Keywords

1 Introduction

“Apoplexia” (“to strike suddenly”) was a term used at least 2500 years ago to describe the sudden onset of loss of consciousness [1]. It is likely that many of the cases of “apoplexia” were caused by cerebrovascular diseases. Over the centuries, the causes of mechanisms of these conditions have been progressively unveiled. Within the past decades, remarkable advances in stroke diagnosis and treatment have been witnessed.

Stroke is still a leading cause of death and disability worldwide but is widely recognized as a preventable and treatable condition. Worldwide, men are slightly more frequently affected than women. Stroke can occur at any age but is more common in the elderly [2]. The burden from stroke is expected to increase, in parallel with global ageing. It is estimated that 80% of all strokes occur in developing countries and that 80–85% of all strokes are ischemic (IS) [3].

2 Pathogenesis of Ischemic Stroke

Irreversible brain injury may occur when there is a decrease in cerebral blood flow due to arterial occlusion or hemodynamic mechanisms. Arterial occlusion may occur due to thrombosis or embolism. The irreversibly injured area due to decreased perfusion is called the “ischemic core”. Around the core, there may be an area in which function is compromised in the absence of cell death. This area, the “ischemic penumbra”, is potentially salvageable if perfusion is restored within a critical time window [4]. The efficiency of the collateral circulation is key to ensure that the penumbra does not become irreversibly injured. The main pathways of collateral circulation are the Willis circle, leptomeningeal anastomoses, as well as connections between branches of the external and internal carotid arteries [5]. One of the main goals of acute stroke treatment is to rescue the penumbra area by early reperfusion. Despite the evolving concept of a “tissue clock” that varies across subjects and determines how fast the penumbra may evolve to a core, the dogma that “time is brain” remains valid. Efforts should be made to limit the interval between onset of symptoms and reperfusion, as much as possible.

3 Diagnosis

Ischemic stroke is characterized by the sudden onset of neurologic symptoms and signs such as hemiparesis, sensory loss, dysarthria, aphasia, hemianopia, diplopia, vertigo, ataxia, and headache [6]. The clinical features vary according to the affected territory (carotid = anterior or vertebrobasilar = posterior) and the extension of ischemia. Specific syndromes point to distinct lesions, such as the Wallenberg’s syndrome in patients with lateral medullary infarcts [7].

The National Institutes of Health Stroke Scale (NIHSS) standardizes fast neurological assessment for patients with ischemic stroke and should be always performed. The scale ranges from zero to 42 and larger scores indicate greater stroke severity [8]. Online certification in NIHSS performance is available in several languages.

Differential diagnosis between ischemic and hemorrhagic strokes cannot be based on clinical grounds alone. Neuroimaging (non-contrast computed tomography, NCCT or magnetic resonance imaging, MRI) is essential for diagnosis [9]. During the first hours after IS, NCCT is often normal or shows sudden changes such as loss of the contrast between gray and white matters or effacement of sulci. Hours to days later, the infarct becomes apparent as a dark hypointense area.

In MRI, diffusion-weighted images (DWI) may show infarct areas, starting at around 30 minutes after onset of ischemia. In patients with brain stem or cerebellar strokes, the sensitivity of NCCT is lower than the sensitivity of MRI. However, during the first 48 hours, posterior fossa strokes may not be diagnosed by NCCT or MRI [10]. Fluid Attenuation Inversion Recovery” (FLAIR) MRI typically show infarcts, starting at around 4.5 to 6 hours after onset of ischemia. Susceptibility-weighted images (SWI) are useful to exclude hemorrhagic stroke. CT or MR perfusion imaging may be necessary in order to assess eligibility for thrombectomy. The mismatch between the DWI volume (to assess the “core”) and the volume of decreased perfusion is used as a surrogate of the ischemic penumbra.

Brain NCCT is the most widely used imaging test in the acute phase, but MRI may also be performed for differential diagnosis between IS, hemorrhagic stroke, and mimics. NCCT can be performed more quickly than MRI and is often preferred in the acute setting. In addition, NCCT requires less collaboration from the subject than MRI. Remaining still inside the scanner may be challenging in subjects with confusion or decreased level of consciousness. Yet, MRI may be useful to select patients for thrombectomy and also for differential diagnosis between IS and mimics.

In particular, in the acute phase of ischemic strokes in the middle cerebral artery territory, the Alberta Stroke Program Early CT Score (ASPECTS) may be used to assess the extent of the ischemic core on NCCT. The score ranges from 0 to 10 (http://www.aspectsinstroke.com). Lower scores indicate greater extension of infarcts. This score is relevant for therapeutic decisions about reperfusion with thrombectomy. NCTT may also show other signs, such as the hyperdense middle cerebral artery that represents a thrombus inside this vessel (Fig. 28.1). Computed tomography angiography (CTA) or, less often, MR angiography (MRA) is also indicated in the acute phase in order to diagnose large-artery occlusions that may be amenable to thrombectomy (Fig. 28.2).

Fig. 28.1
figure 1

Hyperdense middle cerebral artery sign

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Fig. 28.2
figure 2

Computed tomography angiography shows middle cerebral artery occlusion (arrow)

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4 Differential Diagnosis

“IS mimics” can be divided in two categories [11, 12]:

  • Vascular conditions: transient ischemic attacks, cerebral venous thrombosis, and hemorrhagic stroke.

  • Nonvascular conditions: psychogenic disorders, seizures, migraine, hypo/hyperglycemia, encephalitis, brain abscess, brain tumors or metastases, hypertensive encephalopathy, hepatic encephalopathy, Wernicke’s encephalopathy, and drug toxicity.

In particular, posterior reversible encephalopathy syndrome (PRES) is caused by reversible subcortical edema that presents as an acute neurological deficit in the setting of renal failure, blood pressure fluctuations, cytotoxic drugs, autoimmune disorders, and pre-eclampsia or eclampsia. Neuroimaging assessment reveals changes consistent with vasogenic edema predominantly in bilateral parieto-occipital regions [13]. There is no specific treatment for PRES but the disorder is usually reversible when the precipitating cause is eliminated or treated.

5 Acute Treatment

The two main objectives of treatment in the acute phase of IS are to maintain clinical stability and to decide whether the patient is a suitable candidate to reperfusion therapy such as intravenous thrombolysis and mechanical thrombectomy. In a typical middle cerebral artery IS, it is estimated that, for each minute without reperfusion, 1.9 million neurons, 14 billion synapses and 12 km (7.5 miles) of myelinated fibers are lost, making the goal of achieving reperfusion in the shortest time possible an urgent matter: time is brain! [14].

The first step, as in every critical patient, is to make sure that the patient is stable, ensure adequate airway support and ventilatory assistance, if necessary. Supplementary oxygen should be provided only to maintain an oxygen saturation of at least 94%. It is common that patients in the acute phase of a stroke present with high blood pressure. However, unless there are other clinical comorbid conditions that require lowering the blood pressure (i.e., acute heart failure, acute coronary event, aortic dissection), blood pressure levels up to 220/120 mmHg can be tolerated in the first 24 hours after stroke onset in patients not submitted to intravenous thrombolysis. For those treated with intravenous alteplase, the blood pressure should be kept below 180/105 mmHg. In hypotensive/hypovolemic patients, adequate fluid replacement and even vasoactive drugs should be used in order to maintain adequate brain perfusion. Blood pressure and heart rate should be monitored [15].

Assessment of peripheral pulses should be performed in the four limbs in order to assess the possibility of aortic dissection, a contraindication to intravenous thrombolysis. An intravenous line should be installed. The first complementary test that should be ordered is the blood glucose level because hypo- or hyperglycemia can mimic stroke symptoms and also are linked to worse prognosis of ischemic stroke. Blood glucose levels under 60 mg/dL should be promptly treated with intravenous 50% glucose until correction. In the hyperglycemic patient, blood glucose levels of 140–180 mg/dL should be targeted.

The HeadPoST clinical trial [16] showed no difference in outcomes in patients lying flat or with the head elevated to 30° in the first 24 hours after stroke onset. Overall, a 30° head elevation should be maintained. However, for patients with occlusion/subocclusion of proximal vessels and a possible hemodynamic mechanism responsible for the stroke, a lying-flat position in the first 24 hours may be beneficial, as long as it is tolerated.

After or during clinical stabilization the stroke rapid-response team (code stroke), if available, should be activated aiming to reduce any delay in the evaluation for reperfusion therapy. NCCT should be promptly performed to exclude intracranial hemorrhage, intraparenchymal brain tumors, signs of recent head trauma, alternative diagnosis and assess IS volume.

5.1 Intravenous Thrombolysis

The first effective treatment described for acute ischemic stroke was intravenous thrombolysis with alteplase (rtPA), which should be considered for patients with less than 4.5 hours of interval from the last time known well and any disabling deficit. Blood glucose level and head NCCT are the only tests required before starting intravenous thrombolysis in most cases. Their results are relevant to exclude hypo/hyperglycemia and intracranial hemorrhage. Coagulation tests are necessary prior to thrombolysis if there is history of coagulopathy or use of anticoagulants. Other recommended tests in the acute phase are partial thromboplastin time, EKG, troponin, complete blood count, urea/BUN, creatinine and electrolytes. Yet, intravenous thrombolysis should be started prior to results of these tests.

The number needed to treat (NNT) to achieve an excellent functional outcome (modified Rankin Scale score of 0–1) in 90 days of intravenous thrombolysis is time-dependent, ranging from 4.5 in the first 1.5 hours from stroke onset to 14, between 3.0 and 4.5 hours [17]. The shorter the time until treatment, the greater are the chances of a good outcome.

Greater flexibility has emerged for several conditions previously considered as contraindications. For example, in the case of an intracranial extra-axial tumor (i.e., meningioma) or unruptured intracranial aneurysm with less than 10 mm, intravenous rtPA is considered “probably recommended” in the last American Heart Association/American Stroke Association (AHA/ASA) Guidelines [9, 15]. The procedure also “may be considered” in case a lumbar puncture has been performed within the past 7 days. In some other conditions of great interest in the neurosurgical field, the use of intravenous alteplase should be discussed in an individual basis. For intracranial vascular malformations and giant aneurysms, the indication of thrombolysis is “not well stablished” according to AHA/ASA guidelines. For intracranial intra-axial tumors, intracranial or spinal surgery in the last 3 months or previous history of intracranial hemorrhage, thrombolysis is considered “potentially harmful”. Under these circumstances, the benefit of rtPA treatment should be weighed against the risks. A list of the main contraindications for intravenous thrombolysis is shown in Table 28.1 and a complete list can be found in the AHA/ASA guidelines [9, 15].

Table 28.1 Main contraindications for IV thrombolysis
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The dose of intravenous alteplase for ischemic stroke is 0.9 mg/kg (10% given as a bolus infusion and the remaining 90%, over 1 hour), a dose that is inferior to that used for acute myocardial infarction. The percentage of patients without any symptomatic intracranial hemorrhage after thrombolysis is around 94% [18].

If the new neurologic deficits are identified upon awakening or the onset of the neurological deficits are unknown and the last time seen well time is longer than 4.5 hours, advanced imaging techniques can be used to assess eligibility for intravenous thrombolysis. Considering that acute strokes may appear on diffusion-weighted MRI but not on FLAIR images up to 4.5–6 hours after the onset of symptoms, the WAKE-UP trial randomized patients with normal FLAIR but abnormal diffusion-weighted results, to either thrombolysis or no treatment. In this study, alteplase was beneficial in patients who fulfilled the eligibility criteria for the protocol [19]. The EXTEND trial confirmed the benefits of intravenous thrombolysis in wake-up strokes [20].

The most feared complication of intravenous thrombolysis is symptomatic intracranial bleeding. Neurological worsening during thrombolysis should prompt the following measures [15]: interruption of alteplase infusion; complete blood count, prothrombin time/international normalized ratio (INR), activated partial thromboplastin time, fibrinogen, blood type and cross-match; head NCCT. If bleeding is confirmed, 10 units of cryoprecipitate should be infused over 10–30 minutes; if the fibrinogen level is below 150 mg/dL, then an additional dose should be administered. Tranexamic acid (1000 mg) should be infused intravenously over 10 min, or 4-5 g of epsilon-aminocaproic acid should be administered intravenously over 1 hour, followed by 1 g until bleeding is controlled. Neurosurgical drainage of the intracranial hematoma may be required. Intensive care should be provided at all times.

5.2 Mechanical Thrombectomy

A major issue of intravenous thrombolysis is the low reperfusion rates in patients with proximal large-vessel occlusions. The rate of recanalization may be as low as 6% in occlusion of the intracranial internal carotid artery, 30% in the M1 segment of the middle cerebral artery (MCA) and 44% in the M2 segment of the MCA [21]. Mechanical thrombectomy emerged as an intervention capable of enhancing reperfusion rates. Several clinical trials around the world proved the benefit of mechanical thrombectomy within the first hours after stroke onset: MR CLEAN in the Netherlands, ESCAPE in Canada, EXTEND-IA in Oceania, REVASCAT in Spain, SWIFT-PRIME in the USA, among others in developed countries; and more recently the RESILIENT trial, in Brazil, the only conducted in a developing country [22,23,24,25,26,27].

The Highly Effective Reperfusion evaluated in Multiple Endovascular Stroke Trials (HERMES) collaboration pooled data from the first five clinical trials cited above and concluded that the NNT for thrombectomy to reduce disability by at least one level on the modified Rankin scale for one patient was 2.6, one of the best NNT in Medicine. According to AHA/ASA guidelines, patients with proximal occlusion of the intracranial internal carotid artery or M1 segment of the middle cerebral artery, less than 6 hours from stroke onset, with a NIHSS score of at least 6 and an ASPECTS of at least 6 should receive mechanical thrombectomy. If also eligible to IV alteplase, the patient should receive it even if mechanical thrombectomy is being planned [9]. Within the 6-hour window there is no need for advanced imaging techniques. NCCT and CTA are sufficient to evaluate imaging eligibility criteria.

Two recent clinical trials extended the time window of possible eligibility to mechanical thrombectomy until 24 h after the last time known well, mainly by selecting patients who are “slow progressors” (still have a big area of salvageable penumbral tissue after several hours). To select those subjects, they assessed either a clinical radiological mismatch using MRI diffusion sequence or CT perfusion to estimate the core of the ischemic stroke compared with the clinical severity of the stroke, or an estimate of the salvageable penumbral area using CT or MRI perfusion. The intervention is highly effective (NNT = 2) in patients who fulfill eligibility criteria up to 6–24 hours after onset of symptoms or after having been seen well for the last time, but only a small percentage of patients typically meet these criteria in clinical practice [28, 29].

Besides the change in the paradigm of time for the classical indication of mechanical thrombectomy, other important questions are being addressed by new research regarding the use of endovascular techniques for occlusions of the M2 or M3 segment of the MCA, for patients with low NIHSS, for large core strokes with low ASPECTS scores, to cite a few examples. These clinical scenarios are still an area of debate between specialists and should be evaluated in an individualized basis. A few clinical trials are currently ongoing to address some of these issues about effectiveness of thrombectomy: TESLA, TENSION and IN EXTREMIS (LASTE) are studying MT in the patients with large cores. ENDOLOW and IN EXTREMIS (MOSTE), in patients with low NIHSS scores.

6 Summary—Reperfusion Therapies

According to current guidelines, specific neuroimaging tests are required to define indication of reperfusion therapies. Advanced neuroimaging is necessary to define whether thrombectomy should be offered to patients who present more than 6 hours after onset of symptom but should not delay intravenous thrombolysis in eligible patients. In summary, in addition to neurological evaluation:

  • For intravenous thrombolysis up to 4.5 hours after onset of symptoms, NCCT is sufficient.

  • For thrombectomy up to 6 hours after onset of symptoms, NCCT and CTA are sufficient.

  • For thrombectomy later than 6 hours after onset of symptoms, either DWI-MRI or CT/MRI perfusion are currently recommended.

  • For wake-up strokes, MRI for assessment of DWI and FLAIR images are currently recommended if thrombectomy is not planned.

7 Complications in the Acute Phase

Neurological or systemic complications may occur after stroke. Progressive neurological worsening after stroke may occur due to recurrent embolism, increase in thrombosis extension or failure of the collateral circulation. Stroke progression may occur in up to 43% of the patients, more often within the first 48 hours after stroke [30,31,32]. There are neither strong evidence-based data to support treatment of an early single seizure, nor to support lack of treatment. Current guidelines recommend that antiepileptic drugs should be administered for patients with recurrent seizures. Drugs should be tailored to individual patients´ characteristics. Prophylactic treatment with antiepileptic drugs is not recommended [15].

Given that the patient’s neurologic status may fluctuate rapidly, serial neurologic assessments are required to identify possible urgent situations. Drowsiness that starts between the first and the fourth day after the onset of symptoms may be the only sign of brain edema, can occur in addition to or be followed by asymmetry in pupillary size, periodic breathing, or new neurological signs [33]. NCCT can confirm mass effect due to edema in infarcts in the internal carotid artery territory as well as in cerebellar strokes. Midline shifts may occur in “malignant” infarcts affecting the territories of the carotid or middle cerebral arteries.

A pooled analysis of the DECIMAL (Decompressive Craniectomy in Malignant Middle Cerebral Artery Infarcts), DESTINY (Decompressive Surgery for the Treatment of Malignant Infarction of the Middle Cerebral Artery) and HAMLET (Hemicraniectomy after Middle Cerebral Artery Infarction with Life-threatening Edema Trial) studies showed that, in patients aged 60 years or less with brain swelling due to large unilateral middle cerebral artery infarcts, who evolve with neurological deterioration within 48 hours after stroke onset, decompressive craniectomy with dural expansion significantly decreases mortality [34]. In untreated patients, mortality rates can be as high as 80%. The NNT are: two for survival with a modified Rankin scale score of four or less; four, for a modified Rankin scale score of three or less; and two, for survival irrespective of functional outcome. The pooled analysis indicated that 14% of surgically treated patients may evolve with mild disability, none with no disability and 86%, with moderate to severe disability or death. Considering the high rates of disability for survivors, individual wishes and beliefs should be taken into account before performing surgery by consulting advanced directives or, in the absence of such directives, family members. Patients typically have a decreased level of consciousness by the time surgery is considered. For patients aged more than 60 years, decompressive surgery also decreases mortality but the burden of disability is higher, compared to younger treated patients [35, 36].

For subjects with large cerebellar infarcts that compress the brain stem, decompressive suboccipital craniectomy with dural expansion is indicated. This procedure is associated with good survival and disability outcomes. In patients with obstructive hydrocephalus, ventriculostomy may be recommended [15, 37].

Medical complications such as pneumonia, venous thromboembolism, urinary tract infection, cardiac complications and pressure ulcers may also occur within the first weeks to months poststroke and decrease the likelihood of a good recovery [38]. Organized treatment in stroke units contributes to prevention, diagnosis and treatment of these events.

8 Stroke Units

In the acute phase, patients with stroke should be admitted to stroke units, specialized wards where multidisciplinary teams exclusively manage stroke patients. Typically, the team includes neurologists, nurses, physical, occupational and speech therapists. Social workers, psychologists, rehabilitation medicine physicians as well as nutritionists may participate in patient care. Rates of death, dependency and the need of institutional care are significantly lower in patients admitted to stroke units, compared to other models of care [39, 40]. Benefits apply to all types of strokes, across all levels of severity.

9 Investigation of Etiology

After the acute phase, clinical features and results of different tests are assessed, in an effort to determine the most likely cause of the IS and thus, plan appropriate measures for secondary prevention. Overall, the following steps are necessary:

  • Review the main risk factors for ischemic stroke: age, arterial hypertension, diabetes mellitus, hypercholesterolemia, obesity, physical inactivity, atrial fibrillation and other heart conditions, smoking, alcohol abuse, sleep apnea and family history of stroke [41, 42].

  • Review the circumstances in which the symptoms started: after cardiac surgery or digital subtraction angiography, history of major or minor trauma, among others.

  • Search for clues of systemic disease on the physical examination including assessment of peripheral arterial pulses, heart murmurs, lesions in the eyes, skin or joints.

  • Tests for cardiac evaluation: electrocardiogram, echocardiogram (transthoracic or, if an atrial abnormality is suspected, transesophageal), rhythm monitoring with Holter or more prolonged evaluation with in-patient/outpatient telemetry or implantable loop recorders.

  • Tests for evaluation of the aorta as well as cervical and intracranial segments of arteries that supply the brain: CTA, MRA, cervical Doppler for evaluation of carotid and vertebral arteries, transcranial Doppler for evaluation of intracranial arteries. Transcranial Doppler can also provide other useful information such as evidence of paradoxical embolism by means of the bubble test. Digital subtraction angiography is rarely performed for diagnostic purposes if non-invasive tests are available.

  • Specific blood tests for investigation of autoimmune, hematological and infectious diseases such as lupus, temporal arteritis, sickle cell anemia, HIV, syphilis, Chagas disease in endemic areas, and other conditions.

  • Urinalysis to assess proteinuria. Nephrotic syndrome, for instance, is a risk factor for thrombosis.

  • Other tests: cerebrospinal fluid analysis may be required if autoimmune or infectious vasculitis is suspected. Genetic tests may confirm diagnoses of CADASIL [43], Fabry disease [44], or inherited thrombophilia—for instance due to prothrombin mutations [45]. Investigation of systemic cancer may be performed if thrombophilia secondary to an occult neoplasm is suspected.

The most likely cause of IS can be determined after clinical, laboratory and imaging features are interpreted. Different classification systems have been developed for research purposes and may help to define etiologies in clinical practice. The TOAST (Trial of Org 10,172 in Acute Stroke Treatment) criteria were published in 1993 [46] while the Causative Classification System (CCS) [47] and the ASCOD criteria [48] were published more than a decade later. Overall, all these systems have in common the classification of ischemic stroke in five subtypes: atherosclerosis affecting large arteries, cardiac or aortic embolism, small-vessel disease (“lacunar” lesions), other determined etiologies or undetermined etiologies. The criteria to define the likelihood of belonging to one of these groups vary according to the chosen classification system. The frequencies of different etiologies vary in different countries but “other determined etiologies” are always the less frequent. Examples of such etiologies are [49]: cervical or intracranial artery dissection, Moyamoya syndrome, reversible cerebral vasoconstriction syndrome, sickle-cell disease, migraine-induced stroke, illicit drug abuse, inflammatory arteriopathies (Takayasu arteritis, giant cell arteritis, primary angiitis of the central nervous system, polyarteritis nodosa, Behçet disease, Churg-Strauss syndrome, Kohlmeier-Degos disease), infectious arteriopathies (syphilis, HIV, herpes zoster, tuberculosis, among others), inherited arteriopathies (Fabry’s disease, Susac syndrome, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, fibromuscular dysplasia), inherited or acquired thrombophilias, primary hematologic disorders (e.g., polycythemia vera, essential thrombocythemia, thrombotic thrombocytopenic purpura, among others).

10 Secondary Prevention

Control of risk factors for vascular diseases is a main goal of secondary prevention. At the moment, the target for blood pressure is to achieve levels below 140/90 mmHg after the acute phase. Statins are prescribed for patients with IS due to atherosclerosis. For other causes, prescription of statins can be managed according to local guidelines [50,51,52].

Diabetes, obesity and physical inactivity should be treated. Treatment of sleep apnea might be considered [53]. Smoking and excessive alcohol intake should be discontinued.

In addition, before etiology is determined, aspirin (50-325 mg qd) is widely used in the absence of contraindications [53]. Alternatively, aspirin 25 mg in combination with extended-release dipyridamole twice a day may be considered. For patients who have stroke recurrence despite these medications and in those allergic to aspirin, clopidogrel 75 mg qd can be prescribed. The choice of the antiplatelet drug should be influenced by individual characteristics of the patients. For specific etiologies, other interventions are necessary.

For instance, if stroke etiology is cardiac embolism due to non-valvular atrial fibrillation, anticoagulation with vitamin K antagonists (such as warfarin) or direct anticoagulants is required in the absence of contraindications [53]. A number of variables must be taken into account to decide if/when to start these drugs, such as extension of the stroke, disability and presence of hemorrhagic transformation. Levels of evidence are lower for other possible indications of vitamin K antagonists, such as: recent myocardial infarction with ventricular akinesis or dyskinesis; left atrial or ventricular thrombi; dilated cardiomyopathy; rheumatic mitral valve disease; prosthetic mitral or aortic valves; Chagas disease.

For patients with minor strokes (NIHSS <4), dual antiplatelet treatment with aspirin and clopidogrel for 3 weeks may be considered [15, 53]. In addition, for patients with intracranial atherosclerosis (70–99%), dual antiplatelet for 90 days is considered reasonable [53]. Angioplasty is not indicated in these patients [54], who should be submitted to aggressive control of risk factors.

In patients with >50% symptomatic stenoses of the cervical internal carotid artery and modified Rankin scores up to two, angioplasty or endarterectomy must be considered as long as the periprocedural rate of periprocedural stroke or death is lower than 6% [53].

For patients with patent foramen ovale (PFO), there are still controversies about the best therapeutic strategy. Three studies contributed to change the overall view about the lack of benefit of endovascular PFO closure in patients in whom no other causes of stroke were found: CLOSE (Patent Foramen Ovale Closure or Anticoagulants versus Antiplatelet Therapy to Prevent Stroke Recurrence), RESPECT (Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment) and Gore REDUCE (GORE® HELEX® Septal Occluder / GORE® CARDIOFORM Septal Occluder for Patent Foramen Ovale (PFO) Closure in Stroke Patients—The Gore REDUCE Clinical Study) [55,56,57]. Despite indications that endovascular closure may be beneficial to patients with large PFOs or atrial septal aneurysms, the risks of IS recurrence were low in these studies, whether or not this intervention was performed.

For patients with arterial dissections, the best approach for secondary prevention is also controversial. In the CADISS (Cervical Artery Dissection in Stroke Study), no significant differences were found between risks of ipsilateral stroke or death after 3 months of treatment with either antiplatelet or anticoagulant drugs in patients with cervical dissections but limitations in the study limit generalization of conclusions and therapy should be tailored according to individual characteristics [58].

For patients with meningovascular syphilis, penicillin is the treatment of choice. For autoimmune vasculitis, steroids and immunosuppression are typically prescribed. Patients with strokes of undetermined etiology are treated with aspirin but the optimal therapeutic strategy for these subjects is still unclear. In particular, it is unknown whether anticoagulation may benefit patients with embolic stroke of undetermined source (ESUS), a particular type of stroke of undetermined etiology. The proposed diagnostic criteria for ESUS are [59]:

  • Non-lacunar IS detected by NCCT or MRI;

  • Absence of extracranial or intracranial atherosclerosis causing ≥50% luminal stenosis in arteries supplying the area of ischemia;

  • No major risk cardioembolic source of embolism such as permanent or paroxysmal atrial fibrillation, sustained atrial flutter, intracardiac thrombus, prosthetic cardiac valve, atrial myxoma or other cardiac tumors, mitral stenosis, recent (<4 weeks) myocardial infarction, left ventricular ejection fraction <30%, valvular vegetations, or infective endocarditis;

  • No other specific cause of stroke identified (for instance, arteritis, dissection, migraine/vasospasm, and drug abuse).

The following conditions have been implicated as possible causes of ESUS [60]: myxomatous valvulopathy with prolapse, mitral annular calcification, aortic valve stenosis, calcific aortic valve, sick-sinus syndrome, atrial appendage stasis with reduced flow velocities or spontaneous echodensities, atrial septal aneurysm, Chiari network, covert paroxysmal atrial fibrillation, covert non-bacterial thrombotic endocarditis in patients with cancer, aortic arch atherosclerotic plaques, cervical and cerebral artery non-stenotic plaques with ulceration, PFO, and atrial septal defect.

11 Rehabilitation

Interventions to prevent complications and possibly facilitate plasticity mechanisms should be provided as soon as possible, when patients are medically stable. Some of the recommendations from the American Heart Association/American Stroke Association are outlined below [61]:

  • Prophylactic-dose subcutaneous heparin (unfractionated or low-molecular weight heparin) should be prescribed during acute and rehabilitation hospital stay or until the patient regains mobility.

  • Patients diagnosed with poststroke depression should be treated with antidepressants in the absence of contraindications; effectiveness of treatment should be monitored.

  • Formal evaluation of basic and instrumental activities of daily living, communication and functional mobility should be performed before discharge. The results should be used to plan the discharge process.

  • Early dysphagia screening is recommended for acute stroke patients to identify dysphagia or aspiration, which can lead to pneumonia, malnutrition, dehydration, and other complications.

  • Nasogastric tube feeding should be used for 2–3 weeks to provide nutritional support for patients who cannot swallow safely. Gastrostomy should be performed if safety is not expected in the chronic phase. Behavioral interventions may be considered to treat dysphagia.

  • Speech therapy is indicated for aphasic patients.

  • Intensive mobility-task training is recommended to improve gait.

  • Task-specific training is recommended to improve upper limb motor function.

It is considered that there is not enough evidence to support the efficacy of routine very early mobilization after stroke compared with conventional care. In the randomized, controlled trial of the efficacy and safety of very early mobilization within 24 hours of stroke onset (A Very Early Rehabilitation Trial [AVERT]), the high-dose, very early mobilization protocol was associated with a reduction in the odds of a favorable outcome at 3 months [62]: Therefore, this type of intervention is not currently recommended.

12 Quality of Care

Over the past decades, measures of quality of care for IS have been developed. Certification systems and methods for evaluation of care vary across countries. In the United States, for instance, hospitals in selected regions were instructed to collected data about the following seven performance measures in the “Get with the Guidelines” program: intravenous rtPA in patients who arrived less than 2 hours after symptom onset, antithrombotic medication within 48 hours of admission, deep vein thrombosis prophylaxis within 48 hours of admission for nonambulatory patients, discharge use of antithrombotic medication, discharge use of anticoagulation for atrial fibrillation, treatment for low-density lipoprotein >100 mg/dL in patients meeting National Cholesterol Education Program Adult Treatment Panel III guidelines, and counseling or medication for smoking cessation [63].

The Joint Commission’s Primary Stroke Center Certification Program, based on the Recommendations for Primary Stroke Centers published by the Brain Attack Coalition and American Stroke Association statements for stroke to evaluate hospitals that function as Primary Stroke Centers, assessed ten performance measures (https://www.jointcommission.org/measurement/measures/stroke/): deep venous thrombosis prophylaxis, discharge on antithrombotics, anticoagulation therapy for patients with atrial fibrillation, assessment of eligibility for intravenous thrombolysis, initiation of antithrombotic medication within 48 hours of hospitalization, assessment of lipid profile, screening for dysphagia, smoking cessation, stroke education, and plan for rehabilitation.

Monitoring of performance measures is encouraged in centers that provide stroke care. Identification of gaps and opportunities for improvement are powerful tools to optimize pathways, daily care and hence, contribute to enhance outcomes.

13 Highlights

  • Stroke is a leading cause of death and disability worldwide.

  • Thrombolysis and thrombectomy can decrease the burden from stroke.

  • Time is brain. Reperfusion therapies should be administered as early as possible to eligible patients.

  • The gold standard for acute stroke care is treatment provided by a multidisciplinary team in a stroke unit.

  • Decompressive craniotomy may be life-saving in large middle cerebral artery or cerebellar ischemic stroke.

  • Definition of the most likely etiology of ischemic stroke is necessary to provide appropriate prevention measures and thus avoid stroke recurrence.