Acute ischemic stroke is in most areas of the world the most prevalent neurological emergency; one American has a stroke every 40 seconds. In the United States alone there are more than 780,000 strokes per year, with the majority being new events.¹ The number of hospitalizations in the United States continues to increase. The cost associated with the care of stroke patients in 2008 was $65.5 billion; the cost of care per patient is almost double for severe strokes. Stroke is the third leading cause of death in the United States, and among adults the leading cause of long-term disability. Stroke is disproportionately a disease of individuals of lower socioeconomic status, African Americans, elderly persons, and women in the older age groups. Ischemic stroke accounts for the majority of stroke subtypes in case series from the United States.¹

The majority of stroke survivors have some form of a residual disability, though 50% to 70% will nonetheless regain functional independence.¹ These patients remain at high risk for subsequent morbidity and mortality. A small proportion of acute ischemic stroke patients will be eligible for reperfusion therapy, and an even smaller proportion will actually receive it. In series from various locations in the United States the rates of thrombolysis varies when considering all stroke patients but remains low at 2% to 8.5%²; however, analysis of data from the Nationwide Inpatient Service reveals this rate to be less than 2%.³ The primary reason for not receiving reperfusion therapy is arrival outside of the appropriate time window.⁴ Those who arrive by the appropriate window still have several reasons within the national guidelines for not being treated, and in some hospital series there are sizeable numbers of patients who do not meet any exclusion criteria but still are not treated.⁵ Prevention and treatment of the complications related to stroke remain the cornerstone of treatment for ischemic stroke.

Risk factors for ischemic stroke are somewhat similar to that of ischemic heart disease, with some notable exceptions. Hypertension remains the most important risk factors for ischemic stroke.⁶ Dyslipidemia, although prominent for ischemic heart disease, is a less potent risk factor for ischemic stroke.⁷ Large population-based cohort studies have failed to find a consistent association between dyslipidemia and ischemic stroke, though for the atherosclerotic stroke subtype this may still be the case.⁸

Atherosclerotic disease of the extra- or intracranial vessels is an important cause of ischemic stroke, most likely due to artery-to-artery emboli or in a smaller proportion of cases due to flow-failure.⁹ Atrial fibrillation is a unique risk factor for ischemic stroke risk and is particularly important because of the severity of the strokes from cardiac embolism and the response to acute treatment. Atrial fibrillation is more likely to be associated with large infarctions that could lead to malignant cerebral edema, as well as hemorrhagic infarcts and transformation.

Stroke remains a clinical diagnosis, and in the acute setting a history and physical examination remain an integral component of evaluation. In the triage area the staff can activate the stroke team, if they have not already been activated based on a notification from the EMTs, and will start the initial evaluation. This includes checking a finger stick glucose, vital signs, and a screening examination such as the Cincinnati Stroke Scale.¹⁰ The latter can be used with excellent reproducibility and sensitivity by nonphysician personnel and involves checking for facial droop, arm drift, and dysarthria. In patients with suspected stroke, two large-bore intravenous (IV) lines (at least 20 gauge) should be placed, and the following serum tests should be sent to the laboratory immediately: complete blood count, coagulation panel, basic metabolic panel, troponin level, and type-and-hold. Our acute stroke pathway involves completing the history, carrying out an examination, and obtaining neuroimaging (Figure 5-1).

The history must be focused, and the initial goal should be to establish the exact time of onset. Frequently patients such as the man described above will not be able to provide an exact time of onset, and in any way possible, it is prudent to confirm the time of onset with friends or family. It is important to establish if there were minor symptoms present before the ones that caused the current symptoms, as well as whether the patient woke up with the deficits. The time of onset is assumed to be the moment the patient fell asleep for wake-up strokes, and otherwise the last time the patient was seen at the baseline.

A complete neurological examination is often not necessary in the initial evaluation in the ED; the National Institutes of Health Stroke Scale (NIHSS) is the initial examination of choice. It has excellent interexaminer reliability and sensitivity for most strokes¹¹ and can be performed quickly; also, training is available free of charge through the American Heart Association. Depending on the clinical scenario, a more detailed examination may be required for suspected nondominant hemisphere injury, subtle aphasia, or cerebellar syndromes with a predominant astasia-abasia picture. Neuroimaging is obtained before or after the examination, but should be completed within 20 minutes of arrival to the ED. Streamlining the process of acute stroke evaluation, termed the “Helsinki model,”¹² which includes ambulance prenotification and ability to obtain a history before the patient arrives, early ordering of thrombolytics, and administration of thrombolytics immediately after the imaging is obtained, can reduce door-to-needle times to as low as 20 minutes without safety concerns. This process, as well as other streamlining protocols, have been successfully implemented in other stroke centers with improved treatment times.^13,14

Given that stroke remains a clinical diagnosis, a noncontrast head computed tomography (CT) is the initial test of choice for most patients.¹⁵ The primary goal of the noncontrast head CT is to rule out intracerebral hemorrhage (ICH). In acute ischemic stroke the head CT will frequently be normal. Early infarct signs can be seen in the head CT and include (1) loss of the insular ribbon, (2) sulcal effacement, and (3) loss of the grey-white junction. Occasionally, the “dense middle cerebral artery sign,” which likely represents intravascular dense clot material, is seen (Figure 5-2). Frequently adjustment of the contrast may be required to visualize the early infarct signs. The degree of early infarct signs in large middle cerebral artery infarcts can be quantified using the validated Alberta Stroke Programme Early CT score (ASPECTS).¹⁶ In the ASPECTS grading system the middle cerebral artery territory is divided into 10 segments, and a point is subtracted if a hypodensity is noted in each of the sections. The maximum score of 10 indicates no early infarct signs, and 0 indicates hypodensity in the entire territory (training in the ASPECTS is available via online portals). The ASPECTS score is increasingly used as an inclusion criterion in acute stroke clinical trials, particularly for endovascular modalities, given the association of low scores with poor outcome and symptomatic ICH.

In many stroke centers in the country, CT angiography (CTA) and perfusion are routinely performed in all acute ischemic stroke patients. CTA has the primary goal of identifying patients who have a major arterial occlusion that may not respond well to IV thrombolysis or that may portend risk of a large hemispheral infarction. CT perfusion is often obtained with CTA (Figure 5-3) and helps to identify tissue that may be ischemic, but not yet infarcted, and therefore are salvageable. CT perfusion allows the measurement of three parameters: cerebral blood volume (CBV), mean transit time (MTT), and cerebral blood flow (CBF). In early cerebral hemodynamic failure the CBV will increase as distal arterioles vasodilate as a means of maintaining CBF as a result of dropping cerebral perfusion pressure (CPP). When CPP is insufficient, CBV may remain increased or begin decreasing to normal or below, and the oxygen extraction fraction will increase; in the next stage, the cerebral metabolic rate of oxygen drops, and soon thereafter CBF will also drop.^17,18 The CBV and CBF maps are particularly useful in detecting the tissue potentially at risk from infarction, particularly when the CBF is low normal and the CBV is increased. A very low CBV alternatively may indicate already infarcted tissue. The MTT is a useful adjunct, but there may be significant asymmetry in the MTT maps without having tissue at risk, and the optimal threshold for defining perfusion failure remains controversial. Administering contrast remains a concern for many radiologists and ED physicians if the serum creatinine level is not available. Unless there is a clinical history of renal disease or diabetes mellitus, the risk of developing contrast nephropathy is low,¹⁹ and contrast should be administered without a serum creatinine level; if the concern still exists, an isotonic sodium bicarbonate infusion can be administered. In one study, 3 ampules of sodium bicarbonate were mixed in 1 L of D5W, and 1 hour before contrast imaging, the patient received 3 cc/kg, followed by 1 cc/kg for the 6 hours after the contrast was administered.²⁰ N-acetyl cysteine, 600 mg, up to three times daily is frequently administered, but its clinical effectiveness may not be as high.

Transcranial Doppler (TCD) is commonly used in acute stroke evaluation to diagnose a major cerebral artery occlusion that may dictate advanced treatment and may have a therapeutic benefit as well. The presence of a portable TCD machine in many institutions has made this a practical diagnostic tool. Magnetic resonance imaging (MRI) is available acutely in some centers, but in most centers it is not used before deciding to provide treatment in the acute setting. MRI can be useful to diagnose “stroke mimics,” distinguish transient ischemic attack (TIA) from stroke, and evaluate for the presence of a large infarction that may require a different degree of monitoring. However, MRI is not necessary to make a recommendation on thrombolysis. The diffusion weighted image (DWI) identifies areas of cytotoxic edema and infarction, though some DWI-positive lesions can be reversible. At the cellular level DWI identifies areas of impaired water molecule diffusion that frequently result from energy failure and inability to maintain membrane gradients, such that Brownian motion of water molecules is restricted.²¹ Magnetic resonance angiography provides information similar to that of CTA, but it may overestimate the degree of stenosis. Magnetic resonance perfusion (Figure 5-4) may be useful in some clinical scenarios to establish a perfusion–diffusion mismatch, but the optimal parameters to define the penumbra remain an area of controversy.

The use of biomarkers in the diagnosis of stroke has received considerable attention in the literature, particularly for diagnosing ischemic stroke, but also for prognosis. Inflammatory markers (C-reactive protein) and measures of glial and endothelial cell injury (matrix metalloproteinase-9, S100B) have been associated with a diagnosis of ischemic stroke, though further data are required to validate their routine clinical use.²²

The patient’s parallel history is obtained when his family arrives, and his last seen normal time was 2 hours before. Head CT is normal, as are all of his laboratory values. The blood pressure is 196/118. His NIHSS is 18 and is notable for global aphasia, right hemiparesis, and a right visual field cut. What are the treatment options?

IV Thrombolysis

Figure 5-5 outlines a suggested treatment paradigm for eligible patients. The only proven therapy to improve clinical outcomes for acute ischemic stroke is IV recombinant tissue plasminogen activator (rTPA). The pivotal National Institute of Neurological Disease and Stroke (NINDS) rt-PA trial indicated that in patients treated within 3 hours of acute ischemic stroke there were significant clinical benefits.²³ The NINDS rt-PA trial did not demonstrate clinical effectiveness at 24 hours, though there was a trend toward benefit. The significant benefit was gleaned at 3 months, at which time rt-PA was superior to placebo in the primary outcome of a composite of the NIHSS, modified Rankin scale, Barthel Index, and Glasgow outcomes scale. The treatment arm was associated with a 13% absolute benefit of attaining minimal-to-no disability after stroke (39% vs 26%), which translated to the number of patents needed to be treated being close to 8. There was no difference in mortality. The exclusion criteria for rTPA need to be reviewed before administration and are summarized in Table 5-1^.24 There are several relative contraindications, such as hypodensity in more than one third of the MCA distribution and major deficits, age older than 80, and minor or rapidly resolving symptoms. This man would be eligible for IV rTPA, but his blood pressure should be reduced to < 185/110 mm Hg before treatment with either IV pushes of labetalol or the use of an IV nicardipine drip.²⁴

The NINDS rt-PA study differed from other acute stroke treatment trials by narrowing the therapeutic window to 0 to 3 hours from stroke onset and by using a dose of 0.9 mg/kg of rt-PA. Since then, analyses from this and other trials have pointed to a greater benefit from earlier treatment, particularly when rTPA is started within 90 minutes of stroke onset.^25,26 Thrombolysis with rTPA is beneficial in all subgroups and stroke subtypes, and its effectiveness has been proven in community cohorts. The typical protocol in the United States includes a door-to-needle of time of no more than 60 minutes, with administration of 0.9 mg/kg rTPA using a 10% bolus given over 1 to 2 minutes, followed by the remainder of the infusion over 60 minutes. Consent is not required for IV rTPA as it is considered the standard of care, but the patient and family should be made aware that the treatment is being provided.²⁷ Thrombolysis can be safely and successfully administered via telemedicine, which is an attractive means for increasing treatment in rural and underserved hospitals.²⁸ Delays while waiting for the coagulation profile to return are common, but rTPA can be safely administered without the coagulation profile.²⁹ After thrombolysis, the blood pressure should remain less than 180/105 mm Hg, and any unacceptably high pressure should be treated promptly with easily titratable IV antihypertensive medications such as labetalol or nicardipine.

IV treatment for thrombolysis is not effective in many individuals and has a low likelihood of achieving vessel recanalization, particularly in individuals with an occlusion in one of the major intracranial arteries. Up to 34% of patients treated with rTPA experience reocclusion after recanalization, with a subsequently high risk of neurological worsening; these patients, however, still have better outcomes than those who do not recanalize.³⁰ Sono-thrombolysis has been one proposed means of improving recanalization. High-frequency sound waves can cause cavitation and the formation of small bubbles that vibrate at a sufficiently high frequency to disrupt the fibrin network in thrombo-emboli, thereby facilitating entry of a thrombolytic agent into the clot. In the CLOTBUST phase II study, 126 patients who received IV rTPA received placebo or a continuous insonation of the MCA via a 2-MHz TCD probe.³¹ The primary end point of vessel recanalization was achieved in 46% of the treatment arm vs 18% in placebo group, and the benefit was maintained at 36 hours; in a secondary outcome, there was a trend toward improved functional outcomes and no differences in safety. Including microparticles to help break up the clot has been an active area of research. In one pilot study, microparticles were able to penetrate MCA thrombi and pass beyond,^32,33 whereas others have demonstrated improved recanalization rates with the use of microbubbles.³⁴ The type and composition of the microbubbles remain under investigation. Other investigators have attempted to combat the difficulties of vessel reocclusion or to potentiate the effects of rTPA by adding pharmacological adjuncts. The CLEAR stroke trial randomized 94 patients to IV rTPA at a reduced dose (0.3 or 0.45 mg/kg) along with eptifibatide compared with IV rTPA alone at full dose (0.9 mg/kg), with the primary end point being symptomatic intracranial hemorrhage (sICH) at 36 hours.³⁵ There was no statistically significant difference in the safety outcome or clinical effectiveness at 3 months, and until further trials are performed, there is no evidence to support this approach. Holding antithrombotics for at least 24 hours after thrombolysis is currently advised.²⁴

The benefit of rTPA has been robust in routine clinical use, though there is still some resistance toward its use. Relative contraindications for rTPA use include difficult-to-control blood pressure, “too-good-to treat” or rapidly improving syndromes, age greater than 80 years, and seizure at onset. Blood pressure that requires aggressive control is not associated with increased rates of hemorrhage in at least one retrospective review,³⁶ whereas the benefit of aggressive glycemic control after thrombolysis remains under investigation. Several investigators have found that a substantial proportion (close to 20% in most case series) of the “too-good-to-treat” patients have poor neurological outcomes.^37-39 It remains an active area of research to identify which of these patients will have worsening conditions and which will not, though a more severe early benefit, primary motor symptoms, or the presence of a major cerebral artery occlusion appear to be notable risk factors for a poor outcome in the “too-good-to-treat” group.^39-41 However other case series have demonstrated that these patients may not have a poor outcome.⁴² On the other hand, the safety of thrombolysis has been established for stroke mimics and these patients with mild stroke.⁴³ Whether these “too-good-to-treat” or rapidly improving patients should be treated remains a clinical decision on a case-by-case basis, with decision making driven by the clinical impression of the disability the patient would have if the condition was left untreated. There is additional controversy as to whether individuals who are older than 80 years should be treated, though they still gain clinical benefit.^44,45 Several case series have reported an acceptable safety profile in the pediatric population,^46,47 though the clinical benefit in the pediatric population remains unknown.⁴⁸ Intravenous rTPA remains beneficial even in patients with an initially severe deficit, and it appears to be safe in patients with cervical artery dissection, seizure at onset, and the presence of abnormality on CT; case series have documented it to be safe in patients with a known unruptured anteriovenous malformation or an aneurysm.⁴⁹ IV rTPA should not be withheld from an otherwise eligible patient in whom there is an incidental finding of unruptured aneurysm.

Whether IV rTPA should be withheld from patients with other exclusion criteria is an additional area of controversy. A recent report demonstrated the safety at a single center of administering rTPA to any patient arriving at less than 3 hours and having no hemorrhage on head CT, whereas another report documented a high ICH rate after thrombolysis in patients taking warfarin and having an INR < 1.7.⁵⁰ Regardless of other factors, the primary reason for not receiving IV thrombolysis remains arrival outside of the appropriate time window.² Interestingly, the bulk of the litigation cases in the United States related to rTPA are related to failure to administer the medication.⁵¹

The most dreaded complication from rTPA infusion is hemorrhage, of which ICH is the most important. The patient will typically present with headache, nausea, and vomiting, worsening of the neurological deficit, and in more severe cases altered level of alertness. In the NINDS rt-TPA trial, the rate of symptomatic ICH (sICH), defined as the presence of hemorrhage on CT of the head characterized by a suspicion of hemorrhage or a decline in neurological status, was present in 6.4% of those receiving rTPA and 0.6% in those receiving placebo.²³ Of those who had an sICH in the rt-PA arm, by 3 months after the trial, nearly 50% had died. Asymptomatic ICH was present in 4.4% overall. Major systemic hemorrhage was rare, whereas minor extracranial hemorrhage occurred in 23% of patients treated with rt-PA (compared with 3% in the placebo arm). In the ECASS studies, hemorrhages were classified as follows (Figure 5-6): Hemorrhage infarction Type 1 (HI-1): small petechiae along the margins of the infarct; Hemorrhage infarction Type 2 (HI-2): more confluent petechiae within the infarcted area but without a space-occupying effect; Parenchymal hematoma Type 1 (PH-1): a hematoma in < 30% of the infarcted area with some space-occupying effect; and Parenchymal hematoma Type 2 (PH-2): a hematoma in > 30% of the infarcted area with substantial space-occupying effect or any hemorrhage lesion outside the infarcted area.⁵² PH-2 is the only one of the 4 groups associated with clinical decline.⁵³ HI-1 and -2 are not predictive of a poor outcome, but their presence may indicate successful reperfusion and an association with subsequent clinical benefit from thrombolysis.⁵⁴ The risk factors for development of sICH after thrombolysis have been variable depending on the study and the use of several scoring systems. The most consistent risk factors across several studies include early hypoattenuation on head CT, elevated serum glucose and history of diabetes mellitus, hypertension,⁵⁵ increased stroke severity and size of stroke on DWI,⁵⁶ especially if there is reperfusion,⁵⁷ and protocol violations with treatment outside of the time window.^56,58-60 It remains controversial whether treatment with antiplatelet agents before thrombolysis,^61,62 pretreatment with statins,^63,64 presence of micro-hemorrhages on T2* sequence or gradient echo of MRI,^65,66 leukoaraiosis,⁶⁷ advanced age,⁴⁵ hemostatic factors,^68,69 early disruption of the blood-brain barrier via permeability imaging,⁷⁰ markers of endothelial cell injury (matrix metalloproteinase 9, S100B),²² fibrinogen degradation product, or persistent arterial occlusion⁷¹ convey an additional risk for sICH. The presence of early signs of infarction correlated with more severe stroke in the NINDS tPA trial, though they did not mitigate the clinical benefit of treatment or alter the safety outcomes.⁷² Perfusion studies may play an additional role in identifying those patients who are at high risk of sICH. The presence of a large area of reduced CBF as measured by Xenon CT correlated well with an increased risk of sICH,⁷³ whereas a very low CBV may be a better predictor than absolute size of the infarct or relative ischemia.⁷⁴ There are insufficient data at this time to recommend withholding thrombolysis for patients with these characteristics, though they may be ones for whom more intensive monitoring in the first 24 to 48 hours is warranted.

Management of sICH after rTPA infusion usually starts with discontinuing the infusion of thrombolytics in those patients for whom there is a clinical suspicion, followed by immediate noncontrast head CT and a full coagulation panel including fibrinogen and a complete blood count. By the time sICH is detected on CT scan, most patients have completed their rTPA infusion. However, if active bleeding is found, options include fresh frozen plasma, prothrombin complex concentrates, cryoprecipitates, platelet transfusions, recombinant factor VII, or even surgery. Unfortunately none of these treatment have been proven to reverse the effects of rTPA.⁷⁵

Another rare clinical complication of rTPA infusion is angioedema, which appears to be caused by a similar pathway that has been implicated in angiotensin-converting enzymes. It typically occurs 30 to 120 minutes after the infusion of rTPA, in typically 1% to 3% of patients and curiously enough tends to occur contralaterally to the ischemic lesion.⁷⁶ It needs to be distinguished from tongue hematoma, which has also been reported. Activation of the complement and kinin cascades due to the presence of increased concentrations of plasmin have been implicated. This latter pathway is implicated in increased risk being present in patients taking ACE inhibitors.⁷⁷ It seems reasonable to assume that patients who develop angioedema may be at an additional risk of the same complication with ACE inhibitors in the future. Management is based on the paradigms from case series and includes administration of diphenhydramine 50 mg IV and H2-blocker as first line, followed by 100 mg IV of methylprednisolone or nebulized epinephrine. In the more severe cases, the rTPA infusion should be stopped because of the possibility of a loss of the airway and the potential need for endotracheal intubation. The latter may require fiber-optic assistance in severe cases; in cases exhibiting stridor and airway compromise, an emergency tracheostomy may be required.

There are additional safety concerns about rTPA as a potentially neurotoxic substance.⁷⁸ Animal studies indicate that rTPA can cross the blood-brain barrier,⁷⁹ and when within the brain parenchyma can increase ischemic injury via potentiation of N-methyl-D-aspartate (NMDA)-induced cell death and increase in NMDA-mediated intracellular calcium levels.⁸⁰

The ATLANTIS^81,82 and ECASS I⁸³ and II⁸⁴ trials were notable for an attempt to try to expand the window for thrombolysis or to alter the dose. In all of these cases rTPA was not associated with a clear clinical benefit in the latter windows and appeared to increase the risk of ICH. The European Medicines Evaluation Agency approved rTPA in 2002 under the condition that a trial of rTPA be carried out and that a prospective registry include safety outcomes.⁸⁵ This registry tracked patients treated up to 4.5 hours after, and there was no difference in complication rates between those who were in the < 3-hour window and those in the 3- to 4.5-hour window.⁸⁶ In 2008, publication of the results from ECASS III revealed a statistically significant clinical benefit in a select group of patients between 3 and 4.5 hours of onset.⁸⁷ The trial excluded patients with an NIHSS > 25, those older than 80 years, those taking oral anticoagulants regardless of prothrombin time, and those with a prior stroke and concomitant diabetes mellitus. The trial randomized 821 patients to rTPA, 0.9 mg/kg, or placebo, with a primary outcome of the modified Rankin Scale (mRS) at 90 days that was achieved in the treatment arm (52.4%) compared with the placebo arm (45.2%). Treatment was not associated with increased mortality, though there was a higher risk of hemorrhage (2.4-0.3%). A science advisory from the American Heart Association/American Stroke Association recommended that IV rTPA be administered up to 4.5 hours from stroke onset, but warned against prolonging time windows in the ED for those at < 3 hours.⁸⁶ A proposed clinical pathway for patients between 3 and 8 hours is presented in Figure 5-7.

To increase the proportion of individuals with acute stroke who receive IV thrombolysis, several strategies have been tried to date. Education of the public has achieved moderate success in improving arrival times to the ED, whereas establishment of acute stroke teams and increased experience over time has led to reduced hemorrhagic complication rates and protocol violations and has improved patient flow in EDs. The ischemic penumbra presented an attractive target beyond 3 hours, based on retrospective reviews of clinical protocols of thrombolysis using perfusion weighted imaging (PWI).^88,89 Moving toward a tissue-based window, rather than the absolute time and “clock-on-the-wall” window, remains the most promising avenue of research to expand the treatment window.

Trials with other thrombolytics besides rTPA have suggested a possible role of treatment beyond 4.5 hours in patients with perfusion-diffusion mismatch on MRI. Phase II trials have been carried out with desmoteplase, a chemical derivative from the saliva of vampire bats. Desmoteplase acts by a different mechanism of action and has a high affinity for fibrin, without having an effect on plasminogen or fibrinogen or apparent neurotoxicity.^78,80,90 In the desmoteplase in acute ischemic stroke trial (DIAS),⁹¹ patients were randomized to placebo vs desmoteplase if they presented in the 3- to 9-hour time window, had an NIHSS of 4 to 20, and evidence of MRI perfusion-diffusion mismatch. In the trial, a non–weight-based dose led to excessive symptomatic hemorrhages (26.7%), with a rate that was significantly lower (2.2%) when it was switched to a weight-based algorithm. The treatment arm was associated with improved reperfusion and subsequent clinical outcomes. In the phase 2 Dose Escalation of Desmoteplase for Acute Ischemic Stroke (DEDAS)⁹² study that included 37 patients, desmoteplase was associated with a trend toward improved clinical outcomes and a favorable safety profile in patients treated in the 3- to 9-hour time window. The findings were not confirmed in the phase III DIAS-2 trial, where desmoteplase resulted in no improvement in clinical outcomes and appeared to be associated with increased mortality.⁹³ In the Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution (DEFUSE) study, patients within 3 to 6 hours from stroke onset received rTPA regardless of their baseline MRI profile. Patients with a favorable diffusion-perfusion pattern (small DWI lesion, with a perfusion-diffusion ratio of 2.6) and subsequent reperfusion had a favorable clinical response.^94-96 This study included only 74 patients and did not include a placebo arm. In the larger EPITHET trial,⁹⁷ 101 patients were randomized to placebo vs rTPA groups at 3 to 6 hours from stroke onset, with a primary hypothesis of clinical benefit in patients with a diffusion-perfusion mismatch. The primary outcome was infarct growth between baseline DWI and 90-day T2 weighted imaging, for which there was a non-statistically significant trend to a benefit with rTPA. Secondary outcomes included improved neurological (NIHSS, 0-1 or ≥ 8 point improvement at 90 days) or functional status (mRS 0-2 at 90 days) that were associated with reperfusion, which was defined as ≥ 90% improvement in PWI volume at days 3 to 5. Reperfusion appeared to be more important than recanalization.⁹⁸ Criticisms of these studies relate to the technique used in measuring the penumbra. There are numerous difficulties with obtaining standardized processing of the perfusion sequences, as well as having these processed in a timely fashion for routine clinical use.

Additionally, the imaging of the penumbra was based on using magnetic resonance perfusion by examining the following parameters: mean time to enhance (mean transit time), negative enhancement integral (CBV), and maximum slope of decrease (cerebral blood flow, calculated as CBV/MTT). Hypoperfused tissue on PWI has been primarily defined in EPITHET and DEFUSE as a > 2-second delay in the Tmax, analogous to the MTT, with reperfusion being defined as a > 90% improvement in this parameter. On the other hand, final infarct volume appears to correlate better with a Tmax ≥ 6 to 8 seconds.⁹⁹ The other image maps are usually processed with a significant delay and are not readily available. In contrast, further understanding of the penumbra has led to the understanding that some portions of the penumbra will remain viable regardless of whether reperfusion occurs, whereas other will not despite treatment.⁸⁸ The role of collateral flow, and imaging it, remains incompletely understood, as does the optimal parameters to define the penumbra. The correlations with quantitative CBF from other modalities also remain imperfect. It remains important to comprehend that recanalization, which thrombolytics may do, is not synonymous with reperfusion, though they tend to be correlated. The former is based on angiographic improvement in the appearance of the vessel, whereas the latter refers to an improvement in PWI parameters. A recent meta-analysis showed reperfusion and recanalization rates that improved using mismatch-guided thrombolysis and that recanalization improves outcomes; however, thrombolysis did not improve outcomes.¹⁰⁰ As of now it remains controversial whether perfusion diffusion imaging should be used in routine clinical care.^101,102

Pharmacological Treatment

Table 5-2 outlines the results of notable pharmacological and device trials in acute ischemic stroke. Glycoprotein (GP) IIb/IIIa inhibitors have been an attractive target for pharmacological treatment beyond thrombolysis. In a phase II dose escalation study enrolling 74 patients, investigators found that the administration of abciximab was associated with a trend toward improved disability, with no significant increase in the rate of sICH.¹⁰³ The AbESST study, a phase II study containing 400 patients, found similar results in terms of safety and a nonsignificant modest trend toward improvement in the mRS at 3 months.¹⁰⁴ The phase III AbESST-II study planned to enroll 1800 patients, with randomization to abciximab or placebo within 5 hours of stroke onset in those who did not receive thrombolysis. The phase III study failed to replicate the phase II findings, as the study was stopped prematurely by the data safety monitoring board after having enrolled 808 patients. There was significant increase in the rate of sICH in the treatment arm (5.5% vs 0.5%), with no difference in the prespecified primary outcome.¹⁰⁵ A completed systematic review of GP IIb-IIIa inhibitors recommended against the use of these agents in ischemic stroke given the significant safety concerns.¹⁰⁶