Memory Impairment in Out-of-Hospital Cardiac Arrest Survivors Is Associated With Global Reduction in Brain Volume, Not Focal Hippocampal Injury

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1 Memory Impairment in Out-of-Hospital Cardiac Arrest Survivors Is Associated With Global Reduction in Brain Volume, Not Focal Hippocampal Injury Neil R. Grubb, MRCP; Keith A.A. Fox, FRCP; Karen Smith, BSc; Jonathan Best, FRCR; Annette Blane, DCR; Klaus P. Ebmeier, PhD; Michael F. Glabus, PhD; Ronan E. O Carroll, PhD Background and Purpose More than 30% of out-of-hospital cardiac arrest (OHCA) survivors suffer significant memory impairment. The hippocampus may be vulnerable to hypoxic injury during cardiac arrest. The purpose of this study was to determine whether selective hippocampal injury is the substrate for this memory impairment. Methods Seventeen OHCA survivors and 12 patients with uncomplicated myocardial infarction were studied. OHCA survivors were divided into those with impaired and intact memory. Memory was assessed by use of the Rivermead Behavioural Memory Test and Doors and People Test. MRI was used to determine intracranial, whole-brain, amygdala-hippocampal complex, and temporal lobe volumes. Brain structure was also examined by statistical parametric mapping. Results Left amygdala-hippocampal volume was reduced in memory-impaired OHCA victims compared with control subjects (mean 3.93 cm 3 and 95% CI 3.50 to 4.36 cm 3 versus mean 4.65 cm 3 and 95% CI 4.37 to 4.93 cm 3 ; P 0.002). Left temporal lobe and whole-brain volumes were also reduced. There were no differences in amygdala-hippocampal volume indexed against ipsilateral temporal lobe volume. Significant correlations were observed between total brain volume and Rivermead Behavioural Memory Test (r 0.56, P 0.05) and Doors and People Test (r 0.67, P 0.01) scores in OHCA survivors. Both recall and recognition were compromised in memory-impaired subjects. Statistical parametric mapping did not detect focal brain abnormalities in these subjects. Global cerebral atrophy was confirmed by qualitative assessment. Conclusions Memory impairment in OHCA survivors is associated with global cerebral atrophy, not selective hippocampal damage. Rehabilitation protocols need to account for the global nature of the brain injury. (Stroke. 2000;31: ) Key Words: atrophy heart arrest magnetic resonance imaging memory As a result of the defibrillation initiatives of the emergency medical services and increased public awareness of cardiopulmonary resuscitation techniques, there has been a substantial increase in the number of individuals surviving out-of-hospital cardiac arrest (OHCA) in many urban areas. 1 3 In Edinburgh, Scotland, a 4-fold increase in the rate of survival to discharge was reported after the introduction of semiautomated ambulance defibrillators. 4 Although these and other centers have achieved impressive improvements in mortality figures, comparatively little attention has been focused on the sequelae of the cardiac arrest itself. Neuropsychological deficits can result from cerebral hypoxia during cardiac arrest and have the potential to interfere with recovery and to affect the patients daily functioning after discharge home. Despite this, only a small number of studies have systematically examined cognitive function in OHCA survivors. Clinically important cognitive impairment has been reported for 20% to 50% of the cases. 5 7 In a previous study, our group investigated the prevalence of chronic memory impairment among OHCA survivors. Moderate or severe impairment, assessed by the Rivermead Behavioural Memory Test (RBMT), was noted in almost 40% of the individuals assessed 6 months after cardiac arrest. 7 These deficits were not present in comparable subjects with previous myocardial infarction (MI) who had not had a cardiac arrest. Examination of the individual subtests in that study indicated that recall function was impaired and that recognition function was preserved in cardiac arrest survivors. This pattern of cognitive impairment has been previously observed in individuals with memory impairment Received November 2, 1999; final revision received March 23, 2000; accepted March 23, From Cardiovascular Research (N.R.G., K.A.A.F.), University of Edinburgh, Royal Infirmary of Edinburgh, Edinburgh, UK; the Psychology Department (K.S.), University of Stirling, Stirling, UK; the Department of Medical and Radiological Sciences (J.B., A.B.) and the Department of Psychiatry (K.P.E., M.F.G.), University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, UK; and the School of Psychology (R.E.O.), University of St Andrews, St Andrews, Fife, UK. Correspondence to Dr Neil R Grubb, MRCP, Cardiovascular Research, University of Edinburgh, Royal Infirmary of Edinburgh, 1 Lauriston Pl, Edinburgh, EH3 9YW, UK. N.Grubb@ed.ac.uk 2000 American Heart Association, Inc. Stroke is available at

2 1510 Stroke July 2000 TABLE 1. Baseline Characteristics of OHCA Subjects and Controls MIC (n 12) INT (n 8) IMP (n 9) Test P Comment Age, y 65.1 ( ) 62.9 ( ) 64.7 ( ) F 0.15 NS NART-estimated premorbid IQ 98.6 ( ) ( ) 99.1 ( ) F INT MIC* Interval (index event to assessment), mo 15 (9 22) 14 (7 22) 13 (6 21) NA All NS All comparisons Sex 10M,2F 8M 8M,1F NS Arrest aetiology Acute MI NA 6 6 Other IHD (ischemia, poor LV function) NA 1 3 Other causes NA NS Medication -Blocker NS ACE inhibitor NS Age and NART scores are mean (95% CI). Interval is median (range). MIC indicates control patients with uncomplicated MI; INT, memory-intact OHCA patients; IMP, memory-impaired OHCA patients; M, male; F, female; IHD, ischemic heart disease; LV, left ventricular; ACE, angiotensin-converting enzyme; and NA, not applicable. *By Scheffé post hoc test. associated with localized hippocampal damage, including patients with the classic amnestic syndrome. 8 The CA1 field of the hippocampus is especially vulnerable to hypoxic damage. This zone is rich in N-methyl-D-aspartate receptors, which have been implicated in the mechanism of hippocampal cell death during hypoxia through the glutamate-mediated entry of calcium into hippocampal cells. 9 Studies in primates and in rats have shown that hypoxia causes specific CA1 field hippocampal damage, leading to anterograde amnesia. 10 Amnesia after human cardiac arrest has also been reported to be associated with specific degeneration of hippocampal CA1 neurons. 11,12 Although it is likely that hypoxia during cardiac arrest results in a generalized brain insult, it is possible that the hippocampus could be selectively damaged. 13,14 If so, N-methyl-D-aspartate receptor antagonism could form a target for neuroprotective treatment during prolonged cardiac arrest. 9 High-resolution MRI can be used to measure absolute hippocampal volume relative to the volumes of other brain structures. A specific reduction in hippocampal volume has previously been demonstrated in patients with the amnestic syndrome, but this has not been specifically examined in cardiac arrest survivors. 15 Although cerebral atrophy has previously been reported in a population of cardiac arrest survivors, regional indices of brain volume and cognitive indices were not measured. 16 The present study addressed the TABLE 2. Results of Memory Tests Adjusted for Estimated Premorbid IQ hypothesis that selective hippocampal injury is the neuroanatomic substrate of memory impairment in OHCA survivors. Two key methods were used to test this hypothesis: (1) examination of brain structure by use of MRI and (2) further examination of recall and recognition memory function by use of a purpose-designed neuropsychological test. 17 Subjects and Methods We attempted to contact all adult OHCA survivors, with a presumed cardiac etiology for their arrest, who had been successfully discharged from the Royal Infirmary of Edinburgh between July 1997 and November Control subjects were enrolled from contemporaneous patients who had survived acute MI and who had not suffered a cardiac arrest. Approval for the present study was granted by the Lothian Research Ethics Committee (Medicine and Oncology subcommittee) and the Royal Infirmary of Edinburgh NHS Trust. General exclusion criteria were as follows: major preexisting psychiatric illness, use of psychotropic drugs, previous cardiac arrest, previously diagnosed organic brain disease or stroke, geographic remoteness (residence outside Lothian region). Exclusion criteria for MRI examinations included the following: cardiac pacemakers and automatic implantable cardioverter-defibrillators, metallic prosthetic heart valves, cochlear implants, aneurysm clips, and intraocular foreign bodies. We noted the use of -adrenoceptor antagonists, which could potentially affect performance in cognitive tests, 18 and angiotensin-converting enzyme inhibitors. On the basis of the results of a previous study in this patient population, we expected that 40% of OHCA victims would have clinically significant memory impairment. By prespecified analysis, MIC (n 12) INT (n 8) IMP (n 9) F P Contrasts Controlling for Premorbid IQ RBMT profile score 20.2 ( ) 19.9 ( ) 14.8 ( ) IMP MIC, INT Overall age-scaled score 11.6 ( ) 11.0 ( ) 4.2 ( ) IMP MIC, INT Recall age-scaled score 10.4 ( ) 11.0 ( ) 5.4 ( ) IMP MIC, INT Recognition age-scaled score 12.7 ( ) 10.5 ( ) 5.0 ( ) IMP MIC, INT Verbal memory age-scaled score 12.3 ( ) 12.3 ( ) 5.9 ( ) IMP MIC, INT Visual memory age-scaled score 10.8 ( ) 9.4 ( ) 4.6 ( ) IMP MIC, INT Values are mean (95% CI).

3 Grubb et al Brain MRI and Memory Function After Cardiac Arrest 1511 TABLE 3. Volumetric Analysis of MRI Scans Contrasts Volume MIC (n 12) INT (n 8) IMP (n 9) F P Controlling for Premorbid IQ % Difference (IMP vs INT) Intracranial, cm ( ) ( ) ( ) % Whole brain, cm ( ) ( ) ( ) IMP INT 14% Left temporal lobe, cm ( ) 71.5 ( ) 59.8 ( ) IMP INT, MIC 16% Right temporal lobe, cm ( ) 74.8 ( ) 63.9 ( ) IMP INT 15% Left AHC, cm ( ) 4.16 ( ) 3.93 ( ) IMP MIC 6% Right AHC, cm ( ) 4.48 ( ) 3.98 ( ) % Lateral ventricles, cm ( ) 36.9 ( ) 49.9 ( ) IMP INT, MIC 35% Left AHC/whole brain, cm ( ) ( ) ( ) INT MIC 0% Left AHC/left temporal lobe, cm ( ) ( ) ( ) % Values are mean (95% CI). AHC indicates amygdala-hippocampal complex. ANCOVA was used to control for premorbid IQ. this group was subdivided into subjects with intact and with impaired memory function. Impaired memory function was defined as a score 1 SD below the age-scaled mean total score of the Doors and People Test (DPT; see below). This allowed comparison of MRI indices in memory-impaired cardiac arrest survivors with those of both memory-preserved cardiac arrest survivors and the main control group. Assessment of Cognitive Function Cognitive testing was performed in a single 1-hour session by a trained graduate psychologist, who was blinded to the patient s medical history. Premorbid intellectual function was estimated by using the revised version of the National Adult Reading Test (NART). 19 This test is relatively ineffectual in patients with dementia and has been previously used as an index of premorbid intellectual function. 20 Memory function was assessed by the use of 2 tests. The RBMT examines episodic long-term memory (the ability to abstract information from short-term memory to true long-term memory) and consists of 12 subtests designed to identify memory deficits that might be encountered during daily living. 21 These include the following: remembering a name, an appointment, the location of a hidden item, objects and faces from picture cards, a short route, and a news story. In addition, orientation is also tested. This test allocates a score of 0 to 2 points for each subtest, giving a maximum total score 24 points. Recall and recognition memory function were assessed by the recently developed DPT. 17 This test provides separate indices of recall, recognition, and verbal and visual memory that are matched for difficulty. The test spans a wide range of abilities, avoiding problems of floor and ceiling effects. MRI Scans and Analysis MRI scans were performed by using a 1-T SPE Magnetom scanner (Siemens) after, but on the same day as, memory testing. After midline localization, 3 scan sequences were used for whole-brain imaging. The first was a double spin-echo sequence, giving simultaneous proton-density and T2-weighted images (relaxation time 3565 ms, excitation time 20 and 90 ms, 31 contiguous 5-mm slices acquired in the Talairach Plane, field of view 250 mm). These data were used to calculate intracranial and cerebrospinal fluid (CSF) volumes with the use of ANALYZE (Mayo Foundation). A threshold was set on the slice above the lateral ventricles to remove extracranial tissues. Other areas were edited manually. Total intracranial volume was summed by use of ANALYZE. The CSF was measured by drawing from around the lateral ventricles and loading the data into the multispectral option of ANALYZE, and the volumes calculated by using the unsupervised chain method. The second scan sequence, for the regional volumetric analysis and whole-brain volume, was a 3D magnetization prepared, rapid-acquisition, gradient echo sequence consisting of an 180 inversion pulse followed by a fast low-angle shot collection (flip angle 12, relaxation time 10 ms, excitation time 4 ms, inversion time 200 ms, relaxation time delay time 500 ms, and field of view 250 mm), giving 128 contiguous 1.88-mm-thick slices in the coronal plane orthogonal to the Talairach plane. Inhomogeneity corrections were performed on the images by using flood phantom data. Image analysis was performed on Sun Microsystem workstations with the use of ANA- LYZE by a single radiographer performing intrarater studies at intervals during analysis to ensure consistency of technique. Wholebrain volume was measured by using manually assisted automatic editing that used a threshold calculated by taking the mean of 2 regions of gray matter and 2 regions of CSF. The temporal lobe and amygdala-hippocampal complexes were identified, the areas were outlined, and volumes were calculated by summing voxels in the regions of interest. 22 A third fluid-attenuated inversion recovery (FLAIR) scan sequence was used to detect lesions in the central white matter and lesions next to CSF in the cortex and periventricular regions. 23 MRI data were also spatially transformed into stereotactic space, segmented, and analyzed voxel by voxel to identify any differences in gray matter density. 24 Statistical parametric mapping (SPM) was used to identify overall differences in gray matter density between groups. 25 SPM uses a computerized transformation algorithm to create an average brain image for each group under study, allowing voxel-by-voxel analysis of regional differences in gray matter signal. This provides an additional method of identifying regions of the brain in which consistent structural differences occur between groups. TABLE 4. Correlation Analysis of Summary Memory Measures and MRI-Derived Volumetric Indices in OHCA Victims DPT Overall RBMT Total Age-Scaled Score Intracranial volume Whole-brain volume 0.56* 0.67 Lateral ventricles Left temporal lobe Right temporal lobe * Left AHC Right AHC 0.48* 0.62 Values are for OHCA victims (n 17). *P 0.05; P 0.01.

4 1512 Stroke July 2000 TABLE 5. Qualitative Rating of MRI Scans Subject Atrophy High-Intensity Signal Leukoaraiosis Lacunar Infarct Cortical Infarct IMP INT MIC Symbols are as follows:, no abnormality; to, mild to major abnormality. MRI scans were also examined qualitatively by an experienced radiologist, who was blinded to the subjects medical histories. This allowed identification of the frequency of specific abnormalities such as leukoaraiosis and discrete cerebral infarct zones. Cerebral atrophy was assessed on the basis of ventricular size and sulcal width from the proton density weighted sequence. High-intensity signal was assessed from the T2-weighted and FLAIR sequences. The extent and density of leukoaraiosis was assessed from the FLAIR sequence. Lacunae, central white matter, and basal ganglia were assessed on T1-weighted images. Cortical infarcts were assessed on all sequences. Statistical Analysis A 3-group analysis comparing baseline variables (age, sex, and estimated premorbid intelligence) of the control group and of the memory-impaired and memory-preserved cardiac arrest groups was performed. Intergroup differences in sex ratio were tested by use of the 2 statistic. Times from index event to assessment were compared by the Mann-Whitney test. Variables for which significant intergroup differences existed were entered as covariates in the analysis of MRI volumetric parameters with the use of ANCOVA. For intergroup comparisons of amygdala-hippocampal volumes, these variables were expressed as absolute values and also as a proportion of whole-brain and ipsilateral temporal lobe volumes. Intergroup comparisons of brain volume indices were examined by ANCOVA. Potential associations between brain volume indices and memory test scores were analyzed by the Pearson correlation coefficient. Results General Characteristics For general characteristics of cardiac arrest and control subjects, see Table 1. There were no significant intergroup differences in age, sex, or use of -adrenoceptor antagonists or angiotensin-converting enzyme inhibitors. A significant intergroup difference was found for NART-estimated premorbid intelligence scores. Post hoc analysis (Scheffé test) showed that this difference was significant between MI controls and memory-intact OHCA subjects (P 0.05). In subsequent analyses of memory and MRI data, the NARTderived IQ score was entered as a covariate. Memory Function Intergroup comparisons of memory test scores are shown in Table 2. Collectively, patients in the cardiac arrest groups achieved lower total scores than did controls in the DPT, which was subsequently used to identify memory-impaired subjects (mean 7.4 points and 95% CI 5.2 to 9.6 points versus mean 11.6 points and 95% CI 9.4 to 13.7 points; P 0.015). The DPT age-scaled score was used to define the memoryimpaired OHCA group; this group exhibited marked impairment of all subtest indices compared with control and memory-intact OHCA subjects. The criterion used to define this group also identified subjects with significant deficits measured by the RBMT. Significantly, both recall and recognition memory function were impaired in this group, in contrast with earlier results with use of the RBMT. There were no significant differences in any of the memory indices between the MI control and memory-intact OHCA groups. Anatomic Data Results of regional and total brain volume analyses are shown in Table 3. There were no intergroup differences in intracranial volume. Several intergroup differences were identified in brain volume parameters. Memory-impaired OHCA subjects had smaller left temporal lobe and left amygdalahippocampal complex volumes than did control subjects. Memory-impaired OHCA subjects also had smaller total brain volume and left and right temporal lobe volumes than did memory-preserved OHCA subjects. Memory-impaired OHCA subjects also had significantly increased lateral ventricle volume than did either memory-preserved OHCA subjects or control subjects. When amygdala-hippocampal volumes were expressed relative to whole-brain and ipsilateral temporal lobe volumes, no significant differences were found between memoryimpaired cardiac arrest subjects and the other 2 groups. Results of correlation analysis of MRI-derived volume indices and summary memory test scores for the combined cardiac arrest groups are shown in Table 4. Moderate corre-

5 Grubb et al Brain MRI and Memory Function After Cardiac Arrest 1513 Examples of MRI scans from memoryimpaired and memory-intact OHCA victims. lations were found between RBMT and DPT test scores and total brain, left temporal, and right amygdala-hippocampal volumes. SPM analysis did not show any significant focal intergroup differences in brain structure. The qualitative ratings of the MRI scans are summarized in Table 5. The memory-impaired OHCA group was rated as having the greatest degree of atrophy, high-intensity signal, and leukoaraiosis. Representative MRI scans of memory-impaired and memory-intact OHCA patients are shown in the Figure. Discussion In the present study, we tested the hypothesis that the anatomic substrate for chronic memory impairment occurring after OHCA is selective hippocampal damage. This hypothesis was based on the known susceptibility of the hippocampus to hypoxic injury, possibly mediated by the N-methyl-Daspartate receptor dependent entry of calcium into CA1 field hippocampal neurons. The hypothesis was neither supported by the results of MRI scanning nor by more detailed testing of recall and recognition memory function. Compared with control subjects who had not had a cardiac arrest, memory-impaired OHCA survivors did have significantly reduced left amygdala-hippocampal volume. However, reference left temporal lobe and total brain volumes were similarly reduced. Furthermore, total brain volume was significantly reduced in memory-impaired compared with memory-preserved OHCA subjects, and significant correlations were found between memory test scores and total brain volume but not left amygdala-hippocampal volume. Taken together, these findings suggest that global brain atrophy rather than selective hippocampal damage is responsible for the deficits seen in the memory-impaired subjects. The finding of a global brain injury, derived from volumetric analysis, is also confirmed by the failure of SPM analysis to identify a regional difference in brain volume when the 3 groups were compared. The groups were too small to draw conclusions on the time course of development of cerebral atrophy. The prevalence and severity of memory impairment was similar to that observed in our previous study, which used the RBMT. 7 The mean memory index scores in the memoryimpaired OHCA group indicate that these individuals have severe memory impairment that is sufficient to compromise everyday activities. In the present study, the DPT was also used to obtain additional information about recall and recognition memory. Overall, cardiac arrest survivors had significantly reduced recall and recognition memory function compared with function in control subjects. This also suggests a global cerebral insult rather than specific hippocampal substrate for the observed memory impairment. However, it is not universally agreed that hippocampal injury affects recall memory in isolation while preserving recognition memory. 8,26,27 The results of the structural and functional studies suggest that in patients who suffer from memory impairment after cardiac arrest, hypoxic injury results in generalized cerebral atrophy. In cognitive neuroscience, survivors of cardiac arrest have previously been used as models of selective hippocampal damage, on the assumption that hypoxic insult was confined to the hippocampal complex neurons. 11,12 The results of the present study do not support that premise and imply that aspects of cognitive function other than memory are also likely to be affected by cardiac arrest. Markowitsch et al 28 recently examined brain function in cardiac arrest victims by using positron emission tomography and concluded that these patients may not be valid models for pure hippocampal or even medial temporal lobe pathology because they suffer much more widespread brain damage. Practical Implications of the Present Study Memory impairment is common among OHCA survivors. From the present study, it is clear that both recall and recognition memory function are significantly impaired in these individuals. Although hippocampal injury may account for some of these patients memory deficits, it is only one component of a more widespread, global, hypoxic cerebral insult. From this, it is likely that other aspects of cognitive function will also be compromised and that further studies of cognition in cardiac arrest survivors are now warranted. It is of note that Wilson, 13 in a study of 18 patients who had suffered cerebral hypoxia, including 4 who suffered hypoxia during cardiac arrest, reported widespread cognitive impairment affecting memory, visuospatial, and executive function. Before a comprehensive rehabilitation strategy can be de-

6 1514 Stroke July 2000 vised for this growing population of patients, it will be important to characterize these and other aspects of cognitive function more fully. Behavioral strategies that are used in patients with the classic amnestic syndrome, a condition usually associated with isolated hippocampal pathology, are unlikely to alleviate all of the neuropsychological deficits from which OHCA survivors suffer. 29 However, novel cognitive strategies, such as errorless learning, which eliminates trial-and-error approaches to learning, have proved useful in other groups of memory-impaired patients and will be the subject of further evaluation. 30 Further evaluation of cognitive deficits is required to provide the platform on which to base a cognitive rehabilitation program. Acknowledgments This work was supported by a project grant provided by the British Heart Foundation. 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