 11-fold with the presence of aspiration [5]. Cough is protective; the lack of reflex cough after swallowing has been associated with an eightfold increase in the risk of post-stroke pneumonia [6]. It is not surprising that the most widely used strategy for the prevention of post-stroke pneumonia is the routine screening of stroke patients for swallowing difficulty, coupled with the implementation of dysphagia management strategies. There is some evidence to suggest that these measures can halve the risk of developing post-stroke pneumonia in dysphagic stroke patients [7, 8]. On the other hand, there is very little research on the role of cough in preventing post-stroke pneumonia or its consequences.
In addition to screening for dysphagia, other measures may further reduce the incidence of post-stroke pneumonia based on different patho-physiological and clinical justifications. Pharmacological approaches include the preventive administration of antibiotics to reduce fever and infection [9], the use of angiotensin-converting enzyme (ACE) inhibitors to improve reflex cough sensitivity [10], selective decontamination of the digestive tract to minimise exposure to pathogens [11], and pharmacological agents targeting stroke-induced immuno-suppression [12]. Non-pharmacological strategies include elevated positioning to prevent aspiration, intensive oral hygiene and dental treatment to reduce oro-pharyngeal colonisation with pathogens [13], passive mobilisation and re-positioning regimens to improve lung ventilation and airway clearance [14], and respiratory muscle training to improve respiratory muscle strength and peak cough flows aimed at facilitating rapid expulsion of aspirate from the bronchi [15].
Preventive use of antibiotics to reduce post-stroke pneumonia has merited considerable attention. A recently published meta-analysis included 5 randomised controlled trials that included 506 patients, 248 of whom were randomised to preventive antibiotic therapy and 258 to control groups. Pooled analysis showed a non-significant reduction in mortality (13 % versus 15 %, RR 0.85, 95 % C.I. 0.47–1.51) and dependence (47 % versus 61 %, RR 0.67, 95 % C.I. 0.32–1.43) with preventive antibiotics [9]. The incidence of infections was, however, reduced significantly (22 % versus 36 %, RR 0.58, 95 % C.I. 0.43–0.79). The analysis was limited by small sample sizes and heterogeneity in study population, design, type of antibiotics used, and definitions of infection. Only 29–41 % of included patients in these studies were dysphagic, and it is not clear whether positioning and feeding strategies to prevent aspiration were being implemented in addition to antibiotic interventions. More importantly, critical adverse events such as toxin-positive Clostridium difficile (C diff) or methicillin-resistant staphylococcus aureus (MRSA) incidence related to antibiotic use were not evaluated in these studies.
The effectiveness of preventive use of antibiotics is being investigated in two large multi-centre trials (the Preventive Antibiotics in Stroke Study [16] and the Antibiotics to Reduce the Incidence and Consequences of Post Stroke Pneumonia Study [17]), which will be reporting their findings imminently. Other strategies have not been researched in any great depth but merit further investigation in future studies. Further research is also needed on strategies to prevent pneumonia in patients with long-standing swallowing problems or those with nasogastric tubes in whom the physiology may be different and on safety issues associated with prolonged antibiotic use.
Post-Stroke Brain Injury
Understanding Recovery After Injury
Recent years have seen significant advances in reperfusion techniques and acute care on specialist units aimed at reducing brain damage. Despite these advances, injury to the brain and consequent disability remain the most salient complications after stroke. It is estimated that 50 % of survivors have residual deficits and up to 30 % have permanent disability [18]. Recent studies show that the adult brain has capacity to reorganise after injury, and processes such as neovascularisation and neuronal plasticity in the unaffected areas around the injury contribute to limitation of impairments and recovery [19, 20]. Angiogenesis triggered by hypoxia in unaffected ipsilesional areas is an early event in plasticity, which promotes neurogenesis and neural cell migration [21]. In post-mortem studies, increased capillary density in peri-infarct areas has been associated with longer survival [22], and in vivo arterial spin labelling (ASL) studies have shown that increased perilesional perfusion correlates with tissue recovery in stroke survivors [23].
Developments in MRI have provided a non-invasive technique for monitoring changes in the recovering brain; most studies have focused on functional imaging or changes in lesion microstructure and its connections [24]. These studies have shown that motor recovery in stroke patients is associated with activation in the peri-infarct cortex and supplementary areas of the affected side and also in additional regions including the ipsilesional sensorimotor and premotor cortex [25]. The cerebellum, thalamus, and prefrontal areas are also known to play an important part in restoration of function. The process of reorganisation is dynamic, and an evolution of changes with time and several different patterns have been described. These include activation of bilateral cerebellar and prefrontal areas, an initial increase followed by a decrease in activation of motor areas, and progression from early contralesion activity to late ipsilesional activity. Recent studies in acute recovery have also shown that the integrity of the corticospinal tract system is critical for motor recovery within the first 4 weeks of stroke, irrespective of involvement of the somatosensory system [26].
The complementary method of Proton Magnetic Resonance Spectroscopy (1H-MRS) provides the opportunity to study changes in metabolites as a window into neural repair, which may be more sensitive and provide greater information on repair processes [27]. N-acetylaspartate (NAA) is synthesised in neuronal mitochondria and is considered a good marker for neuronal integrity. A 1H-MRS signal at 1.28 parts per million (ppm) has been suggested as an exclusive biomarker of adult neural progenitor cells but needs confirmation [28].
Longitudinal studies suggest that evolution of injury may continue beyond the acute insult. A progressive decrease in NAA concentrations over 12 weeks, indicative of progressive neuronal loss, has been seen in infarcted areas in acute stroke patients [29]. Progressive neuronal loss may be present in areas remote from the infarct and from the time of injury; diffusion tensor imaging has shown progressive increase in diffusivity in the unaffected ipsilesional thalamus between 1 and 6 months after stroke [30]. Stroke patients have been shown to have lower NAA and higher myo-inositol concentrations in spared ipsilesional areas compared with healthy controls 6 months post stroke, which correlated with the extent of residual motor impairment [31].
Hence, stroke recovery is a complex interplay of evolving injury and regenerative processes consisting of vascular, neuronal, and microglial events occurring not only within areas directly involved in injury but also in spared regions. A limitation of existing studies is that most have either concentrated on evolution of injury or on regeneration but not on both simultaneously, or used single modalities in isolation. Although the majority of physiological processes involved with recovery may occur in the intact perilesional areas, most human studies have concentrated on structural characteristics of the lesion and its direct connections. New research that combines different modalities to follow in vivo the complex events associated with recovery, not only in infarcted but in other areas of the brain, will provide insight into endogenous repair mechanisms, which can be used to predict recovery after stroke or identify potential therapeutic targets.
Enhancing Post-Stroke Regeneration
Regenerative treatment approaches provide a novel intervention strategy that potentially has the capacity not only to modify disease pathology but also to repair and reverse damage. Given the emerging data on the longer-lasting effects of acute ischaemia [29, 30], early reperfusion with thrombolytic agents or endovascular procedures remains the only available intervention to limit progressive post-ischaemic neuronal loss and reduce complications due to impairments after stroke. Preclinical studies show that cell-based and pharmacological therapies can both enhance brain repair processes substantially and improve functional recovery [20]. Cell-based therapies under investigation include use of bone marrow mesenchymal cells, cord blood cells, foetal cells, and embryonic cells. Pharmacological treatments of interest include already available growth factors such as erythropoietin and granulocyte colony-stimulating factor, drugs such as sildenafil, statins, nicotinic acid, minocycline, cholinesterase inhibitors, or fluoxetine, and novel agents such as cannabinoid CB2 receptor agonists or retinoids. These agents are known to result in a threefold or greater increase in neurogenesis in rodent models, but their potential in humans is not known. Nevertheless, these are extremely attractive candidate ‘regenerative’ therapies for stroke which, if proven in animal models, can be rapidly progressed to clinical trials and translated into clinical practice.
Translating cellular or pharmacological regenerative treatments proven to be successful in animal models for human use presents several challenges [20]. Although the success of stem cell implantation in experimental studies offers exciting opportunities for stroke repair, safety issues, including tumour formation and immune rejection, as well as ethical and technical challenges, have hampered progress of such treatments into clinical practice. Pharmacological treatments to modulate endogenous neurogenesis have their own ethical and technical challenges, but many are known to be safe as they are already in human use for other indications with known safety/tolerability profiles. At present, there are at least two ongoing stem cell therapy studies and a few studies of pharmaceutical modulators of neural repair in Phase II of development in the United Kingdom.
Post-Stroke Loss of Motor Function
Loss of motor function and the ability to walk or participate in daily living activities is a major complication of stroke, seen in about 50 % of survivors. Imaging research has shown that brain reorganisation responsible for motor recovery is a dynamic process involving not only the affected motor areas but also primary and supplementary motor areas on the contralesional side. It is now known that all muscles receive cortical outputs from both the right and the left hemispheres, but contralateral cortical outputs strongly dominate in health, and there is interaction between the two sides of the brain with transcallosal inhibition of the weak ipsilateral outputs by the contralateral hemisphere during normal activity. In stroke, interhemispheric transcallosal inhibition of the contralesional hemisphere from the ipsilesional hemisphere is decreased because of injury, resulting in the unveiling and/or recruitment of the functionally silent ipsilateral motor pathways from the contralesional unaffected hemisphere to the affected side of the body, and unopposed inhibition of mechanisms for recruitment of surviving contralateral motor pathways in the affected hemisphere [32]. However, the recruitment of ipsilateral motor pathways from the unaffected hemisphere and inhibition of the dominant contralateral motor pathways that would normally be responsible for motor function is not always a harbinger for good recovery. Ipsilateral motor pathways to the same side of the body as the hemisphere have additional synapses, low fibre density, and little output to upper limb muscles. A poor motor outcome is more often seen in stroke patients who recover by ipsilateral pathways from the contralesional hemisphere compared with those recovering through perilesional motor reorganisation and activation of the contralateral pathways [33]. Stroke patients with the most successful recovery of motor function are those whose patterns of brain activity are comparable with healthy volunteers in stroke studies [34]. Hence, there is a strong case to support research on interventions that inhibit contralesional motor cortex and facilitate ipsilesional motor cortex activity for reducing the consequences of damage to the primary motor regions following a stroke and improving recovery in hemiparetic stroke patients.
The imbalance between hemispheres caused by unilateral damage following stroke may be addressed by several different techniques, using either the time-honoured physical therapy treatments or the newer, emerging non-invasive brain stimulation (NIBS) techniques. Of the physical therapy interventions, constraint-induced movement therapy (CIMT) has been most extensively investigated. It is based on the assumption that immobilisation of the unaffected side will prevent learned ‘non-use’ and promote use of the affected limb resulting in faster (and more complete) recovery. In the seminal Extremity Constraint-Induced Therapy Evaluation (EXCITE) trial [35], CIMT was associated with statistically significant and clinically relevant improvements in arm motor function that persisted for at least 1 year. In fact, recovery in some domains was comparable with non-stroke controls. Another technique, bilateral movement training, which is aimed at balancing cortico-motor outputs between the affected and the unaffected hemispheres, has also shown to be effective in improving functional and mobility outcomes in stroke patients [36].
Related posts:
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
