Neurocrit Care DOI 10.1007/s12028-014-9980-0
ORIGINAL ARTICLE
Severe Leukoaraiosis Portends a Poor Outcome After Traumatic Brain Injury Nils Henninger • Saef Izzy • Raphael Carandang Wiley Hall • Susanne Muehlschlegel
•
Ó Springer Science+Business Media New York 2014
Abstract Background and Purpose It is now well accepted that traumatic white matter injury constitutes a critical determinant of post-traumatic functional impairment. However, the contribution of preexisting white matter rarefaction on outcome following traumatic brain injury (TBI) is unknown. Hence, we sought to determine whether the burden of preexisting leukoaraiosis of presumed ischemic origin is independently associated with outcome after TBI. Methods We retrospectively analyzed consecutive, prospectively enrolled patients of C50 years (n = 136) who were admitted to a single neurological/trauma intensive care unit. Supratentorial white matter hypoattenuation on head CT was graded on a 5-point scale (range 0–4) reflecting increasing severity of leukoaraiosis. Outcome was ascertained according to the modified Rankin Scale
Electronic supplementary material The online version of this article (doi:10.1007/s12028-014-9980-0) contains supplementary material, which is available to authorized users. N. Henninger (&) S. Izzy R. Carandang W. Hall S. Muehlschlegel Department of Neurology, University of Massachusetts Medical School, 55 Lake Ave, North, Worcester, MA 01655, USA e-mail: [email protected] N. Henninger Department of Psychiatry, University of Massachusetts Medical School, 55 Lake Ave, North, Worcester, MA 01655, USA R. Carandang W. Hall S. Muehlschlegel Department of Surgery, University of Massachusetts Medical School, Worcester, MA, USA S. Muehlschlegel Department of Anesthesia/Critical Care, University of Massachusetts Medical School, Worcester, MA 01655, USA
(mRS) and Glasgow outcome scale (GOS) at 3 and 12 months, respectively. Results After adjustment for other factors, leukoaraiosis severity was significantly associated with a poor outcome at 3 and 12 months defined as mRS 3–6 and GOS 1–3, respectively. The independent association between leukoaraiosis and poor outcome remained when the analysis was restricted to patients who survived up to 3 months, had moderate-to-severe TBI [enrollment Glasgow Coma Scale (GCS) B12; p = 0.001], or had mild TBI (GCS 13–15; p = 0.002), respectively. Conclusion We provide first evidence that preexisting cerebral small vessel disease independently predicts a poor functional outcome after closed head TBI. This association is independent of other established outcome predictors such as age, comorbid state as well as intensive care unit complications and interventions. This knowledge may help improve prognostic accuracy, clinical management, and resource utilization. Keywords Cerebral small vessel disease CT Leukoaraiosis Old age Outcome Traumatic brain injury White matter injury
Introduction Traumatic brain injury (TBI) remains a leading cause of adult disability and death with annual related costs in excess of 60 billion dollars in the US [1]. There are an estimated 57 million individuals living with TBI-related disability worldwide [2] and more than 5 million Americans live with long-term disability related to TBI [3]. Despite this significant societal impact and substantial research, the pathophysiology underlying functional
123
Neurocrit Care
deficits encountered after TBI remains poorly understood. Nevertheless, traumatic white matter injury has been increasingly recognized as a critical contributor to postTBI neurological dysfunction [4]. While numerous studies have focused on post-traumatic white matter injury, the potential contribution of preexisting white matter rarefaction to TBI outcome remains unknown. White matter rarefaction (leukoaraiosis) is frequently encountered in the elderly [5], contributes to cognitive impairment and dementia [6], and has been shown to worsen outcome after acute stroke [7, 8]. Considering the expected tripling of the number of persons aged 60 or over in developed nations by 2050 [9], disproportionate representation of elderly among those requiring hospitalization for head injuries [10], and worse post-TBI outcomes in the elderly [11], it is critical to understand the contribution of leukoaraiosis to the functional deficits caused by TBI. To elucidate this issue, we sought to investigate the association between preexisting leukoaraiosis and outcome as assessed by the 3- and 12-month modified Rankin Scale (mRS) as well as Glasgow Outcome Scale (GOS) in consecutive patients admitted for non-penetrating head injury to a single academic level one trauma center.
Methods Study Population This study was reviewed and approved by our Institutional Review Board. We conducted a retrospective analysis of 312 consecutive, prospectively collected patients with acute TBI admitted to a single level one academic trauma center between November, 2009 and August, 2013. All patients were admitted to a neurological/trauma intensive care unit (ICU) and were enrolled in the Outcome Prognostication in Traumatic Brain Injury (OPTIMISM) Study. Details of this ongoing study including data collection as well as the standards of clinical management have previously been published [12]. To allow for better generalization we included patients with all trauma severities [Glasgow Coma Scale (GCS) 3–15] in the current analysis. Of note, a verbal GCS of ‘‘T’’ (intubated patients) was transformed as previously detailed to allow statistical analysis of GCS as a continuous variable [13]. Given that leukoaraiosis is rarely present in the young [5], we included only patients of C50 years of age. TBI was diagnosed based on the provided history and injury mechanism. Patients with an acute non-traumatic brain lesion (e.g., hypoxic-ischemic injury) on admission non-contrast computed tomography (CT) were not enrolled [12]. GOS and
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modified Rankin Scale (mRS), which are validated outcome measures for neurocritical care patients [14], were assessed at follow-up or over the phone at 3 and 12 months after trauma by a trained physician or study nurse using a structured interview [12]. For patients with unknown functional status prior to trauma, the pre-admission mRS was retrospectively reconstructed from medical records according to the mRS criteria [7]. Image Review and Analysis All patients had a head computed tomogram (CT) performed at admission [12]. Details of the neuroimaging protocol as well as image review have previously been reported [12, 15]. In brief, the initial CT was reviewed, graded, and adjudicated weekly by three experienced board certified neurointensivists (R.C.; W.H.; and S.M.) according to the Marshall CT grading scale [12, 16]. The main lesion noted on admission CT was classified according to one of eight subtypes: Subdural hematoma, contusion, traumatic subarachnoid hemorrhage, intraventricular hemorrhage, intraparenchymal hemorrhage, epidural hemorrhage, global edema, and diffuse (traumatic) axonal injury. Diffuse axonal injury was defined as multiple small (1–15 mm in diameter) ovoid focal traumatic lesions as previously described [17]. Leukoaraiosis was retrospectively defined by two readers (N.H. and S.I.) blinded to Marshall CT grading, clinical data, and any follow-up scans as supratentorial white matter hypoattenuation on admission head CT according to the STandards for ReportIng Vascular changes on nEuroimaging (STRIVE) criteria [18] and graded on a 5-point scale utilizing the van Swieten scale (VSS) as previously detailed [7, 15, 19]. Though diffuse axonal injury is typically not associated with acute hypodense lesions on CT [20], we nevertheless sought to exclude ovoid lesions of
ORIGINAL ARTICLE
Severe Leukoaraiosis Portends a Poor Outcome After Traumatic Brain Injury Nils Henninger • Saef Izzy • Raphael Carandang Wiley Hall • Susanne Muehlschlegel
•
Ó Springer Science+Business Media New York 2014
Abstract Background and Purpose It is now well accepted that traumatic white matter injury constitutes a critical determinant of post-traumatic functional impairment. However, the contribution of preexisting white matter rarefaction on outcome following traumatic brain injury (TBI) is unknown. Hence, we sought to determine whether the burden of preexisting leukoaraiosis of presumed ischemic origin is independently associated with outcome after TBI. Methods We retrospectively analyzed consecutive, prospectively enrolled patients of C50 years (n = 136) who were admitted to a single neurological/trauma intensive care unit. Supratentorial white matter hypoattenuation on head CT was graded on a 5-point scale (range 0–4) reflecting increasing severity of leukoaraiosis. Outcome was ascertained according to the modified Rankin Scale
Electronic supplementary material The online version of this article (doi:10.1007/s12028-014-9980-0) contains supplementary material, which is available to authorized users. N. Henninger (&) S. Izzy R. Carandang W. Hall S. Muehlschlegel Department of Neurology, University of Massachusetts Medical School, 55 Lake Ave, North, Worcester, MA 01655, USA e-mail: [email protected] N. Henninger Department of Psychiatry, University of Massachusetts Medical School, 55 Lake Ave, North, Worcester, MA 01655, USA R. Carandang W. Hall S. Muehlschlegel Department of Surgery, University of Massachusetts Medical School, Worcester, MA, USA S. Muehlschlegel Department of Anesthesia/Critical Care, University of Massachusetts Medical School, Worcester, MA 01655, USA
(mRS) and Glasgow outcome scale (GOS) at 3 and 12 months, respectively. Results After adjustment for other factors, leukoaraiosis severity was significantly associated with a poor outcome at 3 and 12 months defined as mRS 3–6 and GOS 1–3, respectively. The independent association between leukoaraiosis and poor outcome remained when the analysis was restricted to patients who survived up to 3 months, had moderate-to-severe TBI [enrollment Glasgow Coma Scale (GCS) B12; p = 0.001], or had mild TBI (GCS 13–15; p = 0.002), respectively. Conclusion We provide first evidence that preexisting cerebral small vessel disease independently predicts a poor functional outcome after closed head TBI. This association is independent of other established outcome predictors such as age, comorbid state as well as intensive care unit complications and interventions. This knowledge may help improve prognostic accuracy, clinical management, and resource utilization. Keywords Cerebral small vessel disease CT Leukoaraiosis Old age Outcome Traumatic brain injury White matter injury
Introduction Traumatic brain injury (TBI) remains a leading cause of adult disability and death with annual related costs in excess of 60 billion dollars in the US [1]. There are an estimated 57 million individuals living with TBI-related disability worldwide [2] and more than 5 million Americans live with long-term disability related to TBI [3]. Despite this significant societal impact and substantial research, the pathophysiology underlying functional
123
Neurocrit Care
deficits encountered after TBI remains poorly understood. Nevertheless, traumatic white matter injury has been increasingly recognized as a critical contributor to postTBI neurological dysfunction [4]. While numerous studies have focused on post-traumatic white matter injury, the potential contribution of preexisting white matter rarefaction to TBI outcome remains unknown. White matter rarefaction (leukoaraiosis) is frequently encountered in the elderly [5], contributes to cognitive impairment and dementia [6], and has been shown to worsen outcome after acute stroke [7, 8]. Considering the expected tripling of the number of persons aged 60 or over in developed nations by 2050 [9], disproportionate representation of elderly among those requiring hospitalization for head injuries [10], and worse post-TBI outcomes in the elderly [11], it is critical to understand the contribution of leukoaraiosis to the functional deficits caused by TBI. To elucidate this issue, we sought to investigate the association between preexisting leukoaraiosis and outcome as assessed by the 3- and 12-month modified Rankin Scale (mRS) as well as Glasgow Outcome Scale (GOS) in consecutive patients admitted for non-penetrating head injury to a single academic level one trauma center.
Methods Study Population This study was reviewed and approved by our Institutional Review Board. We conducted a retrospective analysis of 312 consecutive, prospectively collected patients with acute TBI admitted to a single level one academic trauma center between November, 2009 and August, 2013. All patients were admitted to a neurological/trauma intensive care unit (ICU) and were enrolled in the Outcome Prognostication in Traumatic Brain Injury (OPTIMISM) Study. Details of this ongoing study including data collection as well as the standards of clinical management have previously been published [12]. To allow for better generalization we included patients with all trauma severities [Glasgow Coma Scale (GCS) 3–15] in the current analysis. Of note, a verbal GCS of ‘‘T’’ (intubated patients) was transformed as previously detailed to allow statistical analysis of GCS as a continuous variable [13]. Given that leukoaraiosis is rarely present in the young [5], we included only patients of C50 years of age. TBI was diagnosed based on the provided history and injury mechanism. Patients with an acute non-traumatic brain lesion (e.g., hypoxic-ischemic injury) on admission non-contrast computed tomography (CT) were not enrolled [12]. GOS and
123
modified Rankin Scale (mRS), which are validated outcome measures for neurocritical care patients [14], were assessed at follow-up or over the phone at 3 and 12 months after trauma by a trained physician or study nurse using a structured interview [12]. For patients with unknown functional status prior to trauma, the pre-admission mRS was retrospectively reconstructed from medical records according to the mRS criteria [7]. Image Review and Analysis All patients had a head computed tomogram (CT) performed at admission [12]. Details of the neuroimaging protocol as well as image review have previously been reported [12, 15]. In brief, the initial CT was reviewed, graded, and adjudicated weekly by three experienced board certified neurointensivists (R.C.; W.H.; and S.M.) according to the Marshall CT grading scale [12, 16]. The main lesion noted on admission CT was classified according to one of eight subtypes: Subdural hematoma, contusion, traumatic subarachnoid hemorrhage, intraventricular hemorrhage, intraparenchymal hemorrhage, epidural hemorrhage, global edema, and diffuse (traumatic) axonal injury. Diffuse axonal injury was defined as multiple small (1–15 mm in diameter) ovoid focal traumatic lesions as previously described [17]. Leukoaraiosis was retrospectively defined by two readers (N.H. and S.I.) blinded to Marshall CT grading, clinical data, and any follow-up scans as supratentorial white matter hypoattenuation on admission head CT according to the STandards for ReportIng Vascular changes on nEuroimaging (STRIVE) criteria [18] and graded on a 5-point scale utilizing the van Swieten scale (VSS) as previously detailed [7, 15, 19]. Though diffuse axonal injury is typically not associated with acute hypodense lesions on CT [20], we nevertheless sought to exclude ovoid lesions of
