Postgraduate Medicine
ISSN: 0032-5481 (Print) 1941-9260 (Online) Journal homepage: http://www.tandfonline.com/loi/ipgm20
How to avert impending stroke John Edmeads MD To cite this article: John Edmeads MD (1992) How to avert impending stroke, Postgraduate Medicine, 92:2, 221-234, DOI: 10.1080/00325481.1992.11701427 To link to this article: http://dx.doi.org/10.1080/00325481.1992.11701427
Published online: 17 May 2016.
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Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ipgm20 Download by: [University of Toronto Libraries]
Date: 27 June 2016, At: 08:51
--@CME credit article
How to avert impending stroke
John Edmeads, MD
Downloaded by [University of Toronto Libraries] at 08:51 27 June 2016
Preview Patients "lucky" enough to have a nondisabling transient ischemic attack as a warning sign of impending stroke deserve the best possible prophylactic treatment in an attempt to avert that catastrophe. Dr Edmeads provides a step-by-step discussion of diagnostic studies and therapeutic regimens that help avoid stroke in middle-aged and older patients who are at risk.
Stroke is a specter that looms larger as we grow older. The annual incidence of symptomatic cerebrovascular disease (as determined in a study at the Mayo Clinic, Rochester, Minnesota') is 170 per 100,000 among people aged 55 to 64 years and rises to 957 per 100,000 among those older than age 75. The annual death rate from cerebrovascular disease in the United States is about 100 per 100,000 for people in their mid-50s.' The death rate almost doubles with each additional 5 years of age, reaching 1,500 per 100,000 for people 80 years of age. 1 Survivors of stroke are often disabled: The older a patient is at the time of stroke, the more likely the related disability is to be severe and permanent. This prospect is not pleasant-prevention is of paramount importance. Various kinds of stroke occur in patients who are middle-aged or older (table 1). (Stroke in
young persons comprises a spectrum of disease sufficiently different ftom that caused by stroke in older persons that it is not considered in this article.) Some of the strokes that occur in older persons give no warning. For example, intracerebral hemorrhage nearly always occurs unheralded, which provides no opportunity to avert it. While the long-term risk of cerebral hemorrhage may be reduced by carefully controlling blood pressure over the years, once the bleeding starts the outcome is inevitable. Subarachnoid hemorrhage, sometimes classified as a type of stroke (especially in epidemiologic studies), is so different from what clinicians generally consider under the heading of stroke that it is not discussed in this article. When subarachnoid hemorrhages are preceded by warnings, the warnings usually take the form of headache rather than focal neurologic disturbances.
In contrast to strokes caused by cerebral hemorrhage, between one quarter and one third of strokes caused by thromboembolic disease are preceded by transient ischemic attacks (TIAs), which give warning of an impending stroke and an opportunity to prevent it. A person who has had a TIA has a 6% per year overall risk of having a stroke at some future time, a risk five times greater than that of a person who has not had a TIA. One third of these cerebral infarctions occur within a month of the TIA, and half occur within a year. Early recognition ofTIAs and prompt, appropriate treatment may avert catastrophe. Here is how to do it (figure 1).
Understanding TIAs A TIA occurs when temporary insufficiency of blood flow to a pan of the brain results in localized, reversible ischemia and dysfunction. In most patients, this evanescent impairment of blood supply is caused by a plateletfibrin embolus that originates on an atherosclerotic plaque in the proximal portion of the internal carotid artery or the vertebrabasilar system. The embolus is carried dow~stream to lodge briefly in a small distal arterial branch before breaking up. In
continued
VOL 92/NO 2/AUGUST 1992/POSTGRADUATE MEDICINE • STROKE
221
Downloaded by [University of Toronto Libraries] at 08:51 27 June 2016
Most older patients with transient focal neurologic deficits are having TIAs.
Table 1. Incidence of different types of stroke in and after middle age Cerebral infarction Artery-to-artery embolism Hemodynamic stenosis Cardiogenic embolism
78% 80% 5% 15%
Cerebral hemorrhage Hypertension Amyloid angiopathy Other
12% 75% 20% 5%
"Pseudostrokes" (stroke mimics) Unwitnessed seizures Mass lesions causing apoplectiform symptoms Other
10%
80% 10% 10%
about 15% of patients the embolus is cardiogenic. In a few patients, probably no more than 5%, the transient ischemia is caused by hemodynamic mechanisms, such as when blood flow across an area of tight arterial stenosis falters because of transient hypotension resulting from cardiac arrhythmia, orthostatic hypotension, side effects of drugs, or similar mechanisms. Figure 2 delineates the proportion of ischemic strokes attributable to various causes. By definition, a TIA clears completely within 24 hours, but
222
the great majority last less than an hour. Sometimes a TIA may take a little longer than 24 hours to resolve, and then it is termed a resolving ischemic neurologic deficit. The patient has narrowly escaped stroke-this time. TIAs and resolving ischemic neurologic deficits indicate the presence of artery-to-artery embolism, cardiogenic embolism, or (rarely) severe arterial stenosis. Investigation of the cerebrovascular system and the heart, as well as treatment that either inhibits clot formation or reopens blood vessels, is indicated.
Recognizing TIAs Most older patients with transient focal neurologic deficits, such as hemiparesis, numbness of a body part, slurred speech, aphasia, visual obscuration, diplopia, or ataxia, are having TIAs. Other causes of these symptoms are uncommon. Occasionally a patient has a seizure in bed at night and awakens in the morning with postictal hemiparesis that clears in a few hours. This can be quite confusing unless someone has witnessed the seizure. Some investigators believe that migraine, even in middle-aged and elderly persons, may produce transient focal deficits, or transient migrainous accompani-
ments, but migraine should be considered as a cause of such deficits only after adequate investigation has excluded the possibility ofTIAs. Rarely, a mass lesion, such as subdural hematoma or cerebral neoplasm, produces intermittent focal symptoms, but sufficient investigation usually excludes this diagnosis. An equally rare small intracerebral hemorrhage may produce a minor deficit that resolves within hours, mimicking a TIA. This is one reason why anticoagulant therapy should not be started until computed tomography (CT) or magnetic resonance imaging (MRI) has been done to confirm the diagnosis ofTIA. Some transient neurologic symptoms, such as confusion, memory loss, dizziness, and fainting, are often attributed to TIAs but are just as likely to be due to another cause. Intermittent confusion may be the result of adverse reactions to medications, withdrawal from drugs (including alcohol), occult infection, metabolic disturbances (eg, hypoglycemia, hypoxia, hypercarbia), or unrecognized seizures. Transient pure memory loss with no accompanying features, or transient global amnesia, is believed by some to be related to cerebral ischemia, but this has not been continued
STROKE • VOL 92/NO 2/AUGUST 1992/POSTGRADUATE MEDICINE
A TIA occurs when temporary insufficiency of blood flow to a part of the brain results in localized, reversible ischemia and dysfunction.
Downloaded by [University of Toronto Libraries] at 08:51 27 June 2016
Transient neurologic symptoms
~
Clinical diagnosis
I
+
Other diagnoses (see table 2)
TIA
~
Routine investigations (laboratory studies)
~
Exclude other causes of transient neurologic deficit (computed tomography or magnetic resonance imaging)
I
+
TIA or small infarct
Other diagnoses (see table 2)
~
Establish cause: artery-to-artery embolism, hemodynemic stenosis, or cardiogenic embolism (see figure 2)
I
+
Electrocardiography and twodimensional echocardiography
Doppler ultrasound studies
I
+
Doppler shows >70% stenosis
+
Doppler shows 70%). Patients selected for this procedure should be good angiegraphic and surgical candidates and willing to undergo surgery if it is indicated. Some types of investigation are of relatively little value in the assessment of patients with Tlfu. An electroencephalogram may show an epileptogenic lesion and
VOL 92/NO 2/AUGUST 1992/POSTGRADUATE MEDICINE • STROKE
prevent the diagnostic pratfall of mistaking postictal palsy for TIA. However, the yield of electroencephalographic studies in general is very low in patients with Tlfu. Radioisotope scanning of the brain is usually of such low resolution that it seldom gives much useful information in these cases. Lumbar puncture is not helpful in patients with Tlfu. Completion of the investigation of a patient with Tlfu should result in reasonably confident answers to the following questions. The answers point the way to appropriate therapy. • Was the episode a true TIA and not one of its mimics? • What risk factors for stroke are present that predispose continued
225
Downloaded by [University of Toronto Libraries] at 08:51 27 June 2016
At one time it was thought that prophylactic aspirin for TIAs and stroke benefited men but not women.
Figure 3. Causes of cardiagenic emboli that result in stroke.
this patient to TIA? • Is there any clinical, electrocardiographic, echocardiographic, or biochemical evidence of cardiac arrhythmia, ischemia, or valvular disease to suggest that this TIA was produced by cardiogenic embolism (figure 3)? • Is there any evidence (from auscultation or Doppler ultrasound studies) of a stenotic lesion in the carotid or vertebral arteries? If so, is this a mild to moderate stenosis (70%), for which endarterectomy may be preferable? • What factors in the patient's general medical status may con-
traindicate the use of platelet disaggregators, anticoagulants, or endarterectomy?
Treating TIAs There is evidence from a number of studies that aspirin reduces not only the recurrence ofTIAs bur also the risk of stroke in people who have had TIAs. 1 In one of these large studies/ the occurrence of stroke in subjects taking aspirin over a 3-year follow-up period was only half that of a control group of subjects who had not been taking aspirin. At one time it was thought that prophylactic aspirin benefited men bur not women. However, this result is now known to have been obtained during high-dose aspirin trials. It is now generally ac-
cepted that women with TIAs obtain the same benefit as men do from aspirin therapy, provided that the dose is low. The issue of "how low is low" in dosages of aspirin for antiplatelet therapy is still somewhat controversial. Many neurologists now favor a dosage of325 mg/day (1 regular-strength aspirin tablet), and some would recommend even lower dosages, such as 80 or even 30 mg/ day (baby aspirin). The lowest dosages seem to confer as much benefit as the higher ones bur with less risk of gastrointestinal side effects. However, even with low-dose aspirin therapy, some physicians prescribe a histamine2 blocker or a cytoprotective agent to minimize the chances of gastrointestinal irritation. Other platelet inhibitors have been tried in patients who are intolerant of aspirin. Sulfinpyrazone (Anturane) and suloctidil have not been shown to be of value in patients with TIA. Dipyridamole (Persantine) has not been demonstrated to be effective, 4 bur the data are incomplete. Ticlopidine hydrochloride (Ticlid) has been shown in large studies to be effective in stroke reduction in patients with TIA. 5 Because ticlopidine is associated with a small
continued
226
STROKE • VOL 92/NO 2/AUGUST 1992/POSTGRADUATE MEDICINE
Aspirin and ticlopidine clearly decrease the risk of stroke in patients with TIAs caused by artery-to-artery embolism.
Downloaded by [University of Toronto Libraries] at 08:51 27 June 2016
John Edmeads, MD Dr Edmeads is professor of medicine (neurology), University of Toronto Faculty of Medicine, and neurologist-in-chief, Sunnybrook Medical Centre, Toronto, the site of Canada's first stroke unit. His major interests are in the management of neurologic emergencies and headache.
but definite risk of neutropenia, it should be reserved for patients intolerant of aspirin. Leukocyte and differential counts should be done every 2 weeks for the first 3 months of ticlopidine therapy. (Since neutropenia did not occur in the trials after the first 90 days, hematologic monitoring is less important after the first 3 months of therapy.) The dosage of ticlopidine is 250 mg twice daily with food.
228
Aspirin and ticlopidine clearly decrease the risk of stroke in patients with TIAs caused by arteryto-artery embolism, probably because in this situation thrombi are formed by platelets aggregating in areas of turbulence. In cardiogenic embolism, in which thrombi are formed primarily by the deposition of fibrin in areas of stasis, the role of platelet inhibitors is much less clearly defined.
The anticoagulant warfarin sodium (Coumadin, Panwarfin, Sofarin) is generally acknowledged to be the agent of choice for prevention of cardiogenic emboli. The risk of adverse reactions (notably hemorrhage) during warfarin therapy is greater than that during aspirin therapy. However, adequate anticoagulant protection can be achieved with small doses of warfarin (sufficient to increase the prothrombin time by only 30% to 50%). These small doses significantly reduce the risk of hemorrhage. The risk is further reduced by careful selection of patients, 6 excluding those with a history of bleeding ulcer or hemorrhage from other sites, those with liver disease, and those unable to fully comply with treatment. Atrial fibrillation has recently been recognized as a major risk factor for stroke, so much so that many neurologists preemptively treat patients who have atrial fibrillation with anticoagulants even if they have never had a TIA. The Framingham Heart Study" has shown that people with nonvalvular atrial fibrillation (ie, atrial fibrillation without associated valvular disease) are five times more likely to have a stroke than age- and sex-matched controls continued
STROKE • VOL 92/NO 2/AUGUST 1992/POSTGRADUATE MEDICINE
Downloaded by [University of Toronto Libraries] at 08:51 27 June 2016
Until quite recently, carotid endarterectomy was considered to be of doubtful value as prophylaxis in patients who had sustained either TIA or minor cerebral infarction arising from internal carotid artery stenosis.
without atrial fibrillation. This study has also shown that people with valvular atrial fibrillation (ie, atrial fibrillation with associated valvular disease) are 17 times more likely than controls to have cardiogenic strokes. This is a powerful argument for preemptive anticoagulant treatment, 8 especially since recent studies9- 11 have demonstrated that warfarin therapy strikingly reduces the incidence of stroke in atrial fibrillation. Once either platelet disaggregation or anticoagulation prophylaxis has been started, treatment should continue on a long-term basis, since the underlying factors that predispose to stroke (eg, atherosclerosis, valvular disease, atrial fibrillation) are unlikely to spontaneously remit. Long-term anticoagulation with warfarin is not without risk, so studies 12'13 have been directed at determining if the risk of thromboembolism in some patients with nonrheumatic atrial fibrillation is too small to justify the use oflong-term anticoagulation. It has been suggested that "fibrillators" who are not diabetic and who have no history of previous thromboembolism, hypertension, or congestive heart failure are at less risk of thromboembolism (1.4o/o/yr) than those who do
have these risk factors (7.2o/o to 17 .6o/o/yr, depending on the number of risk factors present). 12 Nonrheumatic fibrillators with none of the described clinical risk factors and no evidence of either left atrial enlargement or left ventricular dysfunction on echocardiography have even less risk of thromboembolism (l.Oo/o/yr). 13 In such patients, the risk of stroke can be less than the risks accruing from long-term anticoagulation.12'13 Until quite recently, carotid endarterectomy was considered to be of doubtful value as prophylaxis in patients who had sustained either TIA or minor cerebral infarction arising from stenosis of the internal carotid artery. However, results from the North American Symptomatic Carotid Endarterectomy Trial (NASCET) 14 indicate that surgery plus medical therapy is superior to medical therapy alone in terms of preventing stroke in patients with stenosis occluding more than 70o/o of the lumen of the artery. Therefore, a patient who has had a TIA (or a minor stroke) and has demonstrable carotid stenosis of70o/o or more should be evaluated by a neurosurgeon or a vascular surgeon as a candidate for endarterectomy. The risks of endarterectomy per-
formed by a competent surgeon do not exceed the risks posed by either the natural progression of disease or anticoagulant therapy.
Conclusion Stroke is a major catastrophe that becomes increasingly common and disabling with age. Often, stroke gives no warning, but sometimes the occurrence of a transient ischemic attack signals an impending stroke. This warning provides an opportunity for rapid diagnostic and therapeutic intervention that may prevent a tragic outcome. Like most of life's evils, stroke is better prevented than remedied. PCIVI
--®
Earn credit on this article.
See CME Quiz.
Address for correspondence: John Edmeads, MD, Sunnybrook Medical Centre, Room A460, 2075 Bayview Ave, Toronto, Ontario M4N 3M5, Canada.
References 1. Kurtzke JF, Kurland LT. The epidemiology
of neurological disease. In: Baker AB, Baker LH, eds. Clinical neurology. Vol4. Chap 66. Philadelphia: JB Lippincott, 1984:14-27 2. Cujec 8, Polasek P, Voll C, et al. Trans-
continued
VOL 92/NO 2/AUGUST 1992/POSTGRADUATE MEDICINE • STROKE
231
~isosor!Jir!&monon/lid!&)
--
20mgtablets
BRIEF SUMMARY (FOR FULL PRESCRIBING INFORMATION AND PATIENT INFORMATION, SEE PACKAGE CIRCULAR.) Indications and Usage lsmo is indicated for prevention of angina pectoris due to coronary artery disease. The onset of action is not rapid enough for it to be useful in aborting an acute anginal episode. Clinical Pharmacology lsosorbide mononitrate is the major active metabolite of isosorbide dinitrate; most of the clinical activity of the dinitrate comes from the mononitrate. lsmo is not subject to first-pass metabolism in the liver and the absolute bioavailability of isosorbide mononitrate from lsmo tablets is nearly tOO%. The rate of clearance of lsmo is the same in healthy young adults, in patients with various degrees of renal, hepatic, or cardiac dysfunction, and in the elderly. Several well-controlled studies have demonstrated that active nitrates were indistinguishable from placebo after 24 hours (or less) of continuous therapy due to the development of tolerance. Only after nitrates are absent from the body for several hours is their antianginal efficacy restored. The drug-free interval sufficient to avoid tolerance to isosorbide mononitrate is not completely defined. The only regimen shown to avoid development of tolerance with isosorbide mononitrate involves two daily doses of lsmo tablets given 7 hours apart, so there is a gap of 17 hours between the second dose of each day and the first dose of the next day. Taking account of the relatively long half-life of isosorbide mononitrate this result is consistent with those obtained for other organic nitrates. The same twice-daily regimen of lsmo tablets successfully avoided significant rebound/withdrawal effects. In studies of other nitrates, the incidence and magnitude of such phenomena appear to be highly dependent upon the schedule of nitrate administration. Contra Indications Allergic reactions are extremely rare, but do occur. lsmo is coniraindicated in patients allergic to it.
Downloaded by [University of Toronto Libraries] at 08:51 27 June 2016
:e~~::~he
effects of lsmo are difficult to terminate rapidly and have not been established in patients with acute myocardial infarction (MI) or congestive heart failure (CHF), this drug is not recommended in these patients. If lsmo is used in these patients, careful clinical or hemodynamic monitoring is required to avoid the hazards of hypotension and tachycardia. Precautions GENERAL Severe hypotension, particularly with upright posture, may occur with even small doses. Therefore, use with caution in patients who may be volume depleted or who are already hypotensive. Paradoxical bradycardia and increased angina pectoris may accompany lsmoinduced hypotension. Nitrates may aggravate angina caused by hypertrophic cardiomyopathy. INFORMATION FOR PATIENTS Tell patients they must carefully follow the prescribed dosing schedule (2 doses taken 7 hours apart) to maintain the antianginal effect (eg, take first dose on awakening and second dose 7 hours later). Daily headaches sometimes accompany treatment with nitrates, including lsmo, and are a marker of drug activity. Patients with headaches should not alter their treatment ~chedule since loss of headache may be associated with simultaneous loss of antianginal efficacy. Headaches may be treated w1th aspmn and/or acetaminophen Without affectmg the ant1angmal act1v1ty of lsmo. Light-headedness on standing, especially just after rising from a recumbent or seated position, may occur. This may be more frequent in patients who have consumed alcohol. DRUG INTERACTIONS Vasodilating effects of lsmo may be additive with those of other vasodilators, especially alcohol. Marked symptomatic orthostatic hypotension has been reported when calcium channel blockers and organic nitrates were used in combination. Dose adjustments of either class of agents may be necessary. CARCINOGENESIS, MUTAGENESIS, AND IMPAIRMENT OF FERTILITY No carcinogenic effects were observed in mice or rats exposed to orallsmo, nor were adverse effects on rat fertility observed. No mutagenic activity was seen in in vitro or in vivo assays. PREGNANCY CATEGORY C lsmo has been shown to have embryocidal effects in rats and rabbits at doses at least 70 times the maximum human dose. There are no adequate and well-controlled studies in pregnant women. Use during pregnancy only if potential benefit justifies potential fetal risk. NURSING MOTHERS Excretion in human milk is unknown. Use caution if administered to a nursing woman. PEDIATRIC USE Safety and effectiveness have not been established. Adverse Reactions Frequency of Adverse Reactions (Oiscontinuations) • Occurring in > 1% of Subjects 6 Controfled U.S. Studies Placebo 20ma 219 204 9% (0%) 38% (9%) 1% (0%) 5% (1%)
ISSN: 0032-5481 (Print) 1941-9260 (Online) Journal homepage: http://www.tandfonline.com/loi/ipgm20
How to avert impending stroke John Edmeads MD To cite this article: John Edmeads MD (1992) How to avert impending stroke, Postgraduate Medicine, 92:2, 221-234, DOI: 10.1080/00325481.1992.11701427 To link to this article: http://dx.doi.org/10.1080/00325481.1992.11701427
Published online: 17 May 2016.
Submit your article to this journal
View related articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ipgm20 Download by: [University of Toronto Libraries]
Date: 27 June 2016, At: 08:51
--@CME credit article
How to avert impending stroke
John Edmeads, MD
Downloaded by [University of Toronto Libraries] at 08:51 27 June 2016
Preview Patients "lucky" enough to have a nondisabling transient ischemic attack as a warning sign of impending stroke deserve the best possible prophylactic treatment in an attempt to avert that catastrophe. Dr Edmeads provides a step-by-step discussion of diagnostic studies and therapeutic regimens that help avoid stroke in middle-aged and older patients who are at risk.
Stroke is a specter that looms larger as we grow older. The annual incidence of symptomatic cerebrovascular disease (as determined in a study at the Mayo Clinic, Rochester, Minnesota') is 170 per 100,000 among people aged 55 to 64 years and rises to 957 per 100,000 among those older than age 75. The annual death rate from cerebrovascular disease in the United States is about 100 per 100,000 for people in their mid-50s.' The death rate almost doubles with each additional 5 years of age, reaching 1,500 per 100,000 for people 80 years of age. 1 Survivors of stroke are often disabled: The older a patient is at the time of stroke, the more likely the related disability is to be severe and permanent. This prospect is not pleasant-prevention is of paramount importance. Various kinds of stroke occur in patients who are middle-aged or older (table 1). (Stroke in
young persons comprises a spectrum of disease sufficiently different ftom that caused by stroke in older persons that it is not considered in this article.) Some of the strokes that occur in older persons give no warning. For example, intracerebral hemorrhage nearly always occurs unheralded, which provides no opportunity to avert it. While the long-term risk of cerebral hemorrhage may be reduced by carefully controlling blood pressure over the years, once the bleeding starts the outcome is inevitable. Subarachnoid hemorrhage, sometimes classified as a type of stroke (especially in epidemiologic studies), is so different from what clinicians generally consider under the heading of stroke that it is not discussed in this article. When subarachnoid hemorrhages are preceded by warnings, the warnings usually take the form of headache rather than focal neurologic disturbances.
In contrast to strokes caused by cerebral hemorrhage, between one quarter and one third of strokes caused by thromboembolic disease are preceded by transient ischemic attacks (TIAs), which give warning of an impending stroke and an opportunity to prevent it. A person who has had a TIA has a 6% per year overall risk of having a stroke at some future time, a risk five times greater than that of a person who has not had a TIA. One third of these cerebral infarctions occur within a month of the TIA, and half occur within a year. Early recognition ofTIAs and prompt, appropriate treatment may avert catastrophe. Here is how to do it (figure 1).
Understanding TIAs A TIA occurs when temporary insufficiency of blood flow to a pan of the brain results in localized, reversible ischemia and dysfunction. In most patients, this evanescent impairment of blood supply is caused by a plateletfibrin embolus that originates on an atherosclerotic plaque in the proximal portion of the internal carotid artery or the vertebrabasilar system. The embolus is carried dow~stream to lodge briefly in a small distal arterial branch before breaking up. In
continued
VOL 92/NO 2/AUGUST 1992/POSTGRADUATE MEDICINE • STROKE
221
Downloaded by [University of Toronto Libraries] at 08:51 27 June 2016
Most older patients with transient focal neurologic deficits are having TIAs.
Table 1. Incidence of different types of stroke in and after middle age Cerebral infarction Artery-to-artery embolism Hemodynamic stenosis Cardiogenic embolism
78% 80% 5% 15%
Cerebral hemorrhage Hypertension Amyloid angiopathy Other
12% 75% 20% 5%
"Pseudostrokes" (stroke mimics) Unwitnessed seizures Mass lesions causing apoplectiform symptoms Other
10%
80% 10% 10%
about 15% of patients the embolus is cardiogenic. In a few patients, probably no more than 5%, the transient ischemia is caused by hemodynamic mechanisms, such as when blood flow across an area of tight arterial stenosis falters because of transient hypotension resulting from cardiac arrhythmia, orthostatic hypotension, side effects of drugs, or similar mechanisms. Figure 2 delineates the proportion of ischemic strokes attributable to various causes. By definition, a TIA clears completely within 24 hours, but
222
the great majority last less than an hour. Sometimes a TIA may take a little longer than 24 hours to resolve, and then it is termed a resolving ischemic neurologic deficit. The patient has narrowly escaped stroke-this time. TIAs and resolving ischemic neurologic deficits indicate the presence of artery-to-artery embolism, cardiogenic embolism, or (rarely) severe arterial stenosis. Investigation of the cerebrovascular system and the heart, as well as treatment that either inhibits clot formation or reopens blood vessels, is indicated.
Recognizing TIAs Most older patients with transient focal neurologic deficits, such as hemiparesis, numbness of a body part, slurred speech, aphasia, visual obscuration, diplopia, or ataxia, are having TIAs. Other causes of these symptoms are uncommon. Occasionally a patient has a seizure in bed at night and awakens in the morning with postictal hemiparesis that clears in a few hours. This can be quite confusing unless someone has witnessed the seizure. Some investigators believe that migraine, even in middle-aged and elderly persons, may produce transient focal deficits, or transient migrainous accompani-
ments, but migraine should be considered as a cause of such deficits only after adequate investigation has excluded the possibility ofTIAs. Rarely, a mass lesion, such as subdural hematoma or cerebral neoplasm, produces intermittent focal symptoms, but sufficient investigation usually excludes this diagnosis. An equally rare small intracerebral hemorrhage may produce a minor deficit that resolves within hours, mimicking a TIA. This is one reason why anticoagulant therapy should not be started until computed tomography (CT) or magnetic resonance imaging (MRI) has been done to confirm the diagnosis ofTIA. Some transient neurologic symptoms, such as confusion, memory loss, dizziness, and fainting, are often attributed to TIAs but are just as likely to be due to another cause. Intermittent confusion may be the result of adverse reactions to medications, withdrawal from drugs (including alcohol), occult infection, metabolic disturbances (eg, hypoglycemia, hypoxia, hypercarbia), or unrecognized seizures. Transient pure memory loss with no accompanying features, or transient global amnesia, is believed by some to be related to cerebral ischemia, but this has not been continued
STROKE • VOL 92/NO 2/AUGUST 1992/POSTGRADUATE MEDICINE
A TIA occurs when temporary insufficiency of blood flow to a part of the brain results in localized, reversible ischemia and dysfunction.
Downloaded by [University of Toronto Libraries] at 08:51 27 June 2016
Transient neurologic symptoms
~
Clinical diagnosis
I
+
Other diagnoses (see table 2)
TIA
~
Routine investigations (laboratory studies)
~
Exclude other causes of transient neurologic deficit (computed tomography or magnetic resonance imaging)
I
+
TIA or small infarct
Other diagnoses (see table 2)
~
Establish cause: artery-to-artery embolism, hemodynemic stenosis, or cardiogenic embolism (see figure 2)
I
+
Electrocardiography and twodimensional echocardiography
Doppler ultrasound studies
I
+
Doppler shows >70% stenosis
+
Doppler shows 70%). Patients selected for this procedure should be good angiegraphic and surgical candidates and willing to undergo surgery if it is indicated. Some types of investigation are of relatively little value in the assessment of patients with Tlfu. An electroencephalogram may show an epileptogenic lesion and
VOL 92/NO 2/AUGUST 1992/POSTGRADUATE MEDICINE • STROKE
prevent the diagnostic pratfall of mistaking postictal palsy for TIA. However, the yield of electroencephalographic studies in general is very low in patients with Tlfu. Radioisotope scanning of the brain is usually of such low resolution that it seldom gives much useful information in these cases. Lumbar puncture is not helpful in patients with Tlfu. Completion of the investigation of a patient with Tlfu should result in reasonably confident answers to the following questions. The answers point the way to appropriate therapy. • Was the episode a true TIA and not one of its mimics? • What risk factors for stroke are present that predispose continued
225
Downloaded by [University of Toronto Libraries] at 08:51 27 June 2016
At one time it was thought that prophylactic aspirin for TIAs and stroke benefited men but not women.
Figure 3. Causes of cardiagenic emboli that result in stroke.
this patient to TIA? • Is there any clinical, electrocardiographic, echocardiographic, or biochemical evidence of cardiac arrhythmia, ischemia, or valvular disease to suggest that this TIA was produced by cardiogenic embolism (figure 3)? • Is there any evidence (from auscultation or Doppler ultrasound studies) of a stenotic lesion in the carotid or vertebral arteries? If so, is this a mild to moderate stenosis (70%), for which endarterectomy may be preferable? • What factors in the patient's general medical status may con-
traindicate the use of platelet disaggregators, anticoagulants, or endarterectomy?
Treating TIAs There is evidence from a number of studies that aspirin reduces not only the recurrence ofTIAs bur also the risk of stroke in people who have had TIAs. 1 In one of these large studies/ the occurrence of stroke in subjects taking aspirin over a 3-year follow-up period was only half that of a control group of subjects who had not been taking aspirin. At one time it was thought that prophylactic aspirin benefited men bur not women. However, this result is now known to have been obtained during high-dose aspirin trials. It is now generally ac-
cepted that women with TIAs obtain the same benefit as men do from aspirin therapy, provided that the dose is low. The issue of "how low is low" in dosages of aspirin for antiplatelet therapy is still somewhat controversial. Many neurologists now favor a dosage of325 mg/day (1 regular-strength aspirin tablet), and some would recommend even lower dosages, such as 80 or even 30 mg/ day (baby aspirin). The lowest dosages seem to confer as much benefit as the higher ones bur with less risk of gastrointestinal side effects. However, even with low-dose aspirin therapy, some physicians prescribe a histamine2 blocker or a cytoprotective agent to minimize the chances of gastrointestinal irritation. Other platelet inhibitors have been tried in patients who are intolerant of aspirin. Sulfinpyrazone (Anturane) and suloctidil have not been shown to be of value in patients with TIA. Dipyridamole (Persantine) has not been demonstrated to be effective, 4 bur the data are incomplete. Ticlopidine hydrochloride (Ticlid) has been shown in large studies to be effective in stroke reduction in patients with TIA. 5 Because ticlopidine is associated with a small
continued
226
STROKE • VOL 92/NO 2/AUGUST 1992/POSTGRADUATE MEDICINE
Aspirin and ticlopidine clearly decrease the risk of stroke in patients with TIAs caused by artery-to-artery embolism.
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John Edmeads, MD Dr Edmeads is professor of medicine (neurology), University of Toronto Faculty of Medicine, and neurologist-in-chief, Sunnybrook Medical Centre, Toronto, the site of Canada's first stroke unit. His major interests are in the management of neurologic emergencies and headache.
but definite risk of neutropenia, it should be reserved for patients intolerant of aspirin. Leukocyte and differential counts should be done every 2 weeks for the first 3 months of ticlopidine therapy. (Since neutropenia did not occur in the trials after the first 90 days, hematologic monitoring is less important after the first 3 months of therapy.) The dosage of ticlopidine is 250 mg twice daily with food.
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Aspirin and ticlopidine clearly decrease the risk of stroke in patients with TIAs caused by arteryto-artery embolism, probably because in this situation thrombi are formed by platelets aggregating in areas of turbulence. In cardiogenic embolism, in which thrombi are formed primarily by the deposition of fibrin in areas of stasis, the role of platelet inhibitors is much less clearly defined.
The anticoagulant warfarin sodium (Coumadin, Panwarfin, Sofarin) is generally acknowledged to be the agent of choice for prevention of cardiogenic emboli. The risk of adverse reactions (notably hemorrhage) during warfarin therapy is greater than that during aspirin therapy. However, adequate anticoagulant protection can be achieved with small doses of warfarin (sufficient to increase the prothrombin time by only 30% to 50%). These small doses significantly reduce the risk of hemorrhage. The risk is further reduced by careful selection of patients, 6 excluding those with a history of bleeding ulcer or hemorrhage from other sites, those with liver disease, and those unable to fully comply with treatment. Atrial fibrillation has recently been recognized as a major risk factor for stroke, so much so that many neurologists preemptively treat patients who have atrial fibrillation with anticoagulants even if they have never had a TIA. The Framingham Heart Study" has shown that people with nonvalvular atrial fibrillation (ie, atrial fibrillation without associated valvular disease) are five times more likely to have a stroke than age- and sex-matched controls continued
STROKE • VOL 92/NO 2/AUGUST 1992/POSTGRADUATE MEDICINE
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Until quite recently, carotid endarterectomy was considered to be of doubtful value as prophylaxis in patients who had sustained either TIA or minor cerebral infarction arising from internal carotid artery stenosis.
without atrial fibrillation. This study has also shown that people with valvular atrial fibrillation (ie, atrial fibrillation with associated valvular disease) are 17 times more likely than controls to have cardiogenic strokes. This is a powerful argument for preemptive anticoagulant treatment, 8 especially since recent studies9- 11 have demonstrated that warfarin therapy strikingly reduces the incidence of stroke in atrial fibrillation. Once either platelet disaggregation or anticoagulation prophylaxis has been started, treatment should continue on a long-term basis, since the underlying factors that predispose to stroke (eg, atherosclerosis, valvular disease, atrial fibrillation) are unlikely to spontaneously remit. Long-term anticoagulation with warfarin is not without risk, so studies 12'13 have been directed at determining if the risk of thromboembolism in some patients with nonrheumatic atrial fibrillation is too small to justify the use oflong-term anticoagulation. It has been suggested that "fibrillators" who are not diabetic and who have no history of previous thromboembolism, hypertension, or congestive heart failure are at less risk of thromboembolism (1.4o/o/yr) than those who do
have these risk factors (7.2o/o to 17 .6o/o/yr, depending on the number of risk factors present). 12 Nonrheumatic fibrillators with none of the described clinical risk factors and no evidence of either left atrial enlargement or left ventricular dysfunction on echocardiography have even less risk of thromboembolism (l.Oo/o/yr). 13 In such patients, the risk of stroke can be less than the risks accruing from long-term anticoagulation.12'13 Until quite recently, carotid endarterectomy was considered to be of doubtful value as prophylaxis in patients who had sustained either TIA or minor cerebral infarction arising from stenosis of the internal carotid artery. However, results from the North American Symptomatic Carotid Endarterectomy Trial (NASCET) 14 indicate that surgery plus medical therapy is superior to medical therapy alone in terms of preventing stroke in patients with stenosis occluding more than 70o/o of the lumen of the artery. Therefore, a patient who has had a TIA (or a minor stroke) and has demonstrable carotid stenosis of70o/o or more should be evaluated by a neurosurgeon or a vascular surgeon as a candidate for endarterectomy. The risks of endarterectomy per-
formed by a competent surgeon do not exceed the risks posed by either the natural progression of disease or anticoagulant therapy.
Conclusion Stroke is a major catastrophe that becomes increasingly common and disabling with age. Often, stroke gives no warning, but sometimes the occurrence of a transient ischemic attack signals an impending stroke. This warning provides an opportunity for rapid diagnostic and therapeutic intervention that may prevent a tragic outcome. Like most of life's evils, stroke is better prevented than remedied. PCIVI
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Address for correspondence: John Edmeads, MD, Sunnybrook Medical Centre, Room A460, 2075 Bayview Ave, Toronto, Ontario M4N 3M5, Canada.
References 1. Kurtzke JF, Kurland LT. The epidemiology
of neurological disease. In: Baker AB, Baker LH, eds. Clinical neurology. Vol4. Chap 66. Philadelphia: JB Lippincott, 1984:14-27 2. Cujec 8, Polasek P, Voll C, et al. Trans-
continued
VOL 92/NO 2/AUGUST 1992/POSTGRADUATE MEDICINE • STROKE
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~isosor!Jir!&monon/lid!&)
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20mgtablets
BRIEF SUMMARY (FOR FULL PRESCRIBING INFORMATION AND PATIENT INFORMATION, SEE PACKAGE CIRCULAR.) Indications and Usage lsmo is indicated for prevention of angina pectoris due to coronary artery disease. The onset of action is not rapid enough for it to be useful in aborting an acute anginal episode. Clinical Pharmacology lsosorbide mononitrate is the major active metabolite of isosorbide dinitrate; most of the clinical activity of the dinitrate comes from the mononitrate. lsmo is not subject to first-pass metabolism in the liver and the absolute bioavailability of isosorbide mononitrate from lsmo tablets is nearly tOO%. The rate of clearance of lsmo is the same in healthy young adults, in patients with various degrees of renal, hepatic, or cardiac dysfunction, and in the elderly. Several well-controlled studies have demonstrated that active nitrates were indistinguishable from placebo after 24 hours (or less) of continuous therapy due to the development of tolerance. Only after nitrates are absent from the body for several hours is their antianginal efficacy restored. The drug-free interval sufficient to avoid tolerance to isosorbide mononitrate is not completely defined. The only regimen shown to avoid development of tolerance with isosorbide mononitrate involves two daily doses of lsmo tablets given 7 hours apart, so there is a gap of 17 hours between the second dose of each day and the first dose of the next day. Taking account of the relatively long half-life of isosorbide mononitrate this result is consistent with those obtained for other organic nitrates. The same twice-daily regimen of lsmo tablets successfully avoided significant rebound/withdrawal effects. In studies of other nitrates, the incidence and magnitude of such phenomena appear to be highly dependent upon the schedule of nitrate administration. Contra Indications Allergic reactions are extremely rare, but do occur. lsmo is coniraindicated in patients allergic to it.
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effects of lsmo are difficult to terminate rapidly and have not been established in patients with acute myocardial infarction (MI) or congestive heart failure (CHF), this drug is not recommended in these patients. If lsmo is used in these patients, careful clinical or hemodynamic monitoring is required to avoid the hazards of hypotension and tachycardia. Precautions GENERAL Severe hypotension, particularly with upright posture, may occur with even small doses. Therefore, use with caution in patients who may be volume depleted or who are already hypotensive. Paradoxical bradycardia and increased angina pectoris may accompany lsmoinduced hypotension. Nitrates may aggravate angina caused by hypertrophic cardiomyopathy. INFORMATION FOR PATIENTS Tell patients they must carefully follow the prescribed dosing schedule (2 doses taken 7 hours apart) to maintain the antianginal effect (eg, take first dose on awakening and second dose 7 hours later). Daily headaches sometimes accompany treatment with nitrates, including lsmo, and are a marker of drug activity. Patients with headaches should not alter their treatment ~chedule since loss of headache may be associated with simultaneous loss of antianginal efficacy. Headaches may be treated w1th aspmn and/or acetaminophen Without affectmg the ant1angmal act1v1ty of lsmo. Light-headedness on standing, especially just after rising from a recumbent or seated position, may occur. This may be more frequent in patients who have consumed alcohol. DRUG INTERACTIONS Vasodilating effects of lsmo may be additive with those of other vasodilators, especially alcohol. Marked symptomatic orthostatic hypotension has been reported when calcium channel blockers and organic nitrates were used in combination. Dose adjustments of either class of agents may be necessary. CARCINOGENESIS, MUTAGENESIS, AND IMPAIRMENT OF FERTILITY No carcinogenic effects were observed in mice or rats exposed to orallsmo, nor were adverse effects on rat fertility observed. No mutagenic activity was seen in in vitro or in vivo assays. PREGNANCY CATEGORY C lsmo has been shown to have embryocidal effects in rats and rabbits at doses at least 70 times the maximum human dose. There are no adequate and well-controlled studies in pregnant women. Use during pregnancy only if potential benefit justifies potential fetal risk. NURSING MOTHERS Excretion in human milk is unknown. Use caution if administered to a nursing woman. PEDIATRIC USE Safety and effectiveness have not been established. Adverse Reactions Frequency of Adverse Reactions (Oiscontinuations) • Occurring in > 1% of Subjects 6 Controfled U.S. Studies Placebo 20ma 219 204 9% (0%) 38% (9%) 1% (0%) 5% (1%)
