Introduction

Stroke is an important cause of death and disability in young patients and may have a devastating impact on their quality of life. Although strokes are more frequent in patients over 60 years of age, young patients are also affected at an incidence between 3 and 66/100,000 [1, 2], with a trend toward increased incidence in recent years [3].

Intravenous thrombolysis (IVT) administered within the first 4.5 h after the beginning of stroke symptoms favors neurological recovery [4–6], and its efficacy and safety in young stroke patients has been demonstrated [7–12]. However, no analysis of the IVT response based on etiological stroke subtype has been conducted in this group. This issue is of relevance because the stroke etiological spectrum is quite different in young patients than in patients over 55 [13]. Cervical artery dissection (CAD) is the most common cause in isolation in the younger group, but more than one-third of cases are of undetermined etiology. Atherothrombotic and small vessel disease (SVD) strokes are less frequent in young patients, while the paradoxical embolism related to patent foramen ovale (PFO), non-atherosclerotic vasculopathies, hypercoagulable states and strokes of undetermined etiology are more prevalent in patients under 50 years of age [14].

Some studies have analyzed the response to IVT according to stroke etiological subtypes with controversial results [15–26]. Whereas some authors described better outcomes after IVT in SVD stroke compared with other etiologies [15–17], others found less benefit of IVT in IS due to lacunar syndromes [18]. Furthermore, some studies have reported that the IVT efficacy is disputed in strokes related to CAD [19–22]. Some authors demonstrated more benefit of IVT in cardioembolic strokes compared to other subtypes [23] but others did not [24].

A number of studies have addressed the influence of stroke severity on the response to IVT, showing similar benefit in IVT-treated and untreated patients with mild strokes [27] and better outcomes in IVT-treated patients with higher stroke severity [28]. This issue has not yet been studied in young stroke patients.

We hypothesized that the different stroke etiology distribution in young patients and the degree of stroke severity could lead to a different response to IVT. Our aim was to analyze the effect of IVT on young patients with ischemic stroke (IS) according to etiological subtype and severity on admission.

Methods

We analyzed consecutive patients with acute IS admitted to a stroke unit (SU) in a university hospital from January 2007 to December 2012. The hospital is a stroke center for a population of approximately 1,000,000 habitants. Data were prospectively collected from medical records and were included in the Stroke Data Bank, as has been previously described [29]. A retrospective analysis was performed for this study. Patients who met inclusion criteria (a) were adults between 18 and 54 years of age, (b) had clinical signs and symptoms attributable to brain ischemia less than 48 h from onset; (c) had cerebral computed tomography (CT) or magnetic resonance imaging (MRI) showing acute brain infarction or an absence of other intracranial lesions; and (d) had prior functional independence. The exclusion criteria were (a) having a transient ischemic attack (TIA), (b) brain hemorrhage and (c) receiving endovascular treatment.

The following parameters were prospectively recorded in a specific data bank: (1) demographic characteristics (age, gender); (2) vascular risk factors such as hypertension (defined as having a previous diagnosis of arterial hypertension, regular treatment with antihypertensive drugs, or two or more pre-stroke blood pressure readings with figures above 140 and/or 90 mmHg); diabetes mellitus (previous diagnosis and/or current treatment with insulin or oral hypoglycemic medications); dyslipidemia (previous diagnosis and/or current treatment with lipid-lowering drugs), heart disease (coronary arterial disease, atrial fibrillation, valvulopathy and valve replacement); cigarette smoking (currently or in the last year); (3) alcohol or other drugs abuse; (4) peripheral vascular disease; (5) prior brain infarct; (6) inherited thrombophilias (Factor V Leiden and prothrombin, G20210A gene mutations; deficiencies in protein S, protein C or antithrombin); (7) myeloproliferative disorders (essential thrombocythemia, polycythemia vera); (8) prior treatments; (9) stroke etiological subtype classification [30, 31]: atherothrombotic, cardioembolic, SVD, other known etiology and stroke of undetermined etiology; (10) stroke severity, evaluated using the NIHSS (all evaluations were performed by NIHSS-certified neurologists) and considering moderate-severe stroke as NIHSS ≥8 [32]; (11) in-hospital outcome: length of stay, systemic and neurological complications and (12) outcomes at 3 months of IS, were evaluated using the modified Rankin Scale (mRS) at a 3-month follow-up visit at the outpatient clinic. For the purpose of this analysis, we dichotomized this scale (mRS ≤2 represented a good outcome).

All patients were initially treated in the emergency room by a neurologist. Each patient was examined according to a standard protocol that included routine laboratory analyses, chest X-rays, ECG, CT scan and/or MRI and transcranial Doppler. During hospitalization, we completed the diagnostic process with cardiac studies (echocardiogram, Holter electrocardiogram) and ultrasound studies (cervical duplex studies and contrast-enhanced transcranial Doppler to detect right–left shunt). After completion of the initial studies, a study to rule out a hypercoagulable state was performed on those patients without a clear stroke etiology.

This study was approved by the Ethics Committee for Clinical Investigation at La Paz University Hospital, Madrid, Spain.

Data analysis

The data analysis was performed with SPSS 20.0 for Windows (SPSS Inc., Chicago, IL, USA). Proportions between the groups were compared using the χ2 and fisher’s exact tests. Continuous data are presented as mean (SD) or median [interquartile range (IQR)]. Continuous variables were tested using the t test or the Mann–Whitney U tests as appropriate. Values of P < 0.05 were considered significant. The statistical analysis was performed in three steps. First, a comparative analysis classified IS patients under 55 years into 2 groups, depending on whether they were treated with IVT or not. Second, a logistic regression analysis was performed to determine those factors independently associated with favorable outcomes (mRS 0–2). Age, sex, IVT and those factors associated with favorable outcomes in the univariate analysis with P < 0.2 were included in the multivariate analysis. A backward procedure was followed as the modelling strategy, using the log likelihood ratio test to assess the goodness of fit and compare nested models. Those variables that, when eliminated, produced a change of ≥15 % of the OR, were considered confounding variables. Third, a subgroup analysis was performed to assess the effect of IVT according to etiological stroke subtype, severity on admission, age, sex, and arterial dissection, with adjustment for the main prognostic variables. We also considered that, for any specific prognostic factor, the distribution of other factors might differ between subcategories. 95 % CIs are presented.

Results

A total of 2778 IS patients were admitted to the SU during the study period. After excluding patients with a brain hemorrhage, TIA, <18 or >54 years of age and those who received endovascular treatment, a total of 262 IS patients between 18 and 54 years of age were included in the analysis (Fig. 1). The mean age was 45.2 ± 7.7 years and 63.7 % were male. 63 patients (24 %) received IVT.

Fig. 1
figure 1

Sample selection flow diagram. Footnote IVT means intravenous thrombolysis

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The demographic data, comorbid conditions and pre-stroke treatments were similar in the IVT and non-IVT group (Table 1).

Table 1 Demographic data, comorbid conditions and pre-stroke treatments
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Table 2 details the stroke etiological subtypes. The IVT group more frequently had cardioembolic (27 vs. 12.1 %, P = 0.004) and less frequently had SVD strokes (9.5 vs. 31.7 %, P = 0.001). A total of 23 patients had an arterial dissection, 4 in the IVT and 17 in the Non-IVT groups. In 19 patients the dissection affected the carotid and in 4 the vertebral artery.

Table 2 Stroke etiological subtypes, vascular territory, stroke severity, brain infarct size and stroke outcomes
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The median NIHSS on admission was higher in the IVT group (median [IQR]: 6.5 [9] vs. 2 [3], P < 0.0001) as was the percentage of moderate-severe strokes (39.7 vs. 14.1 %, P < 0.0001) (Table 2). The in-hospital and 3-month outcomes were similar in both groups, although 22 patients were lost to follow-up (Table 2).

The multivariate analyses showed that IVT was associated with a higher probability of a favorable outcome (OR, 95 % CI: 4.652, 1.294–16.722) whereas arterial dissection (OR, 95 % CI: 0.191, 0.056–0.654) and NIHSS (OR, 95 % CI: 0.727, 0.664–0.797) were associated with a lower probability of a favorable outcome (Table 3).

Table 3 Multivariate analysis of factors associated with favorable 3-month outcomes (mRS ≤2)
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The subgroup analysis showed that IVT was significantly associated with favorable outcomes in the 45–54 year age group. Regarding stroke severity, IVT was significantly associated with better outcomes in moderate-severe strokes (OR, 95 % CI: 3.782, 1.095–13.069) but not in mild strokes, where most patients had favorable outcomes irrespective of IVT (Fig. 2). According to stroke etiology, IVT was significantly associated with mRS 0–2 in cardioembolism (OR, 95 % CI: 41.887, 1.001–1751.596) and showed a trend toward a favorable effect in other known etiology strokes (OR, 95 % CI: 11.527, 0.729–182.245). Furthermore, the IVT was significantly associated with better outcomes in the non-arterial dissection group whereas this beneficial effect was not significant in patients with arterial dissection (Fig. 2).

Fig. 2
figure 2

Effect of IVT on favorable 3-month outcomes (mRS ≤2). Subgroup analysis. Asterisk adjusted by age, male sex, arterial dissection and NIHSS. NIHSS means National Institutes of Health Stroke Scale, SVD small vessel disease

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Discussion

This study shows that, in IS patients under 55 years of age, those with moderate-severe strokes (NIHSS ≥8) on admission benefit more from IVT than those with mild strokes. Regarding etiological subtypes, cardioembolic infarctions seem to benefit more from IV tPA than other etiologies, although the OR confidence intervals are large, probably due to the small sample size.

Few studies have addressed the response to IVT treatment in young IS patients and most have demonstrated its benefit and safety in this age group [7–11]. However, Poppe et al. [12] compared the outcome of stroke in patients ≤50 and >50 years of age treated with IVT and described a decreased risk of death in the younger patients but unfavorable outcomes. Kristensen et al. [14] described a lower frequency of SVD and atherothrombotic etiology in stroke patients under 44 years of age and a higher frequency of undetermined, cardioembolic and unusual strokes. In our study, SVD was the most frequent etiology in young patients, and the explanation for this discrepancy may be that we included young patients up to 54 years of age.

Some studies have addressed the influence of stroke etiology in response to IVT in patients of all ages, but none of these studies specifically analyzed this influence in young adults. A number of these studies have shown a trend toward less benefit of IVT in patients with SVD [18], others show better outcomes [15–17], and still others show no differences when compared with other etiological subtypes of IS [25, 26]. Our study did not find differences between IVT-treated and untreated patients with lacunar stroke, showing favorable outcomes in almost 100 % of patients in both groups, which may be related to the low severity of this etiological subtype. Regarding unusual stroke etiology, some studies have shown poorer outcomes in IVT-treated patients with stroke secondary to CAD [19], while others did not find differences [20] and others found some benefit of IVT [22]. A meta-analysis showed similar safety and outcomes in IVT-treated patients with stroke due to CAD than in other stroke etiologies [21]. Our study did not find significant differences in patients treated or not with IS secondary to CAD, probably due to the small number of patients with this pathology. However, CAD was an independent factor related to unfavorable 3-month outcomes.

With regards to cardioembolic stroke, only a few studies have analyzed the effect of IVT in this stroke subtype in patients of all ages, with contradictory results. Molina et al. [23] demonstrated that early recanalization was more frequent, faster and more complete in patients with proximal middle cerebral artery occlusion secondary to cardioembolic stroke treated with IVT than in the other etiologies. Furthermore, early recanalization was associated with a higher degree of neurological improvement and better long-term outcomes than stepwise and slow recanalization [23]. In contrast, Rocha et al. [24] did not find differences in IVT benefit in cardioembolic stroke compared to non-cardioembolic in patients with a median age of 67 years. Our study suggests that, in patients under 55 years of age, cardioembolism may benefit more from IVT than other etiologies, although the confidence intervals are probably very high.

On the other hand, we have found a tendency toward a greater benefit from IVT in young patients with strokes of other known etiologies, a datum that has not been suggested until now. Future studies are needed to clarify whether uncommon causes of stroke that are frequent in young patients, such as hypercoagulable states [33, 34], could affect the response to IVT.

A number of studies have compared stroke outcomes in patients treated with IVT according to stroke severity on admission [27, 28] but not specifically in young adults. Our results are in agreement with those of Huisa et al. [27] who compared the outcomes of IVT-treated and untreated patients with mild strokes and concluded that IVT-treated patients had similar outcomes to those of untreated patients. Mishra et al. [28] showed better outcomes in IVT-treated than in untreated patients across a baseline NIHSS of 5–24 and suggested that patients with NIHSS ≤4 or ≥25 may still benefit from treatment, although the evidence supporting this was weak. Our study showed that mild strokes had favorable outcomes with or without IVT. In contrast, the group of patients with moderate-severe strokes showed a significant benefit from IVT.

Our study has several limitations. First, it is based on a retrospective analysis of our stroke database. However, patients were consecutively added, the database was prospectively updated, and the analysis was not restricted to IVT-treated patients as it was in many of the previous studies assessing the influence of IS etiology. Thus, we could compare IVT and non-IVT treated patients admitted to an SU in the same time period, reflecting daily clinical practice. Second, the small number of IS patients under 55 years of age in each stroke etiology subgroup limits the statistical power for comparisons, but allowed us to obtain significant differences.

In conclusion, in IS patients under 55 years of age, those with moderate-severe strokes on admission benefit more from IVT than those with mild strokes. Furthermore, cardioembolic infarctions may benefit more from IV tPA than other etiologies, although these results need to be confirmed in further studies.