NEUROLOGY FOR INTERNISTS: TIAs/EPILEPSY
| TRANSIENT ISCHEMIC ATTACKS: APPROACHES TO DIAGNOSIS AND TREATMENT —S. Claiborne Johnston,
MD, PhD, Associate Professor of Neurology and Epidemiology and Director, Stroke Service, University of California, San
Francisco, School of Medicine
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| Transient ischemic attacks (TIAs): definition—traditionally defined as neurologic deficit lasting <24 hr and due to
focal ischemia in brain or retina; newly proposed definition (2001) more vague about time, ie, “clinical symptoms typically
lasting <1 hr,” and integrates absence of infarction, ie, “without evidence of acute infarction”; however, if brain imaging
not done, unknown whether new infarction present; also, magnetic resonance imaging (MRI) more likely to show
infarction than computed tomography (CT); similarities with stroke—TIA and stroke identical in etiology, evaluation,
secondary prophylaxis, and presence of infarct (according to traditional definition); ≈50% of patients who meet clinical
criteria under traditional definition of TIA show changes in diffusion weighted image (DWI) on MRI; differences from
stroke—management of TIA different from that of stroke; patients with TIA neurologically normal; pathophysiology of
TIA different from that of stroke (TIAs more unstable); also, patients diagnosed with TIA may not actually have TIA
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| Prognosis: short-term prognosis determines management of patients; many studies looking at prognosis, but most do not include
first hours to days immediately after TIA; Oxfordshire Community Health Project found 4.4% risk for stroke in first
month after TIA (small study; missed first 3 days after TIA); old study (1960s-1970s) done in Rochester, Minnesota found
higher risk for stroke in first month after TIA; speaker’s cohort study—looked at all Kaiser-Permanente enrollees (≈1700
patients; mean age 72 yr; ≈50% women) given diagnosis of TIA in emergency department (ED) during 1 yr; 10.6% of patients
had stroke during 90 days after TIA, half of these within first 2 days; looked at hospitalization for recurrent TIA, major cardiac
event (eg, ventricular arrhythmia, myocardial infarction [MI]), or vascular-related death and found 26% adverse event rate,
with most events occurring early; independent risk factors for stroke included age >60 yr, diabetes, duration >10 min, weakness
or speech difficulty during TIA; of patients with no risk factors, 0% had stroke within 90 days, while >35% of patients
with 5 risk factors had stroke in 90 days; ABCD2 scoring system—age ≥60 yr, blood pressure (BP) >140/90 mm Hg on initial
evaluation, focal weakness, duration >60 min, and diabetes; each has 1 point, giving final score of 0 to 5; system validated
and ready for clinical use; overall stroke risk after TIA—studies show higher risk (11%) for stroke within 90 days
after TIA than after stroke (≈4%)
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| Pathophysiology: possible explanations—TIA may represent more unstable situation; more thromboembolic events may
occur after TIA or events more apparent (ischemia seen more easily after TIA than after stroke); instability—platelet thrombus
develops on ruptured plaque and stays; tissue already infarcted, so new symptoms do not occur; highly thrombogenic
plaque no longer as thrombogenic while attached to platelets; if platelet thrombus lyses and flow returns, then ruptured plaque
remains highly thrombogenic and tissue downstream remains at risk for stroke; more unstable situation indicated by early recovery
(TIA); recovery—stroke is neurologic deficit that comes and stays, TIA is neurologic deficit that comes and goes; in
some events labeled “stroke,” patients experience incomplete recovery, and these should be similar to TIAs prognostically
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| Acute stroke trials: involve detailed monitoring of neurologic function during acute phase; National Institute of Neurological
Disorders and Stroke (NINDS) tissue plasminogen activator (tPA) trial—defined TIA as complete recovery
at 24 hr (40 patients); 57 patients had major but incomplete recovery; subsequent neurologic deterioration considered indicative
of new ischemia (12% of patients); in patients who had >75% improvement, risk for event during subsequent 90
days 22%; risk <10% in those with less recovery; some degree of recovery indicates higher risk for stroke; greater recovery
associated with higher risk for subsequent event leading to neurologic deterioration; in Trial of ORG 10172 in Acute
Stroke Treatment (TOAST), results similar; conclusion—short-term risk substantial in patients with rapid recovery
from cerebral ischemia; complete resolution unimportant to prognosis
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| Diagnostic issues: questions about whether TIA really TIA—focal cerebral ischemia responsible for symptoms? event
ischemic, or related to seizure or migraine? nature of event focal, cardiac, or vasovagal? little agreement, even among neurologists,
about accuracy of diagnosis of TIA; generally, non-neurologists make diagnosis; risk factors for stroke may be
best way to identify true TIA, ie, patient who goes on to have stroke probably had real TIA
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| Risk factors for recurrent TIA: include age >60 yr, history of multiple TIAs, short-duration TIA, numbness, and
weakness (also risk factor for stroke); benign recurrent “TIA”—may not be TIA; possibly due to some other pathophysiology;
characterized by sensory symptoms only, with duration of <10 min; recurrence likely, but subsequent major
events unlikely; thought to be vasospastic events or migrainous accompaniments of elderly; calcium channel blockers
used to treat symptoms in these patients; TIA—diagnose TIA when infarct present (by old definition); new infarct on CT
strong predictor of stroke; 38% of patients with new infarct experience stroke within 90 days, compared to 10% without
new infarct; recently shown that new infarct present on MRI also predictor of stroke; 5-fold increase in risk with new lesion
on baseline MRI; risk for stroke—subset of patients with TIA at high risk for recurrent TIA but low risk for stroke;
may have different pathophysiology; risk factors for stroke may be best tools to identify true TIA; other biomarkers may
help; best biomarker is presence of infarction on MRI (prognostic relevance independent of clinical factors); risk for recurrence
increases with likelihood that patient had true TIA; as proportion of recovery increases, risk for recurrence increases
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 | Evaluation: acute assessment—history and physical examination; laboratory testing, including complete blood count
(CBC), electrolytes, serum urea nitrogen (BUN), glucose, calcium, erythrocyte sedimentation rate (ESR), and rapid
plasma reagin (RPR); head imaging (usually CT); cardiac assessment should include electrocardiography (ECG); consider
cardiac monitoring if cardiac examination or ECG abnormal; consider echocardiography; CT and CT angiography
(CTA)—start with noncontrast CT, then get CT perfusion study to look at blood flow; CTA shows clots and
carotid atherosclerosis (allows visualization of cerebrovascular axis from intracranial vessels to aortic arch and heart;
sensitivity and specificity not yet known); carotid artery atherosclerosis (CAA)—accounts for ≈11% of TIAs; short-
term risk for stroke appears higher in patients with CAA (20% at 90 days in 1 study); speaker’s data show risk for
stroke ≥30% in patients with significant carotid stenosis; risk increases with degree of stenosis
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| Treatment issues: importance of timing—if endarterectomy performed within 2 wk of TIA, absolute risk reduction at 5 yr
for stroke or operative death 20%; after 2 wk, absolute risk reduction at 5 yr small (0.8%); imaging studies important and
urgent; hospital admission—study looking at cost-effectiveness of admitting patients with recent TIA for observation and
potential to give tPA more rapidly if stroke occurs; looked at patients who had TIA within last 24 hr and only those who
would be candidates for tPA if stroke occurred; new stroke occurs in ≈4.2% of patients hospitalized for ED diagnosis of
TIA; administration of tPA more likely in patients who have stroke in hospital (≈3%) than in those who have stroke as outpatients
(1 in 200); additional cost associated with hospitalization balanced by benefit measured as quality-adjusted life years
(QALY; cost <$50,000/QALY); anything ≤$100,000/QALY considered cost-effective; conclusions—hospitalization may
be cost-effective solely on basis of increased use of tPA; other benefits to hospitalization include more rapid work-up, cardiac
monitoring, and more reliable initiation of treatment (data show physicians more likely to prescribe correct medications
for inpatients, and patients admitted acutely more likely to keep taking medications)
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| Recommendations: management—for all patients, urgent work-up, including CBC, glucose, ESR, ECG, head CT,
and carotid imaging within 24 hr (unless patient not candidate for endarterectomy); consider CTA; treatment—in patients
with atrial fibrillation, heparin (or enoxaparin) and warfarin (population of patients with TIA not at risk for hemorrhagic
conversion); for all other patients, aspirin (preferably with dipyridamole) or clopidogrel; early endarterectomy for
stenosis >70% (consider in patients with stenosis 50%-69%); consider use of high-dose statin in all patients; angiotensin-
converting enzyme (ACE) inhibitor, angiotensin-2 receptor blocker (ARB), and diuretic agent
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| EPILEPSY THERAPY UPDATE —Joseph F. Drazkowski, MD, Assistant Professor of Neurology, Mayo Clinic, Tucson,
AZ
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| Terminology: seizure—massive disruption of electrical communication between neurons, leading to temporary release
of excessive energy in synchronized form; other terms used include convulsion and ictus (event); epilepsy—condition
characterized by recurrent (≥2) unprovoked seizures
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| Epilepsy: basic facts—prevalence 1% to 4%; incidence ≈180,000/yr; average length of seizure 1 min; impairment of consciousness
not necessary; incontinence not proof of seizure; memory may be impaired after seizure; etiology—idiopathic
seizures most common; vascular etiologies also common
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| Seizure classification: partial—begin in focal area of brain; symptomatology may be simple (no loss of consciousness)
or complex (loss of awareness); can become secondary generalized (associated with major motor seizure and loss
of consciousness); generalized—usually inherited; primary generalized (eg, juvenile myoclonic epilepsy, absence
[petit mal] seizures); myoclonic seizures involve brief, “lightning-like,” jerks; also tonic-clonic types
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| Incidence: 2 peak ages; infants (high incidence of seizures in newborns); older adults (incidence increases as population
ages, especially >65 yr of age)
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| Partial epilepsy: affects 1 to 3 million people in United States; 90% of adult incident cases; 30% to 40% have medically
refractory seizures; 20% to 30% have intractable epilepsy
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| Management: goals—make patient seizure-free; avoid morbidity and mortality; improve quality of life; therapeutic
agents—many new agents on market; helpful, but not “blockbusters”; most new drugs niche drugs used in specific populations;
surgery—consider for patient who has failed maximal medical therapy; average wait ≈15 yr before referral for
surgery; patients usually fail 3 to 5 antiepilepsy drugs (AEDs) before referral; patients with focal epilepsy good candidates
for surgery; goals of surgery— eliminate or reduce seizures; improve quality of life; relieve suffering; improve patient
safety and morbidity; reduce mortality
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| Diagnosis: epilepsy monitoring unit (EMU)—place patients in unit to make diagnosis, classify seizure type, modify
medications, and for presurgical evaluation; diagnostic tests—work-up includes high-resolution MRI, awake and asleep
electroencephalography (EEG), laboratory tests, cardiovascular testing (especially for older patients), ambulatory ECG,
and tilt-table testing; phase 1 studies—admit patients to EMU; average stay 4 to 5 days; withdraw usual medications;
record habitual seizures; subtraction ictal single photon emission computed tomography (SPECT) coregistered on
MRI (SISCOM)—involves ictal injection of nuclear tracer (technetium 99); get ictal scan, then interictal scan at 24 hr;
computer software subtracts 2 images; “hot spot” then put on MRI; helps with localization of seizure origin
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| Partial epilepsy: 80% of adult partial epilepsy of temporal lobe origin, and 90% of those from mesial structures (ie,
amygdala and hippocampus); most temporal lobe seizures associated with unusual auras, eg, sense of fear, deja vu; most
not major motor seizures
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| Comorbidities: uncontrolled epilepsy leads to worse outcomes over time; epilepsy-related encephalopathy occurs in elderly
people who have brain injury from multiple seizures; psychologic comorbidities often more debilitating than disease
and include postictal psychosis, depression, and anxiety; increased risk for morbidity and mortality related to epilepsy;
sudden unexplained death in epilepsy (SUDEP) can occur; drowning number 1 cause of death in epileptic patients, and
suffocation during sleep number 2 cause of death
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| Treatment efficacy: medication—study looking at 526 unselected patients newly diagnosed with epilepsy and followed
for 5 yr; patients had maximal medical treatment; 63% seizure-free at 5 yr; only 11% of patients who failed first AED became
seizure-free; 30% to 40% of patients have difficult-to-control seizures; patients on 3 AEDs have zero chance of becoming seizure-free;
surgery—study of patients with temporal lobe epilepsy randomized to early surgery or maximal medical therapy;
concluded surgery effective and results in greater improvement in quality of life
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| Epilepsy surgery: complications—short-term memory loss biggest issue; temporal lobectomy in dominant hemisphere
more difficult for patients to recover from than in nondominant hemisphere; also, visual field defects can occur after surgery
(eg, “pie-in-the-sky” defect); complication rate 1% to 2%; temporal lobectomy most common type of surgery (65%-
85% cure rate); other resective surgeries, eg, frontal, parietal lobe surgeries, associated with 50% cure rate
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| Other studies: may perform high-resolution volume study of temporal lobe, positron emission tomography (PET), neuropsychologic
testing, Wada testing (involves intracarotid sodium amobarbital [ICA]; localizes memory and language
function); phase 2 studies—for patients who are not candidates for temporal lobectomy; require intracranial monitoring
in EMU; brain mapped using depth wires for electrical stimulation to localize areas where seizures originate, while
avoiding areas of vital functions; can perform tailored resections of specific area or lesion involved in seizures
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| Vagus nerve stimulation (VNS): implanted device that stimulates vagus nerve by generating on/off pulse every 3 to
5 min 24 hr/day 7 days/wk; approved for treatment of depression; effectiveness improves and side effects reduced over
time
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| Future directions: intracranial stimulation—can be performed by responsive neurostimulation (RNS) and anterior thalamic
stimulation
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Educational Objectives
| The goal of this activity is to provide the listener with a greater understanding of the management of transient ischemic attacks
(TIAs) and epilepsy. After hearing and assimilating this program, the clinician will be better able to:
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| 1. Discuss the short-term prognosis associated with TIAs.
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| 2. Describe the pathophysiology of TIAs and its relationship to the risk for stroke.
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| 3. Evaluate the benefit of hospitalization and tissue plasminogen activator (tPA) administration in patients with TIAs.
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| 4. Refer a patient with medically intractable epilepsy for surgery.
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| 5. Discuss the effectiveness of medical and surgical therapy for epilepsy.
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Discussed on This Program
Aspirin (acetylsalicylic acid; ASA) [several trade names]
Dipyridamole and aspirin [Aggrenox]
Heparin sodium injection
Low molecular weight heparins (LMWHs)—dalteparin [Fragmin], enoxaparin [Lovenox], tinzaparin [Innohep]
Pregabalin [Lyrica]
Warfarin sodium [Coumadin]
Suggested Reading
Bambauer KZ et al: Reasons why few patients with acute stroke receive tissue plasminogen activator. Arch Neurol.
63:661, 2006; Bhatt DL et al: Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events.
N Engl J Med. 354:1706, 2006; Cascino GD et al: Peri-ictal SPECT and surgical treatment for intractable epilepsy related
to schizencephaly. Neurology. 63:2426, 2004; Drazkowski JF: Management of the social consequences of seizures.
Mayo Clin Proc. 78:641, 2003; Hills NK et al: Duration of hospital participation in a nationwide stroke registry is
associated with improved quality of care. BMC Neurol. 6:20, 2006; Johnston SC et al: National Stroke Association
guidelines for the management of transient ischemic attacks. Ann Neurol. 2006 Sep;60(3):301, 2006; Johnston SC:
Transient ischemic attack: a dangerous Harbinger and an opportunity to intervene. Semin Neurol. 25:362, 2005; Nguyen-
Huynh MN et al: Is hospitalization after TIA cost-effective on the basis of treatment with tPA? Neurology. 65:1799,
2005; Nguyen-Huynh MN et al: Transient ischemic attack: a neurologic emergency. Curr Neurol Neurosci Rep. 5:13,
2005; Ovbiagele B et al: Secondary-prevention drug prescription in the very elderly after ischemic stroke or TIA. Neurology
. 66:313, 2006; Rothwell PM et al: Recent advances in management of transient ischaemic attacks and minor ischaemic
strokes. Lancet Neurol. 5:323, 2006; Rothwell PM et al: Transient ischemic attacks: stratifying risk. Stroke.
37:320, 2006; Sacco RL et al: Guidelines for prevention of stroke in patients with ischemic stroke or transient ischemic
attack: a statement for healthcare professionals from the American Heart Association/American Stroke Association Council
on Stroke: co-sponsored by the Council on Cardiovascular Radiology and Intervention: the American Academy of Neurology
affirms the value of this guideline. Circulation. 113:e409, 2006; Sheth RD et al: Protracted ictal confusion in elderly
patients. Arch Neurol. 63:529, 2006; Sirven JI et al: MRI changes in status epilepticus. Neurology. 60:1866, 2003;
Zimmerman R et al: SISCOM localization of a seizure focus within a heterotopia. Neurology. 62:2328, 2004.
Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any significant financial
relationship with the manufacturer or provider of any commercial product or service discussed. The following has been disclosed:
Dr. Johnston receives research support from Sanofi-Aventis/BMS.
Dr. Johnston was recorded June 19-23, 2006, in San Francisco, at the 34th Annual Advances in Internal Medicine,
sponsored by the University of California, San Francisco, School of Medicine. Dr. Drazkowski was recorded October
6-9, 2006, in Sedona, AZ, at the 8th Annual Mayo Clinic Internal Medicine Update: Sedona 2005, sponsored by the
Mayo Clinic Foundation. The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in
the production of this program.
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