Archives of Physical Medicine and Rehabilitation journal homepage: www.archives-pmr.org Archives of Physical Medicine and Rehabilitation 2014;95(3 Suppl 2):S245-56
REVIEW ARTICLE
Systematic Review of the Risk of Dementia and Chronic Cognitive Impairment After Mild Traumatic Brain Injury: Results of the International Collaboration on Mild Traumatic Brain Injury Prognosis Alison K. Godbolt, MBChB, MD,a Carol Cancelliere, DC, MPH,b,c Cesar A. Hincapie´, DC, MHSc,b,d Connie Marras, MD, PhD,e,f Eleanor Boyle, PhD,d,g Vicki L. Kristman, PhD,d,h,i,j Victor G. Coronado, MD, MPH,k J. David Cassidy, PhD, DrMedScb,c,d,g From the aUniversity Department of Rehabilitation Medicine, Danderyd Hospital, Karolinska Institute, Stockholm, Sweden; bDivision of Health Care and Outcomes Research, Toronto Western Research Institute, University Health Network, University of Toronto, Toronto, Ontario, Canada; c Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada; dDivision of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada; eDepartment of Medicine, University of Toronto, Toronto, Ontario, Canada; fMorton and Gloria Shulman Movement Disorders Centre, and the Edmond J. Safra Program in Parkinson’s Research, Toronto Western Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada; gFaculty of Health, Institute of Sport Science and Clinical Biomechanics, University of Southern Denmark, Odense, Denmark; hDepartment of Health Sciences, Lakehead University, Thunder Bay, Ontario, Canada; iInstitute for Work and Health, Toronto, Ontario, Canada; jDivision of Human Sciences, Northern Ontario School of Medicine, Lakehead University, Thunder Bay, Ontario, Canada; and kNational Center for Injury Prevention and Control, Centers for Disease Control and Prevention, Atlanta, GA.
Abstract Objective: To synthesize the best available evidence regarding the risk of dementia and chronic cognitive impairment (CCI) after mild traumatic brain injury (MTBI). Data Sources: MEDLINE and other databases were searched (2001e2012) using a previously published search strategy and predefined criteria. Peer-reviewed reports in 6 languages were considered. Study Selection: Systematic reviews, meta-analyses, randomized controlled trials, cohort studies, and case-control studies, with a minimum of 30 MTBI cases in subjects of any age, assessing the risk of dementia or CCI after MTBI were selected. Data Extraction: Eligible studies were critically appraised using a modification of the Scottish Intercollegiate Guidelines Network criteria. Two reviewers independently reviewed each study and extracted data from accepted articles (ie, with a low risk of bias) into evidence tables. Data Synthesis: Evidence from accepted studies was synthesized qualitatively according to modified Scottish Intercollegiate Guidelines Network criteria, and prognostic information was prioritized as exploratory or confirmatory according to design. Of 77,914 records screened, 299 articles were eligible and reviewed. Methodological quality was acceptable for 101 (34%) articles, of which 1 article considered dementia and 7 articles considered CCI. The study examining the risk of dementia after MTBI did not find an association. One randomized controlled trial found that being informed about possible cognitive dysfunction after MTBI was associated with worse cognitive performance on standard tests. Children Supported by the Ontario Neurotrauma Foundation (grant reference no. 2010-ABI-MTBIWHO-871). The funder was involved neither in the design or preparation of the study protocol nor in the management of the project, the analysis or interpretation of data, or the preparation of the final article. No commercial party having a direct financial interest in the results of the research supporting this article has or will confer a benefit on the authors or on any organization with which the authors are associated. The findings and conclusions in this research are those of the authors alone and do not necessarily represent the official views or policies of the Centers for Disease Control and Prevention or any agency of the United States government. Inclusion of individuals, programs, or organizations in this article does not constitute endorsement by the United States government.
0003-9993/14/$36 - see front matter ª 2014 by the American Congress of Rehabilitation Medicine http://dx.doi.org/10.1016/j.apmr.2013.06.036
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with MTBI and intracranial pathology (“complicated” MTBI) performed worse than did children without intracranial pathology. Children showed higher rates of cognitive symptoms a year after MTBI than did a control group. Conclusions: There is a lack of evidence of an increased risk of dementia after MTBI. In children, objective evidence of CCI exists only for complicated MTBI. More definitive studies are needed to inform clinical decisions, assessment of prognosis, and public health policy. Archives of Physical Medicine and Rehabilitation 2014;95(3 Suppl 2):S245-56 ª 2014 by the American Congress of Rehabilitation Medicine
Mild traumatic brain injury (MTBI) or concussion is a major public health issue, with an incidence of 100 to 300 per 100,000 people per year.1 Dementia is also a major public health issue, and its incidence and prevalence are strongly related to age. The incidence of dementia is estimated at approximately 7.5 per 1000 people per year,2 while prevalence data show that about 1.5% of 60- to 69-year-olds have dementia, rising to more than 40% for those older than 90 years.3 Treatment options for the common diseases causing dementia (eg, Alzheimer’s disease, vascular dementia, dementia with Lewy bodies, frontotemporal dementia) are currently limited and focus on the stabilization of symptoms rather than on modifying the underlying pathological progress.4 Modification of risk factors as a strategy for minimizing the risk of developing dementia is therefore of major importance in reducing the disease burden in society. A review of the evidence regarding the risk of dementia after MTBI could guide clinical practice and public health strategies. MTBI could alter the risk of developing any of the above diseases causing dementia or could cause a distinct neuropathological process. Indeed, traumatic brain injury (TBI) was first linked to dementia via studies of boxers5 who developed a distinct clinical syndrome “dementia pugilistica.” Since then, neuropathological case series have demonstrated primarily tau-related pathology in the brains of individuals who suffered from a clinical syndrome encompassing dementia and movement disorders after repeated head trauma.6 The syndrome has been called chronic traumatic encephalopathy (CTE). However, there are no established clinical criteria for CTE,6 and uncertainties remain regarding the relation between brain injury and dementia, especially when the brain injury is mild. Repeated MTBIs may occur in many contexts, for example in sports,7 and the hypothesis that these injuries could have significant long-term consequences has face validity. However, the actual consequences of such injuries remain to be elucidated. The relevance of CTE to, for example, a young football player who may suffer 1 or more concussions during his playing career is unknown. The severity and frequency of brain injury may be considerably less than that suffered by the boxers studied in the original descriptions of CTE. Numbers of reported cases of CTE in nonboxers remain extremely small, both in terms of absolute numbers (a recent review reported neuropathologically verified CTE in 5 football players, 1 wrestler, and 1 soccer player8) and in relation to the large numbers of youths and adults exposed to the risk of sports-related concussion.
List of abbreviations: CCI CSHA CTE ICoMP MCI MTBI RCT TBI
chronic cognitive impairment Canadian Study of Health and Aging chronic traumatic encephalopathy International Collaboration on MTBI Prognosis mild cognitive impairment mild traumatic brain injury randomized controlled trial traumatic brain injury
Dementia in its many forms is a devastating, largely untreatable condition, and any person, young or old, will want to do all he/she can to minimize the risk of developing dementia later in life. Some authorities have already acted to warn athletes of the risk of CTE: the nonprofit Sports Legacy Institute issued a press release in June 2012 calling on the National Collegiate Athletic Association to begin to warn athletes about the risk of developing CTE from repetitive brain trauma in sports. Since 2010, the National Football League players have received concussion education materials9 developed by the National Football League, the National Football League Players Association, and the Centers for Disease Control and Prevention. Some of these include warnings about the risk of early-onset dementia. It is important to consider the strength of the evidence underlying such statements. An analysis of the strength of the evidence linking MTBI to dementia is also necessary to allow appropriate consideration of possible negative effects of such advice. Inactivity and obesity have been linked to a rise in diabetes and cardiovascular disease, which are in themselves major public health issues.10 Many sports involve some risk of MTBI, and it is possible (though not demonstrated) that overcautious efforts to avoid such injuries may result in increased inactivity, and actually have a negative impact on public health. A previous systematic review of prognosis after MTBI11 found that the evidence regarding the role of MTBI as a risk factor for dementia was inconclusive. Only 3 studies of acceptable quality addressed this issue,12-14 and the results were inconsistent. This study aimed to provide an update, through a systematic review of the literature published since the previous review, regarding the risk of dementia and/or chronic cognitive impairment (CCI) after MTBI. Findings of this review may inform both public health agencies and individual clinicians working with patients after MTBI.
Methods This systematic review is part of the work of the International Collaboration on MTBI Prognosis (ICoMP). The objective is to provide a systematic update of the evidence published since the World Health Organization Collaborating Centre Task Force on Mild Traumatic Brain Injury findings,11 which considered studies through 2000. The protocol registration, case definition, literature search, critical review strategy, and data synthesis were compliant with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and are described in detail elsewhere.15,16 Briefly, the electronic databases MEDLINE, PsycINFO, Embase, CINAHL, and SPORTDiscus were systematically searched from 2001 to 2012. The search terms included “craniocerebral trauma,” “prognosis,” and “recovery of function.” The reference lists of all reviews and meta-analyses related to MTBI and articles meeting the eligibility criteria were screened for additional studies. In addition, ICoMP members provided www.archives-pmr.org
Dementia and cognitive impairment after mild TBI information about studies of which they had knowledge but that were not found in the databases or reference lists, as an extra measure to ensure completeness. In fact, only 1 additional study for the whole project, and no studies relevant to this article, was identified in this way. Articles were screened for eligibility according to predefined criteria. Inclusion criteria included original, published, peerreviewed research reports in English, French, Swedish, Norwegian, Danish, and Spanish, human participants of all ages, an accepted definition of MTBI, and (additionally for this article) examination of the risk of dementia or cognitive impairment 1 year or more after injury. The definition of MTBI had to fall within the definitions provided by the World Health Organization Collaborating Centre Task Force on Mild Traumatic Brain Injury and the Centers for Disease Control and Prevention. The task force states that MTBI is an acute brain injury resulting from mechanical energy to the head from external physical forces. Operational criteria for clinical identification include: (i) one or more of the following: confusion or disorientation, loss of consciousness for 30 minutes or less, post-traumatic amnesia for less than 24 hours, and/or other transient neurological abnormalities such as focal signs, seizure, and intracranial lesion not requiring surgery; and (ii) Glasgow Coma Scale score of 13e15 after 30 minutes post-injury or later upon presentation for healthcare. These manifestations of MTBI must not be due to drugs, alcohol, medications, caused by other injuries or treatment for other injuries (e.g. systemic injuries, facial injuries or intubation), caused by other problems (e.g. psychological trauma, language barrier or coexisting medical conditions) or caused by penetrating craniocerebral injury.15 Persons with fractured skulls were included if they fit this case definition. The Centers for Disease Control and Prevention provides an additional definition based on clinical records data. MTBI is recognized if an Abbreviated Injury Severity Scale score of 2 for the head region is documented.15 An administrative data definition for surveillance or research is also provided.17 Specifically, cases of MTBI are recognized among persons who are assigned certain International Classification of Diseases, Ninth Revision, Clinical Modification diagnostic codes. Eligible study designs were systematic reviews and metaanalyses, randomized controlled trials (RCTs), cohort studies, and case-control studies. Exclusion criteria included study designs such as cross-sectional studies, case reports and case series, and cadaveric studies, biomechanical studies, and laboratory studies. Studies with fewer than 30 subjects with MTBI were also excluded to provide a sufficient sample size to validly estimate associations between exposures and outcomes. Systematic reviews and meta-analyses that did not consider the methodological quality of included articles were also excluded. For the first level of screening, 1 reviewer read the titles of all the citations retrieved from the electronic database searches and removed all citations that were clearly not related to TBI. The second level of screening involved abstract review. Full-text articles were obtained for all abstracts except for those that clearly did not meet the eligibility criteria. If after analyzing the full text, the eligibility of an article was still uncertain, a second reviewer undertook a full-text analysis of the article to determine eligibility. A third reviewer was consulted in the event of any disagreements.
www.archives-pmr.org
S247 All eligible articles were critically appraised using a modification of the Scottish Intercollegiate Guidelines Network criteria.17 These criteria are well established and appropriate to evaluate common design points and biases of different study designs including RCTs, cohort studies, and case-control studies. Detailed information on modifications can be found in a previously published article on methodology.15 In brief, the following were added: a checklist on definitions of MTBI, a section on references to be checked, and general comments on strengths and weaknesses to optimize later integration of findings. Two reviewers performed independent, in-depth reviews of each eligible study, and a third reviewer was consulted in case of disagreements. Data from accepted articles (ie, those with a low risk of bias) were independently extracted into evidence tables by 2 reviewers, and the evidence was synthesized according to the modified Scottish Intercollegiate Guidelines Network criteria and the phases of study framework described by Coˆte´ et al.18 Phase I studies are hypothesis-generating investigations that explore the associations between potential prognostic factors and disease outcomes in a descriptive or univariate way. Phase II studies are extensive exploratory analyses that focus on particular sets of prognostic factors or attempt to discover which factors have the highest prognostic value. Last, phase III studies are large confirmatory studies of explicit prestated hypotheses that allow for a focused examination of the strength, direction, and independence of the proposed relation between a prognostic factor and the outcome of interest. Information from accepted phase III studies is considered the strongest evidence, followed by evidence from accepted phase II studies. Phase I studies do not consider confounding and are considered more limited evidence. A bestevidence synthesis was performed with the most emphasis placed on the better quality studies (ie, phase III studies) to provide clear and useful conclusions. This process yielded only a small number of studies of acceptable methodological quality. It was considered important to identify reasons for this, given the degree of clinical and public health importance. The database of articles identified in the searches was therefore rescreened, via article abstracts, to identify any further articles relevant to the risk of dementia or CCI that did not meet the inclusion criteria or that had been found to have a high risk of bias by 2 independent reviewers. Rescreening was performed by A.K.G. and C.C., with reference to in-depth reviews already performed by ICoMP members. Reasons for exclusion or unacceptable bias were summarized to inform future research.
Results After applying the inclusion and exclusion criteria to 77,914 titles and abstracts for our entire review, 299 articles were determined to be eligible and were critically reviewed. Of these, 101 (34%) articles were judged scientifically admissible, with a low risk of bias.15 Eight of these studies were eligible for inclusion in this substudy on dementia and CCI after MTBI (figure 1, table 1 and table 2). These encompass 6 studies of children (1 phase I, 4 phase II, and 1 phase III) and 2 studies of adults (1 phase III and 1 RCT). Length of follow-up was 1 year for all 6 studies of children and 1 to 5 years for studies of adults. Only 1 study19 directly considered the risk of dementia after MTBI (phase III cohort study) and found that a history of MTBI was not associated with a future diagnosis of dementia according
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Fig 1 Flow chart of literature review. Abbreviations: dat, date; def, definition; des, study design; I, ineligibility code; lan, language; out, outcomes; pop, population; typ, publication type. From Moher et al.62 For more information, visit www.prisma-statement.org.
to Diagnostic and Statistical Manual Version 3 revised criteria or with other cognitive outcomes. This study analyzed data collected in the 1990s from 2 waves of the community-based Canadian Study of Health and Aging (CSHA).20 Following screening of more than 10,000 potential participants from 18 centers, detailed clinical assessments were performed for 2,914 participants in the first wave (CSHA-1) in 1991 and 2,431 in the second wave (CSHA-2) 5 years later. In CSHA-1, patients were noted to have suffered a previous head injury if this was reported by the patient or by an informant. Injury was defined as mild if there was no reported loss of consciousness or loss of consciousness of less
than 30 minutes. At follow-up after 5 years, a consensus diagnosis was reached regarding cognitive status, with possible diagnoses: dementia (Diagnostic and Statistical Manual Version 3 revised criteria), no cognitive impairment, or cognitive impairment not dementia. The latter group was excluded from further analysis. Of the 648 patients with head injury before CSHA-1, 137 had mild injury. Head injury occurred a mean of 27.822.6 years before CSHA-1 (median age, 57y). A history of MTBI before study entry was not associated with the development of dementia 5 years later. The other low risk of bias studies evaluated possible CCI (rather than dementia) after MTBI, with 6 of 7 of these studies www.archives-pmr.org
Studies with objective measures of cognition or documented diagnosis of dementia as outcome measure
Author, Year, Country, Study Phase Cohort studies Babikian et al, 2011, U.S.,21 phase II
Helmes et al, 2011, Canada,19 phase III
Levin et al, 2008, U.S. and Canada,23 phase II
Source Population, Study Size, Participation Rate, Follow-Up, Time After Injury
MTBI Case Definition
Risk Factors/Outcomes
Findings
Inclusion: Injured subjects: aged 8 e17y; no injuries above AIS 2; unintentional injury; no litigation; no preexisting CNS pathology; Additional criteria: MTBI group: AIShead 1 e2; “other injuries” group: injury AIS 1e2 to nonhead area of body. Exclusion: injuries impacting hand function during testing Inclusion: age > 65y
Concussion causing AIShead 1 (GCS score w15) or AIShead 2 (GCS score w13e14)
Risk factors: MTBI, other injury, no injury. Preinjury learning and behavior, alcohol use, parental education Outcomes: Performance on neuropsych tests
No difference in proportion of MTBI and other injury groups scoring 1.5 SDs below the mean on 3 neuropsych tests: 29% MTBI group, 32% “other injury” group, 18% of the noninjured control group
Self- or informant report of TBI with LOC 0e24h after injury; penetrating brain injury
Inclusion: single MTBI 1 y before testing, verbal PIQ >70 Exclusion: preexisting neurologic disorder, severe preexisting psychiatric disorder, inflicted or gunshot injury
MTBI subgroup: GCS score 13e15, LOC or AOC
REVIEW ARTICLE
Systematic Review of the Risk of Dementia and Chronic Cognitive Impairment After Mild Traumatic Brain Injury: Results of the International Collaboration on Mild Traumatic Brain Injury Prognosis Alison K. Godbolt, MBChB, MD,a Carol Cancelliere, DC, MPH,b,c Cesar A. Hincapie´, DC, MHSc,b,d Connie Marras, MD, PhD,e,f Eleanor Boyle, PhD,d,g Vicki L. Kristman, PhD,d,h,i,j Victor G. Coronado, MD, MPH,k J. David Cassidy, PhD, DrMedScb,c,d,g From the aUniversity Department of Rehabilitation Medicine, Danderyd Hospital, Karolinska Institute, Stockholm, Sweden; bDivision of Health Care and Outcomes Research, Toronto Western Research Institute, University Health Network, University of Toronto, Toronto, Ontario, Canada; c Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada; dDivision of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada; eDepartment of Medicine, University of Toronto, Toronto, Ontario, Canada; fMorton and Gloria Shulman Movement Disorders Centre, and the Edmond J. Safra Program in Parkinson’s Research, Toronto Western Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada; gFaculty of Health, Institute of Sport Science and Clinical Biomechanics, University of Southern Denmark, Odense, Denmark; hDepartment of Health Sciences, Lakehead University, Thunder Bay, Ontario, Canada; iInstitute for Work and Health, Toronto, Ontario, Canada; jDivision of Human Sciences, Northern Ontario School of Medicine, Lakehead University, Thunder Bay, Ontario, Canada; and kNational Center for Injury Prevention and Control, Centers for Disease Control and Prevention, Atlanta, GA.
Abstract Objective: To synthesize the best available evidence regarding the risk of dementia and chronic cognitive impairment (CCI) after mild traumatic brain injury (MTBI). Data Sources: MEDLINE and other databases were searched (2001e2012) using a previously published search strategy and predefined criteria. Peer-reviewed reports in 6 languages were considered. Study Selection: Systematic reviews, meta-analyses, randomized controlled trials, cohort studies, and case-control studies, with a minimum of 30 MTBI cases in subjects of any age, assessing the risk of dementia or CCI after MTBI were selected. Data Extraction: Eligible studies were critically appraised using a modification of the Scottish Intercollegiate Guidelines Network criteria. Two reviewers independently reviewed each study and extracted data from accepted articles (ie, with a low risk of bias) into evidence tables. Data Synthesis: Evidence from accepted studies was synthesized qualitatively according to modified Scottish Intercollegiate Guidelines Network criteria, and prognostic information was prioritized as exploratory or confirmatory according to design. Of 77,914 records screened, 299 articles were eligible and reviewed. Methodological quality was acceptable for 101 (34%) articles, of which 1 article considered dementia and 7 articles considered CCI. The study examining the risk of dementia after MTBI did not find an association. One randomized controlled trial found that being informed about possible cognitive dysfunction after MTBI was associated with worse cognitive performance on standard tests. Children Supported by the Ontario Neurotrauma Foundation (grant reference no. 2010-ABI-MTBIWHO-871). The funder was involved neither in the design or preparation of the study protocol nor in the management of the project, the analysis or interpretation of data, or the preparation of the final article. No commercial party having a direct financial interest in the results of the research supporting this article has or will confer a benefit on the authors or on any organization with which the authors are associated. The findings and conclusions in this research are those of the authors alone and do not necessarily represent the official views or policies of the Centers for Disease Control and Prevention or any agency of the United States government. Inclusion of individuals, programs, or organizations in this article does not constitute endorsement by the United States government.
0003-9993/14/$36 - see front matter ª 2014 by the American Congress of Rehabilitation Medicine http://dx.doi.org/10.1016/j.apmr.2013.06.036
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with MTBI and intracranial pathology (“complicated” MTBI) performed worse than did children without intracranial pathology. Children showed higher rates of cognitive symptoms a year after MTBI than did a control group. Conclusions: There is a lack of evidence of an increased risk of dementia after MTBI. In children, objective evidence of CCI exists only for complicated MTBI. More definitive studies are needed to inform clinical decisions, assessment of prognosis, and public health policy. Archives of Physical Medicine and Rehabilitation 2014;95(3 Suppl 2):S245-56 ª 2014 by the American Congress of Rehabilitation Medicine
Mild traumatic brain injury (MTBI) or concussion is a major public health issue, with an incidence of 100 to 300 per 100,000 people per year.1 Dementia is also a major public health issue, and its incidence and prevalence are strongly related to age. The incidence of dementia is estimated at approximately 7.5 per 1000 people per year,2 while prevalence data show that about 1.5% of 60- to 69-year-olds have dementia, rising to more than 40% for those older than 90 years.3 Treatment options for the common diseases causing dementia (eg, Alzheimer’s disease, vascular dementia, dementia with Lewy bodies, frontotemporal dementia) are currently limited and focus on the stabilization of symptoms rather than on modifying the underlying pathological progress.4 Modification of risk factors as a strategy for minimizing the risk of developing dementia is therefore of major importance in reducing the disease burden in society. A review of the evidence regarding the risk of dementia after MTBI could guide clinical practice and public health strategies. MTBI could alter the risk of developing any of the above diseases causing dementia or could cause a distinct neuropathological process. Indeed, traumatic brain injury (TBI) was first linked to dementia via studies of boxers5 who developed a distinct clinical syndrome “dementia pugilistica.” Since then, neuropathological case series have demonstrated primarily tau-related pathology in the brains of individuals who suffered from a clinical syndrome encompassing dementia and movement disorders after repeated head trauma.6 The syndrome has been called chronic traumatic encephalopathy (CTE). However, there are no established clinical criteria for CTE,6 and uncertainties remain regarding the relation between brain injury and dementia, especially when the brain injury is mild. Repeated MTBIs may occur in many contexts, for example in sports,7 and the hypothesis that these injuries could have significant long-term consequences has face validity. However, the actual consequences of such injuries remain to be elucidated. The relevance of CTE to, for example, a young football player who may suffer 1 or more concussions during his playing career is unknown. The severity and frequency of brain injury may be considerably less than that suffered by the boxers studied in the original descriptions of CTE. Numbers of reported cases of CTE in nonboxers remain extremely small, both in terms of absolute numbers (a recent review reported neuropathologically verified CTE in 5 football players, 1 wrestler, and 1 soccer player8) and in relation to the large numbers of youths and adults exposed to the risk of sports-related concussion.
List of abbreviations: CCI CSHA CTE ICoMP MCI MTBI RCT TBI
chronic cognitive impairment Canadian Study of Health and Aging chronic traumatic encephalopathy International Collaboration on MTBI Prognosis mild cognitive impairment mild traumatic brain injury randomized controlled trial traumatic brain injury
Dementia in its many forms is a devastating, largely untreatable condition, and any person, young or old, will want to do all he/she can to minimize the risk of developing dementia later in life. Some authorities have already acted to warn athletes of the risk of CTE: the nonprofit Sports Legacy Institute issued a press release in June 2012 calling on the National Collegiate Athletic Association to begin to warn athletes about the risk of developing CTE from repetitive brain trauma in sports. Since 2010, the National Football League players have received concussion education materials9 developed by the National Football League, the National Football League Players Association, and the Centers for Disease Control and Prevention. Some of these include warnings about the risk of early-onset dementia. It is important to consider the strength of the evidence underlying such statements. An analysis of the strength of the evidence linking MTBI to dementia is also necessary to allow appropriate consideration of possible negative effects of such advice. Inactivity and obesity have been linked to a rise in diabetes and cardiovascular disease, which are in themselves major public health issues.10 Many sports involve some risk of MTBI, and it is possible (though not demonstrated) that overcautious efforts to avoid such injuries may result in increased inactivity, and actually have a negative impact on public health. A previous systematic review of prognosis after MTBI11 found that the evidence regarding the role of MTBI as a risk factor for dementia was inconclusive. Only 3 studies of acceptable quality addressed this issue,12-14 and the results were inconsistent. This study aimed to provide an update, through a systematic review of the literature published since the previous review, regarding the risk of dementia and/or chronic cognitive impairment (CCI) after MTBI. Findings of this review may inform both public health agencies and individual clinicians working with patients after MTBI.
Methods This systematic review is part of the work of the International Collaboration on MTBI Prognosis (ICoMP). The objective is to provide a systematic update of the evidence published since the World Health Organization Collaborating Centre Task Force on Mild Traumatic Brain Injury findings,11 which considered studies through 2000. The protocol registration, case definition, literature search, critical review strategy, and data synthesis were compliant with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and are described in detail elsewhere.15,16 Briefly, the electronic databases MEDLINE, PsycINFO, Embase, CINAHL, and SPORTDiscus were systematically searched from 2001 to 2012. The search terms included “craniocerebral trauma,” “prognosis,” and “recovery of function.” The reference lists of all reviews and meta-analyses related to MTBI and articles meeting the eligibility criteria were screened for additional studies. In addition, ICoMP members provided www.archives-pmr.org
Dementia and cognitive impairment after mild TBI information about studies of which they had knowledge but that were not found in the databases or reference lists, as an extra measure to ensure completeness. In fact, only 1 additional study for the whole project, and no studies relevant to this article, was identified in this way. Articles were screened for eligibility according to predefined criteria. Inclusion criteria included original, published, peerreviewed research reports in English, French, Swedish, Norwegian, Danish, and Spanish, human participants of all ages, an accepted definition of MTBI, and (additionally for this article) examination of the risk of dementia or cognitive impairment 1 year or more after injury. The definition of MTBI had to fall within the definitions provided by the World Health Organization Collaborating Centre Task Force on Mild Traumatic Brain Injury and the Centers for Disease Control and Prevention. The task force states that MTBI is an acute brain injury resulting from mechanical energy to the head from external physical forces. Operational criteria for clinical identification include: (i) one or more of the following: confusion or disorientation, loss of consciousness for 30 minutes or less, post-traumatic amnesia for less than 24 hours, and/or other transient neurological abnormalities such as focal signs, seizure, and intracranial lesion not requiring surgery; and (ii) Glasgow Coma Scale score of 13e15 after 30 minutes post-injury or later upon presentation for healthcare. These manifestations of MTBI must not be due to drugs, alcohol, medications, caused by other injuries or treatment for other injuries (e.g. systemic injuries, facial injuries or intubation), caused by other problems (e.g. psychological trauma, language barrier or coexisting medical conditions) or caused by penetrating craniocerebral injury.15 Persons with fractured skulls were included if they fit this case definition. The Centers for Disease Control and Prevention provides an additional definition based on clinical records data. MTBI is recognized if an Abbreviated Injury Severity Scale score of 2 for the head region is documented.15 An administrative data definition for surveillance or research is also provided.17 Specifically, cases of MTBI are recognized among persons who are assigned certain International Classification of Diseases, Ninth Revision, Clinical Modification diagnostic codes. Eligible study designs were systematic reviews and metaanalyses, randomized controlled trials (RCTs), cohort studies, and case-control studies. Exclusion criteria included study designs such as cross-sectional studies, case reports and case series, and cadaveric studies, biomechanical studies, and laboratory studies. Studies with fewer than 30 subjects with MTBI were also excluded to provide a sufficient sample size to validly estimate associations between exposures and outcomes. Systematic reviews and meta-analyses that did not consider the methodological quality of included articles were also excluded. For the first level of screening, 1 reviewer read the titles of all the citations retrieved from the electronic database searches and removed all citations that were clearly not related to TBI. The second level of screening involved abstract review. Full-text articles were obtained for all abstracts except for those that clearly did not meet the eligibility criteria. If after analyzing the full text, the eligibility of an article was still uncertain, a second reviewer undertook a full-text analysis of the article to determine eligibility. A third reviewer was consulted in the event of any disagreements.
www.archives-pmr.org
S247 All eligible articles were critically appraised using a modification of the Scottish Intercollegiate Guidelines Network criteria.17 These criteria are well established and appropriate to evaluate common design points and biases of different study designs including RCTs, cohort studies, and case-control studies. Detailed information on modifications can be found in a previously published article on methodology.15 In brief, the following were added: a checklist on definitions of MTBI, a section on references to be checked, and general comments on strengths and weaknesses to optimize later integration of findings. Two reviewers performed independent, in-depth reviews of each eligible study, and a third reviewer was consulted in case of disagreements. Data from accepted articles (ie, those with a low risk of bias) were independently extracted into evidence tables by 2 reviewers, and the evidence was synthesized according to the modified Scottish Intercollegiate Guidelines Network criteria and the phases of study framework described by Coˆte´ et al.18 Phase I studies are hypothesis-generating investigations that explore the associations between potential prognostic factors and disease outcomes in a descriptive or univariate way. Phase II studies are extensive exploratory analyses that focus on particular sets of prognostic factors or attempt to discover which factors have the highest prognostic value. Last, phase III studies are large confirmatory studies of explicit prestated hypotheses that allow for a focused examination of the strength, direction, and independence of the proposed relation between a prognostic factor and the outcome of interest. Information from accepted phase III studies is considered the strongest evidence, followed by evidence from accepted phase II studies. Phase I studies do not consider confounding and are considered more limited evidence. A bestevidence synthesis was performed with the most emphasis placed on the better quality studies (ie, phase III studies) to provide clear and useful conclusions. This process yielded only a small number of studies of acceptable methodological quality. It was considered important to identify reasons for this, given the degree of clinical and public health importance. The database of articles identified in the searches was therefore rescreened, via article abstracts, to identify any further articles relevant to the risk of dementia or CCI that did not meet the inclusion criteria or that had been found to have a high risk of bias by 2 independent reviewers. Rescreening was performed by A.K.G. and C.C., with reference to in-depth reviews already performed by ICoMP members. Reasons for exclusion or unacceptable bias were summarized to inform future research.
Results After applying the inclusion and exclusion criteria to 77,914 titles and abstracts for our entire review, 299 articles were determined to be eligible and were critically reviewed. Of these, 101 (34%) articles were judged scientifically admissible, with a low risk of bias.15 Eight of these studies were eligible for inclusion in this substudy on dementia and CCI after MTBI (figure 1, table 1 and table 2). These encompass 6 studies of children (1 phase I, 4 phase II, and 1 phase III) and 2 studies of adults (1 phase III and 1 RCT). Length of follow-up was 1 year for all 6 studies of children and 1 to 5 years for studies of adults. Only 1 study19 directly considered the risk of dementia after MTBI (phase III cohort study) and found that a history of MTBI was not associated with a future diagnosis of dementia according
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A.K. Godbolt et al
Fig 1 Flow chart of literature review. Abbreviations: dat, date; def, definition; des, study design; I, ineligibility code; lan, language; out, outcomes; pop, population; typ, publication type. From Moher et al.62 For more information, visit www.prisma-statement.org.
to Diagnostic and Statistical Manual Version 3 revised criteria or with other cognitive outcomes. This study analyzed data collected in the 1990s from 2 waves of the community-based Canadian Study of Health and Aging (CSHA).20 Following screening of more than 10,000 potential participants from 18 centers, detailed clinical assessments were performed for 2,914 participants in the first wave (CSHA-1) in 1991 and 2,431 in the second wave (CSHA-2) 5 years later. In CSHA-1, patients were noted to have suffered a previous head injury if this was reported by the patient or by an informant. Injury was defined as mild if there was no reported loss of consciousness or loss of consciousness of less
than 30 minutes. At follow-up after 5 years, a consensus diagnosis was reached regarding cognitive status, with possible diagnoses: dementia (Diagnostic and Statistical Manual Version 3 revised criteria), no cognitive impairment, or cognitive impairment not dementia. The latter group was excluded from further analysis. Of the 648 patients with head injury before CSHA-1, 137 had mild injury. Head injury occurred a mean of 27.822.6 years before CSHA-1 (median age, 57y). A history of MTBI before study entry was not associated with the development of dementia 5 years later. The other low risk of bias studies evaluated possible CCI (rather than dementia) after MTBI, with 6 of 7 of these studies www.archives-pmr.org
Studies with objective measures of cognition or documented diagnosis of dementia as outcome measure
Author, Year, Country, Study Phase Cohort studies Babikian et al, 2011, U.S.,21 phase II
Helmes et al, 2011, Canada,19 phase III
Levin et al, 2008, U.S. and Canada,23 phase II
Source Population, Study Size, Participation Rate, Follow-Up, Time After Injury
MTBI Case Definition
Risk Factors/Outcomes
Findings
Inclusion: Injured subjects: aged 8 e17y; no injuries above AIS 2; unintentional injury; no litigation; no preexisting CNS pathology; Additional criteria: MTBI group: AIShead 1 e2; “other injuries” group: injury AIS 1e2 to nonhead area of body. Exclusion: injuries impacting hand function during testing Inclusion: age > 65y
Concussion causing AIShead 1 (GCS score w15) or AIShead 2 (GCS score w13e14)
Risk factors: MTBI, other injury, no injury. Preinjury learning and behavior, alcohol use, parental education Outcomes: Performance on neuropsych tests
No difference in proportion of MTBI and other injury groups scoring 1.5 SDs below the mean on 3 neuropsych tests: 29% MTBI group, 32% “other injury” group, 18% of the noninjured control group
Self- or informant report of TBI with LOC 0e24h after injury; penetrating brain injury
Inclusion: single MTBI 1 y before testing, verbal PIQ >70 Exclusion: preexisting neurologic disorder, severe preexisting psychiatric disorder, inflicted or gunshot injury
MTBI subgroup: GCS score 13e15, LOC or AOC
