RESEARCH PAPER Acute ischaemia after subarachnoid haemorrhage, relationship with early brain injury and impact on outcome: a prospective quantitative MRI study Jennifer A Frontera, 1 Wamda Ahmed, 2 Victor Zach, 2 Maximo Jovine, 2 Lawrence Tanenbaum, 3 Fatima Sehba, 2 Aman Patel, 2 Joshua B Bederson, 2 Errol Gordon 2 1 Cleveland Clinic, Cerebrovascular Center of the Neurological Institute, Cleveland, Ohio, USA 2 Neuroscience Intensive Care Unit, Departments of Neurosurgery and Neurology, Mount Sinai School of Medicine, New York, New York, USA 3 Neuroradiology Department, Mount Sinai School of Medicine, New York, New York, USA Correspondence to Dr Jennifer A Frontera, Cleveland Clinic, Foundation Cerebrovascular Center, 9500 Euclid Ave. S80, Cleveland, OH 44195, USA; [email protected]Received 22 November 2013 Revised 7 February 2014 Accepted 18 March 2014 To cite: Frontera JA, Ahmed W, Zach V, et al. J Neurol Neurosurg Psychiatry Published Online First: [ please include Day Month Year] doi:10.1136/ jnnp-2013-307313 ABSTRACT Objective To determine if ischaemia is a mechanism of early brain injury at the time of aneurysm rupture in subarachnoid haemorrhage (SAH) and if early MRI ischaemia correlates with admission clinical status and functional outcome. Methods In a prospective, hypothesis-driven study patients with SAH underwent MRI within 0–3 days of ictus (prior to vasospasm) and a repeat MRI (median 7 days). The volume and number of diffusion weighted imaging (DWI) positive/apparent diffusion coefficient (ADC) dark lesions on acute MRI were quantitatively assessed. The association of early ischaemia, admission clinical status, risk factors and 3-month outcome were analysed. Results In 61 patients with SAH, 131 MRI were performed. Early ischaemia occurred in 40 (66%) with a mean DWI/ADC volume 8.6 mL (0–198 mL) and lesion number 4.3 (0–25). The presence of any early DWI/ADC lesion and increasing lesion volume were associated with worse Hunt-Hess grade, Glasgow Coma Scale score and Acute Physiology and Chronic Health Evaluation II physiological subscores (all p<0.05). Early DWI/ADC lesions significantly predicted increased number and volume of infarcts on follow-up MRI (p<0.005). At 3 months, early DWI/ADC lesion volume was significantly associated with higher rates of death (21% vs 3%, p=0.031), death/severe disability (modified Rankin Scale 4–6; 53% vs 15%, p=0.003) and worse Barthel Index (70 vs 100, p=0.004). After adjusting for age, Hunt- Hess grade and aneurysm size, early infarct volume correlated with death/severe disability (adjusted OR 1.7, 95% CI 1.0 to 3.2, p=0.066). Conclusions Early ischaemia is related to poor acute neurological status after SAH and predicts future ischaemia and worse functional outcomes. Treatments addressing acute ischaemia should be evaluated for their effect on outcome. INTRODUCTION Admission neurological status after subarachnoid haemorrhage (SAH) reflects early brain injury and is a larger predictor of death or severe disability than any other factor or complication that occurs as a consequence of aneurysm rupture (such as vasospasm). 1–5 Indeed, poor Hunt-Hess grade patients (grade 4–5) have devastating outcomes, with 12-month mortality rates ranging from 43% to 100%. 6 7 However, the mechanisms for this early brain injury are not well understood and no therapeutic intervention currently exists. Based on animal studies, one possible mechanism is acute ischaemia. 8 At the time of aneurysm rupture intra- cranial pressure becomes transiently elevated, exceeding mean arterial pressure, leading to low or absent intracranial blood flow and consequent hypoperfusion ischaemia. 8–11 Additionally, endo- thelial collagen exposure that occurs after aneurysm rupture has been correlated with platelet activation, aggregation and microcirculatory thrombosis in animal models, suggesting another possible mech- anism of ischaemia. 12 13 Early platelet activation has also been documented in clinical studies of SAH and correlates with worse admission neuro- logical function. 14 Though CT studies have detected acute infarction following SAH in a small percentage of patients, 15 16 the sensitivity and specificity of CT for acute infarction is inferior to MRI. Clinical studies of patients with SAH with poor admission neurological status (Hunt-Hess 4–5) have revealed that MRI evidence of ischaemia (diffusion weighted imaging (DWI) positive lesions) occurs in 71–86% of patients within the first 24–96 h of aneurysm rupture. 17–19 In contrast, MRI ischaemia is less common in patients with better neurological status (Hunt-Hess grade 1–3), suggesting that ischaemia may play a pivotal role in early brain injury. 17 The limitations of these studies were varied and included small patient samples, non-standardised MRI protocols, biased indications for MRI, retro- spective design and lack of quantification of ischaemia. In this prospective, hypothesis-driven study using serial, quantitative MRI, we sought to evaluate the relationship of early ischaemia and clinical status, as well as identify predictors for early ischaemia and its impact on long-term functional outcome. METHODS Study population A prospective, hypothesis-driven study of patients with spontaneous (non-traumatic) SAH, admitted to the Neuroscience Intensive Care Unit at the Mount Sinai Hospital in New York City, was conducted between August 2008 and October 2011. The diagnosis of SAH was established on the Frontera JA, et al. J Neurol Neurosurg Psychiatry 2014;0:1–8. doi:10.1136/jnnp-2013-307313 1 Cerebrovascular disease JNNP Online First, published on April 8, 2014 as 10.1136/jnnp-2013-307313 Copyright Article author (or their employer) 2014. Produced by BMJ Publishing Group Ltd under licence. group.bmj.com on August 12, 2014 - Published by jnnp.bmj.com Downloaded from
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RESEARCH PAPER
Acute ischaemia after subarachnoid haemorrhage,relationship with early brain injury and impacton outcome: a prospective quantitative MRI studyJennifer A Frontera,1 Wamda Ahmed,2 Victor Zach,2 Maximo Jovine,2
Lawrence Tanenbaum,3 Fatima Sehba,2 Aman Patel,2 Joshua B Bederson,2
Errol Gordon2
1Cleveland Clinic,Cerebrovascular Center of theNeurological Institute,Cleveland, Ohio, USA2Neuroscience Intensive CareUnit, Departments ofNeurosurgery and Neurology,Mount Sinai School ofMedicine, New York,New York, USA3Neuroradiology Department,Mount Sinai School ofMedicine, New York,New York, USA
Correspondence toDr Jennifer A Frontera,Cleveland Clinic, FoundationCerebrovascular Center, 9500Euclid Ave. S80, Cleveland,OH 44195, USA;[email protected]
Received 22 November 2013Revised 7 February 2014Accepted 18 March 2014
To cite: Frontera JA,Ahmed W, Zach V, et al.J Neurol NeurosurgPsychiatry Published OnlineFirst: [please include DayMonth Year] doi:10.1136/jnnp-2013-307313
ABSTRACTObjective To determine if ischaemia is a mechanism ofearly brain injury at the time of aneurysm rupture insubarachnoid haemorrhage (SAH) and if early MRIischaemia correlates with admission clinical status andfunctional outcome.Methods In a prospective, hypothesis-driven studypatients with SAH underwent MRI within 0–3 days ofictus (prior to vasospasm) and a repeat MRI (median7 days). The volume and number of diffusion weightedimaging (DWI) positive/apparent diffusion coefficient(ADC) dark lesions on acute MRI were quantitativelyassessed. The association of early ischaemia, admissionclinical status, risk factors and 3-month outcome wereanalysed.Results In 61 patients with SAH, 131 MRI wereperformed. Early ischaemia occurred in 40 (66%) with amean DWI/ADC volume 8.6 mL (0–198 mL) and lesionnumber 4.3 (0–25). The presence of any early DWI/ADClesion and increasing lesion volume were associated withworse Hunt-Hess grade, Glasgow Coma Scale score andAcute Physiology and Chronic Health Evaluation IIphysiological subscores (all p<0.05). Early DWI/ADClesions significantly predicted increased number andvolume of infarcts on follow-up MRI (p<0.005). At3 months, early DWI/ADC lesion volume was significantlyassociated with higher rates of death (21% vs 3%,p=0.031), death/severe disability (modified Rankin Scale4–6; 53% vs 15%, p=0.003) and worse Barthel Index(70 vs 100, p=0.004). After adjusting for age, Hunt-Hess grade and aneurysm size, early infarct volumecorrelated with death/severe disability (adjusted OR 1.7,95% CI 1.0 to 3.2, p=0.066).Conclusions Early ischaemia is related to poor acuteneurological status after SAH and predicts futureischaemia and worse functional outcomes. Treatmentsaddressing acute ischaemia should be evaluated for theireffect on outcome.
INTRODUCTIONAdmission neurological status after subarachnoidhaemorrhage (SAH) reflects early brain injury andis a larger predictor of death or severe disabilitythan any other factor or complication that occursas a consequence of aneurysm rupture (such asvasospasm).1–5 Indeed, poor Hunt-Hess gradepatients (grade 4–5) have devastating outcomes,with 12-month mortality rates ranging from 43%
to 100%.6 7 However, the mechanisms for thisearly brain injury are not well understood and notherapeutic intervention currently exists. Based onanimal studies, one possible mechanism is acuteischaemia.8 At the time of aneurysm rupture intra-cranial pressure becomes transiently elevated,exceeding mean arterial pressure, leading to low orabsent intracranial blood flow and consequenthypoperfusion ischaemia.8–11 Additionally, endo-thelial collagen exposure that occurs after aneurysmrupture has been correlated with platelet activation,aggregation and microcirculatory thrombosis inanimal models, suggesting another possible mech-anism of ischaemia.12 13 Early platelet activationhas also been documented in clinical studies ofSAH and correlates with worse admission neuro-logical function.14
Though CT studies have detected acute infarctionfollowing SAH in a small percentage ofpatients,15 16 the sensitivity and specificity of CTfor acute infarction is inferior to MRI. Clinicalstudies of patients with SAH with poor admissionneurological status (Hunt-Hess 4–5) have revealedthat MRI evidence of ischaemia (diffusion weightedimaging (DWI) positive lesions) occurs in 71–86%of patients within the first 24–96 h of aneurysmrupture.17–19 In contrast, MRI ischaemia is lesscommon in patients with better neurological status(Hunt-Hess grade 1–3), suggesting that ischaemiamay play a pivotal role in early brain injury.17 Thelimitations of these studies were varied andincluded small patient samples, non-standardisedMRI protocols, biased indications for MRI, retro-spective design and lack of quantification ofischaemia.In this prospective, hypothesis-driven study using
serial, quantitative MRI, we sought to evaluate therelationship of early ischaemia and clinical status,as well as identify predictors for early ischaemiaand its impact on long-term functional outcome.
METHODSStudy populationA prospective, hypothesis-driven study of patientswith spontaneous (non-traumatic) SAH, admittedto the Neuroscience Intensive Care Unit at theMount Sinai Hospital in New York City, wasconducted between August 2008 and October2011. The diagnosis of SAH was established on the
basis of CT scans and/or lumbar puncture. All consecutive, non-traumatic patients with SAH were screened for enrolment by aresearch coordinator at the time of admission to the neuro-ICU.Criteria for inclusion in the study were defined as: (1) age≥18 years, (2) consent to participate by either the patient orlegally authorised representative and (3) MRI performed within72 h of SAH onset. Exclusion criteria were: (1) non-aneurysmalSAH, (2) clinical or radiographic evidence of vasospasm at thetime of the acute MRI, (3) unknown time of SAH onset and (4)contraindication to MRI, such as non-MRI compatible implan-tables. This study was approved by the Mount Sinai InstitutionalReview Board.
Radiographic assessmentsAdmission CTwas assessed using the modified Fisher scale 20 21
and the SAH sum score.22 Serial MRI scans were performed aspart of a standard clinical protocol on all spontaneous SAHadmissions on days 0–3, and day 4 or later from SAH ictus. Inthis cohort, all MRIs completed within 0–3 days of aneurysmrupture were performed prior to the onset of clinical or radio-graphic vasospasm. MRI was performed on a 1.5-T scanner(HdxT General Electric, Fairfield, Connecticut, USA). DWI/apparent diffusion coefficient (ADC), fluid attenuation inversionrecovery (FLAIR), T1, T2 and T2* gradient echo sequenceswere obtained. DWI was obtained using echo-planar, spin-echosequence (matrix size 96–128× 128, field of view 24×24, repe-tition time (TR) 8000 ms, echo time 80–95 ms, b values 0 s/mm−2, 1000 s/mm−2 and 2000 s/mm−2). Thirty 5 mm thickaxial slices with an interslice gap of 0 mm were imaged for 8 s.Isotropic T2 trace weighted images were reconstructed at eachslice location from six individual direction images. Average ADCmaps were automatically generated. Fast spin-echo axialsequences were obtained with following parameters: repetitiontime 6000s, echo time (TE) 88 ms, matrix 320×320 and fieldof view 21×21 cm.
MRI was assessed by two investigators (WA, VZ) to identifyearly ischaemia occurring within 0–3 days of aneurysm rupture,prior to the onset of radiographic or clinical vasospasm. Earlyischaemia was radiographically defined as b-1000 T2 trace(DWI) positive, ADC dark lesions, excluding lesions that wereprocedure related (along a known external ventricular drain(EVD) tract, craniotomy trajectory, adjacent to the site of clip-ping), due to blood products (correlating areas on susceptibilityweighted imaging), or related to herniation. Shine-through DWIpositive, FLAIR bright lesions that were not dark on ADC wereexcluded. The volumes of these selected ADC dark lesions weremeasured by two investigators (WA, VZ), blinded to thepatient’s clinical condition and outcome using Neuroscape soft-ware (Olea, La Ciotat, France).23 Lesions were considered to bedistinct if they were separated by 5 mm. Follow-up MRI FLAIRlesions correlating to DWI T2 trace positive/ADC dark lesionscoded as ischaemia on initial early MRI were assessed forvolume and number using Olea software (La Ciotat, France) bythe same investigators (WA, VZ). These FLAIR lesions wereconsidered to indicate final infarct burden. If no follow-up MRIwas performed, any DWI positive, ADC dark lesions that werealready hyperintense on FLAIR were counted as final infarcts.FLAIR lesions not correlating to ADC dark lesions wereexcluded from analysis. Collaborator LT served as the supervis-ing neuroradiologist for this project and oversaw MRI dataacquisition and analysis.
Clinical assessmentAdmission demographic data and details of the clinical presenta-tion were collected from the patient or healthcare representativeat the time of admission. Admission clinical status was evaluatedby one of three study physicians using the Glasgow Coma Scale(GCS),24 Hunt-Hess grade6 and Acute Physiology and ChronicHealth Evaluation II (APACHE-II) physiological subscore(APACHE-II score minus GCS contribution).25 GCS andHunt-Hess scores were documented after resuscitation(eg, external ventricular drainage) to reduce the confoundingeffect of hydrocephalus on admission neurological assessments.
Outcome measures:All outcomes were assessed at 3 months via telephone interviewconducted by research assistants blinded to the MRI data.Survival and functional outcome was measured using the modi-fied Rankin Scale (mRS, 0=full recovery, 6=death). Pooroutcome was defined as death-or-severe-disability (mRS score 4–6). Independent activities of daily living were assessed using theBarthel Index (scored: 100=best, 0=worst).26–28 Global cogni-tive function was evaluated with the telephone interview forcognitive status (scored: 51=best, 0=worst).29 30
Statistical analysisThe association between demographic characteristics, admissionradiographic features, admission clinical status and the presenceof early MRI DWI/ADC lesions, DWI/ADC lesion volume andDWI/ADC lesion number (on MRI performed 0–3 days fromictus) were assessed using Pearson’s χ2 or Mann-Whitney U non-parametric analysis for continuous non-normally distributeddata. Continuous variables were dichotomised at the median.Receiver operating characteristic (ROC) curves were constructedto determine the DWI/ADC volume and number of lesions thatpredict functional outcome with the optimal sensitivity and spe-cificity. The impact of the presence of early DWI/ADC lesions,DWI/ADC lesion volume (using the ROC cut point that opti-mises sensitivity and specificity) and DWI/ADC lesion number(using the ROC cut point that optimises sensitivity and specifi-city) on 3-month outcomes was assessed using univariate logisticregression analyses.
Multivariable logistic regression models were constructed tocalculate adjusted ORs and 95% CIs for the effect of early MRIischaemia and final MRI infarct (as measured by FLAIR corre-sponding to DWI/ADC lesions on follow-up MRI) on 3-monthfunctional outcomes. Candidate variables for the final multivari-able model were tested in univariate logistic regression includ-ing: age, admission Hunt-Hess grade, admission systolic bloodpressure (BP), history of hypertension, SAH sum score, modifiedFisher score, history of statin use, aneurysm size, radiographicglobal cerebral oedema at admission and angiography durationprior to early MRI. Only variables with a p value <0.100 inunivariate analysis were entered into the final model, which con-sisted of admission Hunt-Hess grade, age and aneurysm size. Allanalyses were performed using SPSS (SPSS V.21). Statistical sig-nificance was set at p<0.05.
RESULTSBetween August 2008 and October 2011, 151 patients withSAH were admitted to our facility and screened for enrolment(figure 1). Of these, 61 were enrolled within 72 h (median2 days) of SAH ictus prior to the clinical or radiographic onsetof vasospasm. The median Hunt-Hess grade was 3 (range 1–5),median age 55 (25–80) years, and 67% were female. A total of
131 MRIs (median 2, range 1–3) were performed in this group.There were no differences in age (p=0.932), Hunt-Hess grade(p=0.700), modified Fisher Score (p=0.767), APACHE-IIscores (p=0.306) or National Institute of Health Stroke Scale(NIHSS) (p=0.423) among those who underwent early MRIand those who did not. Early DWI restriction with correspond-ing ADC darkness occurred in 66% (N=40), with a meanvolume of 8.6 mL (median 0.25, range 0–198 mL) and meannumber of lesions of 4.3 (median 1, range 0–25) (table 1). EarlyMRI was performed prior to angiography or aneurysm repair in48% (N=29) of patients. Early MRI was performed after crani-otomy and clipping in 7 of 61 patients (11%). Comparing thosewho underwent early MRI prior to angiography and/or aneur-ysm repair and those who underwent MRI after, there were nosignificant differences in the rates of ADC/DWI positivity, ADC/DWI volume or lesion number, or admission clinical status(table 2).
Patients with clinical evidence of acute brain injury as measuredby worse admission neurological exams (Hunt-Hess grade andGCS scores) and worse admission physiological status (APACHE-IIphysiological subscore) were significantly more likely to have acuteMRI DWI/ADC lesions, have higher lesion volume and a greaternumber of lesions (table 3). Of the most neurologically impairedpatients with SAH (Hunt-Hess grade 4–5), 84% had early MRIischaemia, with a mean ischaemic volume of 25 mL (median2.25 mL). Additionally, patients with early MRI ischaemia weresignificantly more likely to be: older, use a statin prior to admis-sion, have a history of hypertension, have higher admission systolicBP, have thicker SAH clot, have evidence of global cerebraloedema on admission head CT and have a longer duration ofinitial angiography (table 4). Of 61 patients, 14 (23%) were on astatin prior to admission and 4/14 (29%) had their statin discon-tinued at admission. However, we did not find a significant effectof discontinuation of statin on the development of DWI/ADC
lesions (p=0.498), DWI/ADC lesion volume (p=0.413) or thenumber of DWI/ADC lesions (p=0.472).
A follow-up MRI was performed in 49 of 61 (80%) patientswith an early MRI (total of 2 MRIs in N=28 and 3 MRIs inN=21 patients). The median time to follow-up MRI was 7 days(range 2–19 days) from SAH ictus. The mean final infarctvolume (FLAIR hyperintense lesions corresponding to DWIbright, ADC dark lesions seen on the early MRI) was 16.1 mL(range 0–470 mL) and the mean number of FLAIR infarcts was4.1 (range 0–15). An example of an acute and follow-up MRIimaging is shown in figure 2. The majority of infarct volume inthis cohort was accrued at the time of the initial MRI, ratherthan during the vasospasm period, as seen in figure 3. Of thosewho had follow-up MRI, 25 of 49 (41%) had new DWI/ADClesions, though the median DWI/ADC lesion volume increasedonly by 0.15 mL overall comparing early MRI with follow-upMRIs (figure 3). As expected, symptomatic vasospasm con-firmed angiographically was significantly associated with thedevelopment of new DWI/ADC lesions on follow-up MRI(p=0.020). Additionally, the presence of DWI/ADC lesions onearly MRI predicted the development of additional DWI/ADClesions on follow-up MRI (mean number of lesions onfollow-up MRI 5.5 in those with early MRI DWI/ADC lesionsvs 1.5 in those with no early ischaemia, OR 6.0, 95% CI 1.7 to21.3, p=0.006).
In 54/66 (89%) of patients 3-month follow-up assessmentswere completed. A DWI/ADC volume of 1.0 mL predicteddeath or severe disability (mRS 4–6) with an area under thecurve of 0.750, 73% sensitivity and 74% specificity. Greaterthan 2.5 DWI/ADC lesions predicted mRS 4–6 with 53% sensi-tivity and 77% specificity (area under the curve 0.656). EarlyDWI/ADC lesion volume (>1 mL) was significantly associatedwith higher rates of death (21% vs 3% for >1 mL, p=0.031)and death or severe disability (53% vs 15%, p=0.003) at3 months. Higher than 2.5 early DWI/ADC lesions was asso-ciated with higher rates of death or severe disability (47% vs19%, p=0.032) (table 5). Independent activities of daily living
Figure 1 Flow chart demonstrating the number of patients screened,excluded and enrolled; AICD; automated implantable cardioverterdefibrillator.
Table 1 MRI characteristics among 61 patients who underwentMRI within 72 h of ictus, prior to clinical or radiographic vasospasmonset
MRI characteristics
Any DWI/ADC positive lesion, N (%) 40 (66)DWI/ADC volume (mL), mean (range) 8.6 (0–198)DWI/ADC lesion number, mean (range) 4.3 (0–25)DWI/ADC characteristics, N (%)Punctate 30 (75)Segmented vessel territory 6 (15)Punctate and segmented vessel lesions 4 (10)
DWI/ADC territory, N (%)Anterior circulation 24 (60)Posterior circulation 21 (53)
(Barthel Index) were worse in patients with early ischaemia (95vs 100, p=0.029), those with higher ischaemic volume (70 vs100, p=0.004) and greater number of ischaemic lesions (83 vs100, p=0.046). There were no associations between cognitiveoutcome (telephone interview for cognitive status scores) andearly ischaemia (table 5). In multivariable analysis, after adjust-ing for Hunt-Hess grade, age and aneurysm size, early DWI/ADC volume was associated with death or severe disability(adjusted OR 1.7, 95% CI 1.0 to 3.2, p=0.066), though therewas a more significant association with final infarct volume onFLAIR (adjusted OR 1.2, 95% CI 1.0 to 1.5, p=0.019).
DISCUSSIONIn this prospective study of 61 patients with SAH, we havefound MRI evidence of ischaemia (DWI positive, ADC darklesions) acutely after aneurysm rupture in 66% of patientsstudied within a median of 2 days from aneurysm rupture. Earlyischaemia was significantly more common in patients withworse early neurological status (84% of sicker patients(Hunt-Hess grade 4–5)), indicating that ischaemia may be acausative mechanism for acute brain injury after SAH.
Additionally, early ischaemia predicted higher volume andgreater number of lesions on subsequent MRI imaging. Somestrengths of this study include that it is, to our knowledge, thelargest, prospective MRI series examining early brain injuryafter SAH. Biases in patient selection for MRI were limited,since patients received protocolised serial MRI. Additionally,lesion volume and final infarct size (corresponding lesionvolume on follow-up FLAIR imaging) were volumetrically char-acterised by blinded reviewers using standardised software.23
This study is also the first to look at risk factors for early MRIischaemia. At the time of aneurysm rupture, intracranial pres-sure (ICP) becomes transiently elevated, exceeding mean arterialpressure in some cases, leading to low or absent intracranialblood flow.8–11 Hypertension and admission BP were strong riskfactors for acute ischaemia in this study. This may be becausepatients with chronic hypertension have a rightward shift intheir autoregulatory curve, and may sustain ischaemic insult inthe context of transiently low intracranial blood flow at the timeof aneurysm rupture. Alternately, hypertensive patients mayhave small vessel disease that predisposes them to ischaemia inthe context of SAH. The fact that statin use prior to admission
Table 2 Differences among patients who underwent early MRI before or after angiography and aneurysm repair
MRI characteristicsMRI prior to angiography or aneurysm repairN=29
MRI after angiography or aneurysm repairN=32 p Value
Any DWI/ADC positive lesion, N (%) 18 (62) 22 (69) 0.583DWI/ADC volume (mL), mean (range) 15.4 (1–28) 2.7 (0–34.4) 0.734DWI/ADC lesion number, mean (range) 2.7 (0–19) 5.8 (0–25) 0.136
Clinical status at admissionAdmission Hunt-Hess grade, median (range) 3 (1–5) 3 (1–5) 0.276Admission GCS, median (range) 15 (4–15) 15 (4–15) 0.994Admission APACHE-II physiological subscore, mean (range) 5 (0–15) 5.5 (0–15) 0.616
3-month outcomesDead, N (%) 1 (3) 4 (12.5) 0.216mRS 4–6, N (%) 7 (24) 8 (25) 0.973TICS, median (range) 36 (10–49) 32.5 (23–48) 0.087Barthel, median (range) 100 (0–100) 100 (0–100) 0.587
APACHE-II; Acute Physiology and Chronic Health Evaluation II; DWI/ADC, diffusion weighted imaging/apparent diffusion coefficient; GCS, Glasgow Coma Scale; mRS, modified RankinScale; TICS, telephone interview for cognitive status.
Table 3 Association of acute MRI ischaemia and clinical evidence of early brain injury
Early DWI/ADC lesionpresent Early DWI/ADC lesion volume Early DWI/ADC lesion number
Clinical status at admission N (%) p Value Median (range) p Value Median (range) p Value
was associated with higher rates of DWI/ADC lesions may indi-cate that use of these medications is a marker for underlyingvascular disease.
A relatively small volume of DWI/ADC ischaemia (mean8.6 mL) was associated with death or severe disability at3 months. This may be due to our conservative methods ofmeasuring ischaemia. We did not specifically threshold ADC,but rather only counted lesions that were visible on DWI, whichmay have led to an underestimation of the true ischaemicvolume. A standardised threshold for assessing ADC in prespeci-fied regions of interest may provide more specific informationon ischaemia.31 32 Additionally, the final infarct volume mea-sured on FLAIR was larger than that observed on the initialDWI/ADC, though the mean number of infarcts was the same.This suggests that the initial infarct either expanded, or weunderestimated the initial volume by only measuring what wasvisible on DWI. Alternately, the FLAIR volume measurementmay have including peri-infarct oedema. In either case, the finalvolume on FLAIR was a more significant predictor of functionaloutcome after adjusting for other confounders, and is a mean-ingful indication of brain injury.
The pathogenesis of the observed radiographic ischaemiaacutely after SAH is not well understood. One possibility is thatendothelial disruption that occurs after aneurysm ruptureexposes the underlying collagen matrix, which is a potent plate-let activator. Platelet activation, subsequent leucocyte activationand platelet-leucocyte aggregates may lead to obstruction ofsmall vessels, loss of endothelial integrity, cytokine signalling
and consequent micro-infarctions.33 This theory is supported byour MRI data which reveals that 75% of acute infarctions arepunctate, occurring at the small vessel level, rather than
Table 4 Demographic, clinical and admission radiographic features of patients with early MRI DWI/ADC ischaemic lesions versus those withoutischaemic lesions
Present early MRI DWI/ADC lesion Absent early MRI DWI/ADC lesion p Value
occurring in a segmented vessel distribution. Intracranial circula-tory arrest may also contribute to ischaemia. This concept issupported by the observation of watershed pattern ischaemia insome MRI studies early after SAH.17 Similarly, early cerebralinfarction has been associated with loss of consciousness at ictusand global cerebral oedema, both of which are thought to berelated to intracranial circulatory arrest at the time of aneurysmrupture.16 34 We also observed a significant relationship betweenglobal cerebral oedema and acute infarction. It is important tonote however, that DWI/ADC signal represents cytotoxicoedema, but is not synonymous with ischaemia or infarction.Other causes of supply-demand mismatch, such as seizure, mito-chondrial dysfunction or hypermetabolic activity, can lead toDWI/ADC signal. However, based on the plausible mechanismsof injury following aneurysm rupture and the animal literature,we feel that ischaemia is the most likely pathophysiologicalexplanation for the observed DWI/ADC signal.
A major implication of this study is that further investigationsfocusing on early ischaemia and acute brain injury at the time ofictus are warranted, and may represent an important steptowards improving outcomes after SAH. Since the brain injurycascade following intracranial circulatory arrest at the time ofaneurysm rupture may be similar to the global insult that occurswith cardiac arrest, it may be reasonable to explore the cardiac
arrest literature for possible therapeutic interventions.35
Therapeutic hypothermia 36 37 and induced normothermia 38
are the only therapies that have been shown to improve mortal-ity and neurological outcome after cardiac arrest.35
Hypothermia has been shown to reduce platelet function andinflammation and improve outcome in animal models of braininjury, including rat models of SAH.39–43 In SAH, hypothermiahas been shown to reduce markers of inflammation (interleukin(IL)-1, IL-6, TGFβ, TNFα, NF-kB, neutrophil migration intotissue), platelet clumping and disruption of the lining of theblood vessels (E-selectin, MMP9, ICAM1), all of which havebeen associated with early ischaemia after aneurysmrupture.44 45 Future studies of neuroprotective agents such asearly induced normothermia, or mild therapeutic hypothermiafor SAH may be reasonable.
Some limitations of this study bear mentioning. First, 51% ofpatients underwent angiography and aneurysm repair prior tothe initial MRI and may have incurred procedure related ischae-mia. Of these patients, seven underwent craniotomy and clip-ping prior to the initial MRI. Others have found a relationshipbetween operatively induced brain injury and outcome.46
Though DWI/ADC lesions that were clearly procedure relatedwere excluded from analysis, it is difficult to determine if smalllesions are a result of angiography, surgery or the SAH itself.
Figure 3 Comparison of diffusion weighted imaging/apparent diffusion coefficient (DWI/ADC) volume on MRI performed at 0–3 days, 4–7 daysand >7 days from ictus among patients with early MRI ischaemia (N=40, dark line) and those without ultra-early ischaemia (N=21, gray line). Thisfigure demonstrates that much of the ischaemic insult occurs early at the time of aneurysm rupture. * indicates p<0.005 for comparison at eachtime point using Mann-Whitney U non-parametric test.
Table 5 Association of early MRI ischaemia and 3-month functional outcomes
Early DWI/ADC lesion present Early DWI/ADC lesion volume Early DWI/ADC lesion number
Absent Present p Value ≤1 mL >1 mL p Value ≤2.5 >2.5 p ValueDead, N (%) 1 (5) 4 (12) 0.408 1 (3) 4 (21) 0.031 3 (8) 2 (10) 0.667mRS 4–6, N (%) 3 (15) 12 (35) 0.108 5 (15) 10 (53) 0.003 7 (19) 8 (47) 0.032TICS, median (range) 35 (10–49) 33 (23–48) 0.611 36 (23–49) 33 (25–48) 0.337 34.5 (10–49) 33 (25–48) 0.392Barthel, median (range) 100 (0–100) 95 (0–100) 0.029 100 (0–100) 70 (0–100) 0.004 100 (0–100) 83 (0–100) 0.046
DWI/ADC, diffusion weighted imaging/apparent diffusion coefficient; mRS, modified Rankin Score; TICS, telephone interview for cognitive status.The bold text indicates P<0.005.
Longer angiography time was significantly related to the pres-ence of MRI ischaemia, however, after adjusting for admissionHunt-Hess grade, this association was lost. This suggests thatsicker patients had longer angiography times and that there maynot be a causal link between angiography and ischaemia.Additionally, when comparing patients who underwent MRIbefore and after angiography and/or aneurysm repair, we didnot find any statistically significant differences in the incidenceof DWI/ADC positive lesions, DWI/ADC volume or lesionnumber. Indeed, those with MRI prior to angiography or aneur-ysm repair trended towards higher infarct volumes. Althoughsome of the infarctions may have been induced by angiography,there are still important implications for patient outcome, whichrequires further study. Indeed, it is also possible that severebrain injury from aneurysm rupture may make some patientsmore vulnerable to ischaemia during angiography. If this isindeed the case, there may be a role for neuroprotective medica-tions, such NA-1, currently studied in the ENACT trial.47 In thefuture, we plan to assess DWI/ADC lesions in control patientswith unruptured aneurysms who undergo angiography andendovascular repair to adjust for rates of procedure relatedinfarct. Clipping or coiling artefact on MRI may have limitedassessment of DWI/ADC lesions adjacent to the aneurysm,leading us to underestimate infarct volume. Another limitationis that 20% of the cohort did not have a follow-up MRI. Inthese circumstances, we used the first and only MRI to measurefluid attenuation inversion recovery (FLAIR) signal that corre-sponded with DWI/ADC positive lesions. We may have underes-timated final infarct volume as some DWI/ADC lesions on theinitial MRI may have not yet converted to FLAIR signal. Finally,the sample size was relatively underpowered to predict 3-monthfunctional outcomes. Though there was a trend towards an asso-ciation between early DWI/ADC lesion volume and 3-monthmRS 4–6 after adjusting for confounders in multivariable ana-lysis, this did not reach statistical significance. A larger studyconfirming these results would be useful.
CONCLUSIONSEarly ischaemia after SAH is common and is associated withworse neurological and physiological status at admission. Earlyischaemia predicts subsequent ischaemia during the hospitalcourse and is associated with death or severe disability andworse independent activities of daily living at 3 months.
Acknowledgements The authors thank Javier Provencio for reviewing thismanuscript.
Contributors JAF: designed this study, acquired and analysed data and drafted themanuscript. WA, MJ and VZ: acquired data, analysed data, critically revised andapproved the manuscript. LT: helped with the design and acquisition of data andcritically revised and approved the manuscript. FS: helped with the design of thestudy and critically revised and approved the manuscript. AP, JBB and EG: helpedacquire data and critically revised and approved the manuscript.
Funding This study was funded in part by an American Heart Association ClinicalResearch Program Grant (11CRP5270003).
Competing interests None.
Ethics approval Mount Sinai IRB.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement Unpublished, de-identified data are made available tocollaborators.
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doi: 10.1136/jnnp-2013-307313 published online April 8, 2014J Neurol Neurosurg Psychiatry
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