Long-Term Prognosis of Cerebral Ischemia in Young Adults
Background and Purpose—Prognosis of ischemic stroke in young adults is reported as favorable, and transient ischemic attack (TIA) is commonly considered a benign event. We investigated long-term outcome and prognostic predictors of cerebral ischemia in patients under 45 years of age.
Methods—Three hundred thirty-three patients aged 15 to 44 years who suffered from a first-ever TIA or ischemic stroke were prospectively followed up with annual clinical evaluation or complete phone interview. End points were the composite outcome event of stroke, myocardial infarction, and vascular or nonvascular death and death from all causes. The probability of event-free survival was estimated by the Kaplan-Meier method. Univariate and multivariate estimates of hazard ratios were calculated according to the Cox proportional hazards analysis.
Results—An average follow-up of 96 months was available in 330 patients (99.1%). Survival was worse in patients with stroke at entry (86.5%) than in those with TIA (97.1%). Mortality in both groups was significantly higher than in the general population (standardized mortality ratio [SMR] 14.5, P<0.0001, Poisson distribution test, and SMR 7.9, P=0.002). The average annual mortality rate was higher during the first (3.94%, 95% CI 1.84 to 6.04) than in the subsequent years. The average annual incidence rate of new stroke was higher in patients with stroke than in those with TIA at entry, and it declined from 1.56% (95% CI 0.21 to 2.91) during the first year to 0.06% (95% CI 0.04 to 0.08) at the end of the follow-up. Myocardial infarction occurred later, after the first year, with similar rates in patients with stroke and TIA at entry. The average annual rates of new stroke (2.36%), myocardial infarction (1.68%), and death (3.05%) were higher in patients with the mixed atherothrombotic and cardioembolic etiology than in the remaining patients. Male gender, age >35 years, stroke at entry, and cardiac diseases were independent predictors of the composite outcome event at the Cox regression analysis, whereas only stroke at entry and cardiac diseases predicted death from all causes.
Conclusions—Stroke and TIA in young adults have severe prognostic implications, because the mortality risk was highly increased with respect to the general population. Preventive measures are strongly recommended in the presence of any unfavorable prognostic profile.
Cerebral ischemia in young adults occurs at an annual incidence rate of about 6/100 000. Although it represents only about 1% of all strokes, it has a relevant impact on years of potential life lost and on socioeconomic costs, considering the long life expectancy at these ages.1 There is general agreement on the role of atherosclerosis in men over age 35 and of cardiac diseases, migraine, and oral contraceptive use in women under age 35 as pathogenic determinants for cerebral ischemia.2 3 Whether the early onset of stroke in young adults might reflect severity of underlying pathology is still an open question.3
The short-term prognosis of stroke in young adults is considered favorable, despite its relationship with the presence and severity of complications at the time of the first event.4 5 Long-term prognosis of young patients with transient ischemic attack (TIA) is reported to be even more favorable, although the risk of new ischemic events depends on the presence of vascular risk factors.6 7 The available prospective studies report annual incidence rates of death and recurrent stroke ranging from 1% to 2.6%, with higher long-term mortality in patients who had a large-vessel stroke.5 8 9 The prognosis has been reported to be severe in patients with carotid stenosis and mild in patients with coexisting stroke and migraine.10
This study assessed the long-term prognosis of cerebral ischemia in patients under 45 years of age with a first-ever stroke or TIA at entry and investigated possible prognostic predictors.
Subjects and Methods
All patients aged 15 to 44 years who had a first-ever TIA or ischemic stroke within the 8 weeks preceding admission into the hospital were prospectively recruited and investigated from April 1, 1984, through March 31, 1988, by 7 departments of neurology (Florence, Genoa, L’Aquila, Milan, Padua, Parma, and Rome). The study protocol was developed in the early 1980s and included clinical and laboratory evaluation of vascular risk factors, continuous-wave Doppler sonography of the neck vessels, brain CT, cardiac evaluation with chest radiography, ECG, and transthoracic echocardiography.3 Selective carotid angiography of the symptomatic vascular territory was also available in 72% of patients. The achievement of a definite etiologic diagnosis was attempted whenever possible. For the purpose of this study, etiology was classified as atherothrombotic; cardioembolic; mixed atherothrombotic and cardioembolic; and miscellaneous, which included events related to other disorders together with those of uncertain and unknown etiology. Definitions of risk factors and diagnostic criteria were reported elsewhere.3
All patients were prospectively followed up for 5 to 10 years, with an annual clinical evaluation or a complete telephone interview with the patient or the next of kin when appropriate, by means of a semistructured questionnaire.10 Onset of symptoms was considered the starting point for the follow-up. No compulsory treatment was adopted. Strict medical control and optimal treatment of vascular risk factors were encouraged. The main study end point was the composite outcome event, including nonfatal stroke, nonfatal myocardial infarction, and death from all causes. Death from all causes was also analyzed separately. All deaths were documented by hospital records, autopsy findings, or general practitioner’s reports.10 Stroke was defined as rapidly developing signs of focal or global disturbance of cerebral function lasting >24 hours or leading to death, with no apparent cause other than that of vascular origin. Myocardial infarction was diagnosed by the presence of at least 2 of the following: typical ischemic chest pain lasting for >30 minutes, specific serum enzyme elevations, and new pathological Q waves on ECG.10 Functional outcome was evaluated by means of the Barthel Index. Patients were regarded as independent when the score was >90.
The probability of event-free survival was estimated by the Kaplan-Meier method. Average annual rates were calculated according to the formula 1−[(1−Ic)1/n], where Ic equals the cumulative incidence rate at n years, obtained by the Kaplan-Meier method. The standardized mortality ratio (SMR) was computed as the ratio of the deaths observed to those expected based on the age and sex stratification reported by the Italian life tables.11 The difference between observed and expected events was compared by the Poisson distribution test. Univariate and multivariate estimates of hazard ratios were calculated according to the Cox regression analysis. A difference was regarded as statistically significant at P<0.05 or when the confidence intervals did not overlap.
Of 333 patients, 330 (99.1%) with a first-ever ischemic stroke (n=190) or TIA (n=140) at entry were followed up for an average of 96 months (range 62 to 124). During this period, 26 patients died (7.8%), 10 had a new stroke (3.2%), and 8 a myocardial infarction (2.5%). The cause of death was cerebral in 11 patients, cardiac in 4, nonvascular in 7, and unknown in 4. Eighty-five patients (26%) were traced by means of a telephone interview. Median time from onset of symptoms to admission was 3 days. Most patients (64.0%) were taking antiplatelet drugs (n=178) or anticoagulants (n=35) during follow-up. Appropriate treatment was adopted for 47 of 63 patients with hypertension and for 6 of 9 with diabetes mellitus. Oral contraceptives were discontinued by all the 20 current users, whereas only 23 out of 117 current smokers quit smoking. Functional outcome was evaluated in 304 surviving patients (92%). At the end of the follow-up, 49 of the surviving patients (16.1%) were still dependent, with a Barthel Index score of <60 (n=11) or between 60 and 90 (n=38), whereas 169 patients (55.6%) had returned to work and 86 (28.3%) were unemployed despite recovery.
The observed survival of the cohort (Figure 1⇓) was worse than that expected for the age- and sex-matched standard Italian population (90.9% versus 99.2%), with an SMR of 10.8 (P<0.0001, Poisson distribution test). Within the cohort, the survival of stroke patients was worse than that of TIA patients (86.5% versus 97.1%). The corresponding SMRs were 14.5 for stroke (P<0.0001) and 7.9 for TIA patients (P=0.002), because mortality in both groups was higher than in the general population.
As shown in Table 1⇓, the average annual mortality rate of the cohort was higher during the first year (3.94%, 95% CI 1.84 to 6.04) than in the subsequent years, mostly because of the high 1-year mortality of stroke patients (6.32%). The average annual mortality rate in the cohort was stable after the first year of follow-up, ranging between 0.55% and 0.61%. However, the average annual mortality rate was higher in patients with stroke (1.44%) than in those with TIA (0.30%). This difference persisted even after excluding deaths that occurred within 30 days. Likewise, the average annual incidence rate of new stroke was higher in patients with stroke (0.52%) than in those with TIA (0.07%), declining from 1.56% (95% CI 0.21 to 2.91) during the first year to 0.06% (95% CI 0.04 to 0.08) between 6 and 10 years of follow-up (Table 1⇓). Myocardial infarction occurred later, after the first year. TIA patients showed a higher average annual incidence rate of myocardial infarction (0.22%) than of new stroke (0.07%).
The average annual incidence rates of new stroke (2.36%), myocardial infarction (1.68%), and death (3.05%) were higher in patients with mixed atherothrombotic and cardioembolic etiology than in patients included in the other diagnostic groups (Table 2⇓), with confidence intervals largely overlapping. No myocardial infarctions were found during the follow-up among patients included in the miscellaneous diagnostic group. In addition, no significant interactions were observed between the qualifying event and the etiologic groups.
As shown by the univariate Cox regression analysis (Table 3⇓), male gender, age >35 years, stroke at entry, cardiac diseases, and hypertension were significant predictors of the composite outcome event and of death from all causes, whereas carotid abnormalities were a significant predictor of the composite outcome event only. The corresponding Kaplan-Meier survival curves were reported in Figures 2⇓ and 3⇓. The multivariate Cox regression analysis confirmed that male gender, age >35 years, stroke at entry, and cardiac diseases were independent predictors of the composite outcome event, whereas stroke at entry and cardiac diseases were independent predictors of death from all causes.
Although the absolute survival probability of our cohort was high, stroke and TIA in young adults do not represent benign events, because mortality risks were highly increased with respect to the general population. Risk did not vanish with time, depending on severity of the underlying vascular pathology and on coexisting risk factors.
This hospital-based, prospectively designed study included the largest cohort to date of young adults with cerebral ischemia. The participating centers contributed an unselected series of all admitted cases. Ninety-nine percent of the included patients completed the long-term follow-up. However, because of the low risk of new events in young adults, the study was underpowered, as shown by the wide confidence intervals of the estimates. Moreover, despite the median time to admission being 3 days, patients with very early death might have been underrepresented in the cohort. In-person follow-up was replaced by a complete phone interview in 26% of patients.
Prognosis was commonly reported as favorable in young stroke patients and even more favorable in young TIA patients.4 6 7 8 Most of the data referred to small cohorts whose follow-up was far from being complete.4 6 7 8 A further study of 74 stroke patients with an average follow-up of 16 years reported an average annual mortality rate of 1% and an average annual incidence rate of new strokes of 0.5%. These proportions were very close to the 1.44% mortality and the 0.52% incidence of new strokes in our patients with a first-ever stroke.5 Additionally, in young stroke survivors, a 1.7% average annual rate of vascular death and a 2.6% average annual incidence rate of recurrent stroke, myocardial infarction, and vascular death were reported.9 These figures were slightly higher than those in our study, possibly because the data came from a series recruited in a tertiary-level hospital facility that enrolled a large number of complicated and less-straightforward cases.9
In our cohort, the 10-year survival rates were 86.5% for stroke and 97.1% for TIA patients. These rates, although higher than the corresponding rates reported for patients of any age, were lower than expected on the basis of the age- and sex-matched Italian population.11 12 13 14 15 16 The SMRs that we found in our stroke patients (14.5) and TIA patients (7.9) were higher than those observed in older stroke patients (SMR 3.7) and TIA patients (SMR between 1.4 and 2.0).12 13 14 15 16 Therefore, despite the high absolute survival probability of patients with stroke and TIA at entry, cerebral ischemia in young adults did not appear to be a benign event, because the mortality risk was highly increased with respect to the general population.
The average annual mortality rate in the cohort was stable after the first year of follow-up, ranging between 0.55% and 0.61%. The risk of a new stroke decreased with time, and the occurrence of myocardial infarction was delayed after the first year.14 15 16 Because the risk of new vascular events did not vanish during follow-up, the early occurrence of the first-ever event in our patients was probably attributable to premature atherosclerosis rather than to any incidental precipitating factor.3 4 14 Patients with stroke of the mixed atherothrombotic and cardioembolic etiology were more likely to present with stroke at entry and were at higher vascular risk, as shown by their higher average annual incidence rates of new stroke, myocardial infarction, and death. Conversely, patients with cerebral ischemia included in the miscellaneous diagnostic group were at very low risk of myocardial infarction and death.
According to survival analyses, the prognostic profile, including male gender, age >35 years, stroke at entry, and cardiac diseases predicted the worst outcome in our series.14 17 18 19 The observed prognostic implications of male gender and age >35 might depend on the specific relevance of early atherosclerosis in men >35.3
Functional outcome was reported as favorable in young stroke survivors.9 20 At the end of the follow-up, 16.1% of the survivors were still dependent, whereas 55.6% had returned back to work, which suggests that in the remaining 28.3% of the patients other factors, such as mood depression, loss of social role, welfare policies, and previous unemployment status, might have influenced social recovery.20
In our opinion, the potential risk of new vascular events together with the low tendency to return back to work in patients <45 years of age might increase the global burden of the disease, considering the life expectancy at these ages.21 Preventive measures focused on atherothrombotic risk factors should be strongly enforced in young adults when vascular pathology and risk factors suggest an unfavorable long-term outcome.
National Research Council Study Group on Stroke in the Young: Participating Neurological Departments and Principal Investigators
University La Sapienza, Rome: C. Fieschi, M. Frontoni, and E. Zanette. University Hospital, Florence: D. Inzitari and P. Nencini. University Hospital, Genoa: C. Gandolfo and C. Finocchi. University Hospital, L’Aquila: M. Prencipe, M. Baldassarre, G. De Matteis, and S. Mearelli. Ospedale Maggiore, Milan: G. Landi and C. Motto. University Hospital, Padua: L. De Zanche. University Hospital, Parma: M. Parma and U. Scoditti.
This study was supported by a grant (CNR 94.00471.PF40) from the Consiglio Nazionale delle Ricerche, Rome, Italy.
↵1 The persons and institutions participating in the National Research Council Study Group on Stroke in the Young are listed in the Appendix.
- Received July 6, 1999.
- Revision received August 9, 1999.
- Accepted August 9, 1999.
- Copyright © 1999 by American Heart Association
Carolei A, Marini C, Di Napoli M, Di Gianfilippo G, Santalucia P, Baldassarre M, De Matteis G, di Orio F. High stroke incidence in the prospective community-based L’Aquila registry (1994–1998): first year’s results. Stroke.. 1997;28:2500–2506.
Tzourio C, Tehindrazanarivelo A, Iglésias S, Alpérovitch A, Chedru F, d’Anglejan-Chatillon J, Bousser M-G. Case-control study of migraine and risk of ischaemic stroke in young women. BMJ. 1995;310:830–833.
Carolei A, Marini C, Ferranti E, Frontoni M, Prencipe M, Fieschi C, and the National Research Council Study Group. A prospective study of cerebral ischemia in the young: analysis of pathogenic determinants. Stroke. 1993;24:362–367.
Chancellor AM, Glasgow GL, Ockelford PA, Johns A, Smith J. Etiology, prognosis and hemostatic function after cerebral infarction in young adults. Stroke. 1989;20:477–482.
Johnson S, Skre H. Transient cerebral ischemic attacks in the young and middle aged: a population study. Stroke. 1986;17:662–666.
Larsen B H, Sorenson PS, Marquardsen J. Transient ischaemic attacks in young patients: a thromboembolic or migrainous manifestation? A 10 year follow-up study of 46 patients. J Neurol Neurosurg Psychiatry. 1990;53:1029–1033.
Kappelle LJ, Adams, HP, Heffner ML, Torner JC, Gomez F, Biller J. Prognosis of young adults with ischemic stroke: a long-term follow-up study assessing recurrent vascular events and functional outcome in the Iowa Registry of Stroke in Young Adults. Stroke. 1994;25:1360–1365.
Carolei A, Marini C, Nencini P, Gandolfo C, Motto C, Zanette E, Prencipe M, Fieschi and the National Research Council Study Group. Prevalence and outcome of symptomatic carotid lesions in young adults. BMJ. 1995;311:1363–1366.
Istituto Nazionale di Statistica (ISTAT). Cause di morte: anno 1988. Vol 4. Rome, Italy: ISTAT; 1991:1–400.
Dennis MS, Bamford JM, Sandercock PAG, Warlow CP. A comparison of risk factors and prognosis for transient ischemic attacks and minor ischemic strokes: the Oxfordshire Community Stroke Project. Stroke.. 1989;20:1494–1499.
Giovannoni G, Fritz VU. Transient ischemic attacks in younger and older patients: a comparative study of 798 patients in South Africa. Stroke. 1993;24:947–953.
Carolei A, Candelise L, Fiorelli M, Francucci BM, Motolese M, Fieschi C, for the National Research Council and Rome Study Groups. Long-term prognosis of transient ischemic attacks and reversible ischemic neurologic deficits: a hospital-based study. Cerebrovasc Dis. 1992;2:266–272.
Dennis M, Bamford J, Sandercock P, Warlow C. Prognosis of transient ischemic attacks in the Oxfordshire Community Stroke Project. Stroke. 1990;21:848–853.
Dennis MS, Burn JPS, Sandercock PAG, Bamford JM, Wade DT, Warlow CP. Long-term survival after first-ever stroke: the Oxfordshire Community Stroke Project. Stroke. 1993;24:796–800.
Burn J, Dennis M, Bamford J, Sandercock P, Wade D, Warlow C. Long-term risk of recurrent stroke after a first-ever stroke: the Oxfordshire Community Stroke Project. Stroke.. 1994;25:333–337.
Hankey GJ, Slattery JM, Warlow CP. Transient ischaemic attacks: which patients are at high (and low) risk of serious vascular events. J Neurol Neurosurg Psychiatry. 1992;55:640–652.
Sacco RL, Shi T, Zamanillo MC, Kargman DE. Predictors of mortality and recurrence after hospitalized cerebral infarction in an urban community: the Northern Manhattan Stroke Study. Neurology. 1994;44:626–634.
Kittner SJ, Stern BJ, Wozniak M, Buchholz DW, Earley CJ, Feeser BR, Johnson CJ, Macko RF, McCarter RJ, Price TR, Sherwin R, Sloan MA, Wityk RJ. Cerebral infarction in young adults: the Baltimore-Washington Cooperative Young Stroke Study. Neurology. 1998;50:890–894.