1 Introduction

The disease commonly described as stroke has diverse and at times confusing vernacular in the medical realm. Terms including cerebrovascular accident (CVA), brain accident, transient ischemic attack (TIA), and apoplexy have all been used to describe the condition [1]. This jargon is further complicated with sub-descriptive terms such as ischemic or hemorrhagic describing the specific etiology as well as transient vs. persistent describing symptom morphology and progression [2]. Stroke has been understood as a cause of debilitating disease for more than 2400 years with Hippocrates recognizing CVA syndromes considerably before science had progressed to the level of accurately describing specific etiologies [2]. As the mysteries of the brain and the basics of how it functions were difficult to study it would not be until 1620 that Jacob Wepfer began to unravel the cause of cerebrovascular disease [3]. Through autopsy reports of patients who developed a sudden onset of what he described as “apoplexy,” the popular term for unexplained paralysis at the time, retrospective anatomical studies began to shed light on this complex medical quandary; his study of patients who had succumbed to this illness clarified that apoplexy was related to the blood supply of the brain, mainly the carotid and vertebral arteries. As medical sciences developed it became clear that not only hemorrhage, but also all forms of vascular occlusion produced similar disease presentation, which we now commonly describe as stroke [2, 3].

The constellation of symptoms seen in CVA is diverse and can mimic the presentation of any neurologic lesion ranging from weakness, difficulties with speech, changes in vision or even vestibular/cochlear derangements. For most of the time that formal medicine has been practiced, a CVA-related illness was considered a cause of permanent disability inevitably ending in death. Research directed at this significant cause of morbidity and mortality has now evolved the idea of what a stroke is. It is now considered a condition which is not only preventable and treatable but no longer needs to be an inevitable result of aging. With this shift in clinical opinion, appropriately driven by evidence-based research, there has been a greater focus on primary and secondary preventative approaches. As we have seen in the setting of chronic diseases the recognition of high-risk groups prior to onset of injury is necessary to improve patient outcomes [4]. A strong contribution toward this goal is the development of a targeted approach to lifestyle alteration, prophylactic intervention, and screening strategies. The litany of research has also targeted the development of care focused after injuries occur with development of treatment algorithms in the acute and chronic stages of brain injury [5, 6]. CVA patient load is estimated at 795,000 patients (approximately one CVA every 40 s) annually with 134,000 lethal outcomes. There are approximately 6.4 million survivors of CVA present in the USA as of 2012 which has more than doubled since 1993, making CVA the most prevalent form of adult disability [7]. In this patient pool approximately 77% of presentations are first time CVAs and the other 23% are recurring CVAs with an economic burden of approximately 36.5 billion dollars in the USA [8]. When evaluating any disease, it is important to understand not only the numbers but also the genetic bias of the disease in terms of racially and genetically driven factors. Statistical analyses have shown that Black as well as Hispanic and Latino populations are proportionally at increased risk, when compared to Caucasian patients, with Black patients presenting almost twice as often as their Caucasian counterparts [9]. Research has shown that this increased relative risk is even more drastic in younger populations allowing for experienced clinicians to include CVA syndromes in their differential diagnostic process, providing for better early detection and improved outcomes [10]. Another significant difference in patient presentation appears in the minor difference of gender representation prevailing in CVA populations. Women experience a slightly higher rate of gross presentation percentage of acute CVA syndrome then men and the extrapolation of this is important since female patients have a greater chance of presenting unconventionally with less distinct symptoms, leading to difficulties in diagnosis [4, 8]. Lastly another issue that warrants further evaluation is the contribution of risk factors such as high blood pressure, tobacco use, coagulopathies, and diastolic heart failure as well as possible genetic factors [7].

2 Pathology

As in all forms of medicine it is important to first understand the pathology of the disease in question. Categorization of acute CVAs is specifically important and in most cases must be performed immediately by clinical examination or non-contrast-enhanced CT (NECT) scan imaging. By grouping CVA disorders it allows for an understanding of the disease mechanics at work and directs physicians toward proper treatment. By recognizing the issue at hand; whether it be related to ischemia, hemorrhage, or vasoconstriction, skilled practitioners can extrapolate possible differential diagnoses that may not be initially apparent by contrasting disease with similar etiology. The initial and most important segregation in a patient presenting with CVA symptomology requires recognizing hemorrhage vs. ischemia. Hemorrhage disrupts downstream tissue blood supply as the vasculature involved is compromised allowing for intraluminal contents to flow into the extravascular space. This has many consequences including inflammatory responses as extravascular blood irritates surrounding tissues and as the extravasated fluid is confined within the tissue it invades, it will begin to exert pressure. This can be extraordinarily dangerous when occurring in a closed space such as the skull that is reinforced by bone and considered the canonical closed vault. The recognition of hemorrhage as the source of symptoms directs skilled clinicians toward the direction of processes that affect the endothelial cells of the vasculature. Endothelial cells are subject to many forms of damage, but common culprits involve hypertension, collagenous disease, arteriolar-venous malformations (AVM), malignancy, and trauma. Diagnostic evidence of hemorrhage separates patients from those that suffer an ischemic cause of CVA as initial treatment options will differ significantly due to intracranial hemorrhage treatment options’ contemporary limitation. Ischemic strokes on the other hand are secondary to partial or complete intraluminal blockage of blood flow and as such there can be a further classification of ischemic strokes that focuses on the progression of symptoms in the first 24 h. Ischemic CVA has two very telling evolutions that give clinicians valuable information in deciding treatment options. In the first case there are ischemic strokes that show resolution or significant improvement of neurologic symptoms in the first 24 h and these are branded transient ischemic attacks (TIA). TIAs are the most beneficial outcome of ischemia for patients, as they suggest the body was able to correct the cause of ischemia by reperfusion, either through the affected vasculature or via collateral vasculature. Secondly CVAs which do not resolve in the short-term progress to eventual neuronal cell death and are designated appropriately as acute ischemic strokes (AIS). The ambiguity of TIA vs. AIS can be confusing, especially to patients and their families, as it can be unclear if neuronal cell death has occurred in the acute setting [10]. Additionally, just as diagnosis of acute hemorrhage can provide insight into potential causes of disease, finding characteristic signs of ischemic CVA can offer differentials toward the cause of neuronal damage such as atherosclerosis, hypoperfusion injury, constriction of the vasculature, cardiac valvular disease, atrial fibrillation, emboli, or thrombus. While having described the basic differences in hemorrhagic vs. ischemic CVA it is important to note that the frequency of ischemia is considerably greater at approximately 87% of acute CVAs while hemorrhagic causes of disease account for only the subsequent 13% of cases [8]. Due to the relative pervasiveness of ischemic disease in the realm of CVA we will focus on its treatment.

On paper, hemorrhage vs. ischemia may seem straight forward, but these two seemingly different pathologies present clinically similar; moreover, without experienced clinical evaluation and the aid of NECT scans, difficulties in accurate diagnosing arise [11]. In some cases, patients present classically with FAST symptoms which stands for (FACE: numbness, uneven smile, drooping, ARM and LEG: weakness, numbness, SPEECH: slurred, mute, TIME: call the ambulance fast), but other times indistinct symptomology can complicate the matter with generalized symptoms of altered mental status, lightheadedness, or variable changes in sensation [8]. A thorough physical examination is important in the diagnosis of acute CVA, but it cannot be the only significant factor. Stroke protocols related to acute treatment are intrinsically reliant on the initial presentation of symptoms and what this means for practitioners is that without proper documentation of a patient’s initial presentation on scene, such as timing and severity, treatment options such as thrombolytics may not be reliably administered as they carry a risk that may not be ignored.

While TIA symptomology may be transient, research within the past 10 years has elucidated that neuronal damage and even cellular death may occur during these short periods of ischemia. A great diagnostic tool in these settings is diffusion weighted MRI scans. Diffusion weighted MRI can determine when acute cellular death is present at a much more sensitive degree than NECT scans and evidence of this is often seen after a patient suffers a TIA. This discovery led to a shift in the vernacular determining the use of AIS when neurologic symptoms persist with known tissue loss, while TIA is preferred in settings of cellular dysfunction in the brain that is not contingent on a diffusion-weighted MRI showing contiguous brain tissue loss [12].

Neuronal tissue is quite sensitive to disturbances in oxygen supply and as such commands approximately 20% of oxygen that is transported in the blood and 15% of all blood leaving the heart [10]. In both cases, ischemia and hemorrhage, the interruption in oxygen and nutrient transport forces neuronal cells into a state of ATP deficiency but due to the mechanism of injury, lesions seen in ischemia tend to be continuous with the affected vasculature while hemorrhagic CVA leads to dissemination of blood into the intracranial space beneath the skull. This collection of fluid in an enclosed space leads to pressure injuries that can be distant from the vascular cause as tissue is forced against the rigid bones of the neurocranium. ATP is the energy currency of neuronal cells and to continue production of ATP in a hypoxemic state the cell is forced to undertake metabolic concessions which produce lactic acid and disrupt homeostasis. The decrease in pH caused by this lactic acidosis causes imbalances in electrolytes especially calcium. The accumulation of calcium allows unopposed interaction with multiple proteins and inactive enzymes in the cellular milieu activating them. Enzyme activation commences the cascade which inevitably ends in cellular damage and death. If blood flow does not return before membrane damage to the cell and organelles becomes irreversible, holes in the cellular membrane will push the cell toward permanent volume and protein loss and mitochondrial membrane damage will activate the apoptotic pathway via cytochrome C efflux into the cytoplasm of the neuron. Inherently a thought experiment about hypoxemic tissue injuries would make it clear that there will be regions where there is complete loss of blood supply. Just as there are areas that will have complete blood supply loss, some surrounding areas will be fed by collateral blood supply leading to a gradient of metabolic changes and differing cellular injury timelines. Areas that have complete blood supply failure will progress rapidly onward to death [6]. Adjacent areas that have either partial or inadequate collateral blood flow experience levels of ischemia that put the cells at risk for metabolic impairment but still provide enough oxygenation to stave off immediate cellular death. This region of the injury has been described as the “penumbra” and allows for cellular survival with the caveat that oxygenation be returned within an adequate timeline. Thus, the penumbra can be thought of as a zone of tissue that has particular interest when investigating treatment options of tissue resuscitation [13].

The homeostatic changes seen in acute ischemic neuronal injury include shifts in electrolyte levels considerably away from the cellular baseline [14]. These changes lead to a significant influx of reactive oxygen species (ROS) produced from mitochondria, lipoxygenase activation and degradation of cellular products. If ROS generation is not controlled through normal cellular detoxification, such as antioxidants and scavenging mechanisms of reactive species, widespread damage to almost all aspects of cellular structure is possible [6, 14]. The most important structures commonly affected are the cellular and organelle membranes, whose integrity is integral to the survival of the cell. The cellular membrane allows the cell to create an isolated internal environment that is appropriate for cellular survival and if it is intact, the cell has an ability to recover from insults that disrupt normal homeostasis. Many organelle membranes house proteins and other cellular products that are held separate from the cytoplasm because their action would be devastating if allowed free reign inside the cell proper. Take the mitochondria for instance which houses elements such as cytochrome C that when released inevitably leads to programmed cell death. Lysosomes are the disposal system of the cell and contain various degradative enzymes able to catabolize cellular structures when left unchecked, which is why they are sequestered behind an organelle membrane. In addition to intracellular homeostatic changes and membrane disruption, neuronal ischemia causes dysfunction in a neuron’s ability to release neurotransmitters, cellular receptor representation on external membranes and effective reuptake of neurotransmitters. The results of these changes are exemplified well through the main excitotoxic neurotransmitter glutamate. The main mechanism through which glutamate exerts its physiologic effect involves receptor mediated influx of calcium which in turn is a potent activator of enzymatic action [15]. In the setting of increased extracellular concentration of glutamate, as in neuronal cell death secondary to ischemic neuronal tissue injury, this influx of calcium can disadvantageously increase activation of enzymes which cleave intracellular proteins and lipids via hydrolytic action. This cellular apparatus is mediated through receptor binding interaction and as such is a possible avenue for research and treatment. Blockade of these receptors in an acute setting could provide treatment options aimed at prolonging the window of normal cellular repair mechanics prolonging the time until more definitive care can be administered [13].

As the mechanism for brain tissue injury is understood to be hypoxemic tissue environments leading to subsequent cellular dysfunction and cell death, injuries of this type, in both hemorrhagic and ischemic conditions, lead to diminished cerebral blood flow (CBF). Most of the investigation for effective treatments has understandably been focused on increasing CBF in hypoxic tissues [13]. The most successful intervention of this type as well as the most widely used is recombinant tissue plasminogen activator (r-tPA). Currently, standard of care therapy for ischemic CVA includes administration of r-tPA to patients who fall into the stringent risk assessment guidelines for administration, but evaluation of r-tPAs safe use, efficacy, and window for treatment is continuing as understanding of cellular death in ischemic disease and pharmacologic treatment in CVA is evolving. Due to the aforementioned risk assessment protocols for r-tPA administration [16], it is projected that a meager 3–5% of CVA patients meet criteria upon arrival to definitive care facilities. As such, research to safely extend these guidelines to include patients who arrive outside of the current acute treatment protocol is understandably ongoing [17]. An interesting way to address this issue is the use of stroke ambulances bringing definitive care to the field allowing for administration of r-tPA in a more timely fashion [13, 18].

3 Prehospitalization

The majority of acute CVA presentations will involve varying forms of hemiparesis, unilateral weakness or flaccid paralysis, with studies citing numbers as high as 75% of acute strokes occurring with this manifestation. CVA symptomology can evolve quickly leading to deficit exacerbation, alleviation, spontaneous resolution, or persistent impairment both in the setting prior to treatment and post therapy. In the case of chronic disability, which is the end result in approximately 25–50% of acute CVAs, patients require constant care and have significantly decreased quality of life [7]. With such diverse causes, presentations, prognoses, and consequences of acute CVA syndromes, it is paramount for treating physicians as well as those interested in research to be familiar with the diagnosis and treatment strategies of acute CVA syndromes. Resources that allow for definitive diagnostics and patient classification such as the National Institute of Health Stroke Scale (NIHSS) provide a framework for physicians to evaluate CVA patients objectively [19]. The importance of this is critical as treatment strategies differ based on the etiology of each individual patient. Due to the importance of timeline, context and patient parameters, it is imperative to separate patients into descriptive categories such as ischemic or hemorrhagic and transient or persistent prior to building a specific treatment plan [10]. The dichotomy of these patients is important not only in treatment but also expected outcomes. Currently the evaluation is secondary to acute evaluation by a specialist with physical examination, lab studies and imaging studies aiding the diagnosis. There is a popular saying in the emergency department (ED) which conveys the necessity for timely management, “Time is tissue” and there exists a no more striking example than the setting of acute stroke. Although there have been significant advances in the recognition of high-risk groups through screening, improvements of diagnostic workup and changes in the treatment of CVA; acute stroke syndromes continue to hover between the second and third most common cause of mortality with no foreseeable decline through to the year 2020 [20]. The fact that this disease is such a significant cause of chronic disability with physical, emotional and financial strain on patients, their families and national medical resources demands that an effort is made to better understand and address it through primary and secondary intervention tactics. A noteworthy improvement could be found through the reliable recognition of acute vs. subacute CVA presentation of patients initially seen by the public and secondarily by prehospital practitioners with an emphasis on the delineation of ischemic vs. hemorrhagic etiology. Advancements in the public teaching of basic clinical evaluation as well as enhancement of imaging and biological markers could expedite this process but each present caveats in the form of sensitivity, specificity, and, most importantly, availability.

The role of physiologic parameters in respect to cellular death was thought to be understood by pathologists broadly in practice for many years but it was not until 1858 that it was first cited by Virchow [21]. Neuronal cell death leads to decreased neuronal functionality and can occur in different forms, such as apoptosis, autophagy, pyroptosis, or oncosis. The nature of cellular death that predominates in an injured tissue is determined by the etiology of the cellular insult in combination with external and internal cellular mechanisms [6, 14, 22]. Specific types of neuronal cell death are understood to require transcription and translation of proteins integral to the process of recycling cellular products and has been acknowledged to occur as soon as 6 h after injury [23]. A more complete understanding of the forms of cellular injury that occur in CVA may be integral to developing contemporary treatments.

As the clinical opinion of acute CVA has shifted toward it being a treatable disease, it is tempered by the fact that current treatment options are severely limited by time windows and specific patient risk assessment profiles. Due to neuronal cells considerable vascular and metabolic demands they undergo progressive changes toward membrane and organelle degradation quickly [24]. With this is mind, intervention must be initiated as soon as possible and a focus on improving prognosis in this time dependent process. When looking at the treatment of CVA “onset to needle time” and “door to needle time” are important parameters for which we can develop standardizations of care around. “Onset to needle time” is a description of the onset of symptoms to the time that definitive treatment is administered which usually involves the patient passing from a public space to emergency medical services (EMS) and finally to an appropriate stroke facility. “Door to needle time” is a description of the delay in when a patient arrives at the hospital to when they receive treatment. As acute CVA syndrome of any etiology is a time-dependent emergency, the enhancement of patient disease recognition, transportation, and diagnostic evaluation are the most important parameters related to patient outcome after an insult to the brain has occurred. Each of these measurements emphasizes a different link in the chain that is the emergency medical response. Improvements in “onset to needle time” are often centered on the recognition of CVA symptoms by either the patient or the family or a bystander and are critical in the initiation of the treatment process [18]. This is because the longest delays in definitive treatment outside of arrival to the hospital usual take place in the patient’s or family’s acknowledgement that an acute emergency is taking place. The difficulty in this is reflected in how acute CVA presentation can be very diverse ranging from coma to slight weakness or even just mild changes in sensation. As this is an acute process, the recognition of the acute disease state must begin with the general public and studies have shown that this area is significantly lacking. This has necessitated educational initiatives such as the “facial droop, arm weakness, speech difficulty, time to call emergency services” (FAST) criteria promoted by the Cincinnati Stroke Scale and various other organizations [25, 26]. These resources hope to promote immediate EMS response by informing the public to allow them to be able to recognize critical symptoms [8]. It is doubtful that anyone who has ever been inside a hospital has not seen a poster demonstrating the FAST criteria, but more significant public education is still needed. The second area of possible enhancement in “onset to needle time” is the quick initiation of transport to the hospital, most appropriately via ambulance as CVA patients are classically unstable. This requires situational education, especially in high-risk patients as well as their family members, to encourage the patient to be seen in the emergency department (ED) even when symptoms are not particularly severe. Lastly the actual transport of the patient should be focused on immediate stabilization by trained EMS professionals with an emergent emphasis on minimizing delay of ambulance transport until arrival to definitive care. On the other hand, enhancing the “door to needle time” requires streamlining of the hospital services including a stroke alert from the transporting ambulance, immediate neurology consultation at arrival with initial intravenous (IV) line placement, prompt imaging with radiology consult, and lastly, the decision of most appropriate treatment with involvement of the patient or their family [18].

4 Initial Management Prehospitalization

A case by case understanding of initial patient presentation and symptom progression is critical in the acute management of CVA patients. Anecdotal evidence demonstrates improvement in patient care secondary to thorough bystander accounts and even in some situations corroborated by video evidence recorded on mobile phones. The importance of this correlation is made increasingly significant as CVA patients with neurologic symptoms can have severe difficulties with the interview process as they are not always able to provide their own history secondary to neurologic dysfunction [8]. As such, emergency medical services (EMS) should be advised that bystanders, whether they are family or not, should be either interviewed extensively or advised to provide an account of the onset of symptoms to the physician managing the patient. In the setting of acute CVA, time is the most important factor and subsequently on scene delay should be restricted to stabilization. An emphasis on timely transport is necessary leading to the logical conclusion that bystanders should be urged to provide a firsthand account upon arrival to the emergency department. EMS is a critical link in patient care during acute processes and evolution of stroke management should include promoting EMS providers to understand beyond initial presenting symptoms. EMS protocols facilitating transport to appropriate care facilities, sometimes meaning that the closest possible hospital may not be appropriate to provide the highest level of care thus negatively impacting patient outcomes. It is important to ensure that during the interview process the timeline of the patient’s progression is thoroughly understood. Reporting when the patient’s symptoms first began, such as a witnessed onset of facial droop and slurred speech when it is available, is the most critical factor in the patient’s personal history. Delineating the onset of symptoms as opposed to when the patient was found to have symptoms is paramount. When there is confusion on these points it can be helpful to ask the family when the patient was last seen to be at their normal baseline and this timeline will be used as the onset of symptoms based on current stroke care guidelines. This distinction is true of patients found with symptoms after sleeping as well and can place patients outside of the therapeutic window for thrombolytic treatment [8].

In the modern era it is not outrageous to expect a streamlined and effective first response protocol when time sensitive disease processes are identified in the field. It is critical to identify ways to produce improvements in response time, in EMS stabilization as well as transport to an appropriate facility with pre-stroke alerts conveyed to the hospital accepting the patient. When analyzing these processes one of the largest obstacles to overcome is diversity of transport distances and local resources. It is a problem that fights broad standardization and as such protocols must be flexible to work in diverse environments. The “door to needle” time is highly reflective of hospital protocol efficiency and is dependent on many departments working together closely. At the time the patient arrives in the ED the hospital should have already acknowledged a pre-stroke alert and will have resources ready when the EMS team arrives with the patient. At the time the patient arrives, immediate evaluation by an emergency physician is done to ensure the patient’s airways, breathing, and circulatory system are stable. Simultaneously, hospital staff should also strive to ensure the patient has at least two appropriately sized IV lines (sides of body check) and once the patient is thought to be stable by the ED physician a thorough neurologic examination should be performed by either the accepting neurologist, if present, or the treating ED physician. Also, drawing blood labs during this period is important for receiving results promptly. CVA presentation includes a variety of traditional and nontraditional symptoms and as such many different etiologies can mimic an acute CVA. Initial examination must include confirmation of possible acute CVA, excluding the mimics and looking for possible comorbidities. The National Institutes of Health Stroke Scale (NIHSS) is the suggested prognostic tool for evaluation of stroke severity during initial presentation. The NIHSS spans 11 categories on its 15-item neurologic evaluation but more importantly it is efficient to use taking less than 10 min to complete by a trained physician and most importantly it yields reproducible results correlating to the size of the suspected infarct [8, 27]. The American Heart Association/American Stroke Association (AHA/ASA) stroke guidelines hope to form “an organized protocol for the emergency evaluation of patients with suspected stroke” once the patient finds themselves being treated in an appropriate care facility [28]. Their goal is the standardization of care aimed at a decision toward proper treatment within the first 60 min of the patient’s entry to the ED. An important hospital administration focus on the creation of a “stroke team” involving all necessary disciplines of necessary care including triage staff, the treating ED physician, on call neurologist, charge nurse, CT, and laboratory staff. The ability of the “stroke team” to quickly recognize and react to the presentation of acute CVA patients prioritizes decreased “door to needle” times regardless of the current state of ED resources.

5 Imaging

Imaging plays an important role in the treatment of acute stroke. Current research-based guidelines for patient’s presenting with stroke symptoms advocate for immediate non-contrast-enhanced CT (NECT) scan for multiple reasons. Primarily NECT scans are necessary to rule out the presence of a hemorrhage as well as other pathologic processes which may mimic the symptoms of a CVA [29]. Secondarily a NECT scan is required as part of the initial workup of patients who may be treated with thrombolytics such as r-tPA. While NECT scans are increasingly helpful in the management of acute CVA patients they often are not enough to diagnose by themselves as acute strokes may not have developed to a sufficiently large extent for detection. Importantly though, NECT scans can increase a practitioner’s confidence that a patient is eligible for thrombolytics when deciding whether to administer r-tPA. As radiologic findings on NECT scans can be subtle, experienced radiologists are key in the treatment of acute CVA and telemedicine allows for instantaneous CT evaluation no matter the on-site resources of the treating facility. While NECT scans are the gold standard for initial investigation of acute CVA symptoms, studies have shown that diffusion-weighted MRI is superior to NECT cans in the diagnosis of acute ischemia. Unfortunately, diffusion-weighted MRI has not been implemented as a devoted resource in the management of acute stroke symptomology due to decreased accuracy in picking up acute hemorrhage as well as significant hurdles involving cost, lack of rapid availability, length of time needed for imaging, and difficulty in administration (patient comfort, MRI technicians, claustrophobia, metal implants). Expanding protocols to include MRI utilization is a possibility as stroke protocol continues to evolve and necessitating research toward overcoming the inherent difficulties of MRI. As the field of medical imaging has become significantly important in the treatment of stroke, other imaging options are being explored. Vascular imaging has been implied as an appropriate choice when endovascular therapy options are considered, and perfusion studies may allow for earlier and greater precision when mapping areas of ischemia, but it is important to note that stroke treatment is time dependent and implementation of new techniques should never prolong administration of r-tPA to suitable patients.

6 Stroke Biomarkers in Biofluids

Although imaging offers some insight and diagnostic value, it is important to note the drawbacks of these imaging techniques. For example, diagnostically, CTs are only a meager 30% sensitive when it comes to the diagnosis of cerebral ischemia. Additionally, the cost, time and difficulties in timely scheduling, do not make MRI any more attractive, in regards to diagnostics tools. Stroke biomarkers have recently become a utile tool that is rapid, sensitive, and offers accurate diagnostic value [30, 31]. Here, some important novel metabolomic biomarkers are highlighted which have found their utility in the field of stroke diagnostics; medically, the aim would be to identify biomarkers which enable the distinction between hemorrhagic and ischemic stroke. NR2 peptide, for example, offers diagnostic potential in the setting of acute cerebrovascular accidents as a biomarker for cerebral ischemia. Studies examining this potential have shown a direct correlation between the concentration of NR2 peptide and the size of the ischemia zone [31].

In 2015, Lui et al., observed two metabolites which seem to decrease substantially in cognitively impaired stroke patients, namely 3-indolepropionic acid and stearoyl-carnitine [32]. Lysophosphocholine, another clinically beneficial biomarker, has been shown to by itself increase the sensitivity of the ABCD2 score—which is a clinical test used outside of a hospital setting for people at high risk of stroke after a transient ischemic attack [30, 33]. In addition, there appears to be a correlation between elevated levels of lactate, pyruvate, and formate, and concomitant decreases in VLDL, LDL CH3, valine as well as 4-hydroxymethyl acetate in stroke patients when assessing plasma levels [34]. Lastly, and just as importantly, microRNAs (miRNAs) are highly beneficial diagnostic markers of hyperacute cerebral infarction (HACI); the expression of miR-16, for example, has lent itself to being a powerful biomarker for not just diagnosis but also stratification, and prognosis of hyperacute cerebral infarction [35].

7 General Treatment of Acute Ischemic CVA

Current generalized treatment that is recommended in the presentation of acute CVA involves consensus-based guidelines agreed upon by specialists with many years of experience. Generalized treatment can be thought of as the absolute basics necessity after the patient has been stabilized and attempts to correct homeostasis by targeting dehydration, hypoxia, hypertension, and blood glucose abnormalities. Each of these conditions has been shown to contribute toward worsened outcomes, which has led to the consensus-based guidelines that have been implemented in acute stroke care. Dehydration has been shown to complicate patients presenting with acute CVA by increasing blood viscosity, increasing incidence of DVTs, decreasing vascular perfusion, and renal dysfunction. The rectification of dehydration involved infusion of isotonic fluids and has only been shown to be effective in hypovolemic states and should not be employed in euvolemic states except when a patient’s blood has been found to be hyperviscous. Oxygen transportation dysfunction is characteristic of ischemia, and as such maintaining red blood cell oxygen saturation above 94% is an obvious goal, and research on CVA mortality has shown improved outcomes with the correction of hypoxia. The treatment of hypertension in the setting of acute CVA is slightly more nuanced depending on whether the patient is a candidate for r-tPA treatment. If the patient does not meet the criteria for r-tPA, then the patient’s hypertension can persist as long as their blood pressure does not rise above 220 mmHg systolic or 120 mmHg diastolic. Dramatically lowering a patient’s blood pressure is almost never done because of the risk of stroke. Hypertension is a chronic condition, and the body becomes accustomed to the higher-pressure state; therefore, in the setting of stroke treating a hypertensive patient’s blood pressure may cause the penumbra to grow. When a patient is being considered for r-tPA therapy there are very strict guidelines surrounding the patient’s blood pressure. Often the goal is to decrease the blood pressure with either labetalol or nicardipine in a controlled and gradual way prior to r-tPA treatment [36]. Blood glucose has a direct effect on neurologic dysfunction as neurons are dependent on glucose for energy. Given the brain’s requirement of glucose, it is not surprising that stress-induced hyperglycemia is commonly seen in acute stroke. Current consensus-based guidelines suggest that blood sugar level should be held between 140 and 180 mg/dl with an emphasis on avoiding hypoglycemic states. The idea being that glucose-derived energy production is necessary to prolong a neurons chance at recovering after a period of hypoxia is resolved [37].

8 Treatments

When discussing treatments in the area of acute ischemic CVA management it is important to remember that patients will present in a wide array of states. As in the management of any other pathology if the patient is unable to swallow due to weakness or unconsciousness, oral medications should be withheld. Current guidelines recommend that the patient be treated with 325 mg of Aspirin within 24–48 h of onset. The only time that this should not be adhered to is when the patient is treated with r-tPA as the antiplatelet therapy should not be combined with thrombolytics. Studies have shown that the use of Aspirin specifically reduces the reoccurrence of ischemia in the days after an acute stroke [38–40]. While Aspirin should be used ubiquitously on all patients that are not receiving r-tPA or have a history of sensitivity, administration of thrombolytics, and specifically r-tPA therapy, is much more tightly scrutinized. Most commonly, a neurologist will make the call if a patient is deemed appropriate for r-tPA therapy by reviewing the patient’s history against a “risk assessment score” or list of relative and absolute contraindications. First the patient’s age, clinical presentation, and the time of symptom onset are reviewed, followed by absolute contraindications such as current or previous intracranial hemorrhage, recent neurosurgical procedure, uncontrolled hypertension, presence of any internal bleeding, diagnosed bleeding diathesis, hypoglycemia, history of arteriovenous malformation, cancer, or aneurysm. Lastly the prescribing physician must consider the soft or relative contraindications. These considerations do not exclude patients from being treated but may help guide the physician with the help of previous experience of patients in similar categories. There are numerous considerations here but one of particular note is when a patient has only minor symptoms or is swiftly improving, there should be significant deliberation before administering a drug such as r-tPA as the severity of complications ranges from worsening CVA secondary to intracerebral hemorrhage, hemorrhages elsewhere in the body, significant angioedema of the face and tongue, often requiring intubation, and even death. Given the possibility for unacceptable consequences when r-tPA is administered inappropriately it is worth noting that with the aid of risk assessment scores it is estimated that only 2–10% of patients who present with ischemic symptomology are ruled into treatment [41, 42]. Lastly, when dealing with a medication such as r-tPA, it is critical to understand that even some patients who are deemed acceptable for treatment may experience unexpected bleeding and what to do when this happens. Current guidelines recommend discontinuation of r-tPA with reversal using a coagulation therapy as hemorrhage may be fatal. Lastly after a patient has been administered r-tPA critical observation by an experienced physician is beneficial and has led to the practice of “drip and ship” stroke protocols where patients may be treated with r-tPA at an initial facility but shortly after will be transferred to a specialty stroke center for further management. Aspirin and r-tPA may be medications that we consider synonymous with treatment of acute CVA, but the field is evolving and treatments that were once considered unconventional are being studied more rigorously. Some promising areas of expansion involve treatments such as therapeutic hypothermia which has shown promising ability to slow tissue death in patients who have undergone myocardial infarction. Inducing hypertension which is theorized to increase the chances of reperfusion in ischemic tissue is another treatment that has expounded out of the common practice of allowing hypertensive states to persist in patients who do not meet criteria for r-TPA treatment. Lastly more invasive endovascular therapies that could provide cleaning of the occlusion or stenting of collapsed vascular pathways and even hemicraniectomy to allow a release from rising intracranial pressure that can be seen in CVA are surgical options that are possible strategies that show promise as treatments progress. With studies focused on such specialized treatments, the evolution of stroke management could move into an even more concentrated realm necessitating the use of “drip and ship” protocol allowing for patients’ best outcomes.

9 Disposition

It is general consensus that all acute CVA patients need to be admitted for observation and management to a certified stroke unit. It has been shown in practice that specialized stroke units provide patients with enhanced care leading to reductions in length of stay at the hospital and a better chance of returning home after treatment even inpatient populations who are not treated with thrombolytics. When the patient requires specialized care even after the post-acute stroke, units have the experience to facilitate transfer to appropriate care facilities delineating specific medical requirements leading to increased rates of neurologic deficit recovery.

10 Heparin and Warfarin/Intermittent Pneumatic Compression/Elastic Stockings Are Effective in DVT Prophylaxis

Once initial stabilization and management of the patient has occurred, acute CVA patients have varying paths to recovery depending on the severity of the initial infarct and progression of symptoms [7]. The most striking facet about acute ischemic stroke is that the median length of stay in hospital is 4 days. This transition may seem truncated as stroke can be a significant life event but as the management of CVA patients relies on a multidisciplinary approach early transfer to specialized facilities to treat stroke patients can often be the best course of action. As the invention of stroke units in hospitals has promoted better treatment so has the understanding that transferring patients to a setting where all their needs can be met simultaneously has shown to be beneficial in overall outcome. Rehabilitation of stroke patients depends primarily on the severity of their deficits as well as their personal support structure necessitating a variety of different types of care facilities. The range varies from subacute care specialties such as inpatient facilities that concentrate on intensive care which allow for hospital level management under the direction of a treating physician while for other patients it may be most appropriate for them to undergo rehabilitation in skilled nursing facilities or even at their own homes with personalized treatment professionals visiting them where they are most comfortable [43]. Some patients will spontaneously recover during their hospitalization while unfortunately others may retain persistent deficits. The most commonly seen issues involve muscular weakness, difficulties with producing or understanding speech, inability to feed themselves, difficulties swallowing normally, changes in cognitive ability, vision changes or even psychiatric disorders brought on by neurologic dysfunction or the understanding of their deficit. Primarily, the goal of post-acute care should involve developing a treatment plan that will ultimately integrate the patient back into their community with the highest quality of life and autonomy possible. Part of this process is to allow for family members to be as involved as much as the patient would like. This is crucial as rehabilitation often requires patient and family efforts as both physical and financial needs can be enormous. There is a strong correlation between outcomes and family support availed by patients, showing that those who have a strong support structure often having better outcomes [7].

Once the patient’s condition is determined to be stable and appropriate treatment has been administered, rehabilitation should be the next immediate goal. Concurrent care should be motivated toward stopping any further complications that could arise in the post-acute setting, with an emphasis on avoiding a recurrent ischemic or hemorrhagic event and secondarily encouraging the patient to be as active as possible; specifically, in the setting of personal care including activities such as grooming, feeding, etc. In the setting of severe deficits, patients should be put through a range of motion exercises with changes in resting position as soon as tolerable, progressing toward personal care activities. The worth of immediate “stroke exercise” movement-based therapies has been well documented and exhibits an important concept. Weakness is the most common quality-of-life deficit reported by stroke survivors and using movement specific measure for deficit improvement has been effective. In a similar light, etiologic specific measures can be implemented when dealing with known diagnoses. Current clinical guidelines support this citing suggested carotid endarterectomy for patients who have majority occlusions of the carotid arteries that measure between 70% and 99% [44]. Other great examples include mandatory anticoagulant prescriptions for patients with a history of atrial fibrillation and standard antiplatelet therapy with Aspirin or Clopidogrel after patients suffer a TIA [45–47]. These prophylactic interventions are important in the discussion of acute CVA syndrome as patients with a history of each of these conditions are at significant risk. There is also significant risk for patients in the post-acute and rehabilitation stages of recovery as patients with deficits often have weakness, ataxia, or depression, leading to an increasingly sedentary lifestyle. On a case-by-case basis, anticoagulation drugs like heparin can be used to prevent deep vein thrombosis. In addition, swallowing studies are able to investigate when patients are able to feed normally and dissuade feeding tube nutrition, educated nursing staffs can prevent unnecessary skin breakdown or pressure ulcers through careful observation, fall prevention measures in patients who are unsteady, antidepressant and therapy protocols in patients facing depression, and management of bowel and bladder function as catheters have complications as well. Many of these complications can continue on in the patient’s life after return to home; moreover, education of both the family and patient is a cornerstone of successful integration back into their baseline [7].

The goal of all hospital and post-acute facility measures should be care directed at returning the patient home as soon as feasible. Discharge either to home or another similar community care setting is promoted for all patients who have recovered to a point where adequate function is achievable. As each patient transitions to their appropriate requested environment, continual effort and active participation toward their personal treatment goals are required. This process allows for patients to feel greater participation in their care, improving compliance as well as evidence of improved outcomes in patients who are able to undergo early supported discharge (ESD) treatment plans [43].

Organizing a safe and effective strategy for discharge should be among the actions taken on the first day of admission. This allows the patient and the family to plan for the extensive rehabilitation process which may consume significant time and resources. Effective organization of the discharge process should be coordinated by a single patient care advocate to allow for planning with the appropriate specialists who will be involved [7]. Stroke units have become very popular not only for experienced, dedicated care but also having support staff such as patient care advocates who are intimately familiar with the rehabilitation process moving forward from a hospital setting.

11 Conclusions

It is clear we are just beginning to understand the subtle distinctions between the varying degrees of presentation in stroke. Studies are currently aimed at both treatment and management, but most importantly, proper and timely diagnosis as these greatly influence patient outcome and subsequent quality of life. Here, recent work is highlighted, and also the importance of timely and accurate diagnosis is discussed. Certainly, it is my hope that this chapter will inspire physicians, scientists, engineers, and patients themselves to together formulate more accurate diagnostic tests directed toward proper treatment, all aimed at more effectively and more efficiently saving lives.