Editorials
Worsening in Ischemic Stroke Patients:
Is it Time for a New Strategy?
L.R. Caplan, MD
W
hat can be more frustrating for physicians (and, of
course, for their patients) than deterioration during
treatment? Expectations are high that patients will
get better when they come to the hospital, not get worse.
Unfortunately, worsening is a common occurrence in patients
with brain ischemia despite present treatment. In this issue of
Stroke, Steinke and Ley show that, among their stroke
patients, worsening of motor function, a very important
component of disability, was most common among those who
had lacunar strokes.1
Categorization of Worsening
The term worsening, as presently used, is arbitrary in that it
depends on an extremely variable starting time— entry into
medical care. If an individual who becomes considerably
more hemiplegic 4 hours after the first symptom of weakness
and then stabilizes enters a hospital at hour 2, he or she is
classified as worsening. If, instead, the patient enters the
hospital at hour 5, he or she would not be classified as
worsening. Present designation of worsening then depends on
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when the clock starts running. I avoid terms based on
worsening such as “stroke-in-evolution” and “progressing
stroke,” since they depend on a shifting start time. Ideally,
physicians should attempt to alter a declining course of illness
graph that begins at the time of symptom onset. Worsening
during the first few hours often has quite different explana-
tions than worsening during hours 12 to 48. Unfortunately, it
is often difficult to quantify deficits present before the patient
is seen by a physician experienced in stroke care using only
the accounts of the patient and observers.
There are mainly 3 different large categories of worsening:
(1) Medical complications, especially febrile illnesses, which
affect the patient systemically and may also lead to increased
brain ischemia. These complications usually do not develop
on the day of admission, and these patients are sick and often
febrile. (2) Brain edema—a complication of mostly large
strokes, especially hemorrhages. This complication is also
delayed for more than 1 day, and headache and decreased
alertness are common features. (3) Gradual or stepwise
increases in focal deficits while the patient usually remains
The opinions expressed in this editorial are not necessarily those of the
editors or of the American Stroke Association.
From the Department of Neurology, Beth Israel Deaconess Medical
Centre, Boston, Mass.
Correspondence to Louis R. Caplan, MD, Beth Israel Deaconess
Medical Centre, Department of Neurology, Dana 779, 330 Brookline
Ave, Boston, MA 02215-5400. E-mail lcaplan@caregroup.harvard.edu
(Stroke. 2002;33:1443–1445.)
© 2002 American Heart Association, Inc.
Stroke is available at http://www.strokeaha.org
DOI: 10.1161/01.STR.0000016924.55448.43
1443
See article on page 1510
alert and free of medical complications. It is this last category,
which usually begins during the first day of admission, that
forms the substance of the study of motor progression in this
issue of Stroke1 that I will focus on herein in this editorial.
How Common Is Worsening, and in Which
Stroke Subtypes Does it Occur?
The frequency of progression of neurological deficits after
onset varies in different series but usually is estimated at
between 1 and 2 patients in 5. Frequency of clinical worsen-
ing after hospitalization varies depending on the mix of stroke
patients and their time of entry into the hospital. In the
Harvard Stroke Registry, 95/471 (20%) of stroke patients
progressed after onset either gradually (10%) or stepwise
(10%).2 Progression was most common in patients with
lacunar infarcts (37%) and large-artery occlusive disease
(33%) and least frequent in patients with embolism (7%). In
the Barcelona Stroke Registry, among ⬎3500 patients, 37%
worsened gradually or stepwise after onset.3 In the Lausanne
Stroke Registry, among ⬎3000 patients, worsening after
admission occurred in 29% of all stroke patients and in 662
(34%) of noncardioembolic ischemic stroke patients.4 Among
the noncardioembolic stroke patients who worsened, 58%
progressed during the first 24 hours.4 Among 350 Japanese
patients in one study, 25% progressed after admission;
worsening in the hospital occurred in 26% of lacunar stroke
patients.5
A number of studies focused on progression and worsening
in series of patients with lacunar strokes. In a Spanish study
of 225 lacunar infarct patients, the deficit accrued within
hours in 50.5% and within days in 16%.6 In a study from
Sweden, among 61 patients with lacunar strokes, all pure
motor hemiplegia, 22 (36%) worsened after the first hour of
symptoms and 18/22 (82%) progressions occurred during the
first 24 hours.7 In the study by Steinke and Ley, 24% of
patients had a worsening of motor deficits after hospitaliza-
tion, and the predominant subtype of stroke was lacunar
infarction.1 Progression of deficits in patients with lacunar
strokes, even evolving within days after onset, has been noted
many times in the past. Mohr, in a 1982 review of lacunar
infarcts, commented that “this surprisingly leisure mode of
onset” characterizes many lacunar strokes.8
Progression occurs in different patterns and time courses
depending on stroke subtype. Patients with intracerebral
hemorrhage develop gradual worsening of focal signs usually
over minutes, occasionally a few hours, followed by head-
ache, vomiting, and decreased consciousness. Patients with
emboli arising from the heart or aorta most often have
 1444 Stroke June 2002
sudden-onset deficits that are maximal at onset (80%); about
20% of patients have a single step of worsening during the
next 24 to 48 hours related to distal passage of emboli. The
signature of noncardioembolic strokes, in patients with both
small penetrating artery and large extracranial and intracra-
nial artery occlusive disease, is a fluctuating changing course.
Fluctuations between normal and abnormal, stepwise or
stuttering accrual of signs, or gradual development of signs
occurred in nearly half the patients with noncardioembolic
strokes in the Harvard Stroke Registry.2 In 37% of patients in
the Harvard Stroke Registry who had noncardioembolic
stroke, the deficit was maximal at onset, probably indicating
an embolus arising from proximal arterial disease.
What Factors Are Present in Patients With
Noncardioembolic Strokes Who Worsen?
Three factors, in my opinion, warrant emphasis in predicting
and explaining progression and significant worsening: (1)
presence of a severe flow-reducing arterial lesion supplying
the ischemic zone, (2) chronic hypertension, and (3) a
diminished frequency of transient ischemic attacks (TIAs)
preceding the stroke.
Bang et al found that severe middle cerebral artery stenosis
was an important predictor of progression in Korean patients
with striatocapsular infarcts.9 Among patients who worsened
in the Michael Reese Stroke Registry, severe large-artery
occlusive disease and lacunar infarcts predominated, and
chronic hypertension and a relatively low frequency of TIAs
were also noted.10 Lacunar infarcts are caused in the great
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majority of patients by occlusive disease, either lipohyalino-
sis or atheromatous branch disease, involving the penetrating
artery (and sometimes also adjacent penetrating arteries)
supplying the territory involved in the small, deep infarcts.8
These penetrating arteries are widely considered to be end
arteries with little potential for collateralization. Recent
studies using newer magnetic resonance technology show
that patients whose perfusion-weighted images (PWI) show a
larger area of involvement than the diffusion-weighted im-
ages (DWI) who have occlusive lesions on magnetic reso-
nance angiography and do not reperfuse develop larger
infarcts and more severe clinical deficits than those patients
with open arteries and no PWI⬎DWI mismatch.11,12 The
situations that most often cause progressing noncardioem-
bolic infarcts—severe stenosis or occlusion of large arteries
and penetrating artery disease— have in common severe flow
reduction to ischemic brain areas. Hypoperfusion and distal
embolization are the 2 mechanisms that lead to progressive
infarction. These 2 mechanisms are interrelated since hypo-
perfusion also diminishes clearance and washout of any
emboli. When perfusion is adequate, microemboli are often
cleared efficiently.13
Chronic hypertension, and also likely diabetes and hyper-
viscosity, impair microvascular function and blood flow. This
likely reduces the potential of the microvasculature to provide
collateral circulation to ischemic areas. Experimental animals
made hypertensive develop larger infarcts when arteries are
occluded than normotensive animals.
By definition, TIAs are reversible. This means that circu-
lation was somehow restored to a previously ischemic area.
Circulation was improved either by passage of emboli (im-
plying the potential for washout) or by collateral circulation
providing adequate blood flow. Thus the presence of TIAs
implies the potential for reversal of abnormal perfusion.
Progression thus is most likely explained by decreased
perfusion and/or decreased potential for rapid development of
adequate collateral blood flow to ischemic zones.
How Should Patients With Nonembolic Brain
Ischemia Be Managed?
If the problem is that there just isn’t enough blood getting
there, then the intuitive obvious solution is simply to try to
augment blood flow. Other solutions— eg, altering coagula-
tion (using either heparins or antiplatelet drugs) and using
neuroprotective agents— have been unproductive and are
unlikely to make a large impact as long as blood flow is
deficient. Reduced blood flow likely has a “Mack truck
effect,” ie, it overrides all other factors. Although thrombus
formation and propagation may play a role in progression,
reducing coagulability while blood flow is still deficient is
unlikely alone to impact progression and has not been
effective in past trials. Neuroprotectants likely will not reach
ischemic zones in sufficient quantities to be effective when
the blood itself isn’t getting there.
Improving blood flow can be accomplished in 2 broad
ways: opening arteries or augmenting collateral blood flow
by systemic strategies. Opening arteries can be accomplished
mechanically (by surgery or angioplasty and/or stenting) or
by thrombolysis. However, many arteries either cannot be
opened or have been occluded long enough that reopening
would have a high complication rate of reperfusion hemor-
rhage and edema.
There is now accruing evidence that manipulation of the
systemic circulation to augment cerebral blood flow can be
therapeutic and can limit brain ischemia. In patients with
positional ischemia, simply having them assume a supine or
Trendelenburg position can reverse ischemic deficits. Phar-
macologically raising blood pressure14,15 and expanding the
circulation in experimental animals16 and humans17,18 using
albumin infusions have been shown to limit the size of brain
infarcts. Constriction of the abdominal aorta in experimental
animals also augments cerebral blood flow.19
The only treatment shown to be effective in patients with
progressing lacunar infarcts is augmentation of cerebral blood
flow.20 Frey, in a small preliminary study of 10 consecutive
patients with lacunar strokes, found that reducing blood
pressure often led to worsening. Furthermore, augmenting
blood flow by giving a volume expander (intravenous
hetastarch) was uniformly effective in improving worsening
and induced improvement in all patients.20 Unfortunately, this
treatment has not been tested in a controlled trial.
The first and most important goal should be to get more
blood flow to the ischemic zone. While anticoagulants and
antiplatelets and neuroprotectants may be useful, their utility
is probably limited if there is persistent perfusion failure.
References
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motor deficits. Stroke. 2002;33:1510 –1516.
 Caplan
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Worsening in Ischemic Stroke Patients 1445
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KEY WORDS: hypertension 䡲 lacunar infarction 䡲 perfusion 䡲 worsening