Does diffusion-weighted magnetic resonance imaging enable detection of early ischemic change following transient cerebral ischemia?

doi:10.1016/S0022-510X(00)00433-0

Journal of the Neurological Sciences

Volume 181, Issues 1–2, 1 December 2000, Pages 73-81

https://doi.org/10.1016/S0022-510X(00)00433-0 Get rights and content

Abstract

To examine the usefulness of diffusion-weighted imaging for detecting neuronal damage following ischemia, dynamic changes in diffusion-, T1- and T2-weighted images of rats subjected to 10 min of 4-vessel occlusion and of humans who had suffered 10–20 min of cardiac arrest were observed. In rats, no remarkable alteration was observed on day 1. On day 3, however, diffusion-weighted images showed high signal intensity in the hippocampal area, in which the apparent diffusion coefficient was significantly lower than that of the control (760±28×10⁻⁶ mm²/s in control vs. 480±29×10⁻⁶ mm²/s on day 3, P<0.0001). Histological observation revealed microvacuolation in 92±4% of pyramidal neurons in the CA1 region. On day 7, the hyperintensity in diffusion-weighted images had disappeared and microvacuolation had also disappeared in the CA1 region, but severely disrupted pyramidal neurons containing pyknotic nuclei had appeared in the CA1 region instead. In humans, diffusion-weighted images did not show any apparent abnormality in the cerebral cortex on the day of resuscitation. On day 3, however, diffusion-weighted images consistently showed hyperintensities in the temporal or occipital cortex, and these hyperintensities had disappeared in images obtained on days 7 and 14. From day 14, T1-weighted images showed laminar hyperintensity, suggesting laminar necrosis, along the cortex, where diffusion-weighted images showed high signal intensity on day 3. These results suggested that diffusion-weighted imaging has a potential for detection of the occurrence of microvacuolation and is useful for detecting the progression of ischemic changes in humans following global ischemia.

Introduction

Since the brain is highly susceptible to ischemia, several minutes of circulatory arrest causes irreversible damage in vulnerable areas, e.g., hippocampus, striatum and cerebral cortex (3rd, 5th and 6th layers) [1], [2]. To determine neuronal damage and prognosis following cardiopulmonary resuscitation, numerous trials using biochemical analysis [3], electrophysiological monitoring [4], [5] CT imaging [6] and clinical signs [7] have been performed. However, none of these examinations have been able to clearly demonstrate the progression of pathological alteration in the vulnerable region of the brain. Therefore, there is a need for techniques that show ischemic change in the acute phase following cardiopulmonary resuscitation.

Recently, diffusion-weighted magnetic resonance (MR) imaging, a new technique for detecting focal cerebral ischemia in the very acute stage, has been used clinically [8], [9], [10]. Unlike T1- and T2-weighted imaging, which mainly represent water contents in the target area, diffusion-weighted imaging indicates diffusibility of water molecules based on Brownian movement. Since with the initiation of ischemia water moves into the intracellular space, where Brownian movement is restricted by intracellular components, diffusion-weighted imaging enables detection of transmembrane influx of water, i.e., cytotoxic edema, within 1.5–2.5 min after onset [11].

Since cytotoxic edema is one of the earliest pathological findings during the reperfusion period following global ischemia [12], it is thought that diffusion-weighted imaging may enable detection of regions in which the first step of pathological change (cytotoxic edema) has been initiated. However, in contrast to the well-known usefulness of diffusion-weighted imaging in detecting focal cerebral ischemia, the dynamic changes in diffusion-weighted images following global cerebral ischemia are not well understood. Therefore, in order to examine the possibility of using diffusion-weighted imaging for detecting the earliest pathological changes (cytotoxic edema) following severe brain ischemia, we serially observed the histological changes and changes in diffusion-, T1- and T2-weighted images following 10 min of four-vessel occlusion in rats. Additionally, the dynamic changes (up to 56 days) in diffusion-, T1- and T2-weighted images of three patients who had been resuscitated following 10–20 min of cardiac arrest were examined.

Section snippets

General procedures for animal study

The animals were housed and manipulated in accordance with the guidelines approved by the National Institutes of Health. Eighteen male Wistar rats weighing 260±20 g were subjected to 4-vessel occlusion according to the method of Pulsinelli [13] with slight modification. Rats were anesthetized with 1% halothane in 30% O₂ and 70% N₂. Following the placement of reversible clasps around common carotid arteries, vertebral arteries were occluded by electrocauterization at the first cervical vertebra.

Animal study

Fig. 1 shows representative MR images and histology of the CA1 region in rats subjected to a sham operation and to 10 min of ischemia on days 1, 3 and 7 before imaging and perfusion-fixation. On day 1, there were no apparent abnormalities in any MR images or in histological findings in the CA1 region. On day 3, however, diffusion-weighted images showed high signal intensity in the area corresponding to the hippocampus. In the same rats, histological observation revealed microvacuolation in most

Discussion

In the present study, dynamic changes in histological findings and diffusion-, T1- and T2-weighted images in the CA1 region were examined in rats that had undergone 10 min of 4-vessel occlusion 1, 3 or 7 days before imaging and perfusion-fixation. The initial pathological alteration in the CA1 region was microvacuolation, observed on day 3, and this was followed by the appearance of pyknotic nuclei and infiltration of gliomesodermal cells on day 7. This time-course of pathological alteration is

Acknowledgments

We thank all of our colleagues in the Department of Anesthesiology and Resuscitology in Okayama University Medical School for their cooperation.

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The cerebral performance category (CPC) scale is a well established tool for evaluation of neurological damage after cardiac arrest and describes patients mental ability from CPC 1 (=return to normal cerebral performance) to CPC 5 (=brain death).4 However, within animal-models both neuropathological and neuroimaging studies revealed specific vulnerability of hippocampal regions after global cerebral ischemia due to cardiac arrest.5,6 Human data in this context remain scarce and not conclusive.
Deficits in cognitive function are a well-known dysfunction in survivors of cardiac arrest. However, data concerning memory function in this neurological vulnerable patient collective remain scarce and inconclusive. Therefore, we aimed to assess multiple aspects of retrospective and prospective memory performance in patients after cardiac arrest.
We prospectively enrolled 33 survivors of cardiac arrest, with cerebral performance categories (CPC) 1 and 2 and a control-group (n = 33) matched in sex, age and educational-level. To assess retrospective and prospective memory performance we administrated 4 weeks after cardiac arrest the “Rey Adult Learning Test” (RAVLT), the “Digit-Span-Backwards Test”, the “Logic-Memory Test” and the “Red-Pencil Test”.
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Episodic long-term memory functioning appears to be particularly impaired after cardiac arrest. In contrast, short-term memory storage, even tested via free-call, seems not to be affected. Based on cranial computed tomography we suggest that global brain ischemia rather than focal brain lesions appear to underlie these effects.
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It is therefore likely that the ischemic insult was the primary cause of hippocampal injury, rather than patient factors. Most patients died or remained in a vegetative state in the few reports of human bilateral hippocampal injury on MRI after cardiac arrest,1,3,7,8 supporting our findings. Mlynash et al8 recently found that hippocampal ADC values trended toward being lower in patients with poor outcomes after cardiac arrest than in controls (patients with normal brains and no hypoxic–ischemic insult).
The role of neuroimaging in assessing prognosis in comatose cardiac survivors appears promising, but little is known regarding the import of particular spatial patterns. We report a specific spatial imaging abnormality on magnetic resonance imaging (MRI) that portends a poor prognosis: bilateral hippocampal hyperintensities on diffusion-weighted imaging (DWI) and fluid-attenuated inversion recovery (FLAIR) sequences.
Eighty sequential comatose cardiac arrest patients underwent MRI scans. Qualitative and quantitative regional analyses were performed. Patients were categorized as HIPPO⁺ (n = 18) or HIPPO⁻ (n = 62) based on whether they had bilateral hippocampal hyperintensities. Poor outcome was defined by a modified Rankin Scale (mRS) score ≥4 at 6 months.
Patients with bilateral hippocampal abnormalities had a higher frequency of poor outcome (P = .032). HIPPO⁺ patients suffered more severe cerebral injury, with lower whole brain apparent diffusion coefficient values (P = .043) and a greater number of affected regions on DWI (P = .001) and FLAIR (P = .001) than HIPPO⁻ patients. The hippocampal approach was 100% specific for a poor prognosis; only 1 patient survived and remained in a vegetative state.
Bilateral hippocampal hyperintensities on MRI may be a specific imaging finding that is indicative of poor prognosis in patients who suffer global hypoxic–ischemic injury. More research on the prognostic significance of this and similar neuroimaging patterns is indicated.
Estradiol protects against hippocampal damage and impairments in fear conditioning resulting from transient global ischemia in mice
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For example, cardiac arrest patients display anterograde amnesia and deficits in semantic memory that are characteristic of medial temporal lobe and hippocampal damage (Cummings et al., 1984; Di Paola et al., 2008; Rempel-Clower et al., 1996; Volpe and Petito, 1985). Post-mortem analysis of patients following cardiac arrest highlights the vulnerability of the hippocampus, striatum, and cortex (Fujioka et al., 2000, 2003; Kawahara et al., 2000; Taraszewska et al., 2002; Wijdicks et al., 2001). In fact, anoxic patients who, like cardiac arrest patients, experience oxygen deficits to the brain show severe atrophy of the hippocampus which correlates with performance on anterograde memory tests (Allen et al., 2006).
Estradiol protects against hippocampal damage and some learning impairments resulting from transient global ischemia in rats. Here, we seek to validate a mouse model of transient global ischemia and evaluate the effects of estradiol on ischemia-induced hippocampal damage and behavioral impairments. Female C57Bl6/J mice were ovariectomized and implanted with estradiol- or oil-secreting capsules. One week later, mice experienced 15-min of 2-vessel occlusion (2-VO) or sham surgical procedures. Five days later, mice were exposed to a fear conditioning protocol in which a specific context and novel tone were paired with mild footshock. Twenty-four hours following conditioning, contextual fear was assessed by measuring freezing behavior in the conditioned context (in the absence of the tone). This was followed by assessment of cue fear by measuring freezing behavior to the conditioned tone presented in a new context. When tested in the conditioned context, oil-treated mice that experienced 2-VO exhibited a significant reduction in freezing behavior whereas estradiol-treated mice that experienced 2-VO showed no disruption in freezing behavior. Freezing behavior when presented with the conditioned tone was unaffected by either surgery or hormone treatment. These findings suggest that global ischemia causes impairments in performance on the hippocampally-dependent contextual fear task but not conditioned cue-based fear. Furthermore, estradiol prevented the ischemia-induced impairment in contextual fear conditioning. Fluoro-Jade (FJ) staining revealed neuronal degeneration throughout the dorsal hippocampus of mice that experienced 2-VO. Estradiol treatment reduced the number of FJ⁺ cells in CA1 and CA2, but not in CA3 or in the dentate gyrus. Together, these findings suggest that 15 min of global ischemia causes extensive hippocampal neurodegeneration and disrupts contextual fear conditioning processes in mice and that estradiol protects against these adverse effects.
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To try to determine the cause of hyperintensity of T1-weighted MR images that occurred on and after day 7 following transient cerebral ischemia, dynamic changes in T1-weighted images and histology of rats subjected to 20 min of 4-vessel occlusion were observed. T1-weighted images showed no remarkable alteration on days 1 and 3, although high signal intensity in the striatal region, in which the T1 value was significantly lower than the values on days 1 and 3, was observed on day 7. High signal intensity in T1-weighted images indicates low T1 values. Histological observation revealed accumulation of microglia in the striatal region on day 7 by lectin staining. There was a tight correlation between T1 values and number of lectin-positive cells. Microglia had stout processes and hypertrophic cell bodies on day 7, resembling lipid-laden phagocytes. Sudan black B staining showed the presence of many fatty droplets in the striatal region on day 7. Furthermore, double staining with lectin and Sudan black B revealed the presence of fatty droplets in bodies of lectin-positive cells on day 7. These results suggest that hyperintensity of T1-weighted images on day 7 following transient ischemia and reperfusion indicates accumulation and phagocytic activation of microglia. T1-weighted images seem to represent the progression of non-reversible tissue injury after transient ischemia and reperfusion.
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View full text

Does diffusion-weighted magnetic resonance imaging enable detection of early ischemic change following transient cerebral ischemia?

Abstract

Introduction

Section snippets

General procedures for animal study

Animal study

Discussion

Acknowledgments

Lancet

Brain Res

Temporal profile of neuronal damage in a model of transient forebrain ischemia

Ann Neurol

Hypoxia and vascular disorder

Neurological outcome after out-of-hospital cardiac arrest. Prediction by cerebrospinal fluid enzyme analysis

Arch Neurol

Prediction of outcome after cardiac arrest

Crit Care Med

Somatosensory evoked potentials in comatose patients: correlation with outcome and neuropathological findings

J Neurol

Cerebral glucose metabolism in acute and persistent vegetative state

J Neurosurg Anesthesiol

Predicting outcome from hypoxic-ischemic coma

J. Am. Med. Assoc.

Identification of major ischemic change. Diffusion-weighted imaging versus computed tomography

Stroke

Diffusion-weighted magnetic resonance imaging in acute stroke

Stroke

Clinical experience with diffusion-weighted MR in patients with acute stroke

AJNR Am J Neuroradiol