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Patient Demographic and Clinical Features and Circadian Variation in Onset of Ischemic Stroke
Ilaria Casetta, MD;
Enrico Granieri, MD;
Elisa Fallica, MD;
Olga la Cecilia, MD;
Ezio Paolino;
Roberto Manfredini, MD
Arch Neurol. 2002;59:48-53.
ABSTRACT
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Background Studies have reported circadian variation in the onset of ischemic stroke,
which may carry important pathophysiological implications. However, there
is no detailed information about circadian variations among the subtypes of
stroke.
Objective To determine whether subgroups of patients with ischemic stroke with
specific clinical characteristics would exhibit different circadian patterns,
to more systematically examine the role of possible triggering or precipitating
factors.
Design and Setting Analysis of the effects of demographic, medical, and pathophysiological
factors on the circadian pattern of an unselected series of patients with
ischemic stroke consecutively admitted to our hospital.
Results The study included 1656 patients. As in other studies, the peak of stroke
onset occurred in the morning, with a second peak in the evening. Circadian
variation in ischemic stroke onset was shown to be independent of clinical
variables considered.
Conclusions Our study confirms the circadian rhythm of stroke reported in previous
studies. There is a chronological pattern of ischemic stroke in the morning,
which appears to be independent of the presence of risk factors and of clinical
stroke subtypes. The role of circadian variability of blood pressure (present
in patients with and without hypertension) and a concurrent morning hypercoagulability
are suggested as possible determinants of this pattern. Preventive pharmacological
interventions aimed at specifically targeting the morning rise in risk factors
could be advantageous in reducing the overall risk of ischemic stroke.
INTRODUCTION
DATA INDICATE that onset of several major cerebrovascular diseases are
not randomly distributed over time.1-10
The existence of a particular chronobiological pattern in the onset of acute
cerebrovascular diseases, characterized by circadian, circaseptan, and circannual
rhythms (1 day, 1 week, and 1 year, respectively), has been detected.10 A significantly higher occurrence in the morning
has been reported1-8
and confirmed by a recent meta-analysis.9 Although
a well-defined pattern of ischemic stroke onset has been proved, few studies8, 11 have addressed the possibility that
different chronobiological patterns may be detected in different clinical
subgroups of patients with ischemic stroke. The aim of the present study was
to investigate whether such circadian variation in ischemic stroke onset could
delineate subgroups of patients with different demographic or pathologic variables
among a large population of patients with ischemic stroke.
PATIENTS AND METHODS
STUDY AREA AND CASE COLLECTION
Ferrara is a town in northeastern Italy, with a mean population of about
170 000. Its only hospital is St Anna Hospital, which is the sole teaching
center for the school of medicine of the local university. St Anna Hospital
also serves the entire province of Ferrara as a center where most patients
with acute stroke are evaluated. House calls are performed by family physicians
during the day and by emergency department physicians at night and on holidays,
at no charge. In the emergency department, key physicians, including neurologists
and neurosurgeons, are available 24 hours a day throughout the year. Between
January 1, 1994, and December 31, 1997, a consecutive series of 1656 patients
with ischemic stroke were recorded. The study area and methods of case collection
have been described previously.12
The diagnosis of stroke was made by a neurologist and was defined, according
to the World Health Organization criteria, as rapidly developing clinical
symptoms or signs of focal or global loss of cerebral function, with symptoms
lasting more than 24 hours or leading to death, with no apparent cause other
than a vascular origin.13 In all patients,
laboratory investigations included computed tomographic scan or magnetic resonance
imaging, blood tests, 12-lead electrocardiogram, chest radiography, carotid
duplex imaging, transcranial Doppler, cerebral angiography, echocardiography
(transthoracic or transesophageal), and assessment of prothrombotic syndromes.
Additional tests were conducted in selected patients.
Stroke onset time was defined as the earliest time the patient or a
witness noted definite neurological symptoms or signs. It was obtained from
patients, their relatives, or bystanders.
Precise determination of the time of symptom onset was possible in 1395
patients. In an additional 187 subjects—although stroke onset time could
not be exactly determined because the stroke occurred while they were asleep,
or they were unconscious, disoriented, or aphasic and a witness was not available
to give reliable information—stroke onset could be assigned to 1 of
4 periods: 12:01 to 6 AM, 6:01 AM to noon, 12:01 to 6 PM, or 6:01 PM to midnight.
For the remaining 74 patients, time of onset was unknown.
For each patient, we recorded demographic data; family history of vascular
diseases, hypertension, and diabetes; medical history, with particular reference
to hypertension, coronary artery diseases, atrial fibrillation, valvular and
other heart diseases, previous transient ischemic attacks or strokes, asymptomatic
carotid stenosis, bruit, diabetes, hyperlipidemia, peripheral arteriopathies,
cigarette smoking, and alcohol consumption; and symptoms and signs at stroke
onset and their evolution.
All patients underwent a physical and neurological examination. A quantitative
evaluation using the Canadian Neurological Scale14
and a disability status determination according to the Rankin scale15 was assessed on admission. Cerebral infarction in
patients was classified as 1 of 4 clinically identifiable subtypes16: total anterior circulation infarcts, partial anterior
circulation infarcts, posterior circulation infarcts, and lacunar infarcts.
Moreover, the cause of ischemic stroke was classified according to the criteria
of the Trial of Org 10172 in Acute Stroke Treatment17
as large artery disease, small artery disease, cardioembolism, other less
common determined causes, and undetermined causes, which included patients
with multiple potential causes.
Diagnoses were based on clinical features and on results from the imaging
and laboratory tests, following the methods of the Trial of Org 10172 in Acute
Stroke Treatment investigators.17
STATISTICAL ANALYSIS
For the patients whose strokes were precisely timed, the hour of each
event was tabulated, rounding the time consistently to cover 24 hours, and
the frequency of the events was computed for each hour of the day. With commercially
available software,18 the analysis of circadian
rhythm was performed using the cosinor method and a partial Fourier series
with up to 4 harmonics (periods of 24, 12, 8, and 6 hours), in which a least
squares minimization is used and a cosine function is fitted to the data via
a regression method. Among all the possible combinations of the periods chosen,
the program permits the selection of the harmonic or the combination of harmonics
that best explains the variance of data. The percentage of rhythm (percentage
of overall variability of data about the arithmetic mean attributable to the
fitted rhythmic function) and the probability value resulting from the F statistic
(used to test the hypothesis of zero amplitude) are reported in the results
as representative factors of goodness of fit of the approximating curve function
and statistical significance of rhythm, respectively. The best fitting curve
indicates the period with the greatest percentage of rhythm. Along with the
peak time of each single harmonic, the program also calculates peak and trough
times (time of occurrence of the absolute maximum and minimum, respectively)
of the overall best fitting curve.
Moreover, the  2 goodness-of-fit test to the null hypothesis
of equal distribution of strokes was applied to the 1582 patients whose onset
could be reasonably included in one of the four 6-hour periods, using available
software (Epi-Info, version 6; Centers for Disease Control and Prevention,
Atlanta, Ga; version 6.04b; World Health Organization, Geneva, Switzerland).
Differences were considered significant at P<.05.
RESULTS
Precise hours of ischemic stroke were recorded for 1395 patients (mean
age ± SD, 74.6 ± 12 years). Forty-four percent of strokes occurred
in the morning between 6:01 AM and noon, and the hypothesis for uniform distribution
of the onset time was rejected on the basis of the 2 test
for all subtypes (23 = 311.77, P<.001). It has been suggested that a morning excess of strokes
could be explained by the exclusion of patients with events occurring during
the night, when time of onset could not be defined. Assuming that the stroke
could have occurred at any time during sleep, we assigned these patients to
a 6-hour interval between the time the patient was last known to be asymptomatic
and the time at which patients or their relatives first became aware of the
event. The null hypothesis of uniformity was still rejected when the 1582
patients whose onset could be categorized into the 6-hour periods were analyzed
(23 = 255, P<.001).
In addition, a worst-case scenario was considered in which the 74 patients
whose strokes were untimed were arbitrarily assigned to the periods having
the fewest observed strokes. There was still a significant circadian variation
in the risk of stroke (1656 patients total, 23
= 207, P<.001).
The results of cosinor analysis, including only patients with precisely
timed strokes, are summarized in Table 1, in which the significant harmonics (24 and 12 hours) and the overall
best fitting curve are reported. The sinusoidal test results showed a statistically
significant circadian pattern, with a major peak at 8:28 AM. Spectral analysis
also detected a significant 12-hour cycle at 8:13 AM and 8:13 PM.
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Table 1. Circadian Rhythm in Onset of Ischemic Stroke According to
Demographic Variables and Risk Factors
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Figure 1 demonstrates the
overall best fitting curve resulting from 2 significant components of 24-
and 12-hour periods, with a maximum occurrence at 8:28 AM, a second minor
peak at 8:13 PM, and a minimum occurrence at 11:28 PM.
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Circadian variation in the onset of ischemic stroke. Histogram represents
the number of total events occurring in each hour of the day. Superimposed
is the overall best fitting curve calculated by rhythm analysis, resulting
from 2 significant harmonics with 24- and 12-hour periods (the variables of
the curve are given in Table 1
under "Total Population"). The horizontal line represents the MESOR (midline
estimating statistic of rhythm), which represents the rhythm-adjusted mean
over the period analyzed.
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The data were similar for both sexes for patients aged 45 to 70 years.
Younger patients (<45 years) and older patients (>85 years) did not show
any significant circadian rhythms.
Hypertension, diabetes, hyperlipemia, smoking habits, previous vascular
events, and treatment with antiplatelet agents or anticoagulant drugs did
not modify the circadian pattern of ischemic stroke onset. The circadian variation
in onset was independent of clinical characteristics of ischemic strokes (Table 2).
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Table 2. Circadian Rhythm in Onset of Ischemic Stroke According to
Clinical Variables
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The morning increase and the second minor peak in the evening were detected
in patients with atherothrombotic strokes, cardioembolic strokes, lacunar
strokes, and strokes of other or unknown mechanisms. A similar pattern was
detected in the clinically identifiable subtypes of ischemic stroke,16 except for the partial anterior circulation infarcts
subtype (Table 2).
After random reallocation of untimed patients to the time frames having
the fewest strokes, the analysis by clinical and demographic subgroups using
the 23 goodness-of-fit test applied to the 1656
patients yielded similar results (all, P<.001,
except for therapy with anticoagulant agents): age 45 to 70 years, 23 = 153; older than 70 years, 23
= 142.5; normotension, 23 = 116.5; hypertension, 23 = 165; diabetes, 23 = 88.3;
dyslipidemia, 23 = 68.5; no smoking, 23 = 170.34; smoking, 23 = 147.6;
previous stroke, 23 = 74.5; first-ever stroke, 23 = 169; therapy with antiplatelets drugs, 23 = 74; therapy with anticoagulant agents, 23
= 8.4, P< .005; atherothrombotic stroke, 23 = 45.71; cardioembolic stroke, 23 = 27.79; small vessel disease, 23 = 80;
other determined cause, 23 = 61.5; undetermined
cause, 23 = 69.6; total anterior circulation infarct, 23 = 26; posterior circulation infarct, 23 = 27.8; and lacunar infarct, 23 = 63.5.
Patients with partial anterior circulation infarcts subtype showed a significant
increase in strokes from 6:01 AM to noon (23 =
9.1, P< .05). The null hypothesis of uniform distribution
across the 4 periods was not rejected for patients younger than 45 years or
older than 85 years.
Finally, a further evaluation considered patients with stroke onset
while asleep, grouped by cause of stroke.17
Lacunar strokes are more likely to occur during sleep (25% of all lacunar
strokes) than other types of strokes (24 goodness
of fit = 36; P<.001).
COMMENT
This study of a large unselected population of patients with stroke
confirmed the findings of other studies1-11
that symptom onset is more frequent in the morning during the first few hours
of diurnal activity, with a second peak in the evening and a minimum occurrence
during the night. These data, added to those of a recently published meta-analysis,9 strengthen the assumption that a circadian timing
of stroke does exist (23 for goodness of fit across
all reports, including the present one = 1405.75, P<.001).
This circadian pattern is similar to that of acute myocardial infarction
and myocardial ischemia, sudden cardiac death, and other vascular events.19-27
Some underlying pathophysiological mechanisms may be common.10, 21, 28
However, because different times of day may reflect different pathophysiological
mechanisms of stroke, subanalyses are important for establishing patterns.
In further exploring the circadian variation in various patient subsets, we
confirmed that each subgroup of patients with ischemic stroke, stratified
according to risk factors, clinical variables, and putative cause of stroke,
was identified with morning and evening peaks of stroke onset. The only significant
common risk factor for these events was hypertension. However, in the present
study, patients with and without hypertension had the same chronobiological
pattern of stroke onset. This suggests that blood pressure, with its circadian
variability, and not strictly hypertension, plays an important role in the
circadian pattern of stroke onset.
The morning increase in stroke onset was attenuated only in patients
younger than 45 and older than 85. One can speculate whether the difference
is because of age or other differences between patients. Although we cannot
exclude the possibility that some differences could not be detected because
of small sample size, we can hypothesize that there may be different pathophysiological
mechanisms in strokes between younger and older persons.
To our knowledge, this is the first study analyzing circadian pattern
of stroke according to sex, stroke type, cause of stroke, age, presence of
risk factors, and clinical characteristics. The circadian rhythm of stroke
seems to be independent of other considered factors, except possibly younger
and older age. This is in agreement with previous studies29-30
on acute myocardial infarction. Although a marked difference in diurnal patterns
of myocardial infarction was initially reported in subgroups of smokers, ß-blocker
users, and patients with non–Q-wave infarction, diabetes, previous congestive
heart failure, and previous myocardial infarction,29
further investigation found only minor differences in symptom onset, and multivariate
analysis showed that only age older than 70 years and a history of previous
myocardial infarction modified the circadian rhythm of symptom onset.30 However, antithrombotic drugs, such as aspirin,31 may modify the temporal pattern of myocardial infarction
by attenuating the morning peak. Conversely, in our study, prior use of anticoagulant
and antiplatelet agents did not affect morning occurrence of ischemic stroke.
In conclusion, our data confirm the existence of a chronological risk
of stroke, although the circumstances surrounding the onset of stroke are
not fully understood. In all subgroups of our patients, a statistically significant
bimodal circadian variation was present and demonstrated that the circadian
rhythm in cerebrovascular diseases is independent of stroke subtypes, patient
demographics and clinical features, and presence or absence of risk factors.
A broad implication of our findings may be stroke prevention. Our results
confirm that early morning is associated with a higher risk of the onset of
stroke symptoms, irrespective of type of stroke. The circadian variability
of blood pressure, resembling the temporal biphasic pattern of stroke, together
with a concurrent morning prothrombotic condition,32-34
may create a final negative synergistic effect.
A chronotherapeutic approach has been suggested for cardiovascular diseases.35 One may speculate that antihypertensive agents that
target morning rise in blood pressure might be advantageous in controlling
this risk factor for stroke. Long-term investigations are addressing this
question.36
AUTHOR INFORMATION
Accepted for publication August 28, 2001.
Author Contributions: Study concept and
design (Drs Casetta, Granieri, Fallica, and Manfredini); acquisition
of data (Drs Casetta, Granieri, Fallica, and la Cecilia, and Mr Paolino); analysis and interpretation of data (Drs Casetta, Granieri, Fallica,
la Cecilia, and Manfredini); drafting of the manuscript (Drs
Casetta, Fallica, la Cecilia, and Manfredini); critical revision of
the manuscript for important intellectual content (Drs Casetta, Granieri,
Fallica, and Manfredini and Mr Paolino); statistical expertise
(Drs Casetta, la Cecilia, and Manfredini); obtained funding (Drs
Casetta and Granieri); administrative, technical, and material support (Drs Casetta, Granieri, Fallica, and la Cecilia and Mr Paolino); study supervision (Drs Casetta, Granieri, and Manfredini).
This work was supported by a grant from the Italian Ministry of the
University and Scientific and Technological Research (MURST 60%), Rome (Dr
Granieri).
Corresponding author and reprints: Ilaria Casetta, MD, Section of
Clinical Neurology, Dipartimento di Discipline Medico-Chirurgiche della Comunicazione
e del Comportamento, University di Ferrara, Corso della Giovecca 203, I-44100
Ferrara, Italy (e-mail: ilaria.casetta{at}libero.it).
From the Sections of Clinical Neurology (Drs Casetta, Granieri, and
Fallica and Mr Paolino) and First Internal Medicine (Drs la Cecilia and Manfredini),
University of Ferrara, Ferrara, Italy.
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