Detection, Diagnosis and Differential Diagnosis

Every patient presenting with neurological focal deficit of sudden onset must be evaluated as a possible case of stroke. The most frequent conditions that mimic an ischemic stroke are conversion disorders, undetected seizures, confusional state, meningitis/encephalitis, hypertensive encephalopathy, syncope, toxic/metabolic disturbances (e.g., hypoglycemia) complicated migraine, brain tumors and subdural hematoma. These conditions can be ruled out in the emergency evaluation.

Those conditions, which are also known as Stroke Mimics, were identified in approximately 3% of the cases in two series of patients that received rtPA. Most of those patients had conversion disorders. ^{5 ,​ 6} However, there was no evidence of complication secondary to the thrombolysis. Recently, in a register of 512 patients treated with rtPA until 3 hours of symptom onset, 21% were classified at the end of the workup as suffering from stroke mimics. ⁷ In this cohort, the majority of the patients had seizures, complicated migraines and conversion disorders, and none of them had symptomatic intracranial hemorrhage. Although the IV thrombolysis apparently does no harm to patients without a stroke, it is recommended to have a rate of less than 3% of stroke mimics receiving rtPA, when using only a CT scan to select the patient. ⁸ The means to find the balance between fast treatment and accurate diagnosis continue to evolve.

Acute Phase Evaluation

It is fundamental to establish the exact time of symptom onset when a stroke is suspected. By convention, it is the last moment in which the patient was seen without deficits; consequently, if the patient wakes up in the morning with stroke signs, the last time the patient was seen asymptomatic would be before bedtime.

After detecting a potential stroke patient on admission at the ED and defining the time of symptom onset, a medical and nursing evaluation should be promptly demanded. While the emergency physician confirms the stroke hypothesis and calls the neurologist for an evaluation, the nurse places two peripheral venous lines, monitors vital signs and checks capillary glycemia. After that, the physician orders a CT scan, an electrocardiogram and laboratory tests. In some hospitals, to expedite the process, as soon as the pre-hospital EMS already recognizes the possibility of a stroke, the patient is moved right away to Radiology. There the medical assessment is completed and, if positive for stroke, a bolus of rtPA is administered.

The neurological evaluation must be rapid and comprehensive. The use of assessment scales allows the evaluation of a great number of components of the neurological examination in a short period of time. The most frequently used scale for the quantification of neurological deficit is the National Institute of Health Stroke Scale (NIHSS) ( Table 2‑1 ), ranging from zero (no deficit) to 42 (complete deficit). It can be performed by neurologist, emergency physician, nurse or any other healthcare professional. The use of a standardized scale facilitates the communication between professionals, contributes to estimating prognosis and helps to decide reperfusion strategies.

Ancillary Testing in the Acute Phase

All stroke patients must have an electrocardiogram, blood and platelet count, prothrombin time (PT) with international normalized ratio (INR) and activated partial thromboplastin time (aPTT), serum electrolyte dosage (sodium, potassium), serum urea and creatinine, and glycemia. Since 2007, it is no longer necessary to wait for laboratory results to initiate thrombolysis. Before that date, checking the platelet count was recommended before rtPA infusion, delaying the start of the treatment. The probability of a platelet count below 100.000/mm³ in a patient with acute stroke is 0,3% if neither history nor clinical features are suggestive of blood diathesis. PT and aTTP must be checked before thrombolysis only in patients on anticoagulants (warfarin and unfractionated heparin, respectively). If there is no history of use of those medications, thrombolysis must be initiated, and the laboratory results will be checked during the rtPA infusion. ^{9 ,​ 10}

In patients on dabigatran, either normal thrombin time (TT), ecarin clotting time (ET) or aPTT can be performed to rule out significant activity. Considering TT and ET are not widely available in the emergency setting, a history of missing the last dose of dabigatran plus a normal aPTT may permit to proceed with thrombolysis, weighing risks versus benefits for each single case. There are no reliable tests to verify the activity of rivaroxaban and apixaban, so patients on those medications are excluded from the thrombolytic therapy – unless the patient has not been taking the medication for the last 48 hours. ⁹

Imaging in the Acute Phase

The non-contrast CT (NCCT) brain scan is indispensable in the emergency evaluation of patients with acute stroke. It identifies 90–95% of subarachnoid hemorrhages and almost 100% of intraparenchymal hemorrhages and helps to rule out non-vascular causes for the neurological symptoms.

Early signs of infarction or arterial occlusion on NCCT can be observed in the first hours after a stroke (60% of cases within 2 hours from symptom onset ¹¹ ). Hyperdense artery sign in the area corresponding to the middle cerebral artery (MCA) indicates presence of thrombus or embolus. Hypodensity in the basal ganglia, loss of differentiation between white and gray matter, and effacement of both the insular cortex and cortical gyri are early signs of ischemia. The presence of these signs affecting a large area of ​​brain tissue is also associated with an increased risk of hemorrhagic transformation after the use of thrombolytic agents, especially when the area is larger than one third of MCA territory. ¹²

Detection of these early signs may increase in sensitivity with the use of standard NCCT evaluation scores such as the Alberta Stroke Program Early CT Score (ASPECTS). ¹³ Changing the NCCT window on the workstation to show the difference between normal and abnormal brain tissue ¹⁴ is also helpful.

The diffusion-weighted sequences on Magnetic Resonance Imaging (MRI) of the brain are more sensitive than NCCT for stroke diagnosis as they identify the ischemic area as early as 35 minutes after the onset of symptoms. This method is especially useful when stroke diagnosis is uncertain. The ischemic area that appears in diffusion-weighted imaging corresponds approximately to the core infarct area in the brain. ¹⁵

Several MRI protocols in SCs use diffusion-weighted and perfusion sequences to evaluate patients with an indeterminate therapeutic window or outside the therapeutic window, by defining in each patient the presence of viable brain tissue (penumbra). The hypothesis that supports this practice is that each individual has his own therapeutic window, based on his physiological tolerance to ischemia and the characteristics of the collateral arterial circulation of his brain. Vascular imaging with either arterial angioCT or angioMRI helps to locate the exact point of flow obstruction and is strongly recommended for endovascular reperfusion (in proximal occlusions of the anterior circulation, for example). ¹¹ Choosing between these two imaging modalities depends on equipment availability and patient characteristics.

Transcranial Doppler (TCD) can be used to diagnose major cerebral artery occlusions and to monitor the effects of thrombolytic therapy; it also helps to determine the prognosis. ^{16 ,​ 17} However, between 7 and 20% of patients with acute stroke do not have an adequate bone window; as a consequence, the scan cannot be performed.

Although brain NCCT has relatively low sensitivity in detecting small acute infarctions, especially in the posterior fossa, it is still the first choice in most centers that use thrombolytic therapy. For evaluation in the acute phase, it is sufficient, rapid, and available in most emergency departments; it can determine the presence of intracranial hemorrhage, and may also give prognostic information (early infarction signs). In patients who are candidates for thrombolytic therapy, NCCT should be performed within 25 minutes after the arrival at the emergency room, and the report should be obtained within the next 20 minutes. ⁹

Supportive Care

Maintaining adequate Blood Pressure (BP) and oxygen saturation (≥92%), keeping body temperature lower than 37.5° C and striving for euglycemia are the most important supportive therapies in the management of acute stroke. Continuous cardiac monitoring is recommended to detect early electrocardiographic signs of ischemia or arrhythmias.

In patients who are candidates for IV thrombolysis, treatment with rtPA should not be initiated if, at the time of administration, the patient has a BP of ≥185/110mmHg. ⁹ This blood pressure reading should be decreased rapidly with IV drugs prior to the initiation of rtPA. Labetalol, nicardipine, esmolol or even sodium nitroprusside (if none of the first are available) are safe options. BP should be monitored before, during and after rtPA use. If the patient develops hypotension with antihypertensive treatment, decrease the dose and start infusion of physiological solution. Avoid infusion of solutions containing glucose to restore volume on account of the risk of dilutional hyponatremia. ⁹

Studies of Intravenous Thrombolysis Use

Three clinical trials tested the use of streptokinase in the acute treatment of stroke and were early discontinued because of increased mortality and high rates of intracerebral hemorrhage. ¹⁷

The use of rtPA in ischemic stroke up to 3 hours after the onset of symptoms was approved following the clinical trial of the National Institute of Neurological Diseases and Stroke (NINDS study, class I, evidence level A). The rtPA- treated group (dosage: 0.9 mg/kg) had 31% more patients with minimal or no neurological deficit at the assessment done three months after the stroke. There was a higher rate of symptomatic intracerebral hemorrhage in the treated group (6.4% x 0.6%, p <0.001) but no increase in mortality (17% in the rtPA group x 21% in placebo). The benefit was demonstrated in all subtypes of stroke and was not affected by factors such as gender or age.

A meta-analysis of 6 studies with rtPA (2775 patients), ¹⁸ analyzed the outcome of patients treated between 0 and 6 hours after the onset of stroke. The results showed that the earlier the administration of rtPA, the better the outcome. The group treated up to 90 minutes after symptom onset had odds of 2.8 for a favorable outcome. Treatment between 181–270 minutes also had benefit (odds ratio 1.4). No benefit was observed among patients treated between 271–360 minutes. The bleeding rate in the rtPA group was 5.9% x 1.1% in the placebo group (p <0.0001). In 2008, the benefit of IV rtPA use up to 4.5 hours after symptom onset was confirmed in the European Cooperative Acute Stroke Study III (ECASS III) trial, ⁴ extending the therapeutic window (class I, evidence level A). Several cohort studies performed after approval of rtPA confirmed the effectiveness of treatment with similar results to those of the NINDS study. ¹⁹

The IST-3 (Third International Stroke Trial) study, ²⁰ published in 2012, randomized patients with ischemic stroke to receive IV rtPA versus placebo up to 6 hours after symptom onset, selected by NCCT. A population outside the formal indication for treatment (elderly and with high baseline NIHSS score) was included; out of the 3035 study patients, 1617 (53%) were over 80 years of age. At 6 months the mortality rate was similar in both groups (26.9% on rtPA versus 26.7% on placebo). There was an increased risk of fatal and nonfatal hemorrhagic transformation with rtPA of 5.8%, as had been demonstrated in previous studies. The Oxford Handicap Score (OHS) assessment of independence after stroke did not differ significantly in the two groups (37% versus 35%). Therefore, there was no benefit with the use of rtPA in ischemic stroke up to 6 hours after symptom onset. The effect of treatment on patients over 80 years-old was at least as good as for those under that age.

In 2012, another meta-analysis ²¹ of 12 studies evaluated 7012 patients who received rtPA versus conventional treatment within 6 hours of the stroke onset. There was no difference in mortality between the groups at 3 months. There was a reduction in the composite outcome of death and severe functional disability of 4% (ARR = 4%, 95% CI 1.7–6%), benefiting 1 in every 25 patients treated at the 3-month assessment (NNT = 25 with 95% CI 16–59). The benefits were more expressive in patients treated up to 3 hours, with 1 in 11 treated patients becoming functionally independent – modified Rankin Score (mRS) 0 to 2 (RRA = 0.9%, 95% CI 0.46–1.34 and NNT = 11 with 95% CI 7–22) and 1 in 19 achieving minimal or no disability at 3 months – mRS 0 to 1 (RRA = 5.4% with 95% CI 3.2–7.6 for NNT = 19 with 95% CI 13–31). When comparing the subgroup of patients over 80 years old to those below that age, who received thrombolysis up to 3 hours after ischemic stroke onset, the use of rtPA brought benefit to both groups, allowing survival and/or functional independence in 20.7%, benefiting 1 out of 5 treated patients (ARR = 20.7%, 95% CI 14.4–27.0 with NNT = 5, 95% CI 4–7). Despite this being a subgroup analysis, the statistical power was 98.1%. In the same population, receiving rtPA within 6 hours of symptom onset, there is survival and/or independence benefit in 25.3%, which means increasing the survival or independence of 1 in 4 treated patients (ARR = 25.3%; 95% CI 21.8–28.8 and NNT = 4, 95% CI 3–5). The IST3 Study demonstrated that patients with NIHSS above 25 also benefit from EV thrombolysis.

Another important study of thrombolysis in stroke was published in 2016: the ENCHANTED study (Enhanced Control of Hypertension and Thrombolysis Stroke Study), ²² which compared the conventional dose of rtPA (0.9 mg kg EV) to the low dose (0.6 mg/ kg) in patients treated up to 4.5 hours after symptom onset. The objective was to evaluate whether the low dose was non-inferior to the conventional dose in achieving minimum or no disability at 3 months (Rankin modified between 0 and 1) and if the lower dose was safer (lower rate of symptomatic intracerebral hemorrhage). As a result, the lower dose did not reach non-inferiority at the primary endpoint, with 47% of patients achieving mRS 0–1 at 3 months when treated at low dose compared to 49% of patients receiving the standard dose, although it was assessed by shift analysis. In improving 1 point in the Rankin score at 3 months, the lower dose was not inferior to the standard dose (p = 0.04). In addition, the lower dose had lower rate of symptomatic intracranial hemorrhage and lower mortality related to the bleeding. The clinical relevance of the study is that the lower dose may be a therapeutic option in patients at higher risk of bleeding.

The main complication of thrombolytic treatment in stroke is symptomatic intracranial hemorrhage (sICH). The factors that most strongly predict the chance of bleeding after rtPA are: brain CT scan hypodensity in over 1/3 of the territory of the MCA (odds ratio 9.38), age above 75 years, BP above 180/105 mmHg at the start of rtPA infusion, diabetes (odds ratio of 2.69) and NIHSS of more than 20. ^{2 ,​ 12 ,​ 23} Despite the increased risk of bleeding, there is no upper age limit for treatment and elderly patients should not be excluded by this criterion alone. In addition to the risk of sICH, other potential adverse effects of medication include systemic bleeding, myocardial rupture in patients with recent transmural acute myocardial infarction, and anaphylactic reaction or angioedema secondary to rtPA, but these events are rare. ²⁴ Orolingual angioedema (edema of the tongue, lips, or oropharynx) occurs in 1.3 to 5% of all patients receiving IV rtPA as treatment for ischemic stroke. Edema is typically mild, transient, and contralateral to the hemisphere of ischemic stroke and is generally associated with both previous use of angiotensin-converting enzyme inhibitor and infarcts involving the insular and frontal cortex. Recommendations for empirical treatment include IV ranitidine, diphenhydramine and methylprednisolone.

Although the efficacy of IV thrombolytic therapy in stroke has been well demonstrated, not all patients achieve vessel recanalization and some have initial recanalization with subsequent reocclusion. The rates of partial or complete recanalization of occlusion in the internal carotid artery are 10% and of the proximal occlusion in the MCA are 25–30%. ^{25 ,​ 26} In addition, IV thrombolysis has a narrow therapeutic window and, due to its systemic effects, is contraindicated in many potential candidates ⁹ : patients with recent ischemic stroke, previous intracranial hemorrhage, recent head trauma, recent surgery or bleeding diathesis.

In an attempt to increase the rates of recanalization and, consequently, improve patient outcomes, endovascular reperfusion has been used in patients with large vessel occlusion. Anyway, IV thrombolysis is more easily implemented (it can be used in medium complexity hospitals without a hemodynamics unit) and, according to current evidence and international guidelines, ^{27 ,​ 28} it should be used in eligible patients up to 4,5 hours after symptom onset, even with large vessel occlusion and endovascular treatment available, while endovascular treatment may be used in patients who fail to undergo IV treatment or in those who are ineligible for IV treatment up to 6 hours from symptom onset.