EDITORIAL
Traumatic Brain Injury and Stroke See also page 163
142
F
rom bicycle, motorcycle, and football helmets to automobile shoulder straps and air bags, interventions aimed at preventing trauma to the brain seem ubiquitous, and yet more prevention is needed. Traumatic brain injury (TBI) ranges in severity from trivial to catastrophic and presents acutely as concussion. When severe, trauma can cause hemorrhage within various intracranial compartments, brain contusion, diffuse axonal shearing, and brain edema. There is increasing appreciation of long-term consequences of TBI. Repeated TBI can cause chronic traumatic encephalopathy, characterized clinically by amnesia, executive dysfunction, aggression, depression, and parkinsonism.1 It is characterized pathologically by tau-immunoreactive neurofibrillary tangles preferentially involving the superficial cortical layers, astrocytic tangles, and neurities.2 Stroke may be yet another long-term complication of TBI. In the current issue of Mayo Clinic Proceedings, Liao et al3 describe TBI research that employed a national administrative database in Taiwan and included 1 million insured individuals. Their investigation validated an association between TBI and stroke.3 This association was present after adjusting for, among other things, age, sex, and conventional vascular risk factors. In addition, they found that patients were more likely to die following stroke if they had a history of TBI, with the association also holding after similarly adjusting for potential confounders. The investigators further explored a possible dose-response relationship, using the presence or absence of skull fracture, brain hemorrhage, and loss of consciousness as markers of severity of TBI. In general, more severe TBI was associated with greater risk of stroke and of poststroke mortality. The results of Liao et al are consistent with those in a previous report by Burke et al,4 which showed an association between TBI and stroke in a California population. Both studies had a retrospective cohort design and used administrative data. Both studies discovered that TBI was a risk factor for stroke independent of conventional vascular risk factors. However, unlike the Taiwan study of Liao et al,3 the California study of Burke et al4 focused on ischemic stroke rather than stroke overall so as not to inadvertently count traumatic hemorrhage
among cases of hemorrhagic stroke. Another important difference was the choice of controls. The California study used non-TBI trauma cases rather than controls from the general population, reasoning that non-TBI trauma patients would have more in common with TBI patients. The usual cautions should be applied when interpreting the results of these 2 studies. Administrative data are subject to diagnostic misclassification. This can be the case both for the exposure (TBI) and the outcome (stroke). Moderate to severe TBI and stroke are not likely to be missed or misdiagnosed. However, mild TBI may escape capture by administrative data sets, as patients may not seek medical attention for what they regard as a self-limiting condition. Similarly, silent brain infarction, which has an incidence that is 5 times that of symptomatic stroke,5 will not be captured, and mildly symptomatic strokes often occur without being diagnosed.6 Additionally, observational studies face the challenge of residual confounding, in which important risk factors along the causal pathway to stroke are not measured, are imprecisely measured, or are not included in the adjusted analysis. Both the Taiwan and California studies adjusted for potential confounders, but the lists of confounders used in the 2 studies were not identical. Investigators were forced to include only those confounders that were observed. It is somewhat reassuring that, despite this variation in methodology, both studies reached similar conclusions. If we stipulate that the association is valid and, in fact, causal, then why might this be so? About 35% to 45% of patients with moderate to severe TBI have a coagulopathy, generally defined as an elevation of prothrombin time or activated partial thromboplastin time with or without thrombocytopenia, detected early in their hospitalization.7,8 Rates of coagulopathy are higher with more severe head injury (lower Glasgow Coma Scale scores) and with the presence of cerebral edema on computed tomography of the head. The presence of coagulopathy portends worse prognosis. It is unclear, however, whether this early coagulopathy has anything to do with the risk of stroke observed in Taiwan. Some biomarker studies of adult trauma suggest that the presence of coagulopathy relates to the
Mayo Clin Proc. n February 2014;89(2):142-143 n http://dx.doi.org/10.1016/j.mayocp.2013.12.006 www.mayoclinicproceedings.org n ª 2014 Mayo Foundation for Medical Education and Research
EDITORIAL
severity rather than the location of the trauma (TBI vs non-TBI).9 If early coagulopathy of trauma were the explanation for increased risk of stroke, we would not expect to see an association of TBI with stroke in the California study because the investigators used non-TBI trauma patients as controls. Further, it is not clear why a coagulopathy would increase the risk of ischemic stroke, unless it is not the coagulopathy but its treatment with plasma, prothrombin complex concentrate, or factor VIIa that increases the risk. These agents are known to carry a risk for thromboembolic events.10 The use of fresh frozen plasma in patients with TBI who have moderate hemostatic laboratory abnormalities has been associated with poorer functional outcomes.11 The reasons for this are unknown but might relate to clinical or subclinical thrombotic events. Perhaps counterintuitive, although TBI is associated with systemic coagulopathy, it is also associated with microthrombi in the cerebral circulation. A pathologic study found microthrombi in every reviewed section of brain in the cortex and hippocampus of patients with fatal TBI.12 Microthrombi are more prevalent in contused areas of brain than contralateral areas.13 The incidence of microthrombi in nonfatal TBI is unknown. Injury from traumatically induced microthrombi might predispose patients to subsequent stroke. Other mechanisms may also contribute to the increased risk of stroke in patients who have previously experienced TBI. In humans, apoptosis, paraptosis, necrosis, and regeneration of cells of the brain vessels themselves can be seen 4 weeks after TBI on light and transmission electron microscopy.14 Prior insults and injury may lower the threshold for future injury, in this case susceptibility to focal brain ischemia, and repeated insults may have a supra-additive effect on neurologic outcome. A deeper understanding of the mechanisms that underlie the association between TBI and subsequent stroke might lead to novel ways to prevent stroke. If steps to reverse traumatic coagulopathy increase stroke risk, perhaps more targeted or limited therapies might be appropriate. If microthrombi cause subclinical injury that predisposes patients to stroke, early antithrombotic therapies might prevent stroke. It must also be acknowledged that the possible supraadditive effects of repeated insults may never be amenable to new therapies. Before future trials of Mayo Clin Proc. n February 2014;89(2):142-143 www.mayoclinicproceedings.org
n
trauma-related stroke prevention are designed and implemented, there ought to be additional observational studies. Future studies should move beyond clinical outcomes found in administrative databases to radiographic outcomes, preferably with centralized review of brain imaging. James F. Meschia, MD Department of Neurology Mayo Clinic Jacksonville, FL Correspondence: Address to James F. Meschia, MD, Department of Neurology, Mayo Clinic, 4500 San Pablo Rd, Jacksonville, FL 32224 ([email protected]).
REFERENCES 1. Stern RA, Daneshvar DH, Baugh CM, et al. Clinical presentation of chronic traumatic encephalopathy. Neurology. 2013;81(13): 1122-1129. 2. McKee AC, Cantu RC, Nowinski CJ, et al. Chronic traumatic encephalopathy in athletes: progressive tauopathy after repetitive head injury. J Neuropathol Exp Neurol. 2009;68(7):709-735. 3. Liao C-C, Chou Y-C, Yeh C-C, Hu C-J, Chiu W-T, Chen T-L. Stroke risk and outcomes in patients with traumatic brain injury: 2 nationwide studies. Mayo Clin Proc. 2014;89(2):163-172. 4. Burke JF, Stulc JL, Skolarus LE, Sears ED, Zahuranec DB, Morgenstern LB. Traumatic brain injury may be an independent risk factor for stroke. Neurology. 2013;81(1):33-39. 5. Vermeer SE, Hollander M, van Dijk EJ, Hofman A, Koudstaal PJ, Breteler MM; Rotterdam Scan Study. Silent brain infarcts and white matter lesions increase stroke risk in the general population: the Rotterdam Scan Study. Stroke. 2003;34(5):1126-1129. 6. Howard VJ, McClure LA, Meschia JF, Pulley L, Orr SC, Friday GH. High prevalence of stroke symptoms among persons without a diagnosis of stroke or transient ischemic attack in a general population: the REasons for Geographic And Racial Differences in Stroke (REGARDS) study. Arch Intern Med. 2006;166(18):1952-1958. 7. Talving P, Benfield R, Hadjizacharia P, Inaba K, Chan LS, Demetriades D. Coagulopathy in severe traumatic brain injury: a prospective study. J Trauma. 2009;66(1):55-61. 8. Chhabra G, Sharma S, Subramanian A, Agrawal D, Sinha S, Mukhopadhyay AK. Coagulopathy as prognostic marker in acute traumatic brain injury. J Emerg Trauma Shock. 2013;6(3):180-185. 9. Genét GF, Johansson PI, Meyer MA, et al. Trauma-induced coagulopathy: standard coagulation tests, biomarkers of coagulopathy, and endothelial damage in patients with traumatic brain injury. J Neurotrauma. 2013;30(4):301-306. 10. Joseph B, Hadjizacharia P, Aziz H, et al. Prothrombin complex concentrate: an effective therapy in reversing the coagulopathy of traumatic brain injury. J Trauma Acute Care Surg. 2013;74(1): 248-253. 11. Anglin CO, Spence JS, Warner MA, et al. Effects of platelet and plasma transfusion on outcome in traumatic brain injury patients with moderate bleeding diatheses. J Neurosurg. 2013; 118(3):676-686. 12. Stein SC, Graham DI, Chen XH, Smith DH. Association between intravascular microthrombosis and cerebral ischemia in traumatic brain injury. Neurosurgery. 2004;54(3):687-691. 13. Huber A, Dorn A, Witzmann A, Cervós-Navarro J. Microthrombi formation after severe head trauma. Int J Legal Med. 1993;106(3):152-155. 14. Danaila L, Popescu I, Pais V, Riga D, Riga S, Pais E. Apoptosis, paraptosis, necrosis, and cell regeneration in posttraumatic cerebral arteries. Chirurgia (Bucur). 2013;108(3):319-324.
http://dx.doi.org/10.1016/j.mayocp.2013.12.006
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Traumatic Brain Injury and Stroke See also page 163
142
F
rom bicycle, motorcycle, and football helmets to automobile shoulder straps and air bags, interventions aimed at preventing trauma to the brain seem ubiquitous, and yet more prevention is needed. Traumatic brain injury (TBI) ranges in severity from trivial to catastrophic and presents acutely as concussion. When severe, trauma can cause hemorrhage within various intracranial compartments, brain contusion, diffuse axonal shearing, and brain edema. There is increasing appreciation of long-term consequences of TBI. Repeated TBI can cause chronic traumatic encephalopathy, characterized clinically by amnesia, executive dysfunction, aggression, depression, and parkinsonism.1 It is characterized pathologically by tau-immunoreactive neurofibrillary tangles preferentially involving the superficial cortical layers, astrocytic tangles, and neurities.2 Stroke may be yet another long-term complication of TBI. In the current issue of Mayo Clinic Proceedings, Liao et al3 describe TBI research that employed a national administrative database in Taiwan and included 1 million insured individuals. Their investigation validated an association between TBI and stroke.3 This association was present after adjusting for, among other things, age, sex, and conventional vascular risk factors. In addition, they found that patients were more likely to die following stroke if they had a history of TBI, with the association also holding after similarly adjusting for potential confounders. The investigators further explored a possible dose-response relationship, using the presence or absence of skull fracture, brain hemorrhage, and loss of consciousness as markers of severity of TBI. In general, more severe TBI was associated with greater risk of stroke and of poststroke mortality. The results of Liao et al are consistent with those in a previous report by Burke et al,4 which showed an association between TBI and stroke in a California population. Both studies had a retrospective cohort design and used administrative data. Both studies discovered that TBI was a risk factor for stroke independent of conventional vascular risk factors. However, unlike the Taiwan study of Liao et al,3 the California study of Burke et al4 focused on ischemic stroke rather than stroke overall so as not to inadvertently count traumatic hemorrhage
among cases of hemorrhagic stroke. Another important difference was the choice of controls. The California study used non-TBI trauma cases rather than controls from the general population, reasoning that non-TBI trauma patients would have more in common with TBI patients. The usual cautions should be applied when interpreting the results of these 2 studies. Administrative data are subject to diagnostic misclassification. This can be the case both for the exposure (TBI) and the outcome (stroke). Moderate to severe TBI and stroke are not likely to be missed or misdiagnosed. However, mild TBI may escape capture by administrative data sets, as patients may not seek medical attention for what they regard as a self-limiting condition. Similarly, silent brain infarction, which has an incidence that is 5 times that of symptomatic stroke,5 will not be captured, and mildly symptomatic strokes often occur without being diagnosed.6 Additionally, observational studies face the challenge of residual confounding, in which important risk factors along the causal pathway to stroke are not measured, are imprecisely measured, or are not included in the adjusted analysis. Both the Taiwan and California studies adjusted for potential confounders, but the lists of confounders used in the 2 studies were not identical. Investigators were forced to include only those confounders that were observed. It is somewhat reassuring that, despite this variation in methodology, both studies reached similar conclusions. If we stipulate that the association is valid and, in fact, causal, then why might this be so? About 35% to 45% of patients with moderate to severe TBI have a coagulopathy, generally defined as an elevation of prothrombin time or activated partial thromboplastin time with or without thrombocytopenia, detected early in their hospitalization.7,8 Rates of coagulopathy are higher with more severe head injury (lower Glasgow Coma Scale scores) and with the presence of cerebral edema on computed tomography of the head. The presence of coagulopathy portends worse prognosis. It is unclear, however, whether this early coagulopathy has anything to do with the risk of stroke observed in Taiwan. Some biomarker studies of adult trauma suggest that the presence of coagulopathy relates to the
Mayo Clin Proc. n February 2014;89(2):142-143 n http://dx.doi.org/10.1016/j.mayocp.2013.12.006 www.mayoclinicproceedings.org n ª 2014 Mayo Foundation for Medical Education and Research
EDITORIAL
severity rather than the location of the trauma (TBI vs non-TBI).9 If early coagulopathy of trauma were the explanation for increased risk of stroke, we would not expect to see an association of TBI with stroke in the California study because the investigators used non-TBI trauma patients as controls. Further, it is not clear why a coagulopathy would increase the risk of ischemic stroke, unless it is not the coagulopathy but its treatment with plasma, prothrombin complex concentrate, or factor VIIa that increases the risk. These agents are known to carry a risk for thromboembolic events.10 The use of fresh frozen plasma in patients with TBI who have moderate hemostatic laboratory abnormalities has been associated with poorer functional outcomes.11 The reasons for this are unknown but might relate to clinical or subclinical thrombotic events. Perhaps counterintuitive, although TBI is associated with systemic coagulopathy, it is also associated with microthrombi in the cerebral circulation. A pathologic study found microthrombi in every reviewed section of brain in the cortex and hippocampus of patients with fatal TBI.12 Microthrombi are more prevalent in contused areas of brain than contralateral areas.13 The incidence of microthrombi in nonfatal TBI is unknown. Injury from traumatically induced microthrombi might predispose patients to subsequent stroke. Other mechanisms may also contribute to the increased risk of stroke in patients who have previously experienced TBI. In humans, apoptosis, paraptosis, necrosis, and regeneration of cells of the brain vessels themselves can be seen 4 weeks after TBI on light and transmission electron microscopy.14 Prior insults and injury may lower the threshold for future injury, in this case susceptibility to focal brain ischemia, and repeated insults may have a supra-additive effect on neurologic outcome. A deeper understanding of the mechanisms that underlie the association between TBI and subsequent stroke might lead to novel ways to prevent stroke. If steps to reverse traumatic coagulopathy increase stroke risk, perhaps more targeted or limited therapies might be appropriate. If microthrombi cause subclinical injury that predisposes patients to stroke, early antithrombotic therapies might prevent stroke. It must also be acknowledged that the possible supraadditive effects of repeated insults may never be amenable to new therapies. Before future trials of Mayo Clin Proc. n February 2014;89(2):142-143 www.mayoclinicproceedings.org
n
trauma-related stroke prevention are designed and implemented, there ought to be additional observational studies. Future studies should move beyond clinical outcomes found in administrative databases to radiographic outcomes, preferably with centralized review of brain imaging. James F. Meschia, MD Department of Neurology Mayo Clinic Jacksonville, FL Correspondence: Address to James F. Meschia, MD, Department of Neurology, Mayo Clinic, 4500 San Pablo Rd, Jacksonville, FL 32224 ([email protected]).
REFERENCES 1. Stern RA, Daneshvar DH, Baugh CM, et al. Clinical presentation of chronic traumatic encephalopathy. Neurology. 2013;81(13): 1122-1129. 2. McKee AC, Cantu RC, Nowinski CJ, et al. Chronic traumatic encephalopathy in athletes: progressive tauopathy after repetitive head injury. J Neuropathol Exp Neurol. 2009;68(7):709-735. 3. Liao C-C, Chou Y-C, Yeh C-C, Hu C-J, Chiu W-T, Chen T-L. Stroke risk and outcomes in patients with traumatic brain injury: 2 nationwide studies. Mayo Clin Proc. 2014;89(2):163-172. 4. Burke JF, Stulc JL, Skolarus LE, Sears ED, Zahuranec DB, Morgenstern LB. Traumatic brain injury may be an independent risk factor for stroke. Neurology. 2013;81(1):33-39. 5. Vermeer SE, Hollander M, van Dijk EJ, Hofman A, Koudstaal PJ, Breteler MM; Rotterdam Scan Study. Silent brain infarcts and white matter lesions increase stroke risk in the general population: the Rotterdam Scan Study. Stroke. 2003;34(5):1126-1129. 6. Howard VJ, McClure LA, Meschia JF, Pulley L, Orr SC, Friday GH. High prevalence of stroke symptoms among persons without a diagnosis of stroke or transient ischemic attack in a general population: the REasons for Geographic And Racial Differences in Stroke (REGARDS) study. Arch Intern Med. 2006;166(18):1952-1958. 7. Talving P, Benfield R, Hadjizacharia P, Inaba K, Chan LS, Demetriades D. Coagulopathy in severe traumatic brain injury: a prospective study. J Trauma. 2009;66(1):55-61. 8. Chhabra G, Sharma S, Subramanian A, Agrawal D, Sinha S, Mukhopadhyay AK. Coagulopathy as prognostic marker in acute traumatic brain injury. J Emerg Trauma Shock. 2013;6(3):180-185. 9. Genét GF, Johansson PI, Meyer MA, et al. Trauma-induced coagulopathy: standard coagulation tests, biomarkers of coagulopathy, and endothelial damage in patients with traumatic brain injury. J Neurotrauma. 2013;30(4):301-306. 10. Joseph B, Hadjizacharia P, Aziz H, et al. Prothrombin complex concentrate: an effective therapy in reversing the coagulopathy of traumatic brain injury. J Trauma Acute Care Surg. 2013;74(1): 248-253. 11. Anglin CO, Spence JS, Warner MA, et al. Effects of platelet and plasma transfusion on outcome in traumatic brain injury patients with moderate bleeding diatheses. J Neurosurg. 2013; 118(3):676-686. 12. Stein SC, Graham DI, Chen XH, Smith DH. Association between intravascular microthrombosis and cerebral ischemia in traumatic brain injury. Neurosurgery. 2004;54(3):687-691. 13. Huber A, Dorn A, Witzmann A, Cervós-Navarro J. Microthrombi formation after severe head trauma. Int J Legal Med. 1993;106(3):152-155. 14. Danaila L, Popescu I, Pais V, Riga D, Riga S, Pais E. Apoptosis, paraptosis, necrosis, and cell regeneration in posttraumatic cerebral arteries. Chirurgia (Bucur). 2013;108(3):319-324.
http://dx.doi.org/10.1016/j.mayocp.2013.12.006
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