Introduction

Cervical artery dissection (CAD), either spontaneous or caused by underlying connective tissue disease or trauma, may result in thromboembolism or hemodynamic impairment [1]. It has been estimated that carotid or vertebral artery dissection accounts for 2 % of all acute ischemic strokes (AIS) and 10–25 % for young stroke patients under the age of 50 years [2].

Even though CAD was not a contraindication for including patients with AIS in trials evaluating systemic fibrinolysis with recombinant tissue plasminogen activator (rt-PA), the safety and efficacy of intravenous thrombolysis (IVT) in dissection-related ischemic stroke (DRIS) have not been yet established [3]. Skepticism on the use of IVT in DRIS is based on the potential risks of IVT in DRIS, which include intramural hematoma extension, intraluminal thrombus dislocation with subsequent distal embolization, development of a subarachnoid hemorrhage due to leakage and formation of a dissecting aneurysm [4]. Moreover, the fear of symptomatic intracranial hemorrhage (sICH) complicating IVT is even more pronounced in patients with CAD extending in intracranial arteries especially in posterior circulation, since anticipated bleeding risk is greater in this specific CAD subgroup [5]. In addition, there are concerns that IVT may be associated with other complications in DRIS including extension or rupture of vessel wall hematomas, dislocation of intralumninal thrombus and formation of a dissecting aneurysm [6].

In view of the former considerations, the aim of the present study was to determine the safety and recovery rates of IVT in DRIS using prospective, international, multicenter data and by conducting a comprehensive meta-analysis of reported case series.

Methods

Multicenter study population and methods

We analyzed consecutive DRIS patients treated with IVT according to national guidelines during a 5-year period (2009–2013) at six tertiary-care stroke centers (University of Tennessee at Memphis, TN, USA; “Attikon” University Hospital, University of Athens, Athens, Greece; University Hospital of Alexandroupolis, Alexandroupolis, Greece; National University Hospital, Singapore; St. Josef Hospital, Ruhr University of Bochum, Bochum, Germany; Brugmann University Hospital, Brussels, Belgium). DRIS was diagnosed according to standard of care at each participating center using carotid duplex ultrasound, cervical MRI with axial T1 fat saturation sequences for depiction of intramural hematoma, CT angiography, or digital subtraction angiography. Patients with DRIS had to present a mural hematoma, aneurysmal dilatation, long tapering stenosis, intimal flap, double lumen or occlusion >2 cm above the carotid bifurcation revealing an aneurysmal dilation, or a long tapering stenosis after recanalization, in a cervical artery (internal carotid or vertebral) [7]. In the participating centers, all potentially eligible DRIS patients were treated with IVT, as standard of care. Patients with aortic dissection were excluded from this analysis. Patients with traumatic dissection and DRIS patients who received endovascular treatment were also excluded from further evaluation.

Non-contrast head CT, NIHSS pre-treatment and modified Rankin scores (mRS) at discharge were obtained as standard of care as previously described [8, 9]. Pre-treatment systolic and diastolic blood pressure levels were measured using automated cuffs. Additional details regarding our international collaborative group that has been evaluating the safety and efficacy of acute reperfusion therapies in patients with AIS have been previously described [10, 11].

Symptomatic intracerebral hemorrhage (sICH) was defined as imaging evidence of ICH with NIHSS increase of ≥4 points [8, 9]. Major and minor extracranial hemorrhagic complications following systemic thrombolysis were documented using GUSTO (Global Use of Strategies to Open Occluded Arteries) bleeding criteria [12]. Recanalization was assessed in real time by transcranial Doppler (TCD) monitoring during tPA infusion using the previously published thrombolysis in brain ischemia (TIBI) criteria [11, 13]. The high inter- and intra-rater reliability of TIBI criteria as well as their satisfactory accuracy parameters for assessment of recanalization when compared with the gold standard of catheter angiography have been previously documented [11, 13]. Reocclusion during TCD-monitoring was also diagnosed using TIBI criteria. Functional independence (FI) at hospital discharge was defined as mRS-scores of 0–2, while FFO was defined as mRS-scores of 0–1 [10]. Functional outcome was assessed by stroke physicians certified in mRS evaluation.

The study was approved by the corresponding institutional ethical standards committees in each participating center and written informed consent was obtained from all patients or guardians before the administration of tPA.

Search strategy and data extraction from previous studies

The meta-analysis has adopted the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for systematic reviews and meta-analyses [14] and was written according to the Meta-analysis of Observational Studies in Epidemiology (MOOSE) proposal [15, 16]. Eligible observational studies reporting the use of intravenous thrombolysis (IVT) in DRIS patients were identified by searching MEDLINE and SCOPUS. The following combination of search strings was used in both database searches: “artery dissection”, “cervical artery dissection”, “carotid artery dissection”, “vertebral artery dissection” “thrombolysis” and “tPA”. No language or other restrictions were imposed. Last literature search was conducted on October 13, 2014. Reference lists of all articles that met the inclusion criteria and of relevant review articles were examined to identify studies that may have been missed by the database search. All retrieved studies and reference lists were scanned independently by two reviewers (GT and AHK). Studies were excluded from further evaluation if they were case reports, or if they evaluated intra-arterial thrombolysis or other intra-arterial reperfusion procedures in combination with intravenous thrombolysis. Studies that presented overlapping data were also excluded from the final analysis.

In each study that met the inclusion criteria, a predefined seven-point quality control was used to address for biases [17, 18]. For each quality item, the corresponding risk of bias was categorized as low, high or unclear according to the suggestions by Higgins et al. [19]. Unavailable data were categorized by convention as unclear risk of bias. Quality control and bias identification was performed by three independent reviewers (GT, RZ, AHK) and all emerging conflicts were resolved with consensus.

Data on both safety and efficacy parameters of IVT in both patients with DRIS and AIS were extracted independently by the two authors, who performed the literature search (GT, AHK). Safety was assessed by estimating the pooled rates of sICH, FI and FFO in DRIS patients treated with intravenous tPA. Efficacy of IVT in patients with DRIS was assessed with the pooled complete recanalization rates of the corresponding occluded vessel. Finally, we compared the pooled rates of FFO between stroke patients with and without CAD treated with IVT in those studies that provided data for both subgroups. Post hoc meta-regression analysis was employed in search of potential moderators in analyses that revealed significant heterogeneity across studies.

Statistical analyses

Multicenter study data

Continuous variables are presented as mean ± SD (normal distribution) and as median with interquartile range (skewed distribution). Categorical variables are presented as percentages with their corresponding 95 % confidence intervals (95 % CI). The adjusted Wald method, which provides the best coverage for binomial CI when samples are less than 150 [20], was used for computation of 95 % CI of sICH and in-hospital mortality prevalence among DRIS. The Statistical Package for Social Science (SPSS Inc, version 13.0 for Windows) was used for statistical analyses.

Meta-analysis

For each study, the numbers of events in IVT-treated stroke patients with and without artery dissection were identified and a risk ratio (RR) was calculated. For studies with a zero cell, we used a continuity correction of 0.5, as appropriate. In cases of two or more zero cells, the assumption of continuity correction was not used and the corresponding point estimates were designated as “not estimable” [21]. The overall RR for all pooled studies was computed using the random-effects method (DerSimonian and Laird). Heterogeneity between studies was assessed by the Cochran Q and I 2 statistic as previously described. Heterogeneity was considered as statistically significant when p value derived from Cochran Q was <0.1. For the qualitative interpretation of heterogeneity, I 2 values of at least 50 % are usually considered to represent substantial heterogeneity, while values of at least 75 % indicate considerable heterogeneity according to the Cochrane handbook [22]. In meta-regression analyses, we used the DerSimonian–Laird method (method of moments). Publication bias was assessed at the overall analysis graphically using a funnel plot and with Egger’s test for funnel plot asymmetry [23].

Statistical analyses were conducted using Review Manager (RevMan) Version 5.3 software (Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014) and Comprehensive Meta-analysis version 2 software (Borenstein M, Hedges L, Higgins J, Rothstein H, Biostat, Englewood NJ, 2005).

Results

Multicenter study data

A total of 39 consecutive DRIS patients (mean age 60 ± 18 years; 59 % men; Caucasians 51 %, African Americans 36 %, Asians 13 %; median NIHSS 13 points, IQR 9–17) were treated with IVT (median onset to treatment time 150 min, IQR 125–172). Baseline characteristics and outcomes of the study population are presented in Table 1. Dissection was located in a cervical segment of internal carotid artery in the majority of patients (87 %). There was one patient with intracranial internal carotid artery dissection (3 %) and four cases with extracranial vertebral artery dissections (10 %). No patient was complicated with sICH (0 %; 95 % CI by adjusted Wald method 0–8 %). Recurrent stroke during the hospital stay occurred in 1 patient (3 %; 95 % CI by adjusted Wald method 0–14 %), while four patients deceased during hospitalization (10 %, 95 % CI by adjusted Wald method 3–24 %). Complete recanalization of initially occluded proximal intracranial arteries was achieved in 21 patients at the end of tPA infusion (55 %, 95 % CI by adjusted Wald method 40–70 %). FFO and FI at hospital discharge were documented in 61 % (95 % CI by adjusted Wald method 45–74 %) and 68 % (95 % CI by adjusted Wald method 52–81 %), respectively.

Table 1 Baseline characteristics and outcome variables in dissection-related ischemic stroke patients treated with intravenous thrombolysis (n = 39)
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Meta-analysis of case series

MEDLINE and SCOPUS database search yielded 135 and 179 results, respectively. After removing duplicates, the titles and abstracts from the remaining 310 studies were screened and 13 potentially eligible studies for the meta-analysis were retained. After retrieving the full-text version of the aforementioned 13 studies, 4 studies were excluded because they reported data that were already published in other studies (Supplemental Table I) [24–27]. In the final presentation of the literature search results, there was no conflict or disagreement between the two reviewers who performed the literature search. A total of nine studies met our inclusion criteria [28–36] and these case series together with the data from the present international multicenter study was included both in the qualitative and quantitative synthesis (Supplemental Figure I). The characteristics and bias assessment of the included studies, comprising 234 total IVT-DRIS patients are shown in Supplemental Table II. A total of 21 patients (9 %) had intracranial extension of the extracranial dissection. Supplemental Figure II summarizes risk of bias in individual case series studies included in the present meta-analysis. The risk of bias was high in terms of unblinding of outcome assessment since the final DRIS and sICH diagnoses were made by the same treating physicians in all studies, except for one [34].

The pooled rates of sICH and mortality among 234 DRIS patients treated with IVT were 2 % (95 % CI by adjusted Wald method 0–5 %; n = 10) and 4 % (95 % CI by adjusted Wald method 0–8 %; n = 10), respectively. The pooled recanalization, FFO and FI rates were 45 % (95 % CI 26–67 %; Fig. 1), 41 % (95 % CI 29–54 %; Fig. 2a) and 61 % (95 % CI 48–72 %; Fig. 2b), respectively. Publication bias was not evident in both the funnel plot inspection (Supplemental Figure III) or in the Egger’s statistical test for funnel plot asymmetry (p = 0.988). No heterogeneity (I 2 < 45 % and p > 0.1 for Cochran Q test) between case series reporting estimates of sICH, mortality, recanalization and FI was found. However, substantial heterogeneity between studies was found for FFO (I 2 = 61 %; p = 0.006 for Cochran Q test) (Table 2). The variance in FFO across different studies was investigated in subsequent post hoc meta-regression analyses of all available patient baseline characteristics in the included studies (Supplemental Table III). Baseline NIHSS and the presence of dissection in the posterior circulation emerged as independent (p < 0.05) predictors of FFO in meta-regression analyses accounting for the variance in FFO across different studies.

Fig. 1
figure 1

Forest plot of complete recanalization rates in dissection-related ischemic stroke patients treated with intravenous thrombolysis

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Fig. 2
figure 2

Forest plots of a favorable functional outcome and b functional independence rates in dissection-related ischemic stroke patients treated with intravenous thrombolysis

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Table 2 Pooled rates of outcomes with corresponding 95 % confidence intervals (95 % CI) of dissection-related ischemic stroke patients treated with intravenous thrombolysis across different case series studies
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Data on the rates of FFO in both IVT-treated patients with and without dissection were available in three case series, comprising a total of 1747 patients (83 IVT-DRIS and 1664 IVT-non DRIS patients) [30, 32, 34]. DRIS tended to be associated with non-significant lower FFO rates after thrombolysis compared to AIS patients without arterial dissection (RR = 0.77; 95 % CI 0.56–1.06; p = 0.11), with no evidence of heterogeneity across studies (I 2 = 0 %, p = 0.38; Fig. 3).

Fig. 3
figure 3

Forest plot of the favorable functional outcome at discharge. Risk ratios are provided for tPA-treated stroke patients with and without cervical artery dissection. Favorable functional outcome at hospital discharge was defined as modified Rankin scale score of 0–1

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Discussion

Our prospectively collected multicenter data, coupled with the findings of the comprehensive meta-analysis, underscore the safety of IVT in DRIS given the low rates of sICH complications and in-hospital mortality. Moreover, the efficacy of IVT in DRIS is further highlighted by our findings documenting high rates of successful recanalization and functional outcome in DRIS patients treated with intravenous tPA. Finally, the likelihood of FFO following tPA infusion did not differ between AIS patients with and without DRIS.

Our findings are in line with the results from an earlier literature review [37], an individual patient data meta-analysis [38] and a retrospective nationwide database study on the same topic [39], indicating that IVT does not adversely affect DRIS patients more than other AIS patients, and thus treatment benefit from tPA would not be counter-balanced by the potential for harm to AIS patients with evidence of extracranial or intracranial artery dissection in the anterior and/or posterior circulation. However, certain methodological differences between our and the earlier meta-analysis by Zinkstok and colleagues [38] need to be addressed. First, we did not include case reports due to the potential increased risk of publication bias in terms of favorable outcome [22], while such case reports were included in the earlier meta-analysis. Second, we did not include case series evaluating safety and efficacy of acute intra-arterial reperfusion therapies (e.g., intra-arterial thrombolysis, mechanical thrombectomy) in DRIS since we wanted to assess outcomes only in DRIS cases treated with IVT. Third, our study population was almost double (n = 234) in comparison to the number of patients treated exclusively with IVT in the meta-analysis by Zinkstok et al. (n = 121) [38]. Fourth and most important, recanalization status following tPA infusion was not assessed in the previous meta-analysis [38]. Consequently, the pooled recanalization rate of 45 % that we documented in our meta-analysis (without any evidence of heterogeneity) has not been previously reported.

The pooled sICH rates among DRIS cases treated solely with IVT were low in both our (2 %; 95 % CI 0–5 %) and the earlier (3 %; 95 % CI 1–9 %) meta-analysis. These observations provide further reassurance to clinicians fearing that sub-adventitial dissections with intracranial extension treated with tPA could cause bleeding into adjacent tissue resulting in subarachnoid hemorrhage (SAH) leading to adverse outcomes [4, 6, 25]. Our meta-analysis included the largest number of patients reported to date with concomitant intracranial extension of dissection (n = 21) that was treated with IVT in the absence of SAH on pre-treatment imaging. These observations are further corroborated by case reports of favorable outcomes in DRIS patients with angiographically proven intracranial extension of the dissection who were treated with tPA [40]. Our findings also indicate that vascular imaging to exclude DRIS prior to the administration of systemic thrombolysis is not required.

Our meta-regression analyses identified two factors that were associated with a higher likelihood of FFO in DRIS patients treated with IVT: lower baseline stroke severity and location of dissection in posterior circulation. The association of increasing stroke severity at hospital admission with adverse outcomes has been well documented in DRIS patients independent of treatment with tPA [3, 4, 6]. Moreover, better functional outcomes in patients with extracranial vertebral artery dissection compared to patients with cervical internal carotid dissection have been also reported in an earlier series of DRIS patients who did not receive IVT [41]. Finally, the former relationship between vertebral artery dissection and higher likelihood of FFO in DRIS patients (both treated and untreated with systemic thrombolysis) may be attributed to the milder stroke severity that has been documented at hospital admission in patients with CAD located in posterior circulation [7].

In the interpretation of this report, certain limitations need to be acknowledged. Physicians who assessed functional outcomes in our case series were aware of previous patient treatments. The lack of standardized imaging protocol for diagnosis of DRIS as well as the absence of central adjudication of diagnostic neuroimaging studies represents additional methodological shortcomings of the present study. Data of acute DRIS patients that were conservatively treated with antithrombotics (anticoagulants or antiplatelets) were not systematically collected in all participating centers, and thus no comparisons can be made between those patients and the reported 39 IVT-treated DRIS patients from our multicenter study protocol. Finally, follow-up data were available only during hospitalization and not at 3 months following stroke onset, since our primary aim was to evaluate the safety of IVT in DRIS. Consequently, we have limited the follow-up period of our multicenter, hospital-based study to the period of hospitalization. However, it should be noted that our observations reflect “real-word” experience in everyday clinical practice settings where alternative neuroimaging modalities are used for diagnosis of DRIS.

In two study protocols, patients were recruited in whole or in part retrospectively [31, 34], while in another two studies patients were excluded [30] or lost to follow-up after initial recruitment [31]. Reporting bias is also probable, as blinding in outcome assessment was reported in only one of the study protocols [34]. Even though the complication rates in this analysis are very reassuring, they are still subject to bias or underestimation because of small numbers of the samples and non-randomized fashion of collection of the patients reported in series and used in the meta-analysis. Other complications of IVT including asymptomatic intracranial hemorrhages were not recorded in the majority of including case series and the prevalence of these complications among DRIS cannot be determined in the present meta-analysis. Finally, it should be noted that non-dissection stroke patients that were treated with systemic thrombolysis were used for comparison of FFO rates (Fig. 3), as data on non-IVT-treated DRIS patients were not reported in the studies included in the meta-analysis and thus, no comparison could be made among IVT and conservatively treated acute DRIS patients.

In conclusion, our prospective, international data coupled with comprehensive meta-analysis results underscore IVT safety in DRIS while functional recovery rates compare favorably with overall IVT efficacy reported in phase III trials. They also provide reassurance to clinicians that the presence of an arterial dissection should not preclude tPA administration on the basis of safety concerns. Our results should be further confirmed in the settings of randomized clinical trials or larger observational registries.