Large ischemic strokes presenting as malignant cerebral

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1 Neurosurg Focus 30 (6):E18, 2011 Decompressive hemicraniectomy after malignant middle cerebral artery infarction: rationale and controversies Omar M. Arnaout, M.D., Salah G. Aoun, M.D., H. Hunt Batjer, M.D., and Bernard R. Bendok, M.D. Department of Neurological Surgery, Feinberg School of Medicine and McGaw Medical Center, Northwestern University, Chicago, Illinois Malignant middle cerebral artery stroke carries a very poor prognosis. Significant retrospective data support the hypothesis that decompressive hemicraniectomy decreases mortality rates due to this disease entity. Recently, 3 randomized controlled studies have been published and shed light on these issues and enhance the quality of evidence revolving around this procedure. In this review, the rationale, risks, benefits, and unanswered questions related to hemicraniectomy for acute ischemic stroke are reviewed with an emphasis on how 3 randomized trials have influenced knowledge on this life-saving yet controversial procedure. Further randomized studies are needed to clarify lingering questions regarding age indications and impact on quality of life. (DOI: / FOCUS1160) Key Words hemicraniectomy craniectomy randomized controlled trial malignant stroke patient outcome quality of life Large ischemic strokes presenting as malignant cerebral edema account for 1% 10% of all ischemic strokes. 18 Mortality rates have been reported to be as high as 80%, 5 and most of the survivors are left severely disabled. An MCA infarction is the usual culprit, but the anterior and posterior cerebral arteries may additionally be affected. Early death is a result of transtentorial herniation while delayed death is typically due to the medical complications of prolonged hospitalization including pneumonia and pulmonary emboli. 22 Although decompressive craniectomy has been shown to significantly decrease mortality, high morbidity rates among survivors have tempered enthusiasm for this procedure. This reluctance has been most pronounced in elderly patients and those with dominant hemisphere infarcts. The span of the optimal operative time window when surgical decompression is superior to medical management alone is also subject to debate. Abbreviations used in this paper: MCA = middle cerebral artery; mrs = modified Rankin Scale; NIHSS = National Institutes of Health Stroke Scale; RCT = randomized controlled trial. Predictors of Malignant Cerebral Edema Severely compressive brain edema is associated with significant mortality and morbidity. From a pathophysiological standpoint, early intervention could minimize secondary ischemia of viable tissue around the infarcted core and possibly prevent herniation. Optimal utility of this procedure would require identifying the population that is most likely to benefit in a way that meets patients a priori expectations as well as those of their families and caretakers. With that objective in mind and by using diffusionweighted MR imaging, Oppenheim et al. 19 reported that a stroke volume greater than 145 cm 3 within 14 hours of onset of stroke symptoms has 100% sensitivity and 94% specificity for predicting the progression to malignant edema. Additionally, in a retrospective multicenter case-control study of 201 patients who suffered a massive MCA stroke, Kasner et al. 12 identified stroke volume greater than 50% of the MCA territory, high white blood cell count, additional involvement of the anterior or posterior cerebral artery, systolic blood pressure higher than 180 mm Hg within 12 hours of stroke onset, and a history 1

2 O. M. Arnaout et al. of hypertension or heart failure as additional risk factors for the progression toward malignant edema. Similarly, Krieger et al. 15 found that patients with an NIHSS score of 20 or greater on admission or who present with nausea or emesis are at high risk for developing malignant cerebral edema. In addition to clinical and radiographic risk factors, serum levels of the astroglial protein S100B have been shown to be predictive of malignant cerebral edema with 94% sensitivity and 83% specificity (for a value of 1.03 mg/l at 24 hours from the ischemic event). 3 This may become a useful monitoring tool at crucial clinical time points at which the development of cerebral edema is believed to be an imminent possibility, once a commercially available bedside kit is available. Best Medical Treatment Optimal medical management for malignant edema due to stroke has not been standardized. In the HAMLET (Hemicraniectomy After Middle cerebral artery infarction With Life-Threatening Edema Trial), recommendations for medical management of stroke-related malignant edema included admission to the intensive care unit, osmotherapy with mannitol or glycerol, invasive monitoring of intracranial pressure, blood pressure control, elevation of the head to 30, and maintenance of normothermia, normoglycemia, and normovolemia. Morbidity and mortality rates are high for this disease entity despite such aggressive measures. Evidence for Decompressive Craniectomy Craniectomy for the relief of cerebral edema associated with ischemic stroke was first described in the 1970s 8,14 and is intended to prevent life-threatening herniation. Although the impact on mortality appeared unequivocal in most studies, several controversies lingered and led to recent randomized trials, which are discussed below. Data Prior to RCTs Gupta et al. 4 performed a review of the literature in 2004, pooling all the data available up to that point. For the purposes of the review, good neurological outcome was defined as a Barthel Index of 60 or more, mrs score of 3 or less, or Glasgow Outcome Scale score of 4 or less. In the pooled analysis of 139 patients, the authors demonstrated a mortality rate of 24% after decompressive craniectomy with 42% of patients experiencing good neurological outcome. Of note, 80% of patients 50 years of age or older experienced poor neurological outcome (mrs Score 5 or 6 [severely disabled or dead]) following decompression. In the absence of randomized controlled data, questions remained regarding optimal patient selection, timing of therapy, and prognosis. Randomized Controlled Trials: DECIMAL, DESTINY, and HAMLET Given the unresolved questions regarding the role of decompressive craniectomy and appropriate patient selection, the following 3 RCTs were conducted, and the results were published recently (Table 1): DECIMAL (DEcompressive Craniectomy In MALignant middle cerebral artery infarcts) in France, published in 2007; 25 DESTINY (DEcompressive Surgery for the Treatment of malignant INfarction of the middle cerebral artery) in Germany, published in 2007; 10 and HAMLET (Hemicraniectomy After Middle cerebral artery infarction With Life-Threatening Edema Trial) in the Netherlands, 6 published in Study Design In all 3 trials, patients were randomized to surgical treatment versus best medical management alone. The study design was similar in the 3 studies, but some noticeable differences are worthy of discussion. The 3 trials included patients with an age of 60 years and younger, and defined the primary outcome by the mrs score at 6 TABLE 1: Randomized controlled trials for hemicraniectomy in malignant cerebral edema* Study Name Year No. of Pts Inclusion Criteria Time to Tx (hrs) Primary Outcome Measure Mortality (%) Good Outcome Surgical Medical Surgical Medical DESTINY age yrs, NIHSS 36 death at 30 days, mrs score <4 at 6 mos >18 20, >2/3 MCA territory DECIMAL age yrs 24 mrs score <4 at 6 mos HAMLET age yrs 96 mrs score <4 at 12 mos HeADDFIRST NA 26 acute unilat MCA territory ischemia HeMMI NA NA ischemic MCA stroke, GCS Score 6 14/ 5 9 DESTINY II NA NA age 61 yrs, MCA malignant infarct * GCS = Glasgow Coma Scale; NA = not available; Pt = patient. 96 death, functional outcome, quality of life, pt perceptions, acute health care use after 21, 90, & 180 days GCS, NIHSS, mrs, & Barthel Index; functional outcome at 6 mos results pending recruiting patients 48 mrs score <5 at 6 mos recruiting patients 2

3 Decompressive craniectomy after malignant MCA infarction months for DESTINY and DECIMAL and 1 year for the HAMLET (Table 2). The primary outcome was dichotomized between an mrs score of 0 3, defined as good outcome, and 4 6, defined as poor outcome. The crucial difference between a score of 3 and a score of 4 is that in the former, individuals still possess the ability to walk and attend to their bodily needs unassisted. A major difference in trial design was the time window for craniectomy. Surgical decompression was initiated within 24 hours of symptom onset in DECIMAL, between 12 and 36 hours in DESTINY, and within 96 hours in HAMLET. After the completion of the HAMLET, the authors published pooled data from the 3 randomized trials. 7 The meta-analysis only included individuals treated within 48 hours of symptom onset from the HAMLET, thus excluding 11 patients and totaling 109 patients. Fifty-eight patients had been assigned to hemicraniectomy and 51 to medical treatment alone. The primary outcome was changed to include an mrs score of 4 in the good outcome category. The dichotomization was thus made between an mrs score of 1 4 for good outcome and an mrs of 5 or 6 for bad outcome. Results of the RCTs Effect on Mortality. The DECIMAL and DESTINY trials were stopped early in 2006 as ongoing data analysis demonstrated significant mortality reduction in the surgical group compared with those receiving medical treatment. All 3 of the European trials showed a significant reduction in mortality in patients belonging to the surgical arm, with an absolute risk reduction of 53% at 6 months in DECIMAL, and 38% at 1 year in HAMLET. DESTINY also showed a 12% mortality rate in surgically treated patients at 30 days, versus 53% in the medical treatment arm. In the meta-analysis, the absolute risk reduction in mortality with surgery was found to be 49.9% (95% CI 33.9% 65.9%), which meant that the number needed to treat to prevent death equaled 2. The authors concluded that surgical decompression within 48 hours of stroke onset reduced the risk of death. Effect on Severe Disability (mrs Score 5). The DECI- MAL, DESTINY, and HAMLET studies showed a statistically significant reduction in severely disabled, bedridden patients (mrs score > 4). In the pooled analysis of the 3 pooled studies, the absolute reduction in risk for a bad functional outcome was 41.9% (95% CI 25.2% 58.6%). As a result, the authors concluded that surgical decompression within 48 hours of stroke onset reduced the risk of significant morbidity. Effect on Moderately Severe Disability (mrs Score 4). The primary outcome measure in the 3 RCTs defined a good outcome as an mrs score of 3 or less. The goal was to prove a significant reduction in the number of patients unable to attend to their bodily needs or walk unassisted (mrs score of 4). Unfortunately, none of the 3 trials reached statistically significant conclusions favoring a good functional outcome after craniectomy as defined by their primary outcome measure, although there was a trend in this direction in DESTINY and DECIMAL TABLE 2: Modified Rankin Scale Score Definition 0 asymptomatic 1 no significant disability; able to carry out all usual activities, despite some symptoms 2 slight disability; able to look after own affairs w/o assistance, but unable to carry out all previous activities 3 moderate disability; requires some help, but able to walk unassisted 4 moderately severe disability; unable to attend to own bodily needs w/o assistance, unable to walk unassisted 5 severe disability; requires constant nursing care & attention, bedridden, incontinent 6 dead studies. This conclusion may not have reached statistical significance because of the small number of patients included in both trials, since they were prematurely terminated. Additional studies with larger patient groups are needed before drawing definite conclusions. Disability in Survivors. Separate and pooled analyses of the DECIMAL, DESTINY, and HAMLET trials, while demonstrating an undeniable increase in the number of survivors among surgical patients, also showed an increase in the number of survivors with moderately severe disability (mrs score of 4). This fact necessitates careful discussion with the patient s family and/or power of attorney to be sure that outcomes associated with craniectomy are in keeping with patient wishes. Quality of life issues are difficult to put in proper perspective, but the randomized studies discussed above help clarify some facets of this important subject. Future studies will need to focus more rigorously on the long-term quality of life in survivors. There exists a difficult balance between increasing survival and poor neurological outcome, which inherently includes the subjective assessment of outcome along a continuum. 20,23 Further investigations regarding the neurological outcome of patients after decompression, as well as better standardization of functional outcome measures in larger series, is certainly warranted. Dominant Hemisphere Involvement While the fear of complete aphasia was classically the reason behind the refusal to operate on large dominant hemispheric strokes, recent data have suggested that nondominant hemispheric injuries leading to serious depression and neglect can be as disabling as aphasia during the rehabilitation process. 27 Additionally a subset analysis in the DECIMAL trial showed no difference in the mrs scores of survivors with or without aphasia at 1 year; in addition, all surgical survivors agreed with the decisions to undergo surgery when asked retrospectively, including patients still experiencing aphasia. 16 Stroke laterality and its correlation with outcome 4,17,21 have also been the subject of subgroup analysis in the other European trials, 6,7,10,24,25 and controlled and uncontrolled studies have 3

4 O. M. Arnaout et al. shown no predicative value for outcome related to laterality. Clearly this issue will continue to warrant debate and should be further studied. Surgical Technique and Craniectomy Size Wagner et al. 26 retrospectively reviewed 60 patients who were admitted with malignant MCA infarcts. They studied the impact of craniectomy size, shape, and location on parenchymal hemorrhagic and ischemic lesions, postoperative bleeding, and mortality. Interestingly, they found a 70% rate of hemicraniectomy-associated infarcts and hemorrhage. Bleeding was associated with a small craniectomy size and sharp bone defects. Parenchymal hemorrhage was the only factor that statistically affected mortality rate, with only 55% of patients surviving compared with 80% in the absence of hemorrhage. Their recommendation for craniectomy size was a diameter larger than 12 cm. This conclusion is validated by the fact that some studies suggest that doubling the diameter from 6 cm to 12 cm potentially increases the decompressive volume from 9 to 86 ml. 26,29 Ideally, hemicraniectomy should be performed in the frontotemporoparietal region and reach the floor of the middle cranial fossa. The midline should be spared to avoid injury to the superior sagittal sinus. Surgical Complications The outcomes of patients undergoing decompressive craniectomy may be impacted by the complications of the procedure. 23 Reported complications include inadequate decompression, 26 infection, 2 hemorrhage, and the development of contralateral fluid collections. 13 Furthermore, delayed sinking flap syndrome may result in headaches, seizure and focal neurological deficits and is typically cured by replacement of the bone flap. 1 Similarly, hydrocephalus may develop in a delayed fashion. 28 Time Window for Surgery The question of the optimal time window for intervention has not yet been completely elucidated. Although the pooled data from the European trials seem to show benefit from early surgery, only a small number of patients (11) was included in the late group in the HAMLET, and definite conclusions cannot be drawn at this time. 23 Additionally, a major systematic review of the literature did not demonstrate a difference in outcome based on timing. 4 Clear definition of a time window for intervention will be essential to creating treatment guidelines. With that purpose in mind, 2 additional RCTs have been initiated. The North American HeADDFIRST (Hemicraniectomy And Durotomy on Deterioration From Infarction Related Swelling Trial), aimed to evaluate patient outcome after hemicraniectomy within 96 hours from symptom onset, and is awaiting publication. The HeMMI trial (Hemicraniectomy for Malignant Middle cerebral artery Infarcts) in the Philippines, is studying patient morbidity and mortality after decompressive surgery within 72 hours from symptom onset and is still in the process of recruiting patients. Surgical Age Limit As noted above, randomized trials to date have focused on patients 60 years of age and younger, thus leaving us with very few data regarding patients older than 60 years of age. The HAMLET displayed conflicting results with previous review series, 4 with a trend toward better outcome in the upper age categories (51 61 years). These results raised questions about the existence of an age limit for surgical benefit. The DESTINY 2 trial is currently underway and will shed more light on the impact of surgery in patients older than 60 years. 9 Conclusions Pooled analysis of the European trials discussed above provides Class I evidence for the performance of early decompressive craniectomy in the setting of large unilateral infarcts (volume > 145 cm 3 ) within 48 hours of the ischemic event. 11 Given the potential tradeoff between survival and good neurological outcome, frank discussion with the patient and the family should be held early in the setting of an envisioned need for surgical decompression, while keeping in mind that 2 RCTs reported a trend of reduced disability among survivors. Although the surgical age limit has not yet been fully defined, very few data exist to support hemicraniectomy for patients older than 60 years, although individual circumstances may outweigh paucity of data issues. Further studies are needed to better define quality of life issues at long-term follow-up as well as age limit issues. Ultimately, MCA infarction with malignant edema is a devastating disease for which hemicraniectomy can play a positive role. New strategies are needed to enhance long-term outcomes, which will likely extend across the entire stroke continuum from the acute phase to the rehabilitation period. Disclosure The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper. Author contributions to the study and manuscript preparation include the following. Conception and design: Bendok, Batjer, Arnaout, Aoun. Acquisition of data: Arnaout, Aoun. Analysis and interpretation of data: Arnaout, Aoun. Drafting the article: Arnaout, Aoun. Critically revising the article: Bendok, Batjer. References 1. 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