Transient Ischemic Attack (TIA)

Definition

Transient ischemic attack (TIA) has traditionally been defined as the sudden onset of a focal neurological deficit that completely resolves within 24 hours and is presumed to be of a vascular origin, that is, caused by an abnormality or interference in the blood flow to the brain. Symptoms of TIA vary widely, depending on the area of the brain involved, but may include transient weakness, numbness, vertigo, or difficulty speaking. Conceptually, TIA can be thought of as similar to an ischemic stroke(ischemic stroke knol), except that the patient returns to normal quickly. Euphemisms, including “mini-stroke,” “warning stroke,” and “silent stroke,” are sometimes used to describe the condition to patients, but it should be emphasized that the distinction between stroke and TIA is somewhat artificial and both require urgent evaluation and treatment. In addition to symptoms referable to transient ischemia in the brain, TIAs also include episodes of transient monocular blindness (“amaurosis fugax”) caused by temporary ischemia to the retina.

The time-based traditional definition of TIA (recovery within 24 hours) is problematic. It was developed in the 1950s and 1960s prior to the advent of modern brain imaging techniques. Magnetic resonance imaging (MRI) scans of the brain have recently revealed that nearly half of patients with TIA actually have evidence of new cerebral infarction (irreversibly damaged brain tissue); the percentage of TIA patients with this finding increases with longer duration of symptoms (Figure 1). A newer proposed tissue-based concept redefines TIA as an event with transient symptoms (usually lasting less than 1 hour) without evidence of infarction on brain imaging studies¹. Using this newer proposed definition, deficits that resolve within 24 hours but are accompanied by imaging evidence of infarction would now be classified as ischemic strokes.

Figure 1: Diffusion-weighted MRI of the brain demonstrating an area of acute infarction in the right subcortical white matter. The patient presented with transient weakness of the left arm that resolved within 2 hours of onset. Using the classic time-based definition, this event would be termed a TIA. Using a more modern tissue-based definition, most would term the event an ischemic stroke in light of the MRI findings of infarction.

Using the classic time-based definition, about 240,000 TIAs occur each year in the United States. A 2003 survey demonstrated that 1 in 15 people in the United States older than 65 years had experienced a TIA, equivalent to about 2.5 million people, making TIA an extremely common condition². TIA has been shown to be a major risk factor for recurrent stroke as well as recurrent TIA, and recent studies have focused on defining this risk of recurrence in individual patients while testing strategies designed to minimize this risk.

Differential Diagnosis

              Because the symptoms of TIA have often completely resolved by the time the patient is seen by a physician, TIA remains a completely clinical diagnosis. TIA must be distinguished from spells that are non-vascular in origin; this is a difficult task and it has been demonstrated that even neurologists show only moderate agreement when diagnosing TIA. There is no simple blood test or imaging study that has the ability to distinguish TIA from other neurologic conditions that may mimic TIA, and therefore the history given by the patient to the physician is the single most important tool used to establish the diagnosis.

The most common mimics of TIA include focal seizures and complicated migraines, each of which can present with a transient neurologic deficit that resolves within minutes to hours. Syncope, a transient loss of consciousness due to global cerebral hypoperfusion, is commonly caused by increases in parasympathetic tone or cardiac arrhythmias and may be, in retrospect, difficult to distinguish from TIA. Serum glucose abnormalities, most commonly hypoglycemia, can also lead to transient neurologic deficits, hence measurement of serum glucose is an important part of stroke and TIA evaluation. Finally, ill-defined spells of memory loss, sensory disturbance, peripheral vertigo (usually due to a problem in the inner ear), or weakness that completely resolves may resemble TIA. In all of these cases, physicians often assume the spell to be a true TIA that is vascular in origin, and proceed accordingly with TIA workup and treatment as the high risk of subsequent stroke following TIA makes the consequences of misdiagnosis substantial.

Short-Term Stroke Risk Following TIA 

            Prior to the late 1990s, TIA was thought by many to be a benign condition which could be evaluated and treated in an elective manner. Multiple studies have challenged this notion, demonstrating that the short-term risk of subsequent stroke is greater than 10% in the 90 days following a TIA, with half of these strokes occurring in the first 48 hours^{3, 4}. TIA patients also have a substantial increased short-term risk of hospitalization for cardiac events such as myocardial infarction (MI) (heart attack) as well as death. Although the majority of patients with TIA will not have an event in the short term, this identified increased risk has led to a major shift in the urgency of TIA evaluation and treatment worldwide.

            Several studies have identified risk factors for recurrent stroke in TIA patients and have aimed to quantify the short-term risk of recurrence in individual patients. The most widely used method of estimating risk is the ABCD² score (Age, Blood Pressure, Clinical Features, Duration, Diabetes) shown in Table 1⁵. The 2-day risk of subsequent stroke after TIA using this model is 1.0% with a score of 0-3 (low risk), 4.1% with a score of 4-5 (medium risk), and 8.1% with a score of 6-7 (high risk). This risk stratification model does not take into account any imaging findings which also have been shown to impact the subsequent risk of stroke in TIA patients; both the presence of an infarct on MRI (still consistent with the classical time-based definition of TIA), and the presence of a large vessel occlusion increase the risk of subsequent stroke in patients with TIA⁶.

TABLE 1: The method of calculating ABCD² score in TIA patients. Points are added to generate a final score.

Greater than or equal to 60                                                   1 Point

            Systolic greater than or equal to 140 mm Hg or                       1 Point

Diastolic greater than or equal to 90 mm Hg

            Unilateral weakness                                                              2 Points

            Speech impairment without weakness                                    1 Point

            Greater than or equal to 60 minutes                                      2 Points

            10-59 minutes                                                                     1 Point

  Diabetes

            Diabetes Present                                   `                            1 Point

            Evaluation and management of patients with TIA have many similarities to the evaluation and management of ischemic stroke(ischemic stroke knol). TIA remains a clinical diagnosis according to the classic definition, and care must be taken during the history and physical examination to screen for clues that an alternative diagnosis mimicking TIA might be present. Recently published National Stroke Association consensus guidelines drive the evidence-based evaluation and management of TIA patients⁷.

Two recent studies have demonstrated that the strategy of urgent evaluation and treatment of TIA can reduce the short-term risk of subsequent stroke by about 80%, as predicted by the ABCD² model^{8, 9}. Given these results, patients and their physicians should now view TIA as a neurological emergency prompting rapid evaluation and initiation of therapy in an attempt to decrease the immediate risk of subsequent stroke.

                Patients with TIA should either be admitted directly to the hospital, as with stroke patients, or referred to urgent outpatient clinics specializing in neurologic conditions including TIA, within a very brief period of time (usually within 24 to 48 hours). Some centers use the ABCD² score to stratify patients, admitting high-risk patients to the hospital and referring low-risk patients for follow-up in an urgent TIA clinic. If a patient with TIA indeed has a subsequent stroke, hours to a few days later, admission to the hospital following the TIA allows for rapid deployment of acute therapies such as intravenous tissue plasminogen activator (IV t-PA)¹⁰.

            All patients with TIA should undergo brain imaging with computed tomography (CT) or MRI in order to help exclude other pathologies that could mimic the clinical diagnosis of TIA. For example, if a patient with transient weakness was found to have a subdural hematoma on head imaging, the possibility of a seizure caused by irritation from the blood might become more likely than a TIA (Figure 2). CT and MR Angiography as well as perfusion techniques may provide additional information that can make the diagnosis of TIA more firm, and many centers now utilize standardized imaging protocols in all patients with suspected TIA or stroke.

            Patients with TIA should undergo imaging of the carotid arteries in the neck with ultrasound, MR Angiography, CT Angiography, or conventional catheter-based angiography. Patients in whom the carotid artery is narrowed from 70-99% ipsilateral (on the same side) to the side of the TIA benefit from surgical endarterectomy in order to reduce the chances of subsequent stroke, as proven in large multicenter trials in North America and Europe in the 1990s^{11, 12}. Ocular TIAs (“amaurosis fugax”) that present with sudden blindness are often caused by carotid disease, as the ophthalmic artery that supplies blood to the retina originates as a branch of the internal carotid artery.

            Patients with TIA also should undergo cardiac evaluation with transthoracic or transesophageal echocardiography in order to identify structural heart disease that might serve as a source for repeated emboli (blood clots) to the brain, leading to TIA and stroke. Detection of cardiac arrhythmias, most importantly atrial fibrillation, is important as these patients are at high risk for subsequent TIA and stroke unless treated with anticoagulant, or less commonly, antiplatelet medications. Electrocardiography (ECG) is the mainstay of arrhythmia detection, but recent studies in patients with stroke have advocated extended inpatient or outpatient cardiac rhythm monitoring in order to identify patients with suspected paroxysmal atrial fibrillation who may be missed using a single ECG.

            Recognition of modifiable vascular risk factors is a key element of TIA evaluation. Patients should be screened for smoking, hypertension, diabetes, and hypercholesterolemia (including high low-density lipoprotein (LDL) levels and low high-density lipoprotein (HDL) levels). Modification of these risk factors is an important element of TIA management in order to prevent subsequent vascular events.

Treatment of TIA

            Since by definition TIA patients have returned to normal, acute therapies that are often used for ischemic stroke patients with persistent deficits, such as intravenous tissue plasminogen activator (IV t-PA), are not given. Instead, the treatment of TIA involves aggressive medical and possibly surgical treatments aimed at reducing the risk of subsequent stroke.

Medical Treatment

            The mainstay of medical treatment for most patients with TIA is antiplatelet drugs. Aspirin, clopidogrel, and a combination of sustained-release dipyridamole and aspirin have each been shown to be effective in reducing the risk of subsequent stroke after TIA or stroke. Daily long-term therapy with one of these medications should be prescribed immediately after TIA unless anticoagulation is indicated (see below).

Both clopidogrel and the combination of sustained-release dipyridamole and aspirin have been demonstrated to be modestly more efficacious than aspirin, although data regarding the effectiveness of sustained-release dipyridamole and aspirin in the acute period immediately following a TIA is lacking^{7, 13}. The results of a large randomized trial (PRoFESS) comparing extended-release dipyridamole and aspirin with clopidogrel for secondary stroke prophylaxis have recently been published, and indicate that the two compounds have essentially equal efficacy¹⁷. Although in general combinations of these antiplatelet medications are not recommended, a recent pilot study demonstrated a possible increased benefit from giving both aspirin and clopidogrel following TIA or minor stroke for a short period of time¹⁴; this dual therapy approach warrants further study.

            Patients in whom TIA is found to be caused by atrial fibrillation should be treated with an anticoagulant medication, usually warfarin, instead of antiplatelet medications. If oral anticoagulation cannot be administered, then aspirin (or clopidogrel if the patient is aspirin intolerant) is a less effective second alternative. There are few other evidence-based indications for a patient to be prescribed anticoagulant medications instead of antiplatelet medications following TIA.

Surgical Treatment

            Patients with TIA found to have carotid narrowing from 70- 99% ipsilateral to the involved hemisphere can reduce their risk of subsequent stroke with carotid endarterectomy performed within 2-4 weeks of their event, emphasizing the importance of urgent carotid artery imaging in all patients with TIA^{11, 12}. Some patients with stenoses measuring 50-69%, especially men, may possibly realize some benefit of this surgery as well, providing that the center and surgeon involved have a low rate of perioperative stroke and death. A less invasive endovascular carotid stenting procedure has also been used recently for this indication, but early trials have failed to show equal efficacy to endarterectomy¹⁵.

Risk Factor Management

            All patients with TIA should aggressively treat their vascular risk factors in order to reduce the risk of subsequent stroke, TIA, and MI. Patients who smoke should be encouraged to stop, utilizing all available medical therapies and support. Treatment of hypercholesterolemia is recommended through diet, exercise, and usually medications such as HMG-CoA reductase inhibitors (“statins”). A recent trial demonstrated a modest benefit in reduction of secondary events when patients with TIA or stroke were treated with a high dose of atorvastatin¹⁶. Blood pressure reduction following a TIA is also important in order to reduce the risk of subsequent stroke; angiotensin-converting enzyme (ACE) inhibitors and the thiazide diuretic class of medications are recommended as first line agents. Finally, patients with diabetes should aim to achieve tight glucose control with diet, exercise, oral hypoglycemics, and/or insulin. Maintaining a healthy lifestyle with a balanced diet and frequent exercise likely also reduces the risk of subsequent events independently of beneficial effects on vascular risk factors.

1.         Albers GW, Caplan LR, Easton JD, et al. Transient ischemic attack--proposal for a new definition. N Engl J Med. 2002;347(21):1713-1716.

2.         Johnston SC, Fayad PB, Gorelick PB, et al. Prevalence and knowledge of transient ischemic attack among US adults. Neurology. 2003;60(9):1429-1434.

3.         Johnston SC, Gress DR, Browner WS, Sidney S. Short-term prognosis after emergency department diagnosis of TIA. Jama. 2000;284(22):2901-2906.

4.         Hill MD, Yiannakoulias N, Jeerakathil T, Tu JV, Svenson LW, Schopflocher DP. The high risk of stroke immediately after transient ischemic attack: a population-based study. Neurology. 2004;62(11):2015-2020.

5.         Johnston SC, Rothwell PM, Nguyen-Huynh MN, et al. Validation and refinement of scores to predict very early stroke risk after transient ischaemic attack. Lancet. 2007;369(9558):283-292.

6.         Coutts SB, Simon JE, Eliasziw M, et al. Triaging transient ischemic attack and minor stroke patients using acute magnetic resonance imaging. Ann Neurol. 2005;57(6):848-854.

7.         Johnston SC, Nguyen-Huynh MN, Schwarz ME, et al. National Stroke Association guidelines for the management of transient ischemic attacks. Ann Neurol. 2006;60(3):301-313.

8.         Rothwell PM, Giles MF, Chandratheva A, et al. Effect of urgent treatment of transient ischaemic attack and minor stroke on early recurrent stroke (EXPRESS study): a prospective population-based sequential comparison. Lancet. 2007;370(9596):1432-1442.

9.         Lavallee PC, Meseguer E, Abboud H, et al. A transient ischaemic attack clinic with round-the-clock access (SOS-TIA): feasibility and effects. Lancet Neurol. 2007;6(11):953-960.

10.       Nguyen-Huynh MN, Johnston SC. Is hospitalization after TIA cost-effective on the basis of treatment with tPA? Neurology. 2005;65(11):1799-1801.

11.       Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. North American Symptomatic Carotid Endarterectomy Trial Collaborators. N Engl J Med. 1991;325(7):445-453.

12.       Randomised trial of endarterectomy for recently symptomatic carotid stenosis: final results of the MRC European Carotid Surgery Trial (ECST). Lancet. 1998;351(9113):1379-1387.

13.       Halkes PH, van Gijn J, Kappelle LJ, Koudstaal PJ, Algra A. Aspirin plus dipyridamole versus aspirin alone after cerebral ischaemia of arterial origin (ESPRIT): randomised controlled trial. Lancet. 2006;367(9523):1665-1673.

14.       Kennedy J, Hill MD, Ryckborst KJ, Eliasziw M, Demchuk AM, Buchan AM. Fast assessment of stroke and transient ischaemic attack to prevent early recurrence (FASTER): a randomised controlled pilot trial. Lancet Neurol. 2007;6(11):961-969. Epub 2007 Oct 2010.

15.       Ringleb PA, Allenberg J, Bruckmann H, et al. 30 day results from the SPACE trial of stent-protected angioplasty versus carotid endarterectomy in symptomatic patients: a randomised non-inferiority trial. Lancet. 2006;368(9543):1239-1247.

16.       Amarenco P, Bogousslavsky J, Callahan A, 3rd, et al. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med. 2006;355(6):549-559.

17.        Sacco RL, Diener H, Yusuf S, et al: Aspirin and Extended-Release Dipyridamole versus Clopidogrel for Recurrent Stroke. N Engl J Med 2008; 359:1238-51.

USEFUL WEBSITES

 www.stroke.org/site/PageServer?pagename=TIA

 www.ninds.nih.gov/disorders/tia/tia.htm