Original Research Prognostic Value of A Qualitative Brain MRI Scoring System After Cardiac Arrest Karen G. Hirsch, MD, Michael Mlynash, MD, MS, Sofie Jansen, MD, Suzanne Persoon, MD, Irina Eyngorn, MD, Michael V. Krasnokutsky, MD, Christine A.C. Wijman, MD, PhD, Nancy J. Fischbein, MD From the Stanford Neurocritical Care Program, Stanford Stroke Center, Stanford University Medical Center, Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA (KGH, MM, SJ, SP, IE, CACW); Department of Neurology, University Medical Center Utrecht, the Netherlands (SP); Department of Radiology, Stanford University School of Medicine, Stanford, CA (NJF); and Department of Radiology, Madigan Army Medical Center, Tacoma, WA (MVK).
ABSTRACT BACKGROUND AND PURPOSE
To develop a qualitative brain magnetic resonance imaging (MRI) scoring system for comatose cardiac arrest patients that can be used in clinical practice. METHODS
Consecutive comatose postcardiac arrest patients were prospectively enrolled. Routine MR brain sequences were scored by two independent blinded experts. Predefined brain regions were qualitatively scored on the fluid-attenuated inversion recovery (FLAIR) and diffusion-weighted imaging (DWI) sequences according to the severity of the abnormality on a scale from 0 to 4. The mean score of the raters was used. Poor outcome was defined as death or vegetative state at 6 months. RESULTS
Sixty-eight patients with 88 brain MRI scans were included. Median time from the arrest to the initial MRI was 77 hours (IQR 58-144 hours). At 100% specificity, the “cortex score” performed best in predicting unfavorable outcome with a sensitivity of 55%-60% (95% CI 41-74) depending on time window selection. When comparing the “cortex score” with historically used predictors for poor outcome, MRI improved the sensitivity for poor outcome over conventional predictors by 27% at 100% specificity.
Keywords: Diffusion weighted MRI, anoxic brain injury, cardiac arrest, prognosis. Acceptance: Received December 23, 2013, and in revised form May 12, 2014. Accepted for publication May 25, 2014. Correspondence: Address correspondence to Karen G. Hirsch, MD, Stanford Neurocritical Care Program, Stanford Stroke Center 1215 Welch Road, Mod D, Stanford, CA 94305, USA. E-mail: [email protected]. Conflict of Interest: None. We thank Marion Buckwalter, Amie Hsia, Monisha Kumar, Maarten Lansberg, Neil Schwartz, and Chitra Venkatasubramanian for their assistance with patient enrollment.
CONCLUSIONS
A qualitative MRI scoring system helps assess hypoxic-ischemic brain injury severity following cardiac arrest and may provide useful prognostic information in comatose cardiac arrest patients.
Introduction Over 320,000 people in the United States have a cardiac arrest each year,1 and survival rates vary between 5% and 35%.2,3 Approximately one-third of comatose survivors regain consciousness.4 Neurological deficits are common in these patients and include varying degrees of cognitive and motor impairment. The increased use of therapeutic hypothermia is projected to favorably affect survival and neurological outcome of these patients.2,3 Many studies have focused on early identification of comatose postcardiac arrest survivors who are expected not to regain consciousness.5–7 Historically, the most specific early predictors for poor outcome are the absence of brain stem reflexes or an extensor or absent motor response at postarrest day 3, absence of cortical responses by somatosensory evoked potentials (SSEP) after 24 hours, serum neuron specific enolase (NSE) levels >33 µg/L in the first 3 days, and early myoclonic status epilepticus.8 These predictors have a low sensitivity for
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poor outcome, however, and many may no longer be valid in patients who have been treated with hypothermia.9 Several studies have reported on brain magnetic resonance imaging (MRI) findings in comatose postcardiac arrest patients.10–20 Typically the presence of extensive and severe cortical signal abnormalities on MRI is associated with poor outcome.10–13,16–20 MR imaging offers the advantage of providing an objective measure of cerebral injury, and may be particularly useful in patients who have received sedative agents or who have metabolic derangements that render the neurological examination unreliable or in those who have been treated with hypothermia. We have previously reported our initial experience on the prognostic utility of brain MRI in postcardiac arrest survivors using quantitative diffusion-weighted imaging (DWI).12 The aim of this study was to assess the prognostic value of a qualitative brain MRI scoring system that can be used in clinical practice. A qualitative scoring system has the potential for broad use
◦ 2014 by the American Society of Neuroimaging C
J Neuroimaging 2015;25:430-437. DOI: 10.1111/jon.12143
and implementation, making it an important tool for those who do not have access to quantitative MRI analysis or in situations where the scans are technically inadequate for such analysis. Such qualitative MRI scoring systems have been described in the pediatric literature as a tool to predict outcome following perinatal asphyxia.21–23
Methods Study Population Comatose patients who were resuscitated after out-of-hospital or in-hospital cardiac arrest at Stanford University Medical Center were screened to be prospectively enrolled during a 5-year time period. Patients were included if they met the following criteria: men and nonpregnant women at least 18 years of age; status postresuscitation for in- or out-of-hospital cardiac arrest; and persistent coma after return of spontaneous circulation, defined as no eye opening to voice and inability to follow commands. Patients were excluded if they had a preexisting “do not resuscitate” status, a baseline modified Rankin Scale (mRS) score ࣙ 3, a severe coexisting systemic disease with limited life expectancy, or if they met criteria for brain death. The study was approved by the institutional review board and written consent from a legally authorized representative was obtained for study participation. Clinical and neurophysiologic studies were obtained in a prospective and standardized fashion at a priori defined time points. Neurologic examinations were performed at 1, 24, 48, and 72 hours and at 1 and 2 weeks following the cardiac arrest by an attending neurointensivist or stroke neurologist. Somatosensory evoked potentials (SSEP) and electroencephalography (EEG) were obtained ࣙ72 hours following resuscitation. Neurologic outcome was determined by the Glasgow Outcome Scale (GOS) score at a 6-month clinic visit. Patients who were alive at 6 months but could not come to the clinic were interviewed utilizing a standardized telephone interview. Intensive Care Unit Care
The study patients were enrolled from 2002 to 2007. The clinical treatment team had access to the MRI images, but the clinical care was done prior to the validation of quantitative MRI scoring as a reliable tool to facilitate outcome predictions. Patients who qualified were treated with therapeutic hypothermia to a target temperature of 32-33 °C for 24 hours, then rewarmed in a controlled manner over the subsequent 24 hours. Hemodynamic parameters were supported per routine ICU care. Decisions about treatment and withdrawal of care were left to the clinical treatment teams.
MR Imaging and Scoring MR images were obtained with 1.5T GE Signa Horizon scanners (GE Medical Systems, Waukesha, WI, USA). The MRI protocol included: fast spin echo fluid-attenuated inversion recovery (FLAIR-FSE), TR/TE/TI= 8802/120/2200 ms, 20-24 contiguous sections, 512 × 512 matrix, field of vision (FOV) = 240 × 240 mm, slice thickness/gap = 5/1.5, 5/2, or 5/2.5 mm and spin echo echo-planar diffusion-weighted imaging (SE EPI DWI), TR/TE= 6000/72 ms, 20-24 contiguous sections,
256 × 256 matrix, FOV= 240 × 240 mm, slice thickness/gap 5/1.5 or 5/2.5 mm, diffusion-encoding along x-, y-, z-axes averaged, b = 0 and 1,000 s/mm2 . Patients were routinely scanned once within the first 7 days after the arrest, though some patients were scanned up to three times in the first 30 days after the arrest, and all MRIs were included in the analyses. The technically adequate MRIs of these patients were previously analyzed in a study investigating quantitative MRI analysis.12 Images were independently assessed by a board certified neuroradiologist and by a board certified neurologist with subspecialty certification in neurocritical care and stroke. Both adjudicators were blinded to patient information and outcome, and also to each other’s readings. Windowing of both FLAIR and DWI images was allowed at the discretion of the examiner. Images were scored with the use of an MRI scoring system that was created to assess the severity of cerebral abnormalities due to cardiac arrest in predefined brain regions (Fig 1). The adjudicators were instructed to only score MRI abnormalities that could be attributed to acute global hypoxic-ischemic brain injury. The brain regions were: cortical gray matter and subcortical white matter in the frontal, parietal, temporal, and occipital lobes, the hippocampus, the insular cortex, the corpus callosum, the deep gray nuclei (caudate, putamen, globus pallidus, and thalamus), the cerebellum (cortex, white matter, and dentate nucleus) and the brainstem (midbrain, pons, and medulla), resulting in 21 brain regions that were scored individually. All brain regions were scored according to the extent and severity of the signal abnormalities on a scale from 0 to 4: 0-no abnormality, 1-possibly abnormal, 2-mildly abnormal, 3-moderately abnormal, and 4-severely abnormal (Fig 2). Only the FLAIR and DWI sequences were scored. Six different scores consisting of the sums of the scores for various brain regions were evaluated. The “overall score” consisted of all points given to all brain regions on both sequences (FLAIR and DWI) combined. The “cortex score” consisted of the FLAIR and DWI scores of the gray matter (cortex) in the frontal, parietal, occipital, and temporal lobes, the insular cortex, and the hippocampus (Fig 1). The “deep gray nuclei score” consisted of the sum of the FLAIR and DWI scores of the putamen, globus pallidus, caudate nucleus, and the thalamus. The “cortex plus deep gray nuclei score” combined the cortex score and the deep gray nuclei score. The “DWI score” combined all scores in all regions on the DWI sequence only, and the “FLAIR score” consisted of the sum score of all regions on the FLAIR sequence only. For each score, the sum scores of the two raters were averaged and the mean sum score was used in the analyses.
Outcome Favorable neurologic outcome was defined as a GOS score of 3, 4, or 5 (severe disability, moderate disability, or good recovery), and unfavorable neurologic outcome as a GOS score of 1 or 2 (dead or vegetative state) at 6 months. A GOS of 3 was considered a good outcome despite the severe disability as it includes patients who have regained consciousness. Deceased patients were further subdivided into “historic standard” nonsurvivors and “historic uncertain” nonsurvivors categories. Historic standard nonsurvivors were classified as
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BRAIN REGION Supratentorial Gray matter
Cortex
FLAIR
DWI
signal
signal
Scoring system: 0=normal
Frontal
1=possibly abnormal
Parietal
2=abnormal, mild
Temporal
3=abnormal, moderate
Occipital
4=abnormal, severe
Insula
DGN*
Hippocampus
Cortex score
Caudate
FLAIR score
Putamen
DWI score
Globus pallidus
DGN score*
Thalamus White matter
Frontal Parietal Temporal Occipital Corpus Callosum
Infratentorial
Brainstem
Midbrain Pons Medulla
Cerebellum
Cortex White matter Dentate nuclei
* DGN – deep gray nuclei Fig 1. Qualitative brain MRI scoring system showing the cortex score in light blue.
Score 0
Score 1
Score 2
Score 3
Score 4
DWI
T2 FLAIR
Fig 2. Scoring of sample representative MRI scans. DWI (top row) and T2 FLAIR (bottom row) images. patients who had an unfavorable neurological outcome and one or more of the following historically used standard prognostic variables for poor outcome: absent motor response, absent pupillary reflexes or absent bilateral N20 responses by SSEP
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after 72 hours, or vegetative state at 1 month.8 Historic uncertain nonsurvivors were those who died (typically due to withdrawal of life support) without having any of these historically specific poor outcome predictors.
Table 1. Clinical characteristics of 68 comatose patients after cardiac arrest with 88 brain MRIs
Age (years) mean ± SD (range) Sex (female), n (%) Diabetes Mellitus, n (%) Hypertension, n (%) Coronary artery disease, n (%) Time from collapse to ROSC (min)—median (IQR) Out-of-hospital arrest, n (%) Therapeutic hypothermia, n (%) Time from collapse to the initial MRI (hours)—median (IQR) “Historic Standard” poor outcome criteria, n (%) Absent pupillary reflexes at 72 h, n (%) No motor response at 72 h, n (%) No motor response in the absence of sedation, n (%) Absent SSEPs at 72 h, n (%) Vegetative state at one month, n (%)
Unfavorable outcome N = 40
Favorable outcome N = 28
57 ± 13 (34-89) 20 (50) 6 (15) 19 (48) 9 (23) 22 (20-30)* 28 (70) 20 (50) 72 (56-93) 26 (65) 10 (40)‡ 20 (80)‡ 9 (35) 17 (77)‡ 4 (15)
55 ± 17 (22-84) 4 (14) 4 (14) 7 (25) 4 (14) 19 (9-26)† 19 (68) 17 (61) 94 (60-182)
P value
.559 .004 1.0 .078 .535 .063 1.0 .462 .054
ROSC = return of spontaneous circulation. * Unknown in seven patients. † Unknown in five patients. ‡ SSEP not done in four patients, motor response not tested in one patient, pupillary reflexes not tested in 1 patient.
Statistical Analysis The optimal score cut-offs were defined as the ones that would predict unfavorable outcome in “historic-standard” patients with 100% specificity, that is, with a false positive rate = 0. These cut-offs were identified using ROC curves, and sensitivity and specificity with 95% confidence interval (CI) were calculated. Interrater agreement was assessed using intraclass correlation coefficient (ICC). Statistical analyses were performed using IBM SPSS statistics 21.
Results Patients and Imaging Over a 5-year time period, 88 patients met inclusion criteria and 69 were included in the analysis. Reasons for noninclusion in the analysis were: unable to obtain consent and therefore not enrolled in study (n = 7) and inability to undergo MRI (n = 12). Reasons for not getting an MRI were: care was withdrawn prior to the MRI (n = 7), MRI could not be obtained due to an incompatible pulmonary artery catheter, an aortic balloon pump or hemodynamic instability (n = 3); a pacemaker was implanted before an MRI could be obtained (n = 1); or the patient awoke and declined the MRI (n = 1). Thus, 69 patients with 91 MRIs remained. Of these, 12 patients had one follow-up MRI, and 5 patients had a second follow-up scan. Three scans (of 3 patients) were too motion degraded to be assessed, which caused one additional patient to be excluded as that patient did not have an adequate MRI. Thus, 68 patients with 88 MRIs were included. Median time to the initial MRI was 77 hours (IQR 58-144 hours). Sixty-six scans were obtained within the first week after the arrest (2-168 hours); 16 scans were obtained in the second week (169-336 hours); and six scans after the second week (336-718 hours). Patient characteristics are shown in Table 1. Of the 68 patients that were included, 28 patients (41%) had a favorable neurological outcome: 9 patients had a GOS of 3 (12 scans), 5
had a GOS of 4 (six scans) and 14 had a GOS of 5 (17 scans). Forty patients had an unfavorable outcome: 38 patients died (GOS of 1) (50 scans), and 2 had a GOS of 2 (3 scans) at 6 months. Of these 40 patients, 26 patients (65%) met at least one of the so-called “historic standard criteria” for poor outcome (32 scans) (Table 1).
MRI Prediction of Outcome The ICC for interrater agreement for both the FLAIR and DWI scores was .91 (95%CI .86-.94). As shown in Table 2, brain regions that showed the most signal abnormalities and thus contributed most to high “overall” scores were the cortical gray matter structures (median (IQR) 34 (19-40) for the unfavorable group versus 3 (2-12) for the favorable outcome group (P < .001)) and the deep gray nuclei (median IQR 18 (10-22) for the unfavorable outcome group and 5 (2-8) for the favorable outcome group [P < .001]). Regions that showed the least abnormalities were the subcortical white matter, the corpus callosum, and the brainstem. Two scans (1 poor outcome patient scanned after 2 hours, and 1 with favorable outcome scanned after 78 hours) were considered normal and received zero points from both raters. Hence, the minimum of all six scores was zero. Table 2 shows that the “overall score,” the “cortex score,” and the “cortex plus deep gray nuclei score” best predicted unfavorable outcome, with a sensitivity between 66% and 69% at a specificity of 100%. Of these, we felt that the “cortex score” was the most practical to use because it requires the fewest brain regions to be scored. The cut-off value of the “cortex score” for unfavorable outcome was >27 in this dataset.
Changes in MRI Scores over Time Three patients with unfavorable outcome had cortex scores that were lower than the cut-off value of 27 for unfavorable outcome. These patients underwent MR imaging at 2, 7, and 14 hours after the arrest and had minimal abnormalities on their brain MRIs, receiving cortex scores of 0, 3, and 17, respectively.
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†
*
HGS = historic standard. For all scores specificity was 100% with 95%CI (88-100) for all scans and 95%CI (83-100) for scans made between 25-192 hours (Nscans 25-192 h = 25 in both unfavorable and favorable outcome groups). ‡ Interquartile range. § Positive predictive value. ¶ Negative predictive value. ** DGN = deep gray nuclei.
78% (60-90) 78% (60-90) 100% (78-100) 100% (78-100) 72% (50-87) 72% (50-87) 63% (44-78) 59% (41-76) 22 27 64 60 29 (15-38) 29 (19-36)
5 (1-11) 8 (4-12)
83% (65-94) 81% (62-92) 76% (57-88) 81% (62-92) 100% (80-100) 100% (79-100) 100% (77-100) 100% (79-100) 80% (59-92) 76% (54-90) 68% (46-84) 76% (54-90) 69% (50-83) 66% (47-81) 56% (38-73) 66% (47-81) 43 27 16 39 124 48 29 77 62 (35-69) 34 (19-40) 18 (10-22) 52 (28-61)
Overall (168) Cortex (88) DGN** (32) Cortex ** + DGN (120) FLAIR (84) DWI (84)
11 (6-22) 3 (2-12) 5 (2-8) 10 (4-19)
NPV¶ (95%CI) 25-192 h PPV§ (95%CI) 25-192 h Sensitivity (95%CI) 25-192 h Median (IQR)‡ Score (possible max.)
Max.
Median (IQR)
Max.
Sensitivity (95%CI) All scans
Prediction of unfavorable outcome† Favorable outcome N scans = 35 N patients = 28 Unfavorable outcome HGS* N scans = 32 N patients = 26
Table 2. Qualitative MRI scores in 54 “historic standard” comatose postcardiac arrest patients with 67 MRIs: 26 patients with unfavorable outcome and 28 patients with favorable outcome
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The patient with a cortex score of 0 at 2 hours after the arrest had a repeat scan 53 hours later that received a cortex score of 36 (Fig 3). Of 4 patients with an unfavorable outcome who were scanned more than 192 hours after the arrest, 2 received a cortex score below the cut-off value for unfavorable outcome. Three patients with cortex scores in the higher range (23, 24, and 27) survived with good outcomes and their brain MRIs are shown in Figure 4. Thus, mild cortical abnormalities on MRI do not preclude an acceptable long-term neurological outcome. The cortex scores in overlapping 48-hour time intervals after the arrest are shown in Figure 5 (panel A for all patients, panel B for the favorable and historic-standard unfavorable outcome patients). The cortex scores from the scans obtained between 25 and 192 hours after the arrest differed between patients with favorable and unfavorable outcomes, while scans that were obtained before 25 hours and after 192 hours did not significantly differ between the two groups; however, the number of patients in later time windows (>192 hours) was limited. Limiting the analysis to the 50 MRIs obtained between 25 and 192 hours after the arrest in the favorable and historic-standard unfavorable outcome patients increased the sensitivity of the cortex score from 66% (95%CI 47-81) to 76% (95%CI 54-90; Table 2). When the cortex score cut-off value of >27 was applied to the scans of “historically uncertain” nonsurvivors (n = 21 scans), 7 additional patients (18%) were identified who would have been predicted to have an unfavorable outcome. Using the cortex score to predict outcome in the entire patient cohort (including the historically uncertain nonsurvivors) resulted in an overall sensitivity of 55% (95%CI 41-69) at all time-points and a sensitivity of 60% (95%CI 44-74) in the optimal time-window of 25-192 hours after cardiac arrest, all with 100% (95%CI 88-100 and 83-100, respectively) specificity. Because other prognostic variables can be affected by therapeutic hypothermia (TH), we also analyzed the cortex scores for those patients treated with therapeutic hypothermia and those not treated with TH. We compared the first scan obtained within 25-192 hours for each patient and found no difference in cortex scores for those treated with TH versus those not treated with TH in both the favorable ( Median [IQR[: 3 [1-6] [n =15] vs. 5 [2-17] [n = 7], P = .210) and unfavorable (37 [25-44] [n = 14] vs. 35 [31-36] [n = 9], P = .403) outcomes groups. Additionally, we analyzed the sensitivity and specificity of the cortex score compared to historic standard predictors for patients treated with TH and those not treated with TH. Using the first scan obtained within the 25-192-hour time window, in both the TH and no TH groups, the cortex score and the historic standard predictors were 100% specific. In the TH group, the historic standard predictors had a trend toward slightly higher sensitivity than the cortex score (74% vs. 63%, P = .73), while in the no TH this relationship reversed (50% vs. 56%, P = 1.0). When the cortex score was combined with the historic standard predictors, additional patients with poor outcome were identified, improving the sensitivity of poor outcome prediction to 84% (95%CI 62-94) in the TH group and 67% (95%CI 44-84) in the no TH group.
Fig 3. Upper panels: MRI two hours after a 19 minute cardiac arrest showing no evidence of hypoxic-ischemic brain injury (cortex score = 0). Lower panels: repeat MRI obtained in the same patient 53 hours later showing widespread areas of reduced diffusion involving the cortex of both hemispheres (cortex score = 36).
Discussion The results of the present study of 68 patients with 88 brain MRIs indicate that a qualitative brain MRI scoring system may be a useful predictor of long-term functional outcome in patients who are comatose after cardiac arrest. Of the different brain regions we evaluated, signal abnormalities in the cortical gray matter regions best correlated with neurological outcome. The extent of these abnormalities in each region can be easily determined by visually grading the severity of hypoxic-ischemic injury in the individual cortical gray matter structures both on the FLAIR and DWI sequences on a scale of 0 to 4, and cumulatively deriving a “cortex score.” Of 81 consented patients, 69 (85%) underwent one or more brain MRIs, and no safety issues were encountered related to the MR acquisitions. Our experience in this study and in previous studies12 suggests that MR imaging is feasible and safe in the majority of comatose postcardiac arrest patients so long as appropriate screening protocols are followed. Consistent with previous studies, we found that brain MRI abnormalities following cardiac arrest are time dependent.17,19 Scans obtained within 24 hours of the arrest typically do not reflect the severity of the global hypoxic-ischemic brain injury. In previous studies, we found that quantitative DWI abnormalities in cortical areas were most severe between 3 and 5 days after the arrest, and differentiated best between good and poor outcome patients between 49 and 108 hours after the arrest.11,19 The optimal time-window for qualitative MRI appears to be a bit wider and ranges from 25 to 192 hours after the arrest. Within that time-window, however, qualitative MRI seems to best distinguish good from poor outcome patients between day
4 and 7 after the arrest (Fig 5). Thus, the timing of the greatest MRI abnormalities reflected by the “cortex score” is slightly later than that of the quantitative DWI abnormalities. This is likely due to the fact that it takes more time for signal changes caused by hypoxic ischemic injury to manifest on the FLAIR sequence (which is incorporated in the cortex score in conjunction with the DWI sequence) than on the DWI sequence (which is the only sequence used for quantitative MRI analyses). Historically used markers of poor outcome after cardiac arrest include SSEPs, NSE, EEG patterns, and physical exam findings; though several studies have shown many of these may not be valid in the era of therapeutic hypothermia. Recognizing this limitation, we defined the “historic standard criteria” for poor outcome as patients who had a poor neurologic outcome and had one of the historically used prognostic criteria (absent motor response or pupillary reflexes or absent bilateral N20 responses by SSEP after 72 hours, or vegetative state at one month). Except for SSEPs and NSE, all other commonly used outcome-determinants in comatose postcardiac arrest patients are influenced by pharmacologic agents and metabolic changes.9,24 MR images are not influenced by these factors, and may therefore add useful prognostic information in patients who require sedation, treatment for seizure activity, or in those with severe metabolic derangements. In addition, since the majority of patients in this study were treated with hypothermia, this MRI scoring system appears to be valid in such patients. Indeed, in patients treated with TH, combining the cortex score with historic standard predictors improved the sensitivity and allowed the identification of additional patients with poor outcome. Previous research has shown
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Fig 5. Panel A shows the cortex MRI scores over time in all comatose postcardiac arrest patients in this study comparing the unfavorable and favorable outcome patients. Note that there is a significant difference at α < .05 between the two groups between 25-192 hours after the arrest (marked by *). Panel B shows the cortex MRI scores over time only in the historic standard patients in this study comparing those with an unfavorable outcome with those with a favorable outcome at 6 months.
Fig 4. Brain diffusion (DWI), apparent diffusion coefficient (ADC) and fluid-attenuated inversion recovery (FLAIR) images of the three patients with the highest cortex scores in the group of survivors in this study. All 3 patients had residual moderate to severe cognitive deficits at 6 months. Note that the MRI window and level settings for each of the three sequences is held constant across all 3 patients and are identical to the settings used in Figure 2. (A) MRI with DWI, ADC and FLAIR obtained at 151 hours after the arrest. The patient received a cortex score of 23. Her Glasgow outcome scale (GOS) score at 6 months was 4. (B) Brain MRI with DWI, ADC and FLAIR obtained at 52 hours after the arrest. The cortex score was 24 and the patient survived with a GOS of 3 at 6 months. (C) Brain MRI with DWI, ADC, and FLAIR obtained 89 hours after the arrest. This patient received a cortex score of 27, which was the highest score in our good outcome patient group. He awoke from coma 10 days after the arrest and his 6 months GOS was 3.
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that in patients undergoing TH, historic standard predictors can be confounded by medications and hypothermia itself,9 so the ability to potentially identify additional patients in this group is particularly clinically relevant. This factor could potentially also explain more consistent performance of the cortex score between the TH and no TH groups (sensitivity 63% vs. 56%, P = .74) compared to the change in the performance of the historic standard predictors (sensitivity 74% vs. 50%, P = .18). Data on the use of a qualitative MRI scoring system to help predict outcome in comatose survivors of cardiac arrest are scarce. Studies that have been published so far suggest a relationship between extensive cortical abnormalities and unfavorable outcome, but most of these studies are based on small numbers of patients.10,13,15,17–19 Studies with larger number of patients have been described in the pediatric literature, demonstrating that brain MRI scoring systems can discriminate between children with favorable and unfavorable cognitive and motor outcome after neonatal asphyxia. As the pathophysiology of brain injury caused by neonatal asphyxia is similar to
global cerebral hypoxia-ischemia in adults, it is not surprising that the results of these studies are consistent with our findings.21–23 A limitation of this study is the relatively small number of patients, which limits its power. Furthermore, the proposed scoring system only applies to brain MRI changes caused by acute global hypoxic-ischemic brain injury. A potential confounder is prolonged seizure activity which can cause MRI changes that may be difficult to differentiate from those caused by hypoxic-ischemic brain injury.25 A small number of the patients in this study had continuous EEG monitoring, though we have since updated our clinical and research practice and now perform continuous EEG monitoring on all cardiac arrest patients. Future studies with the newer patient cohort will address this potential confounder. Another limitation is that the clinical team was not blinded to the MRI results, which may have introduced a bias and potentially a self-fulfilling prophecy; we tried to minimize this problem by determining the cortex-score cut-off for unfavorable outcome on our “historic standard” population only, that is, patients who died while also meeting one or more other conventional relatively specific predictors for poor outcome. We acknowledge the limitations of defining a “historic standard” outcome prediction as many of these tests lack sensitivity and specificity, especially in the era of therapeutic hypothermia. Finally, like any qualitative scoring system, the interpretation by the radiologist or neurologist is subjective, and different readers may produce different scores. Although we found a high interrater agreement for the MRI readings, further validation of the reproducibility of the “cortex score” is needed among different raters. In conclusion, this study shows that a brain MRI qualitative scoring system provides a framework to help grade the severity of global cerebral hypoxic-ischemic injury between 1 and 3 days after cardiac arrest and may yield useful additive prognostic information. This type of qualitative scoring may be particularly useful when quantitative measurements are not available, as may be the case in both community and academic settings. MRI may increase the sensitivity of poor outcome prediction and may especially be of value when other prognostic variables cannot be reliably obtained or are inconclusive. Before we can advocate the routine use of this scoring system in clinical practice, however, it will need to be validated in an independent patient sample.
This work was supported by the American Heart Association (National Scientist Development Award (0430275N, C.A.C.W.), the Netherlands Heart Association (2003B263, S.P.), and the Foundation “De Drie Lichten” (41/09, S.P.).
References 1. Lloyd-Jones D, Adams RJ, Brown TM, et al. Heart disease and stroke statistics—2010 update: a report from the American Heart Association. Circulation 2010;121(7):e46-e215. 2. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med 2002;346(8):549-556. 3. Bernard SA, Gray TW, Buist MD, et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med 2002;346(8):557-563.
4. Zandbergen EG, de Haan RJ, Reitsma JB, et al. Survival and recovery of consciousness in anoxic-ischemic coma after cardiopulmonary resuscitation. Intensive Care Med 2003;29(11): 1911-1915. 5. Rossetti AO, Oddo M, Logroscino G, et al. Prognostication after cardiac arrest and hypothermia: a prospective study. Ann Neurol 2010;67(3):301-307. 6. Zandbergen EG, Hijdra A, Koelman JH, et al. Prediction of poor outcome within the first 3 days of postanoxic coma. Neurology 2006;66(1):62-68. 7. Young GB, Clinical practice. Neurologic prognosis after cardiac arrest. N Engl J Med 2009;361(6):605-611. 8. Wijdicks EF, Hijdra A, Young GB, et al. Practice parameter: prediction of outcome in comatose survivors after cardiopulmonary resuscitation (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2006;67(2):203-210. 9. Samaniego EA, Persoon S, Wijman CA. Prognosis after cardiac arrest and hypothermia: a new paradigm. Curr Neurol Neurosci Rep 2011;11(1):111-119. 10. Lovblad KO, Wetzel SG, Somon T, et al. Diffusion-weighted MRI in cortical ischaemia. Neuroradiology 2004;46(3):175-182. 11. Wu O, Sorensen AG, Benner T, et al. Comatose patients with cardiac arrest: predicting clinical outcome with diffusion-weighted MR imaging. Radiology 2009;252(1):173-181. 12. Wijman CA, Mlynash M, Caulfield AF, et al. Prognostic value of brain diffusion-weighted imaging after cardiac arrest. Ann Neurol 2009;65(4):394-402. 13. Wijdicks EF, Campeau NG, Miller GM. MR imaging in comatose survivors of cardiac resuscitation. Am J Neuroradiol 2001;22(8): 1561-1565. 14. Singhal AB, Topcuoglu MA, Koroshetz WJ. Diffusion MRI in three types of anoxic encephalopathy. J Neurol Sci 2002;196(1-2):37-40. 15. McKinney AM, Teksam M, Felice R, et al. Diffusion-weighted imaging in the setting of diffuse cortical laminar necrosis and hypoxic-ischemic encephalopathy. Am J Neuroradiol 2004;25(10):1659-1665. 16. Greer DM. MRI in anoxic brain injury. Neurocrit Care 2004;1(2):213-215. 17. Barrett KM, Freeman WD, Weindling SM, et al. Brain injury after cardiopulmonary arrest and its assessment with diffusionweighted magnetic resonance imaging. Mayo Clin Proc 2007;82(7): 828-835. 18. Arbelaez A, Castillo M, Mukherji SK. Diffusion-weighted MR imaging of global cerebral anoxia. Am J Neuroradiol 1999;20(6):9991007. 19. Els T, Kassubek J, Kubalek R, et al. Diffusion-weighted MRI during early global cerebral hypoxia: a predictor for clinical outcome? Acta Neurol Scand 2004;110(6):361-367. 20. Mlynash M, Campbell DM, Leproust EM, et al. Temporal and spatial profile of brain diffusion-weighted MRI after cardiac arrest. Stroke 2010; 41(8):1665-1672. 21. Haataja L, Mercuri E, Guzzetta A, et al. Neurologic examination in infants with hypoxic-ischemic encephalopathy at age 9 to 14 months: use of optimality scores and correlation with magnetic resonance imaging findings. J Pediatr 2001;138(3):332-337. 22. Barkovich AJ, Hajnal BL, Vigneron D, et al. Prediction of neuromotor outcome in perinatal asphyxia: evaluation of MR scoring systems. AJNR Am. J Neuroradiol 1998;19(1):143-149. 23. Christophe C, Fonteyne C, Ziereisen F, et al. Value of MR imaging of the brain in children with hypoxic coma. Am J Neuroradiol 2002;23(4):716-723. 24. Zandbergen EG, de Haan RJ, Stoutenbeek CP, et al. Systematic review of early prediction of poor outcome in anoxic-ischaemic coma. Lancet 1998;352(9143):1808-1812. 25. Szabo K, Poepel A, Pohlmann-Eden B, et al. Diffusion-weighted and perfusion MRI demonstrates parenchymal changes in complex partial status epilepticus. Brain 2005;128(Pt 6):1369-1376.
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ABSTRACT BACKGROUND AND PURPOSE
To develop a qualitative brain magnetic resonance imaging (MRI) scoring system for comatose cardiac arrest patients that can be used in clinical practice. METHODS
Consecutive comatose postcardiac arrest patients were prospectively enrolled. Routine MR brain sequences were scored by two independent blinded experts. Predefined brain regions were qualitatively scored on the fluid-attenuated inversion recovery (FLAIR) and diffusion-weighted imaging (DWI) sequences according to the severity of the abnormality on a scale from 0 to 4. The mean score of the raters was used. Poor outcome was defined as death or vegetative state at 6 months. RESULTS
Sixty-eight patients with 88 brain MRI scans were included. Median time from the arrest to the initial MRI was 77 hours (IQR 58-144 hours). At 100% specificity, the “cortex score” performed best in predicting unfavorable outcome with a sensitivity of 55%-60% (95% CI 41-74) depending on time window selection. When comparing the “cortex score” with historically used predictors for poor outcome, MRI improved the sensitivity for poor outcome over conventional predictors by 27% at 100% specificity.
Keywords: Diffusion weighted MRI, anoxic brain injury, cardiac arrest, prognosis. Acceptance: Received December 23, 2013, and in revised form May 12, 2014. Accepted for publication May 25, 2014. Correspondence: Address correspondence to Karen G. Hirsch, MD, Stanford Neurocritical Care Program, Stanford Stroke Center 1215 Welch Road, Mod D, Stanford, CA 94305, USA. E-mail: [email protected]. Conflict of Interest: None. We thank Marion Buckwalter, Amie Hsia, Monisha Kumar, Maarten Lansberg, Neil Schwartz, and Chitra Venkatasubramanian for their assistance with patient enrollment.
CONCLUSIONS
A qualitative MRI scoring system helps assess hypoxic-ischemic brain injury severity following cardiac arrest and may provide useful prognostic information in comatose cardiac arrest patients.
Introduction Over 320,000 people in the United States have a cardiac arrest each year,1 and survival rates vary between 5% and 35%.2,3 Approximately one-third of comatose survivors regain consciousness.4 Neurological deficits are common in these patients and include varying degrees of cognitive and motor impairment. The increased use of therapeutic hypothermia is projected to favorably affect survival and neurological outcome of these patients.2,3 Many studies have focused on early identification of comatose postcardiac arrest survivors who are expected not to regain consciousness.5–7 Historically, the most specific early predictors for poor outcome are the absence of brain stem reflexes or an extensor or absent motor response at postarrest day 3, absence of cortical responses by somatosensory evoked potentials (SSEP) after 24 hours, serum neuron specific enolase (NSE) levels >33 µg/L in the first 3 days, and early myoclonic status epilepticus.8 These predictors have a low sensitivity for
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poor outcome, however, and many may no longer be valid in patients who have been treated with hypothermia.9 Several studies have reported on brain magnetic resonance imaging (MRI) findings in comatose postcardiac arrest patients.10–20 Typically the presence of extensive and severe cortical signal abnormalities on MRI is associated with poor outcome.10–13,16–20 MR imaging offers the advantage of providing an objective measure of cerebral injury, and may be particularly useful in patients who have received sedative agents or who have metabolic derangements that render the neurological examination unreliable or in those who have been treated with hypothermia. We have previously reported our initial experience on the prognostic utility of brain MRI in postcardiac arrest survivors using quantitative diffusion-weighted imaging (DWI).12 The aim of this study was to assess the prognostic value of a qualitative brain MRI scoring system that can be used in clinical practice. A qualitative scoring system has the potential for broad use
◦ 2014 by the American Society of Neuroimaging C
J Neuroimaging 2015;25:430-437. DOI: 10.1111/jon.12143
and implementation, making it an important tool for those who do not have access to quantitative MRI analysis or in situations where the scans are technically inadequate for such analysis. Such qualitative MRI scoring systems have been described in the pediatric literature as a tool to predict outcome following perinatal asphyxia.21–23
Methods Study Population Comatose patients who were resuscitated after out-of-hospital or in-hospital cardiac arrest at Stanford University Medical Center were screened to be prospectively enrolled during a 5-year time period. Patients were included if they met the following criteria: men and nonpregnant women at least 18 years of age; status postresuscitation for in- or out-of-hospital cardiac arrest; and persistent coma after return of spontaneous circulation, defined as no eye opening to voice and inability to follow commands. Patients were excluded if they had a preexisting “do not resuscitate” status, a baseline modified Rankin Scale (mRS) score ࣙ 3, a severe coexisting systemic disease with limited life expectancy, or if they met criteria for brain death. The study was approved by the institutional review board and written consent from a legally authorized representative was obtained for study participation. Clinical and neurophysiologic studies were obtained in a prospective and standardized fashion at a priori defined time points. Neurologic examinations were performed at 1, 24, 48, and 72 hours and at 1 and 2 weeks following the cardiac arrest by an attending neurointensivist or stroke neurologist. Somatosensory evoked potentials (SSEP) and electroencephalography (EEG) were obtained ࣙ72 hours following resuscitation. Neurologic outcome was determined by the Glasgow Outcome Scale (GOS) score at a 6-month clinic visit. Patients who were alive at 6 months but could not come to the clinic were interviewed utilizing a standardized telephone interview. Intensive Care Unit Care
The study patients were enrolled from 2002 to 2007. The clinical treatment team had access to the MRI images, but the clinical care was done prior to the validation of quantitative MRI scoring as a reliable tool to facilitate outcome predictions. Patients who qualified were treated with therapeutic hypothermia to a target temperature of 32-33 °C for 24 hours, then rewarmed in a controlled manner over the subsequent 24 hours. Hemodynamic parameters were supported per routine ICU care. Decisions about treatment and withdrawal of care were left to the clinical treatment teams.
MR Imaging and Scoring MR images were obtained with 1.5T GE Signa Horizon scanners (GE Medical Systems, Waukesha, WI, USA). The MRI protocol included: fast spin echo fluid-attenuated inversion recovery (FLAIR-FSE), TR/TE/TI= 8802/120/2200 ms, 20-24 contiguous sections, 512 × 512 matrix, field of vision (FOV) = 240 × 240 mm, slice thickness/gap = 5/1.5, 5/2, or 5/2.5 mm and spin echo echo-planar diffusion-weighted imaging (SE EPI DWI), TR/TE= 6000/72 ms, 20-24 contiguous sections,
256 × 256 matrix, FOV= 240 × 240 mm, slice thickness/gap 5/1.5 or 5/2.5 mm, diffusion-encoding along x-, y-, z-axes averaged, b = 0 and 1,000 s/mm2 . Patients were routinely scanned once within the first 7 days after the arrest, though some patients were scanned up to three times in the first 30 days after the arrest, and all MRIs were included in the analyses. The technically adequate MRIs of these patients were previously analyzed in a study investigating quantitative MRI analysis.12 Images were independently assessed by a board certified neuroradiologist and by a board certified neurologist with subspecialty certification in neurocritical care and stroke. Both adjudicators were blinded to patient information and outcome, and also to each other’s readings. Windowing of both FLAIR and DWI images was allowed at the discretion of the examiner. Images were scored with the use of an MRI scoring system that was created to assess the severity of cerebral abnormalities due to cardiac arrest in predefined brain regions (Fig 1). The adjudicators were instructed to only score MRI abnormalities that could be attributed to acute global hypoxic-ischemic brain injury. The brain regions were: cortical gray matter and subcortical white matter in the frontal, parietal, temporal, and occipital lobes, the hippocampus, the insular cortex, the corpus callosum, the deep gray nuclei (caudate, putamen, globus pallidus, and thalamus), the cerebellum (cortex, white matter, and dentate nucleus) and the brainstem (midbrain, pons, and medulla), resulting in 21 brain regions that were scored individually. All brain regions were scored according to the extent and severity of the signal abnormalities on a scale from 0 to 4: 0-no abnormality, 1-possibly abnormal, 2-mildly abnormal, 3-moderately abnormal, and 4-severely abnormal (Fig 2). Only the FLAIR and DWI sequences were scored. Six different scores consisting of the sums of the scores for various brain regions were evaluated. The “overall score” consisted of all points given to all brain regions on both sequences (FLAIR and DWI) combined. The “cortex score” consisted of the FLAIR and DWI scores of the gray matter (cortex) in the frontal, parietal, occipital, and temporal lobes, the insular cortex, and the hippocampus (Fig 1). The “deep gray nuclei score” consisted of the sum of the FLAIR and DWI scores of the putamen, globus pallidus, caudate nucleus, and the thalamus. The “cortex plus deep gray nuclei score” combined the cortex score and the deep gray nuclei score. The “DWI score” combined all scores in all regions on the DWI sequence only, and the “FLAIR score” consisted of the sum score of all regions on the FLAIR sequence only. For each score, the sum scores of the two raters were averaged and the mean sum score was used in the analyses.
Outcome Favorable neurologic outcome was defined as a GOS score of 3, 4, or 5 (severe disability, moderate disability, or good recovery), and unfavorable neurologic outcome as a GOS score of 1 or 2 (dead or vegetative state) at 6 months. A GOS of 3 was considered a good outcome despite the severe disability as it includes patients who have regained consciousness. Deceased patients were further subdivided into “historic standard” nonsurvivors and “historic uncertain” nonsurvivors categories. Historic standard nonsurvivors were classified as
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BRAIN REGION Supratentorial Gray matter
Cortex
FLAIR
DWI
signal
signal
Scoring system: 0=normal
Frontal
1=possibly abnormal
Parietal
2=abnormal, mild
Temporal
3=abnormal, moderate
Occipital
4=abnormal, severe
Insula
DGN*
Hippocampus
Cortex score
Caudate
FLAIR score
Putamen
DWI score
Globus pallidus
DGN score*
Thalamus White matter
Frontal Parietal Temporal Occipital Corpus Callosum
Infratentorial
Brainstem
Midbrain Pons Medulla
Cerebellum
Cortex White matter Dentate nuclei
* DGN – deep gray nuclei Fig 1. Qualitative brain MRI scoring system showing the cortex score in light blue.
Score 0
Score 1
Score 2
Score 3
Score 4
DWI
T2 FLAIR
Fig 2. Scoring of sample representative MRI scans. DWI (top row) and T2 FLAIR (bottom row) images. patients who had an unfavorable neurological outcome and one or more of the following historically used standard prognostic variables for poor outcome: absent motor response, absent pupillary reflexes or absent bilateral N20 responses by SSEP
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after 72 hours, or vegetative state at 1 month.8 Historic uncertain nonsurvivors were those who died (typically due to withdrawal of life support) without having any of these historically specific poor outcome predictors.
Table 1. Clinical characteristics of 68 comatose patients after cardiac arrest with 88 brain MRIs
Age (years) mean ± SD (range) Sex (female), n (%) Diabetes Mellitus, n (%) Hypertension, n (%) Coronary artery disease, n (%) Time from collapse to ROSC (min)—median (IQR) Out-of-hospital arrest, n (%) Therapeutic hypothermia, n (%) Time from collapse to the initial MRI (hours)—median (IQR) “Historic Standard” poor outcome criteria, n (%) Absent pupillary reflexes at 72 h, n (%) No motor response at 72 h, n (%) No motor response in the absence of sedation, n (%) Absent SSEPs at 72 h, n (%) Vegetative state at one month, n (%)
Unfavorable outcome N = 40
Favorable outcome N = 28
57 ± 13 (34-89) 20 (50) 6 (15) 19 (48) 9 (23) 22 (20-30)* 28 (70) 20 (50) 72 (56-93) 26 (65) 10 (40)‡ 20 (80)‡ 9 (35) 17 (77)‡ 4 (15)
55 ± 17 (22-84) 4 (14) 4 (14) 7 (25) 4 (14) 19 (9-26)† 19 (68) 17 (61) 94 (60-182)
P value
.559 .004 1.0 .078 .535 .063 1.0 .462 .054
ROSC = return of spontaneous circulation. * Unknown in seven patients. † Unknown in five patients. ‡ SSEP not done in four patients, motor response not tested in one patient, pupillary reflexes not tested in 1 patient.
Statistical Analysis The optimal score cut-offs were defined as the ones that would predict unfavorable outcome in “historic-standard” patients with 100% specificity, that is, with a false positive rate = 0. These cut-offs were identified using ROC curves, and sensitivity and specificity with 95% confidence interval (CI) were calculated. Interrater agreement was assessed using intraclass correlation coefficient (ICC). Statistical analyses were performed using IBM SPSS statistics 21.
Results Patients and Imaging Over a 5-year time period, 88 patients met inclusion criteria and 69 were included in the analysis. Reasons for noninclusion in the analysis were: unable to obtain consent and therefore not enrolled in study (n = 7) and inability to undergo MRI (n = 12). Reasons for not getting an MRI were: care was withdrawn prior to the MRI (n = 7), MRI could not be obtained due to an incompatible pulmonary artery catheter, an aortic balloon pump or hemodynamic instability (n = 3); a pacemaker was implanted before an MRI could be obtained (n = 1); or the patient awoke and declined the MRI (n = 1). Thus, 69 patients with 91 MRIs remained. Of these, 12 patients had one follow-up MRI, and 5 patients had a second follow-up scan. Three scans (of 3 patients) were too motion degraded to be assessed, which caused one additional patient to be excluded as that patient did not have an adequate MRI. Thus, 68 patients with 88 MRIs were included. Median time to the initial MRI was 77 hours (IQR 58-144 hours). Sixty-six scans were obtained within the first week after the arrest (2-168 hours); 16 scans were obtained in the second week (169-336 hours); and six scans after the second week (336-718 hours). Patient characteristics are shown in Table 1. Of the 68 patients that were included, 28 patients (41%) had a favorable neurological outcome: 9 patients had a GOS of 3 (12 scans), 5
had a GOS of 4 (six scans) and 14 had a GOS of 5 (17 scans). Forty patients had an unfavorable outcome: 38 patients died (GOS of 1) (50 scans), and 2 had a GOS of 2 (3 scans) at 6 months. Of these 40 patients, 26 patients (65%) met at least one of the so-called “historic standard criteria” for poor outcome (32 scans) (Table 1).
MRI Prediction of Outcome The ICC for interrater agreement for both the FLAIR and DWI scores was .91 (95%CI .86-.94). As shown in Table 2, brain regions that showed the most signal abnormalities and thus contributed most to high “overall” scores were the cortical gray matter structures (median (IQR) 34 (19-40) for the unfavorable group versus 3 (2-12) for the favorable outcome group (P < .001)) and the deep gray nuclei (median IQR 18 (10-22) for the unfavorable outcome group and 5 (2-8) for the favorable outcome group [P < .001]). Regions that showed the least abnormalities were the subcortical white matter, the corpus callosum, and the brainstem. Two scans (1 poor outcome patient scanned after 2 hours, and 1 with favorable outcome scanned after 78 hours) were considered normal and received zero points from both raters. Hence, the minimum of all six scores was zero. Table 2 shows that the “overall score,” the “cortex score,” and the “cortex plus deep gray nuclei score” best predicted unfavorable outcome, with a sensitivity between 66% and 69% at a specificity of 100%. Of these, we felt that the “cortex score” was the most practical to use because it requires the fewest brain regions to be scored. The cut-off value of the “cortex score” for unfavorable outcome was >27 in this dataset.
Changes in MRI Scores over Time Three patients with unfavorable outcome had cortex scores that were lower than the cut-off value of 27 for unfavorable outcome. These patients underwent MR imaging at 2, 7, and 14 hours after the arrest and had minimal abnormalities on their brain MRIs, receiving cortex scores of 0, 3, and 17, respectively.
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†
*
HGS = historic standard. For all scores specificity was 100% with 95%CI (88-100) for all scans and 95%CI (83-100) for scans made between 25-192 hours (Nscans 25-192 h = 25 in both unfavorable and favorable outcome groups). ‡ Interquartile range. § Positive predictive value. ¶ Negative predictive value. ** DGN = deep gray nuclei.
78% (60-90) 78% (60-90) 100% (78-100) 100% (78-100) 72% (50-87) 72% (50-87) 63% (44-78) 59% (41-76) 22 27 64 60 29 (15-38) 29 (19-36)
5 (1-11) 8 (4-12)
83% (65-94) 81% (62-92) 76% (57-88) 81% (62-92) 100% (80-100) 100% (79-100) 100% (77-100) 100% (79-100) 80% (59-92) 76% (54-90) 68% (46-84) 76% (54-90) 69% (50-83) 66% (47-81) 56% (38-73) 66% (47-81) 43 27 16 39 124 48 29 77 62 (35-69) 34 (19-40) 18 (10-22) 52 (28-61)
Overall (168) Cortex (88) DGN** (32) Cortex ** + DGN (120) FLAIR (84) DWI (84)
11 (6-22) 3 (2-12) 5 (2-8) 10 (4-19)
NPV¶ (95%CI) 25-192 h PPV§ (95%CI) 25-192 h Sensitivity (95%CI) 25-192 h Median (IQR)‡ Score (possible max.)
Max.
Median (IQR)
Max.
Sensitivity (95%CI) All scans
Prediction of unfavorable outcome† Favorable outcome N scans = 35 N patients = 28 Unfavorable outcome HGS* N scans = 32 N patients = 26
Table 2. Qualitative MRI scores in 54 “historic standard” comatose postcardiac arrest patients with 67 MRIs: 26 patients with unfavorable outcome and 28 patients with favorable outcome
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The patient with a cortex score of 0 at 2 hours after the arrest had a repeat scan 53 hours later that received a cortex score of 36 (Fig 3). Of 4 patients with an unfavorable outcome who were scanned more than 192 hours after the arrest, 2 received a cortex score below the cut-off value for unfavorable outcome. Three patients with cortex scores in the higher range (23, 24, and 27) survived with good outcomes and their brain MRIs are shown in Figure 4. Thus, mild cortical abnormalities on MRI do not preclude an acceptable long-term neurological outcome. The cortex scores in overlapping 48-hour time intervals after the arrest are shown in Figure 5 (panel A for all patients, panel B for the favorable and historic-standard unfavorable outcome patients). The cortex scores from the scans obtained between 25 and 192 hours after the arrest differed between patients with favorable and unfavorable outcomes, while scans that were obtained before 25 hours and after 192 hours did not significantly differ between the two groups; however, the number of patients in later time windows (>192 hours) was limited. Limiting the analysis to the 50 MRIs obtained between 25 and 192 hours after the arrest in the favorable and historic-standard unfavorable outcome patients increased the sensitivity of the cortex score from 66% (95%CI 47-81) to 76% (95%CI 54-90; Table 2). When the cortex score cut-off value of >27 was applied to the scans of “historically uncertain” nonsurvivors (n = 21 scans), 7 additional patients (18%) were identified who would have been predicted to have an unfavorable outcome. Using the cortex score to predict outcome in the entire patient cohort (including the historically uncertain nonsurvivors) resulted in an overall sensitivity of 55% (95%CI 41-69) at all time-points and a sensitivity of 60% (95%CI 44-74) in the optimal time-window of 25-192 hours after cardiac arrest, all with 100% (95%CI 88-100 and 83-100, respectively) specificity. Because other prognostic variables can be affected by therapeutic hypothermia (TH), we also analyzed the cortex scores for those patients treated with therapeutic hypothermia and those not treated with TH. We compared the first scan obtained within 25-192 hours for each patient and found no difference in cortex scores for those treated with TH versus those not treated with TH in both the favorable ( Median [IQR[: 3 [1-6] [n =15] vs. 5 [2-17] [n = 7], P = .210) and unfavorable (37 [25-44] [n = 14] vs. 35 [31-36] [n = 9], P = .403) outcomes groups. Additionally, we analyzed the sensitivity and specificity of the cortex score compared to historic standard predictors for patients treated with TH and those not treated with TH. Using the first scan obtained within the 25-192-hour time window, in both the TH and no TH groups, the cortex score and the historic standard predictors were 100% specific. In the TH group, the historic standard predictors had a trend toward slightly higher sensitivity than the cortex score (74% vs. 63%, P = .73), while in the no TH this relationship reversed (50% vs. 56%, P = 1.0). When the cortex score was combined with the historic standard predictors, additional patients with poor outcome were identified, improving the sensitivity of poor outcome prediction to 84% (95%CI 62-94) in the TH group and 67% (95%CI 44-84) in the no TH group.
Fig 3. Upper panels: MRI two hours after a 19 minute cardiac arrest showing no evidence of hypoxic-ischemic brain injury (cortex score = 0). Lower panels: repeat MRI obtained in the same patient 53 hours later showing widespread areas of reduced diffusion involving the cortex of both hemispheres (cortex score = 36).
Discussion The results of the present study of 68 patients with 88 brain MRIs indicate that a qualitative brain MRI scoring system may be a useful predictor of long-term functional outcome in patients who are comatose after cardiac arrest. Of the different brain regions we evaluated, signal abnormalities in the cortical gray matter regions best correlated with neurological outcome. The extent of these abnormalities in each region can be easily determined by visually grading the severity of hypoxic-ischemic injury in the individual cortical gray matter structures both on the FLAIR and DWI sequences on a scale of 0 to 4, and cumulatively deriving a “cortex score.” Of 81 consented patients, 69 (85%) underwent one or more brain MRIs, and no safety issues were encountered related to the MR acquisitions. Our experience in this study and in previous studies12 suggests that MR imaging is feasible and safe in the majority of comatose postcardiac arrest patients so long as appropriate screening protocols are followed. Consistent with previous studies, we found that brain MRI abnormalities following cardiac arrest are time dependent.17,19 Scans obtained within 24 hours of the arrest typically do not reflect the severity of the global hypoxic-ischemic brain injury. In previous studies, we found that quantitative DWI abnormalities in cortical areas were most severe between 3 and 5 days after the arrest, and differentiated best between good and poor outcome patients between 49 and 108 hours after the arrest.11,19 The optimal time-window for qualitative MRI appears to be a bit wider and ranges from 25 to 192 hours after the arrest. Within that time-window, however, qualitative MRI seems to best distinguish good from poor outcome patients between day
4 and 7 after the arrest (Fig 5). Thus, the timing of the greatest MRI abnormalities reflected by the “cortex score” is slightly later than that of the quantitative DWI abnormalities. This is likely due to the fact that it takes more time for signal changes caused by hypoxic ischemic injury to manifest on the FLAIR sequence (which is incorporated in the cortex score in conjunction with the DWI sequence) than on the DWI sequence (which is the only sequence used for quantitative MRI analyses). Historically used markers of poor outcome after cardiac arrest include SSEPs, NSE, EEG patterns, and physical exam findings; though several studies have shown many of these may not be valid in the era of therapeutic hypothermia. Recognizing this limitation, we defined the “historic standard criteria” for poor outcome as patients who had a poor neurologic outcome and had one of the historically used prognostic criteria (absent motor response or pupillary reflexes or absent bilateral N20 responses by SSEP after 72 hours, or vegetative state at one month). Except for SSEPs and NSE, all other commonly used outcome-determinants in comatose postcardiac arrest patients are influenced by pharmacologic agents and metabolic changes.9,24 MR images are not influenced by these factors, and may therefore add useful prognostic information in patients who require sedation, treatment for seizure activity, or in those with severe metabolic derangements. In addition, since the majority of patients in this study were treated with hypothermia, this MRI scoring system appears to be valid in such patients. Indeed, in patients treated with TH, combining the cortex score with historic standard predictors improved the sensitivity and allowed the identification of additional patients with poor outcome. Previous research has shown
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Fig 5. Panel A shows the cortex MRI scores over time in all comatose postcardiac arrest patients in this study comparing the unfavorable and favorable outcome patients. Note that there is a significant difference at α < .05 between the two groups between 25-192 hours after the arrest (marked by *). Panel B shows the cortex MRI scores over time only in the historic standard patients in this study comparing those with an unfavorable outcome with those with a favorable outcome at 6 months.
Fig 4. Brain diffusion (DWI), apparent diffusion coefficient (ADC) and fluid-attenuated inversion recovery (FLAIR) images of the three patients with the highest cortex scores in the group of survivors in this study. All 3 patients had residual moderate to severe cognitive deficits at 6 months. Note that the MRI window and level settings for each of the three sequences is held constant across all 3 patients and are identical to the settings used in Figure 2. (A) MRI with DWI, ADC and FLAIR obtained at 151 hours after the arrest. The patient received a cortex score of 23. Her Glasgow outcome scale (GOS) score at 6 months was 4. (B) Brain MRI with DWI, ADC and FLAIR obtained at 52 hours after the arrest. The cortex score was 24 and the patient survived with a GOS of 3 at 6 months. (C) Brain MRI with DWI, ADC, and FLAIR obtained 89 hours after the arrest. This patient received a cortex score of 27, which was the highest score in our good outcome patient group. He awoke from coma 10 days after the arrest and his 6 months GOS was 3.
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that in patients undergoing TH, historic standard predictors can be confounded by medications and hypothermia itself,9 so the ability to potentially identify additional patients in this group is particularly clinically relevant. This factor could potentially also explain more consistent performance of the cortex score between the TH and no TH groups (sensitivity 63% vs. 56%, P = .74) compared to the change in the performance of the historic standard predictors (sensitivity 74% vs. 50%, P = .18). Data on the use of a qualitative MRI scoring system to help predict outcome in comatose survivors of cardiac arrest are scarce. Studies that have been published so far suggest a relationship between extensive cortical abnormalities and unfavorable outcome, but most of these studies are based on small numbers of patients.10,13,15,17–19 Studies with larger number of patients have been described in the pediatric literature, demonstrating that brain MRI scoring systems can discriminate between children with favorable and unfavorable cognitive and motor outcome after neonatal asphyxia. As the pathophysiology of brain injury caused by neonatal asphyxia is similar to
global cerebral hypoxia-ischemia in adults, it is not surprising that the results of these studies are consistent with our findings.21–23 A limitation of this study is the relatively small number of patients, which limits its power. Furthermore, the proposed scoring system only applies to brain MRI changes caused by acute global hypoxic-ischemic brain injury. A potential confounder is prolonged seizure activity which can cause MRI changes that may be difficult to differentiate from those caused by hypoxic-ischemic brain injury.25 A small number of the patients in this study had continuous EEG monitoring, though we have since updated our clinical and research practice and now perform continuous EEG monitoring on all cardiac arrest patients. Future studies with the newer patient cohort will address this potential confounder. Another limitation is that the clinical team was not blinded to the MRI results, which may have introduced a bias and potentially a self-fulfilling prophecy; we tried to minimize this problem by determining the cortex-score cut-off for unfavorable outcome on our “historic standard” population only, that is, patients who died while also meeting one or more other conventional relatively specific predictors for poor outcome. We acknowledge the limitations of defining a “historic standard” outcome prediction as many of these tests lack sensitivity and specificity, especially in the era of therapeutic hypothermia. Finally, like any qualitative scoring system, the interpretation by the radiologist or neurologist is subjective, and different readers may produce different scores. Although we found a high interrater agreement for the MRI readings, further validation of the reproducibility of the “cortex score” is needed among different raters. In conclusion, this study shows that a brain MRI qualitative scoring system provides a framework to help grade the severity of global cerebral hypoxic-ischemic injury between 1 and 3 days after cardiac arrest and may yield useful additive prognostic information. This type of qualitative scoring may be particularly useful when quantitative measurements are not available, as may be the case in both community and academic settings. MRI may increase the sensitivity of poor outcome prediction and may especially be of value when other prognostic variables cannot be reliably obtained or are inconclusive. Before we can advocate the routine use of this scoring system in clinical practice, however, it will need to be validated in an independent patient sample.
This work was supported by the American Heart Association (National Scientist Development Award (0430275N, C.A.C.W.), the Netherlands Heart Association (2003B263, S.P.), and the Foundation “De Drie Lichten” (41/09, S.P.).
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