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(Stroke. 1996;27:1999-2004.)
© 1996 American Heart Association, Inc.

Articles

Precipitants of Brain Infarction

Roles of Preceding Infection/Inflammation and Recent Psychological Stress

Richard F. Macko, MD; Sebastian F. Ameriso, MD; Robert Barndt, MD; Wendy Clough, MD; John M. Weiner, DrPH Mark Fisher, MD

the Departments of Neurology (R.F.M., S.F.A., M.F.) and Internal Medicine (R.B., W.C., J.M.W.), University of Southern California School of Medicine, Los Angeles.

Correspondence to Richard F. Macko, MD, University of Maryland School of Medicine, Department of Neurology, 22 N Greene St, Baltimore, MD 21201-1595.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Background and Purpose Antecedent febrile infection and psychological stress are described as predisposing risk factors for brain infarction. We examined the temporal relationship between preceding infection/inflammation and stroke onset as well as the role of recent psychological stress as a potential precipitant for brain infarction.

Methods In this case-control study, a standardized evaluation including a signs/symptoms-based questionnaire was used to characterize the prevalence and timing of recent prior (<1 month) infectious and inflammatory syndromes in 37 adults with acute brain infarction, 47 community control subjects, and 34 hospitalized nonstroke neurological patient controls. Recent psychological stress was measured with scales of stressful life events and negative affect.

Results The prevalence of infection/inflammation was significantly higher in the stroke group only within the preceding 1 week compared with either community control subjects (13/37 versus 6/47, P<.02) or hospitalized neurological patient controls (3/34, P<.02). Upper respiratory tract infections constituted the most common type of infection. A substantial proportion of stroke patients with preceding (<1 week) infection/inflammation (5/13) had no accompanying fever or chills. There were no significant differences between the stroke and control groups in the levels of stressful life events within the prior 1 month or in negative-affect scale scores within the prior 1 week.

Conclusions Our data suggest that both febrile and nonfebrile infectious/inflammatory syndromes may be a common predisposing risk factor for brain infarction and that the period of increased risk is confined within a brief temporal window of less than 1 week. Results of this study argue against a role for recent psychological stress as a precipitant for cerebral infarction.

Key Words: cerebral infarction • infection • inflammation • risk factors • stress, psychological

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Stroke is a leading cause of death in the United States, yet our knowledge of underlying mechanisms remains limited.¹ Cerebral infarction of "unknown etiology" represents approximately 40% of cases in stroke data banks, and the importance of potential precipitants has not been well defined.² It is now recognized that many myocardial infarctions are linked to specific "physiological triggers," including acute physical exertion, psychological stress or negative affect,^{3 4 5 6} and possibly infectious/inflammatory processes.^{7 8 9} Likewise, infection appears to be an important predisposing risk factor for brain infarction. Prior studies indicate that as many as one third of patients hospitalized with acute ischemic stroke had a history of febrile infection within the preceding month.^{10 11 12 13} Some studies also suggest that psychological stress may serve as a risk factor for stroke.^{14 15} The precise temporal window defining infection-associated stroke risk, as well as the role of recent psychological stress and negative affect as potential trigger mechanism(s), remains unclear.

This study characterized the prevalence and timing of infectious/inflammatory syndromes within the preceding month in subjects with acute ischemic stroke and in two control groups lacking signs and symptoms of cerebrovascular disease. We also administered a questionnaire regarding stressful life events and negative-affect scale to measure recent psychological stress. This case-control study included community control subjects and hospitalized patient controls. Patients hospitalized with a nonstroke neurological illness were included to account for potential systematic bias from acute medical illness on estimates of psychological stress or infection prevalence.¹⁶ Our aims were to better define the character and temporal window for increased stroke risk associated with preceding infectious/inflammatory syndromes and to investigate recent psychological stress as a potential trigger mechanism for acute cerebral infarction.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
We evaluated 37 patients with acute ischemic stroke and 81 control subjects lacking history, signs, and symptoms of cerebrovascular disease (47 community control subjects and 34 hospitalized neurological patient controls). Patients admitted to Los Angeles County–University of Southern California Medical Center (LAC-USC) with a diagnosis of acute brain infarction (within 4 days of onset) and evaluated by the stroke service were consecutively entered. Initial head CT scans were performed to exclude hemorrhagic and mass lesions. Control subjects were matched with stroke patients by age and season of recruitment. Neurological patient controls randomly selected within 4 days of admission included subjects hospitalized with a recent onset of noncerebrovascular neurological illness. Patients with demyelinative disorders were excluded to avoid bias from the known association between infection and multiple sclerosis exacerbation.¹⁷ Community control subjects included LAC-USC volunteers or employees and patients selected from a prescheduled outpatient hypertension clinic by a cardiologist blinded to infection/inflammation status. The study was conducted according to LAC-USC Institutional Review Board guidelines.

Medical history and examination were performed on all subjects. Chest x-ray films, electrocardiograms, urinalyses, and routine laboratory tests, including complete blood count and blood chemistries, were obtained for hospitalized patients. Stroke risk factors were characterized according to standard criteria,¹⁸ and medications used within 2 weeks were noted. The Toronto Stroke Scale was used to grade initial neurological deficits.¹⁹ Ischemic strokes were classified as large-vessel occlusive disease, small-vessel or lacunar disease, cardioembolic, or other/undetermined, as previously described.²⁰

Exclusion criterion included renal, hepatic, or congestive heart failure, recent (<2 months) myocardial infarction, venous thrombosis, pregnancy, sickle cell disease, thrombocytopenia, thrombocytosis, or other myeloproliferative disorder. Patients with history of collagen vascular disease, central nervous system infection, recent alcohol or intravenous drug abuse, infectious endocarditis, human immunodeficiency virus, and tuberculosis (diagnosis >1 month before, treated <6 months) were excluded. Patients with infection/inflammation with onset after stroke or history of any chronic or recurrent infectious processes were also excluded.

A standardized evaluation including questionnaire and examination characterized infection/inflammation prevalence and timing within the preceding month. Common types of infection were categorized based on signs, symptoms, and ancillary diagnostics as upper respiratory tract, urinary tract, nonspecific viral illness, dental, lower respiratory tract, gastrointestinal, skin infection, or pyelonephritis.²¹ Types of infection were discussed in conference with an infectious disease collaborator (W.C.). "Positive" infection status required presence of the predefined infection syndrome and lack of alternate noninfectious etiology. The latency in days from the most recent infectious/inflammatory syndrome until enrollment (control subjects) or index brain infarction was determined, and subjects were then classified as having antecedent infection/inflammation present within 7 days, beyond 7 days but within the prior month, or no infection/inflammation within 30 days. All infection questionnaires were administered by the same two physicians (R.F.M. and S.F.A.). Inflammatory processes were defined as noninfectious conditions associated with local or systemic activation of the immune system. Histories were obtained from relatives when available and in all cases when patients had altered mental status or aphasia.¹⁶

Psychological stress was evaluated with the use of scales of negative affect and stressful life events. The negative-affect scale, modified from the list of negative emotions of Zevon and Tellegen,²² included five categories: (1) nervous, distressed, scared; (2) sad, depressed; (3) angry, upset, irritated; (4) angry at self, guilty, dissatisfied with self; (5) calm, content (scored negatively). Subjects were instructed to indicate the intensity for each emotion category during the preceding week using a 5-point scale ranging from 0 (none) to 4 (very much).²³ An elevated negative-affect score of 10 points was defined based on the upper quartile of scores from community control subjects (n=47). The questionnaire regarding stressful life events, as described previously,²⁴ was based on a previous study examining effects of psychosocial stress on outcome after myocardial infarction.²⁵ The questionnaire included five descriptions of potentially major stressful experiences, and subjects were asked to answer whether they had such experience(s) within the past month. Those answering "yes" were instructed to indicate the intensity they had been upset by such event(s), using a 5-point scale with "0" indicating none, "2" indicating moderately upset, and "4" indicating "upset very much." An elevated stressful life events score was defined as the presence of at least one stressful experience within the preceding month subjectively perceived as greater than moderately upsetting (score 3 points).²⁴

Unpaired two-tailed t tests, ² analysis, and Fisher's exact test were used for data analysis. Goodness-of-fit by ² was used to evaluate seasonal matching of case patients to control subjects. Infection/inflammation prevalence data were calculated based on the latency in days from presence of infectious/inflammatory syndrome until enrollment (control subjects) or index brain infarction. Simple linear regression analysis was used to examine correlations between selected variables.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Stroke patients included 9 men and 28 women evaluated a mean of 2.5±1 days (range, 1 to 4 days) after stroke onset. Control subjects included a total of 39 men and 42 women. Clinical and demographic features of the stroke and control groups are shown in Table 1. Clinical and diagnostic evaluations, including transesophageal echocardiography (performed on 12 patients), supported a cardioembolic etiology in 4 of 37 stroke patients (11%): 3 with atrial fibrillation and large-vessel territory infarction and 1 with mitral valve disease. The enrollment period included 9 fall-winter months and 7 spring-summer months. Seasonal enrollment ratios, defined as the proportion of subjects entered during fall-winter versus spring-summer, were similar in pooled control subjects (52:29) and stroke patients (23:14, P=.84) and not different from that expected based on the predicted optimal seasonal matching (P=.65).

View this table: [in this window] [in a new window]   Table 1. Demographic Features, Negative-Affect Scale, and Stressful Life Events Data for Stroke and Control Groups

The prevalence of preceding (<1 month) infection/inflammation was higher in ischemic stroke patients than in pooled control subjects (43% [16/37] versus 26% [21/81]). This difference was entirely due to the elevated prevalence of infection/inflammation in the stroke group within 1 week preceding the index stroke (35% [13/37] versus 11% [9/81], P<.01). The prevalence of infection/inflammation within 1 week was significantly higher in the stroke group than in hospitalized neurological patient controls (9%) and community control subjects (13%) (Table 2). There were no differences in the prevalence of previous infection/inflammation during weeks 2 to 4 between the stroke group and hospitalized neurological patient controls (11% [4/37] versus 9% [3/34], P=.99) or community control subjects (19% [9/47], P=.37). Twelve of the 13 stroke patients with infection/inflammation present within 1 week preceding the index stroke were enrolled between September and April.

View this table: [in this window] [in a new window]   Table 2. Prevalence of Antecedent (<1 Week and <1 Month) Infection/Inflammation and Prevalence of Increased Recent (<1 Month) Stressful Life Event(s) and Elevated Negative-Affect Scores for Stroke and Control Groups

Antecedent infectious/inflammatory syndromes present within 1 week preceding stroke included upper respiratory tract infections (7), bronchitis (1), urinary tract infection (1), febrile gastroenteritis (1), paroxysmal urticaria (1), oligoarticular gout exacerbation (1), and psoriasis (1) (Table 3). As in the stroke group, upper respiratory tract infections were the most common type of infection found in control subjects. Infectious/inflammatory syndromes tended to cluster very close to the time of stroke onset. Five patients had intercurrent infectious/inflammatory syndromes still present at the time of index stroke, including patient 2, a 56-year-old man with brain infarction and three transient ischemic attacks, which all occurred in association with bouts of paroxysmal urticaria. Stroke patient 34, a 57-year-old woman with her index stroke 3 days after febrile upper respiratory tract infection, also had a hemispheric transient ischemic attack at the time of preceding infection. Only 62% (8/13) of the infectious/inflammatory syndromes preceding stroke were accompanied by fever or chills.

View this table: [in this window] [in a new window]   Table 3. Clinical Data for Stroke Patients and Control Subjects With Preceding (<1 Week) Infection/Inflammation

We observed no significant differences between the stroke group, community control subjects, and hospitalized neurological patient controls in the mean scores for negative affect and stressful life events (Table 1). There was a nonsignificant trend toward increased prevalence of recent life event(s) perceived as stressful in the community control group (Table 2). Prevalence of stressful life events in the stroke group and hospitalized nonstroke neurological patient controls was similar (P=.61), and there were no significant differences between the stroke and control groups in prevalence of elevated negative affect (Table 2). Psychological stress data were not available from three stroke patients and four hospitalized neurological patient controls. There was a strong positive correlation between scores for stressful life events and negative affect (r=.61, P<.0001), which indicated that these measures were related and jointly assessed the common variable of recent psychological stress. Stress scale scores were not normally distributed, and therefore we did not combine their values using nominal scales. Instead, we examined the prevalence of either significant antecedent scores for stressful life events or elevated negative affect as an indicator of increased recent psychological stress and found no significant differences between the stroke and control groups (Table 2).

Clinical and demographic features of stroke patients with and without recent infection/inflammation are shown in Table 4. Except for the observation that patients with antecedent infection/inflammation within 1 week were all nonsmokers, there were no significant differences between groups. Diagnostic classifications for hospitalized nonstroke neurological patient controls included new-onset or frequent seizures (n=8), intracranial mass/tumor presenting with seizure(s) (n=4), spinal cord and/or acute root compression (n=9), cranial neuropathy syndrome (n=5), elevated intracranial pressure (n=2), acute peripheral neuropathy (n=2), headache (n=1), craniocervical junction tumor (n=1), and new diagnoses of myasthenia gravis (n=1) and movement disorder (n=1).

View this table: [in this window] [in a new window]   Table 4. Clinical and Demographic Data for Stroke Groups With and Without Preceding (<1 Week) Infection/Inflammation

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Clinicians have long suspected that systemic infection may serve as a predisposing risk factor for stroke, but few studies have systematically examined this relationship.^{10 26 27} Syrjanen et al¹¹ found that young adults presenting with acute cerebral infarction had a significantly higher prevalence of febrile infection in the preceding month than matched community control subjects. These investigators further demonstrated that levels of selected serum bacterial antibody titers in the stroke group exceeded those in matched control subjects.²⁸ Prevalence rates for febrile infection within the preceding month (range, 28% to 34%) comparable to those found by Syrjanen et al in young adults have since been reported in non–age-selected consecutive ischemic stroke patients.^{12 13} Prothrombotic sequelae mediated by inflammatory processes are hypothesized to link infectious processes with enhanced risk for stroke.^{7 11 12} Therefore, we examined the relationship between ischemic stroke onset and antecedent noninfectious inflammatory processes as well as infectious syndromes. We found a surprisingly high prevalence of infection/inflammation (35%) exclusively within a single week preceding the index stroke. These findings are strikingly similar to those of Grau et al,¹³ further indicating that most infectious/inflammatory processes preceding stroke appear to be clustered very close to the neurological ictus.

In the present study we report somewhat higher prevalence rates for infection/inflammation preceding stroke than have been reported by other investigators.^{11 12 13} We attribute this to differences in seasonal recruitment rates and our more inclusive criteria for defining infection/inflammation. First, we observed a strong winter-fall seasonal predilection for infection-associated stroke occurrence, as initially described by Hindfelt and Nilsson¹⁰ in a retrospective study of stroke in young adults. This study had a greater number of fall-winter versus spring-summer enrollment months (9 versus 7), which could serve to increase the infection/inflammation exposure rates in all groups. Since our case and control enrollment rates were seasonally matched, this cannot explain the observed differences between preceding infection/inflammation prevalence rates between the stroke group and control subjects. Second, we included noninfectious inflammatory syndromes that had not been considered in previous studies. Although these constituted only 23% (3/13) of all infectious/inflammatory syndromes in the stroke group, these findings suggest that inflammatory mechanisms, and not exclusively infection per se, may augment risk for cerebral infarction. Third, previous studies considered only febrile infection. However, many common infections may not be accompanied by fever, particularly in the frail elderly.²⁹ In contrast to Grau et al,¹³ we found that approximately half of the infectious/inflammatory syndromes preceding stroke were not accompanied by signs of fever or chills. Thus, our findings suggest that nonfebrile infection and noninfectious inflammatory syndromes may also function as predisposing risk factors for ischemic stroke.

We considered the possibility that different interviewers could introduce bias in estimates of the prevalence of infection/inflammation. To minimize interviewer bias, a standardized signs and symptoms–based evaluation with predefined syndromes for common types of infection was developed and administered by the same two physicians. Using this standardized evaluation, we found infection prevalence rates in our pooled control population that were similar to that determined based on face-to-face interviews during biweekly home nurse evaluations in the Seattle Virus Watch (a community-based prospective study of infection prevalence), supporting the validity of our infection assessment methodology.³⁰

Recall bias due to differences between groups in the proportions of covariates such as smoking or acute medical illness could confound estimates of antecedent infection exposure in case-control studies.¹⁶ It is unlikely that the higher prevalence rate of infection/inflammation observed in our stroke group was due to recall bias related to acute medical illness, since neurological patient controls were matched on the basis of hospitalization for a recent-onset neurological illness. Other variables that may affect recall bias, such as recent psychological stress, were also not different between the stroke and control groups. As has been previously reported, upper respiratory tract infections were the most common antecedent infectious/inflammatory syndrome observed.^{12 13} In the present study patients with symptomatic chronic obstructive pulmonary disease were excluded to avoid bias introduced by a population prone to frequent respiratory tract infections.³¹ Long-term cigarette smoking is also known to increase risk for respiratory tract infections.³² Surprisingly, none of the stroke patients with infection/inflammation within the preceding week were current smokers, and smoking rates were somewhat lower in the stroke group as a whole than in the control groups. Hence, these differences in smoking rates could only have resulted in bias toward our underestimation of the magnitude of preceding infection/inflammation prevalence rates within the previous week in the stroke group.

A link between negative affect, psychological stress, and myocardial infarction has been clearly established.^{5 6 33} However, the notion that acute stress is a precipitant for ischemic brain infarction remains speculative.³⁴ We evaluated recent psychological stress as a potential trigger mechanism for brain infarction and found no significant differences between stroke patients and control subjects in recent scores on scales of stressful life events or negative affect. Intercurrent medical illness leading to hospitalization could potentially bias subjective affect ratings or perceptions of stress intensity.¹⁶ For this reason, psychological stress ratings from stroke patients were compared with those from a group of hospitalized patients also admitted with a recent-onset (nonstroke) neurological illness. There were no differences between stroke patients and hospitalized nonstroke control subjects, findings that argue against a relationship between recent psychological stress and acute brain infarction.

Interpretation of these findings is limited by the small sample size and restriction of the study to recent psychological stress only. Based on stress data from our control group, a greater number (75 per group) would have been required to detect a twofold difference in prevalence of elevated psychological stress, as reported by House et al¹⁴ in the Oxfordshire Community Stroke Study. These investigators evaluated stressful life events during a 1-year period preceding stroke and found that patients reported fewer nonthreatening events than control subjects but had nearly double the incidence of severe or long-term threatening events distributed throughout the previous year. The present study was not designed to evaluate the role of chronic psychological stress, a factor that has been reported as independently associated with increased risk for both cerebral and myocardial infarction.^{15 35 36}

In summary, we found that systemic infection is common preceding brain infarction. There appears to be a brief period of elevated infection/inflammation prevalence exclusively within the week preceding the index cerebral infarction. In contrast to previous studies,^{10 11 12 13} our results further suggest that infectious syndromes preceding stroke may be nonfebrile and that noninfectious inflammatory processes may also serve as a predisposing risk factor for acute ischemic stroke. We observed no trends suggesting that recent stressful life events or elevated negative affect may serve as a precipitant for cerebral infarction, as has been reported for myocardial infarction. These findings support the hypothesis that infection/inflammation is a common and important predisposing risk factor for cerebral infarction and suggest that the increased stroke risk is confined to a brief temporal window within 1 week of the infectious/inflammatory syndrome. Further studies are needed to investigate underlying biological mechanisms.

	Acknowledgments

 
This study was supported by a National Stroke Association/CIBA-GEIGY Research Fellowship (R.F.M.) and by research grants NS-20989 (M.F.), P01NS31945 (M.F.), HL-15722 (R.F.M.), and CA-32197 (R.F.M.) from the National Institutes of Health, Bethesda, Md.

	Footnotes

 
Reprint requests to Mark Fisher, MD, University of Southern California School of Medicine, Department of Neurology, 1333 San Pablo St, MCH 246, Los Angeles, CA 90033. E-mail mjfisher@hsc.usc.edu.

Received April 1, 1996; revision received June 18, 1996; accepted June 24, 1996.

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