Neurology -- Correspondence for Wunderlich et al., 68 (17) 1364-1368

Correspondence published:

Recanalization after intravenous thrombolysis: Does a recanalization time window exist?: Marc Gotkine, Gilad Rosenberg, Israel Steiner (4 September 2007)

Reply from the authors: Erwin Stolz, Michael Wunderlich, for the Duplex Sonography in Acute Stroke Study Group. (4 September 2007)

Recanalization after intravenous thrombolysis: Does a recanalization time window exist? 4 September 2007

Marc Gotkine,
Department of Neurology, Hadassah University Hospital,
Department of Neurology, Hadassah University Hospital, Jerusalem, Israel,
Gilad Rosenberg, Israel Steiner
Send Correspondence to journal:
Re: Recanalization after intravenous thrombolysis: Does a recanalization time window exist?

marc{at}gotkine.com Marc Gotkine, et al.

We read the study by Wunderlich et al [1] and the accompanying editorial by Uchino and Anderson [2] with interest. Both reports suggest that the upper time limit for therapeutic recanalization may be longer than previously established and up to 24 hours.
Many patients achieved a detectable degree of recanalization within 30 minutes, yet recanalization improved prognosis even when it was observed to occur 6-24 hours after stroke onset. One might conclude that if "fast recanalizers" were able to be identified a priori, they could benefit from recanalization measures administered as long as 20 hours or more following stroke onset.
However, previous clinical trials [3] suggest an upper limit of around 6 hours for initiating treatment in order to produce a meaningful salvage of brain tissue. Whereas selected patients may benefit from recanalization after the 6th hour post-stroke onset, a comprehensive` meta-analysis has recently shown that the odds ratio for favorable outcome is higher if the recanalization occurs within the first 6 hours [4].
We would like to know how Wunderlich et al reconcile this data with their conclusion that �Not the specific time point of recanalization at 6 or 24 hours after stroke onset, but recanalization per se within 24 hours was significantly associated with a favorable outcome.� Moreover, if the observed recanalization time accurately reflects the onset of tissue reperfusion, what time-independent mechanisms may be responsible for the lack of correlation between reperfusion time and prognosis?
We submit that one possible explanation might be the lack of sensitivity of trans-cranial doppler (TCD) in the detection of very low flow rates. Thus, the reported positive effect of recanalization occurring 6-24 hours post stroke-onset may only be observed in patients who re-established a low degree of perfusion much earlier but to a degree not detectable by TCD.
Perhaps there is currently no practical "gold standard" for in-vivo detection of minimal flow rates that may both herald the onset of more complete recanalization and provide the ischemic tissue with sufficient metabolic substrates to hinder the onset of irreversible necrosis. Proof that a therapy has achieved timely recanalization should rest on clinical evidence and investigative measures demonstrating functional, viable brain tissue rather than flow in the tissue�s supplying vessels.
References
1. Wunderlich MT, Goertler M, Postert T, et al for the Duplex Sonography in Acute Stroke (DIAS) Study Group and the Competence Network Stroke. Recanalization after intravenous thrombolysis: does a recanalization time window exist? Neurology 2007; 68: 1364-1368.
2. Uchino K, Anderson DC. Better late than never?: the story of arterial recanalization in acute ischemic stroke. Neurology 2007; 68:1335-1336.
3. Hacke W, Donnan G, Fieschi C, et al and ATLANTIS Trials Investigators; ECASS Trials Investigators; NINDS rt-PA Study Group Investigators. Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials. Lancet. 2004; 363: 768�774.
4. Rha J-H, Saver JL. The impact of recanalization on ischemic stroke outcome: a meta-analysis. Stroke 2007:38;967-973.
Disclosure: The authors report no conflicts of interest.

Reply from the authors 4 September 2007

Erwin Stolz,
Department of Neurology, Justus-Liebig-University
Am Steg 14, D-35385 Giessen, Germany,
Michael Wunderlich, for the Duplex Sonography in Acute Stroke Study Group.
Send Correspondence to journal:
Re: Reply from the authors

erwin.stolz{at}neuro.med.uni-giessen.de Erwin Stolz, et al.

We thank Gotkine et al for their interest in our recent contribution. [1] Their main question is how recanalization between 6 to 24 hours after systemic thrombolysis can still have a significant effect on clinical outcome considering the findings of the large thrombolysis trials and a recent metaanalysis by Rha and Saver which suggest that the chance of clinical improvement in late recanalization beyond 6 hours after symptom onset is low. [3, 4]
None of the large trials of systemic thrombolysis required the knowledge of the vascular status and are principally not comparable to our approach. Within 6 hours after symptom onset about one third of acute stroke patients have no detectable vessel occlusion. This implies that the populations examined in the thrombolysis trials and our patients are markedly different.
Diffusion (DWI) and perfusion (PWI) MRI mismatch are regarded as a surrogate marker for penumbral tissue. In a recent study, vessel occlusion on MR angiography had a sensitivity of 0.91 regarding the presence of DWI/PWI mismatch. [5] PWI/DWI MRI selected thrombolysis patients had a significantly higher chance for a favorable outcome even in a 3-6 hour window compared to the pooled data of the rt-PA groups of the large clinical thrombolysis trials. [3, 6]
Furthermore, recanalization > 6 hours was shown to decrease MRI lesion growth. [7] Complete and partial recanalization within 24 h, i.e. in cohorts with a considerable number of late recanalizers, were associated with improved clinical outcome after thrombolysis. [8] This implies that the vascular status does matter in thrombolysis and time windows are not as static as previously thought.
The intention of the meta-analysis by Rha and Saver [4] was to prove that recanalization is a surrogate marker for improved clinical outcome. None of the 53 studies entered into the analysis were designed to examine clinical outcome in relation to recanalization stratified by time intervals. In a considerable number of studies recanalization time was estimated. A meta-analysis cannot answer questions which were not addressed by the included studies.
The mechanism by which late recanalization decreases lesion growth and improves outcome compared to patients with persistent occlusion is still unclear. As pointed out by Uchino and Anderson, [2] leptomeningeal collateral blood supply might play an important role.
References
5. R�ther J, Schellinger PD, Gass A. Effect of intravenous thrombolysis on MRI parameters and functional outcome in acute stroke < 6 hours. Stroke 2002;33:2438�2445.
6. Thomalla G, Schwark C, Sobesky, J et al. Outcome and symptomatic bleeding complications of intravenous thrombolysis within 6 hours in MRI-selected stroke patients comparison of a German multicenter study with the pooled data of ATLANTIS, ECASS, and NINDS tPA trials. Stroke 2006;37:852-858.
7. Humpich M, Singer OC, du Mesnil de Rochemont R, Foerch C, Lanfermann H, Neumann-Haefelin T. Effect of early and delayed recanalization on infarct pattern in proximal middle cerebral artery occlusion. Cerebrovasc Dis 2006;22:51-56.
8. Neumann-Haefelin T, du Mesnil de Rochemont R, Fiebach JB, et al. Effect of incomplete (spontaneous and postthrombolytic) recanalization after middle cerebral artery occlusion. A magnetic resonance imaging study. Stroke 2004;35:109-115.
Disclosure: The authors report no conflicts of interest.