The consensus statement  was proposed by the chairperson in the session, Professor Veronika Skvortsova and the session secretary dr Per Holmberg, together with the speakers in the session. The statement was then finally approved by the participants of the meeting, after listening to the different presentations.

The speakers in this session were Professor Per Wester, Umeå, dr Erich Jüttler, Heidelberg, and Professor Kennedy R Lees, Glasgow.

Is there sufficient evidence to support a recommendation of hemicraniectomy for malignant middle cerebral artery infarcts? Are more randomised trials warranted?

Can NXY-059 have a therapeutic potential both in ischaemia and in reperfusion? Is a dual potential also applicable for other neuropotential agents, such as NMDA and AMPA antagonists?

Pharmacological neuroprotection

As yet, no drug has shown convincing neuroprotective effects in the setting of clinical acute ischaemic stroke. No neuroprotective agent can be recommended at present for routine use in acute stroke patients. There are numerous possible  reasons for the lack of effect on outcome of several relatively large randomised clinical trials.
Future studies should be devoted to novel protective approaches which induce mechanisms of endogenous anti-ischaemic brain tolerance and act at several different levels in the ischaemic cascade, which influence survival of all brain cell pools: neurons, glial and endothelial cells and have an anti-stress influences on neuro-immune-endocrine system, which easily pass the blood-brain barrier.

The combined thrombolysis and neuroprotection, as well as the combination of various neuroprotective agents (including antiapoptotic ones) and neurorestorative therapies could be tested and evaluated in both well-organised experimental and clinical trials.

The following strategies may be considered for future clinical trials:

- Diffusion-perfusion MR, CT-perfusion, SPECT may be used to delineate treatable region/penumbra in individual patients and thereby identify more rationally appropriate candidates for neuroprotective therapy. These data may be used as co-variables to explain the effects. 

- Unless very large trials are conducted, stratification of patients at baseline should be done taking into account factors of known prognostic importance (age, stroke subtype, stroke severity) in order to balance groups at baseline.

New fundamental advances over the past decade raise expectations that successful stroke neuroprotection is imminent.

Hemicraniectomy:

Hemicraniectomy in malignant middle cerebral artery (MCA) infarction has been one of the major controversies over years in neurocritical care medicine. So, far numerous case reports, case series, and several prospective, but non-randomised suggest that hemicraniectomy (decompressive surgery) reduces mortality: Case fatality rates in patients treated conservatively have been reported to be as high as 80%. Decompressive surgery reduced mortality to about 25%. Furthermore, early decompressive surgery has also been reported to further reduce case fatality rates to about 16%. However, so far no randomised trial had been performed to prove the effect of hemicraniectomy in a prospective, randomised way. Also, in most of these trials the control group consisted of patients with higher age, more co-morbidity, and more often a lesion of the dominant hemisphere. Another problem is, that there is no overall agreement on the definition of “malignant” MCA infarction.
So, controversy among neurologists and neurosurgeons remains concerning the effectiveness of the procedure. The fear of many critics is, that hemicraniectomy may be life-saving, but at the same time increases the number of survivors in a complete dependent state, whereas intercessors point out, that although most survivors do not reach independence, most patients are only mildly to moderately disabled and the quality of life of these is good concerning the severity of the disease.
However, there are only very few data on the quality of life, and long-term outcome after decompressive surgery, and data of survivors after conservative treatment is almost lacking.

There are currently 5 randomised trials of decompressive surgery versus conservative treatment:

HeADDFIRST (1) was a first trial designed as a pilot study, which randomised 26 patients. Although hemicraniectomy reduced mortality from about 46% to 27%, these results were not statistically significant due to the low number of patients. There are so far no data on the outcome of survivors.

Early 2006 the results of another two randomised trials have been presented: The DESTINY trial (2) was the first randomised controlled trial that demonstrated that hemicraniectomy statistical significantly reduced mortality from 88% to 47% compared to conservative treatment alone. However, the primary endpoint modified Rankin Scale (mRS) 0-3 versus 4-death did not reach statistical significance (32 patients). The DECIMAL trial (3) randomised 38 patients and also demonstrated a statistical significant reduction in mortality by decompressive surgery from 78% to 25%. However, mRS 0-3 versus 4-death also did not reach statistical significance. Both trials demonstrated that the number of very severely disabled (mRS 5) survivors was not increased. Both trials performed early hemicraniectomy up to 36 hours after symptom onset.

HAMLET and HeMMI are two other trials that are still ongoing. 

Conclusions:

- Early hemicraniectomy reduces mortality in malignant MCA infarction (1, Grade A)

- Early hemicraniectomy does not increase the proportion of patients in a completely dependent state. By reducing mortality, hemicraniectomy increases the proportion of patients with a modified Rankin scale of 3-4 (2, Grade B).

- Early hemicraniectomy improves clinical outcome of survivors (3, Grade C)
.

Addendum and modified Conclusions 2007:

In 2007 a pooled analysis of the three European randomised trials including all patients from DESTINY and DECIMAL and a subgroup of patients from HAMLET was published (4). This pooled analysis is the first in the field of stroke, in which individual patient data from three different randomised trials were pooled while these trials were still ongoing. For the pooled analysis, a maximum time window from stroke onset to treatment start of 48 hours was adopted.  Outcome measures in the pooled analysis were the scores on the mRS at 1 year, dichotomized between 0-4 and 5 and death, as well as between 0-3 and 4-6, and the case fatality at one year. 93 patients were included, of whom 51 were randomised to decompressive surgery and 42 to conservative treatment. Results demonstrated that after decompressive surgery, more patients had an mRS ≤4 (75% vs 24%, p<0.0001), with a pooled absolute risk reduction (ARR) of 51% (95%CI 34-69). Decompressive surgery was beneficial in all pre-defined subgroups, including age (dichotomized at 50 years), presence of aphasia, and time to randomisation (dichotomized at 21.5 hours), as measured by mRS ≤ 4 at 12 months. In addition, more patients had an mRS ≤3 (43% vs 21%, p=0.014), with a pooled ARR of 23% (95%CI 5-41). Case fatality rate in the surgical group was 78% versus 29% in the conservative treatment group (p<0.0001) indicating a pooled ARR of 50% (95%CI: 33-67). The resulting numbers needed to treat are 2 for survival with an mRS ≤4, 4 for survival with an mRS ≤3, and 2 for survival irrespective of outcome. However, by reducing mortality, hemicraniectomy also more than 10-fold increased the number of patients with an mRS of 4 compared to conservative treatment.

Conclusions (modified 2007):

After publication of this pooled analysis of three randomised controlled trials of decompressive surgery for malignant middle cerebral artery infarction (1), the writing group agrees to modify the conclusions to the following:

- Early hemicraniectomy reduces mortality in malignant MCA infarction (Grade A)

- Early hemicraniectomy does not increase the number of patients in a completely dependent state. By reducing mortality, hemicraniectomy increases the number of patients with a modified Rankin scale of 3-4 and doubles the proportion of patients with a modified Rankin score of ≤3  (Grade A).

- Early hemicraniectomy improves clinical outcome of survivors (Grade A) 

Future directions:

1. The long-term outcome and the quality of life of survivors is one major issue that is currently assessed in the ongoing randomised trials.
2. The question of timing of surgery is currently investigated in the HAMLET and the HeMMI trial, which randomise patients up to 72 hours after symptom onset.
3. The question of a probable age limit for hemicraniectomy in malignant MCA infarction is still unresolved and justifies further randomised trials specifically addressing this question.

References:

1. Frank JI, Krieger D, Chyatte D, Cancian S: Hemicraniectomy and durotomy upon deterioration from massive hemispheric infarction: A proposed multicenter, prospective, randomized study. Stroke 1999, 30:243.
2. Juttler E, Schwab S, Schmiedek P, Unterberg A, Hennerici M, Woitzik J, Witte S, Jenetzky E, Hacke W; DESTINY Study Group. Decompressive Surgery for the Treatment of Malignant Infarction of the Middle Cerebral Artery (DESTINY): a randomized, controlled trial. Stroke 2007, 38:2518-2525
3. Vahedi K, Vicaut E, Mateo J, Kurtz A, Orabi M, Guichard JP, Boutron C, Couvreur G, Rouanet F, Touze E, Guillon B, Carpentier A, Yelnik A, George B, Payen D, Bousser MG; DECIMAL Investigators. Sequential-design, multicenter, randomized, controlled trial of early decompressive craniectomy in malignant middle cerebral artery infarction (DECIMAL Trial). Stroke 2007, 38:2506-2517.
4. Vahedi K, Hofmeijer J, Juettler E, Vicaut E, George B, Algra A,  Amelink GJ, Schmiedek P, Schwab S, Rothwell PM, Bousser MG, van der Worp HB, Hacke W; for the DECIMAL, DESTINY, and HAMLET investigators: Early decompressive surgery in malignant middle cerebral artery infarction: a pooled analysis of three randomised controlled trials. Lancet Neurology 2007, 6:215-222.