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Diffusion tensor imaging as a surrogate marker for outcome after perimesencephalic subarachnoid hemorrhage
Clinical Neurology and Neurosurgery 114 (2012) 798–800
Contents lists available at SciVerse ScienceDirect
Clinical Neurology and Neurosurgery journal homepage: www.elsevier.com/locate/clineuro
Case report
Diffusion tensor imaging as a surrogate marker for outcome after perimesencephalic subarachnoid hemorrhage Tom A. Schweizer a,b,c,d,∗ , Timour Al-Khindi a , R. Loch Macdonald a,b,c a
Division of Neurosurgery, St. Michael’s Hospital, Toronto, ON, Canada Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, ON, Canada Keenan Research Centre of the Li Ka Shing Knowledge Institute at St. Michael’s Hospital, Toronto, ON, Canada d Heart and Stroke Foundation of Ontario Centre for Stroke Recovery, Toronto, Canada b c
a r t i c l e
i n f o
Article history: Received 25 February 2011 Received in revised form 14 December 2011 Accepted 31 December 2011 Available online 7 February 2012 Keywords: Diffusion tensor imaging Magnetic resonance imaging Outcome Subarachnoid hemorrhage
1. Introduction Perimesencephalic subarachnoid hemorrhage (pSAH) accounts for approximately 5% of all spontaneous subarachnoid hemorrhage and is characterized by the accumulation of blood in the midbrain cisterns. Angiography usually reveals no source of hemorrhage. Initially, pSAH was associated with a favorable prognosis: patients with pSAH had a low risk of rebleeding, no decrease in quality of life, and no problems with returning to work or other activities. More recent reports, however, suggest that pSAH may not be as benign as previously believed. Madureira et al. [1] found that 72% of patients with pSAH were impaired in at least 1 cognitive domain and 33% exhibited depressive symptoms over 3 years after pSAH. Neuroimaging, however, was not used to explain pSAH survivors’ persistent cognitive deficits. Thus, the neuroanatomical changes responsible for pSAH-associated cognitive impairment remain largely unknown. Although magnetic resonance imaging (MRI) has been instrumental in advancing our understanding of how brain injury contributes to cognitive impairment, a growing body of literature
∗ Corresponding author at: Division of Neurosurgery, St. Michael’s Hospital, 30 Bond Street, Toronto, ON M5B 1W8, Canada. Tel.: +1 416 864 5504; fax: +1 416 864 5857. E-mail addresses: [email protected] (T.A. Schweizer), [email protected] (T. Al-Khindi), [email protected] (R. Loch Macdonald). 0303-8467/$ – see front matter © 2012 Elsevier B.V. All rights reserved. doi:10.1016/j.clineuro.2011.12.045
suggests that MRI may not detect all cases of brain injury. Other neuroimaging techniques, such as diffusion tensor imaging (DTI), may be more sensitive to brain injury than conventional MRI; Hugenschmidt et al. [2] found that alterations in white matter integrity detected by DTI may precede observable white matter atrophy on conventional MRI. In the present case report, we investigated whether DTI represents a surrogate marker for active white matter degeneration in a pSAH patient with documented cognitive and functional impairment. 2. Case report A 60 year old, right-handed male (S.L.) with 20 years of education was brought to hospital following sudden onset of severe headache. The patient had not engaged in any strenuous activity beforehand and there was no loss of consciousness or transient amnesia. Glasgow coma scale on admission was 15. Patient S.L. had a history of hypercholesterolemia but was otherwise healthy. Initial computed tomography (CT) revealed subarachnoid blood in the interpeduncular and prepontine cisterns, as well as in the bilateral Sylvian fissures (thicker in the right hemisphere; Fig. 1). Hemorrhage was classified as World Federation of Neurosurgical Societies grade 1, Fisher grade 3, and Hijdra scale 18/30. Catheter angiography revealed no aneurysm or arteriovenous malformation that could account for the hemorrhage. Initial MRI showed mild hydrocephalus with a ventriculocranial ratio of 0.21 (upper
T.A. Schweizer et al. / Clinical Neurology and Neurosurgery 114 (2012) 798–800
Fig. 1. CT on admission. Acute non-contrast CT scan showing subarachnoid blood confined to the midbrain cisterns. Note the thicker subarachnoid blood in the right hemisphere compared to the left hemisphere (arrows). Image is in neurological convention.
limit of 95% confidence interval for 60 year old healthy control subjects is 0.19). Hydrocephalus resolved within 2 days of admission. MRI revealed no signs of ischemia or infarction. CT angiography 3 days after admission revealed mild basilar artery vasospasm. S.L. remained in hospital for 7 days. Glasgow coma scale throughout the hospital stay was 15. Detailed neuropsychological assessment and 3T structural MRI and DTI were conducted 229 days and 303 days after hospital admission, respectively. At 229 days post-ictus, S.L. had not returned to work as a partner in a large law firm. S.L. scored 26/30 on the Mini Mental State Examination. The Hospital Anxiety and Depression Scale revealed no depression and borderline anxiety. Performance on tests of psychomotor function, information processing, visuospatial function, and language was within normal limits (z > −1.00, p > 0.32). S.L., however, exhibited significant long-term memory impairment, as measured by delayed recall on the California Verbal Learning Test (z = −2.00, p = 0.04). Additionally, S.L. presented with impaired planning abilities, as measured by the Stockings of Cambridge Test (z = −2.47, p = 0.01). Examination of T1-weighted, T2-weighted, and fluidattenuated inversion recovery (FLAIR) MRI at 303 days post-admission revealed no evidence of infarction or any other brain changes that could account for S.L.’s cognitive and functional impairments. Compared to three healthy, age-matched control participants, S.L.’s hippocampal volumes were in the above average range (right hippocampus: z = 1.47, p = 0.14; left hippocampus: z = 1.28, p = 0.20). Mean fractional anisotropy (FA), a DTI measure of white matter integrity, was in the above average range in the left hippocampus (z = 1.57, p = 0.12), but markedly reduced in the right hippocampus (z = −3.62, p < 0.001). Tractography also revealed a smaller, less dense bundle of white matter tracts in the right hippocampus compared to the left hippocampus (Fig. 2). There was a distinct asymmetry in mean FA in the dorsolateral prefrontal region, with the left dorsolateral prefrontal region showing substantially reduced FA (z = 0.88, p = 0.38) compared to the right dorsolateral prefrontal region (z = 2.01, p = 0.04).
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Fig. 2. DTI results at 303 days post-ictus. Diffusion tensor image of white matter tracts in the hippocampi at 303 days post-pSAH. The right hippocampus has a smaller, less dense bundle of white matter tracts than the left hippocampus. Image is in neurological convention.
3. Discussion At 229 days post-ictus, S.L. exhibited severely impaired longterm memory and planning. Many day-to-day activities, including successful work performance, depend heavily on cognitive processes like memory and planning. S.L.’s failure to return to work as a partner in a large law firm may be partially attributed to his severe planning and memory impairment. This is consistent with prior research demonstrating a correlation between return to work and impaired memory and planning after aneurysmal subarachnoid hemorrhage [3]. Our results are the first to report that DTI used in patients with pSAH may increase the ability to detect early and subtle neuropathological changes. Indeed, prior studies have found DTI to be an effective means of detecting subtle white matter injury in healthy older adults [2]. In the present case, careful examination of T1-weighted, T2-weighted, and FLAIR MRI revealed no infarction or brain atrophy. Although hippocampal volumes were in the above average range, S.L. showed reduced white matter integrity in the right hippocampus, a region implicated in long-term memory. Reduced hippocampal white matter integrity may explain S.L.’s long-term memory impairment. Selective targeting of the right hippocampus may be attributed to thicker subarachnoid blood in the right hemisphere observed on the acute CT (Fig. 1). DTI also revealed hemispheric asymmetry in dorsolateral prefrontal white matter integrity. S.L.’s impaired planning may be explained by comparatively reduced white matter integrity in the left dorsolateral prefrontal region, an area involved in plan execution [4]. Reduced white matter integrity in the absence of grey matter atrophy demonstrates the sensitivity of DTI. White matter injury after pSAH has not been previously described. Several mechanisms of brain injury after subarachnoid hemorrhage have been proposed but none definitively explain the selective white matter injury observed in the present case. Brain injury after pSAH may result from transient global ischemia,
800
T.A. Schweizer et al. / Clinical Neurology and Neurosurgery 114 (2012) 798–800
but this is unlikely given that S.L. did not lose consciousness. S.L. did not have substantial hydrocephalus that might stretch and injure white matter fibers. Cortical ischemia was absent, thereby ruling out cortical spreading ischemia. Mild vasospasm was observed, but it involved the basilar artery remote from areas of white matter damage. Brain injury after pSAH may result from microthromboemboli. After basal cisternal subarachnoid hemorrhage in rats, microthromboemboli were observed in a scattered, patchy distribution throughout both hemispheres [5]. Whether microthromboemboli could damage white matter fibers is unknown. 4. Conclusion In summary, we describe a unique white matter injury occurring after pSAH. Additional studies are needed to determine the mechanisms by which subarachnoid blood affects white matter. The present findings provide preliminary evidence of DTI as a valuable clinical tool and suggest that DTI may be more effective than standard MRI in explaining cognitive and functional outcome after subarachnoid hemorrhage. Future research should test this hypothesis in a larger cohort of subarachnoid hemorrhage survivors.
Conflicts of interest None. Acknowledgments We gratefully acknowledge the Brain Aneurysm Foundation and the Heart and Stroke Foundation Centre for Stroke Recovery for providing financial support for the present research. References [1] Madureira S, Canhão P, Guerreiro M, Ferro JM. Cognitive and emotional consequences of perimesencephalic subarachnoid hemorrhage. J Neurol 2000;415:862–7. [2] Hugenschmidt CE, Peiffer AM, Kraft RA, Casanova R, Deibler AR, Burdette JH, et al. Relating imaging indices of white matter integrity and volume in healthy older adults. Cereb Cortex 2008;18:433–42. [3] Vilkki JS, Juvela S, Siironen J, Ilvonen T, Varis J, Porras M. Relationship of local infarction to cognitive and psychosocial impairments after aneurysmal subarachnoid hemorrhage. Neurosurgery 2004;55:790–803. [4] Newman SD, Carpenter PA, Varma S, Just MA. Frontal and parietal participation in problem solving in the Tower of London: fMRI and computational modeling of planning and high-level perception. Neuropsychologia 2003;41:1668–82. [5] Sabri M, Ai J, Knight B, Tariq A, Jeon H, Shang X, et al. Uncoupling of endothelial nitric oxide synthase after experimental subarachnoid hemorrhage. J Cereb Blood Flow Metab 2011;31:190–9.
Contents lists available at SciVerse ScienceDirect
Clinical Neurology and Neurosurgery journal homepage: www.elsevier.com/locate/clineuro
Case report
Diffusion tensor imaging as a surrogate marker for outcome after perimesencephalic subarachnoid hemorrhage Tom A. Schweizer a,b,c,d,∗ , Timour Al-Khindi a , R. Loch Macdonald a,b,c a
Division of Neurosurgery, St. Michael’s Hospital, Toronto, ON, Canada Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, ON, Canada Keenan Research Centre of the Li Ka Shing Knowledge Institute at St. Michael’s Hospital, Toronto, ON, Canada d Heart and Stroke Foundation of Ontario Centre for Stroke Recovery, Toronto, Canada b c
a r t i c l e
i n f o
Article history: Received 25 February 2011 Received in revised form 14 December 2011 Accepted 31 December 2011 Available online 7 February 2012 Keywords: Diffusion tensor imaging Magnetic resonance imaging Outcome Subarachnoid hemorrhage
1. Introduction Perimesencephalic subarachnoid hemorrhage (pSAH) accounts for approximately 5% of all spontaneous subarachnoid hemorrhage and is characterized by the accumulation of blood in the midbrain cisterns. Angiography usually reveals no source of hemorrhage. Initially, pSAH was associated with a favorable prognosis: patients with pSAH had a low risk of rebleeding, no decrease in quality of life, and no problems with returning to work or other activities. More recent reports, however, suggest that pSAH may not be as benign as previously believed. Madureira et al. [1] found that 72% of patients with pSAH were impaired in at least 1 cognitive domain and 33% exhibited depressive symptoms over 3 years after pSAH. Neuroimaging, however, was not used to explain pSAH survivors’ persistent cognitive deficits. Thus, the neuroanatomical changes responsible for pSAH-associated cognitive impairment remain largely unknown. Although magnetic resonance imaging (MRI) has been instrumental in advancing our understanding of how brain injury contributes to cognitive impairment, a growing body of literature
∗ Corresponding author at: Division of Neurosurgery, St. Michael’s Hospital, 30 Bond Street, Toronto, ON M5B 1W8, Canada. Tel.: +1 416 864 5504; fax: +1 416 864 5857. E-mail addresses: [email protected] (T.A. Schweizer), [email protected] (T. Al-Khindi), [email protected] (R. Loch Macdonald). 0303-8467/$ – see front matter © 2012 Elsevier B.V. All rights reserved. doi:10.1016/j.clineuro.2011.12.045
suggests that MRI may not detect all cases of brain injury. Other neuroimaging techniques, such as diffusion tensor imaging (DTI), may be more sensitive to brain injury than conventional MRI; Hugenschmidt et al. [2] found that alterations in white matter integrity detected by DTI may precede observable white matter atrophy on conventional MRI. In the present case report, we investigated whether DTI represents a surrogate marker for active white matter degeneration in a pSAH patient with documented cognitive and functional impairment. 2. Case report A 60 year old, right-handed male (S.L.) with 20 years of education was brought to hospital following sudden onset of severe headache. The patient had not engaged in any strenuous activity beforehand and there was no loss of consciousness or transient amnesia. Glasgow coma scale on admission was 15. Patient S.L. had a history of hypercholesterolemia but was otherwise healthy. Initial computed tomography (CT) revealed subarachnoid blood in the interpeduncular and prepontine cisterns, as well as in the bilateral Sylvian fissures (thicker in the right hemisphere; Fig. 1). Hemorrhage was classified as World Federation of Neurosurgical Societies grade 1, Fisher grade 3, and Hijdra scale 18/30. Catheter angiography revealed no aneurysm or arteriovenous malformation that could account for the hemorrhage. Initial MRI showed mild hydrocephalus with a ventriculocranial ratio of 0.21 (upper
T.A. Schweizer et al. / Clinical Neurology and Neurosurgery 114 (2012) 798–800
Fig. 1. CT on admission. Acute non-contrast CT scan showing subarachnoid blood confined to the midbrain cisterns. Note the thicker subarachnoid blood in the right hemisphere compared to the left hemisphere (arrows). Image is in neurological convention.
limit of 95% confidence interval for 60 year old healthy control subjects is 0.19). Hydrocephalus resolved within 2 days of admission. MRI revealed no signs of ischemia or infarction. CT angiography 3 days after admission revealed mild basilar artery vasospasm. S.L. remained in hospital for 7 days. Glasgow coma scale throughout the hospital stay was 15. Detailed neuropsychological assessment and 3T structural MRI and DTI were conducted 229 days and 303 days after hospital admission, respectively. At 229 days post-ictus, S.L. had not returned to work as a partner in a large law firm. S.L. scored 26/30 on the Mini Mental State Examination. The Hospital Anxiety and Depression Scale revealed no depression and borderline anxiety. Performance on tests of psychomotor function, information processing, visuospatial function, and language was within normal limits (z > −1.00, p > 0.32). S.L., however, exhibited significant long-term memory impairment, as measured by delayed recall on the California Verbal Learning Test (z = −2.00, p = 0.04). Additionally, S.L. presented with impaired planning abilities, as measured by the Stockings of Cambridge Test (z = −2.47, p = 0.01). Examination of T1-weighted, T2-weighted, and fluidattenuated inversion recovery (FLAIR) MRI at 303 days post-admission revealed no evidence of infarction or any other brain changes that could account for S.L.’s cognitive and functional impairments. Compared to three healthy, age-matched control participants, S.L.’s hippocampal volumes were in the above average range (right hippocampus: z = 1.47, p = 0.14; left hippocampus: z = 1.28, p = 0.20). Mean fractional anisotropy (FA), a DTI measure of white matter integrity, was in the above average range in the left hippocampus (z = 1.57, p = 0.12), but markedly reduced in the right hippocampus (z = −3.62, p < 0.001). Tractography also revealed a smaller, less dense bundle of white matter tracts in the right hippocampus compared to the left hippocampus (Fig. 2). There was a distinct asymmetry in mean FA in the dorsolateral prefrontal region, with the left dorsolateral prefrontal region showing substantially reduced FA (z = 0.88, p = 0.38) compared to the right dorsolateral prefrontal region (z = 2.01, p = 0.04).
799
Fig. 2. DTI results at 303 days post-ictus. Diffusion tensor image of white matter tracts in the hippocampi at 303 days post-pSAH. The right hippocampus has a smaller, less dense bundle of white matter tracts than the left hippocampus. Image is in neurological convention.
3. Discussion At 229 days post-ictus, S.L. exhibited severely impaired longterm memory and planning. Many day-to-day activities, including successful work performance, depend heavily on cognitive processes like memory and planning. S.L.’s failure to return to work as a partner in a large law firm may be partially attributed to his severe planning and memory impairment. This is consistent with prior research demonstrating a correlation between return to work and impaired memory and planning after aneurysmal subarachnoid hemorrhage [3]. Our results are the first to report that DTI used in patients with pSAH may increase the ability to detect early and subtle neuropathological changes. Indeed, prior studies have found DTI to be an effective means of detecting subtle white matter injury in healthy older adults [2]. In the present case, careful examination of T1-weighted, T2-weighted, and FLAIR MRI revealed no infarction or brain atrophy. Although hippocampal volumes were in the above average range, S.L. showed reduced white matter integrity in the right hippocampus, a region implicated in long-term memory. Reduced hippocampal white matter integrity may explain S.L.’s long-term memory impairment. Selective targeting of the right hippocampus may be attributed to thicker subarachnoid blood in the right hemisphere observed on the acute CT (Fig. 1). DTI also revealed hemispheric asymmetry in dorsolateral prefrontal white matter integrity. S.L.’s impaired planning may be explained by comparatively reduced white matter integrity in the left dorsolateral prefrontal region, an area involved in plan execution [4]. Reduced white matter integrity in the absence of grey matter atrophy demonstrates the sensitivity of DTI. White matter injury after pSAH has not been previously described. Several mechanisms of brain injury after subarachnoid hemorrhage have been proposed but none definitively explain the selective white matter injury observed in the present case. Brain injury after pSAH may result from transient global ischemia,
800
T.A. Schweizer et al. / Clinical Neurology and Neurosurgery 114 (2012) 798–800
but this is unlikely given that S.L. did not lose consciousness. S.L. did not have substantial hydrocephalus that might stretch and injure white matter fibers. Cortical ischemia was absent, thereby ruling out cortical spreading ischemia. Mild vasospasm was observed, but it involved the basilar artery remote from areas of white matter damage. Brain injury after pSAH may result from microthromboemboli. After basal cisternal subarachnoid hemorrhage in rats, microthromboemboli were observed in a scattered, patchy distribution throughout both hemispheres [5]. Whether microthromboemboli could damage white matter fibers is unknown. 4. Conclusion In summary, we describe a unique white matter injury occurring after pSAH. Additional studies are needed to determine the mechanisms by which subarachnoid blood affects white matter. The present findings provide preliminary evidence of DTI as a valuable clinical tool and suggest that DTI may be more effective than standard MRI in explaining cognitive and functional outcome after subarachnoid hemorrhage. Future research should test this hypothesis in a larger cohort of subarachnoid hemorrhage survivors.
Conflicts of interest None. Acknowledgments We gratefully acknowledge the Brain Aneurysm Foundation and the Heart and Stroke Foundation Centre for Stroke Recovery for providing financial support for the present research. References [1] Madureira S, Canhão P, Guerreiro M, Ferro JM. Cognitive and emotional consequences of perimesencephalic subarachnoid hemorrhage. J Neurol 2000;415:862–7. [2] Hugenschmidt CE, Peiffer AM, Kraft RA, Casanova R, Deibler AR, Burdette JH, et al. Relating imaging indices of white matter integrity and volume in healthy older adults. Cereb Cortex 2008;18:433–42. [3] Vilkki JS, Juvela S, Siironen J, Ilvonen T, Varis J, Porras M. Relationship of local infarction to cognitive and psychosocial impairments after aneurysmal subarachnoid hemorrhage. Neurosurgery 2004;55:790–803. [4] Newman SD, Carpenter PA, Varma S, Just MA. Frontal and parietal participation in problem solving in the Tower of London: fMRI and computational modeling of planning and high-level perception. Neuropsychologia 2003;41:1668–82. [5] Sabri M, Ai J, Knight B, Tariq A, Jeon H, Shang X, et al. Uncoupling of endothelial nitric oxide synthase after experimental subarachnoid hemorrhage. J Cereb Blood Flow Metab 2011;31:190–9.