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Systematic Review of Prognosis After Mild Traumatic Brain Injury in the Military: Results of the International Collaboration on Mild Traumatic Brain Injury Prognosis

  • Eleanor Boyle
    Correspondence
    Corresponding author Eleanor Boyle, PhD, Institute of Sports Science and Clinical Biomechanics, University of Southern Denmark, Campusvej 55, Odense M 5230, Denmark.
    Affiliations
    Institute of Sports Science and Clinical Biomechanics, Faculty of Health, University of Southern Denmark, Odense, Denmark

    Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada
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  • Carol Cancelliere
    Affiliations
    Division of Health Care and Outcomes Research, Toronto Western Research Institute, University Health Network, University of Toronto, Toronto, Ontario, Canada

    Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada
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  • Jan Hartvigsen
    Affiliations
    Institute of Sports Science and Clinical Biomechanics, Faculty of Health, University of Southern Denmark, Odense, Denmark
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  • Linda J. Carroll
    Affiliations
    School of Public Health and Alberta Centre for Injury Control and Research, University of Alberta, Edmonton, Alberta, Canada
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  • Lena W. Holm
    Affiliations
    Division of Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
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  • J. David Cassidy
    Affiliations
    Institute of Sports Science and Clinical Biomechanics, Faculty of Health, University of Southern Denmark, Odense, Denmark

    Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada

    Division of Health Care and Outcomes Research, Toronto Western Research Institute, University Health Network, University of Toronto, Toronto, Ontario, Canada

    Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada
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      Abstract

      Objective

      The World Health Organization Collaborating Centre Task Force on Mild Traumatic Brain Injury (MTBI) published its findings on the prognosis of MTBI in 2004. This is an update of that review with a focus on deployed military personnel.

      Data Sources

      Relevant literature published between January 2001 and February 2012 listed in MEDLINE and 4 other databases.

      Study Selection

      Controlled trials and cohort and case-control studies were selected according to predefined criteria. After 77,914 titles and abstracts were screened, 13 articles were rated eligible for this review and 3 (23%) with a low risk of bias were accepted. Two independent reviewers critically appraised eligible studies using a modification of the Scottish Intercollegiate Guidelines Network criteria.

      Data Extraction

      The reviewers independently extracted data from eligible studies and produced evidence tables.

      Data Synthesis

      The evidence was synthesized qualitatively and presented in evidence tables. Our findings are based on 3 studies of U.S. military personnel who were deployed in Iraq or Afghanistan. We found that military personnel with MTBI report posttraumatic stress disorder and postconcussive symptoms. In addition, reporting of postconcussive symptoms differed on the basis of levels of combat stress the individuals experienced. The evidence suggests a slight decline in neurocognitive function after MTBI, but this decline was in the normal range of brain functioning.

      Conclusions

      We found limited evidence that combat stress, posttraumatic stress disorder, and postconcussive symptoms affect recovery and prognosis of MTBI in military personnel. Additional high-quality research is needed to fully assess the prognosis of MTBI in military personnel.

      Keywords

      List of abbreviations:

      ICoMP (International Collaboration on MTBI Prognosis), MTBI (mild traumatic brain injury), PCL-C (Posttraumatic Stress Disorder Check List–Civilian), PTSD (posttraumatic stress disorder), TBI (traumatic brain injury)
      Injuries sustained in combat today differ from the injuries sustained in previous wars.
      • Hoge C.W.
      • McGurk D.
      • Thomas J.L.
      • Cox A.L.
      • Engel C.C.
      • Castro C.A.
      Mild traumatic brain injury in U.S. soldiers returning from Iraq.
      • Warden D.
      Military TBI during the Iraq and Afghanistan wars.
      The proportion of head and neck wounds has doubled from the Vietnam War, whereas thoracic and abdominal injuries have declined.
      • Belmont P.J.
      • Schoenfeld A.J.
      • Goodman G.
      Epidemiology of combat wounds in Operation Iraqi Freedom and Operation Enduring Freedom: orthopaedic burden of disease.
      This change can be explained by various factors including the use of body armor and Kevlar helmets, which have reduced life-threatening injuries to the head, chest, and abdomen. Also, advances in in-theater medical care have reduced the killed-wounded ratio to less than 1 in 10.
      • Ling G.
      • Bandak F.
      • Armonda R.
      • Grant G.
      • Ecklund J.
      Explosive blast neurotrauma.
      Furthermore, the use of mine-resistant ambush-protected vehicles that diminish the effects of improvised explosive devices has resulted in a reduction in fatalities from roadside explosives.
      • Belmont P.J.
      • Schoenfeld A.J.
      • Goodman G.
      Epidemiology of combat wounds in Operation Iraqi Freedom and Operation Enduring Freedom: orthopaedic burden of disease.
      Traumatic brain injury (TBI) and posttraumatic stress disorder (PTSD) are being referred to as the “signature” injuries in the current U.S. conflicts.
      • Burke H.S.
      • Degeneffe C.E.
      • Olney M.F.
      A new disability for rehabilitation counselors: Iraq War veterans with traumatic brain injury and post-traumatic stress disorder.
      One of the most common causal agents for injuries is exposure to blasts, which can result in TBIs with different degrees of severity.
      • Wojcik B.E.
      • Stein C.R.
      • Bagg K.
      • Humphrey R.J.
      • Orosco J.
      Traumatic brain injury hospitalizations of U.S. army soldiers deployed to Afghanistan and Iraq.
      Based on the mechanism by which blast-related injuries are produced, these are classified into 4 groups.
      Centers for Disease Control and Prevention
      Explosions and blast injuries: a primer for clinicians.
      • Horrocks C.L.
      Blast injuries: biophysics, pathophysiology and management principles.
      A primary blast injury occurs when the injury is sustained from the explosive materials. A secondary blast injury results from being hit by matter thrown by the explosion or by the fragments of the weapon casing. A tertiary blast injury is the result of the individual's being thrown by the explosive blast and hitting another object such as a wall or the ground. Last, a quaternary blast injury can occur from burns, toxic fumes, and other causes not covered in the previous 3 definitions.
      It has been estimated that 60% to 80% of the military personnel who are exposed to a blast acquire a TBI.
      • Burke H.S.
      • Degeneffe C.E.
      • Olney M.F.
      A new disability for rehabilitation counselors: Iraq War veterans with traumatic brain injury and post-traumatic stress disorder.
      • Wilk J.E.
      • Thomas J.L.
      • McGurk D.M.
      • Riviere L.A.
      • Castro C.A.
      • Hoge C.W.
      Mild traumatic brain injury (concussion) during combat: lack of association of blast mechanism with persistent postconcussive symptoms.
      From 2000 to the first quarter of 2012, 244,217 cases of TBIs were reported among U.S. military personnel by the Defense Medical Surveillance System and the Theater Medical Data Store.
      United States Department of Defense
      Numbers for traumatic brain injury.
      Slightly over 75% of the TBIs were classified as mild, and only 1.6% were penetrating head injuries. Approximately 58% of these injuries occurred in U.S. Army personnel, and the remaining injuries occurred evenly in the Navy, Marines, and Air Force. According to the Defense Medical Surveillance System, the incidence rate of mild traumatic brain injury (MTBI) between 1997 and 2007 in the U.S. military was approximately 6.6 per 1000 person-years.
      • Cameron K.L.
      • Marshall S.W.
      • Sturdivant R.X.
      • Lincoln A.E.
      Trends in the incidence of physician-diagnosed mild traumatic brain injury among active duty U.S. military personnel between 1997 and 2007.
      This incidence rate significantly varies by age groups (younger have higher rates), sex (men higher than women), race (white higher than other races), rank (enlisted higher than officer), and branch of service (Army and Marines higher than other branches). The cost of care for TBI in the U.S. military population has risen from $21 million in 2003 to approximately $646 million in 2010.
      United States Department of Defense
      Report to congress on expenditures for activities on traumatic brain injury and psychological health, including posttraumatic stress disorder, for 2010.
      The majority of the prognostic research in MTBI has been conducted in the civilian population. For example, the World Health Organization Collaborating Centre Task Force on Mild Traumatic Brain Injury published the first systematic review on MTBI prognosis in 2004. It accepted only 1 article involving a military population.
      • Carroll L.J.
      • Cassidy J.D.
      • Peloso P.M.
      • et al.
      Prognosis for mild traumatic brain injury: results of the WHO Collaborating Centre Task Force on Mild Traumatic Brain Injury.
      In that study, conducted 1 year after the Gulf War, the authors found a 1.8 times greater risk of a behavioral-related discharge in military personnel who had an MTBI than in persons who were discharged without a brain injury.
      • Ommaya A.K.
      • Salazar A.M.
      • Dannenberg A.L.
      • Ommaya A.K.
      • Chervinsky A.B.
      • Schwab K.
      Outcome after traumatic brain injury in the U.S. military medical system.
      The majority of the head injuries in that study were related to falls (31.8%) and motor vehicle collisions (30.4%); these mechanisms are similar to those seen in civilian injuries. It is unclear whether these results of the study would be generalizable to MTBIs that occurred in-theater.
      • Ommaya A.K.
      • Ommaya A.K.
      • Dannenberg A.L.
      • Salazar A.M.
      Causation, incidence, and costs of traumatic brain injury in the U.S. military medical system.
      There are inherent differences in the combat military population and civilian population.
      • Warden D.
      Military TBI during the Iraq and Afghanistan wars.
      Depending on the country, military personnel might have been evaluated with predeployment health screens and physical fitness standards. All military personnel are employed at the time of injury, which may not be true in the civilian population. The prevalence of MTBI is higher in the military population than in civilian populations living in noncombat zones, and in particular, blast TBIs are higher.
      • Duckworth J.L.
      • Grimes J.
      • Ling G.S.
      Pathophysiology of battlefield associated traumatic brain injury.
      Depending on the length of deployment and the probability of being exposed to improvised explosive devices, there is a greater chance that military personnel may experience repeated TBIs.
      • Rigg J.L.
      • Mooney S.R.
      Concussions and the military: issues specific to service members.
      Last, standardized triage and care is provided to military personnel throughout the recovery period.
      • Xydakis M.S.
      • Ling G.S.
      • Mulligan L.P.
      • Olsen C.H.
      • Dorlac W.C.
      Epidemiologic aspects of traumatic brain injury in acute combat casualties at a major military medical center: a cohort study.
      In the present study, we aimed to update and expand on the original World Health Organization Collaborating Centre Task Force on Mild Traumatic Brain Injury on the prognosis of MTBI by focusing solely on the military population. The specific objective of this study was to synthesize the best available evidence on the course and prognosis of MTBI in the military population.

      Methods

      The literature search and synthesis strategy has been outlined in detail elsewhere and in this issue.
      • Cancelliere C.
      • Cassidy J.D.
      • Côté P.
      • et al.
      Protocol for a systematic review of prognosis after mild traumatic brain injury: an update of the WHO Collaborating Centre Task Force findings.
      • Cancelliere C.
      • Cassidy J.D.
      • Li A.
      • Donovan J.
      • Côté P.
      • Hincapié C.A.
      Systematic search and review procedures: results of the International Collaboration on Mild Traumatic Brain Injury Prognosis..
      In brief, using a detailed search strategy, MEDLINE, PsycINFO, Embase, CINAHL, and SPORTDiscus were searched from January 1, 2001, to February 10, 2012. In addition, the reference lists of eligible articles were screened for potentially relevant articles and members of the International Collaboration on MTBI Prognosis (ICoMP) provided titles of articles that were not found in the search strategy. Using predefined inclusion and exclusion criteria, articles were screened for eligibility. Inclusion criteria were as follows: controlled trials, cohort studies, or case-control studies; published in peer-reviewed journals; written in English, French, Swedish, Norwegian, Danish, or Spanish; and included a minimum of 30 MTBI cases of military personnel that were independent of duty status at the time of injury (ie, active duty, reservist, or veteran). Cross-sectional studies and case reports and series were excluded. In addition, cadaveric studies, biomechanical studies, and laboratory studies were excluded. Systematic reviews and meta-analyses reference lists were checked for relevant studies, but these designs were not included in our review.
      MTBI was defined using criteria established by the World Health Organization Collaborating Centre Task Force on Mild Traumatic Brain Injury and the U.S. Centers for Disease Control and Prevention. It was defined as follows: (1) 1 or more of the following symptoms: confusion or disorientation, loss of consciousness for 30 minutes or less, posttraumatic amnesia for less than 24 hours, and/or other transient neurological abnormalities such as focal signs, seizure, and intracranial lesion not requiring surgery; and (2) Glasgow Coma Scale score of 13 to 15 thirty minutes postinjury or later on presentation for health care. These symptoms of MTBI must not be due to drugs, alcohol, or medications; caused by other injuries or treatment for other injuries (eg, systemic injuries, facial injuries, or intubation); caused by other problems (eg, psychological trauma, language barrier, or coexisting medical conditions); or caused by penetrating craniocerebral injury.
      • Carroll L.J.
      • Cassidy J.D.
      • Holm L.
      • Kraus J.
      • Coronado V.G.
      WHO Collaborating Centre Task Force on Mild Traumatic Brain Injury
      Methodological issues and research recommendations for mild traumatic brain injury: the WHO Collaborating Centre Task Force on Mild Traumatic Brain Injury.
      Persons with fractured skulls were included if they fit this case definition. The causal agent could not be bullet(s) and/or fragment(s) because this may have resulted in a penetrating brain injury. 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.
      Centers for Disease Control and Prevention
      Explosions and blast injuries: a primer for clinicians.
      An administrative data definition for surveillance or research is also provided. Specifically, cases of MTBI are recognized among persons who are assigned certain International Classification of Diseases, Ninth Revision, Clinical Modification, diagnostic codes.
      • Cancelliere C.
      • Cassidy J.D.
      • Li A.
      • Donovan J.
      • Côté P.
      • Hincapié C.A.
      Systematic search and review procedures: results of the International Collaboration on Mild Traumatic Brain Injury Prognosis..
      Two reviewers independently appraised each study using a modification of the Scottish Intercollegiate Guidelines Network criteria.

      Scottish Intercollegiate Guidelines Network. Available at: http://www.sign.ac.uk/. Accessed 2011.

      A third reviewer was consulted if any disagreements arose between the 2 reviewers. Data from the accepted articles were extracted by 2 reviewers independently and placed into evidence tables (table 1). The evidence on prognostic factors was categorized into phases on the basis of study designs as described by Côté et al.
      • Côté P.
      • Cassidy J.D.
      • Carroll L.
      • Frank J.W.
      • Bombardier C.
      A systematic review of the prognosis of acute whiplash and a new conceptual framework to synthesize the literature.
      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 for a prognostic factor, followed by evidence from accepted phase II studies. Phase I studies do not consider confounding factors and are considered more limited evidence.
      Table 1Evidence table
      Author, Year, and CountrySource Population, Study Size, Participation, Follow-UpInclusion/Exclusion CriteriaMTBI Case DefinitionPrognostic Factors/OutcomesFindings
      Cohort studies
       Phase III studies
      Cooper et al, 2010,

      United States
      • Cooper D.B.
      • Mercado-Couch J.M.
      • Critchfield E.
      • et al.
      Factors influencing cognitive functioning following mild traumatic brain injury in OIF/OEF burn patients.
      Consecutive admissions of OIF and OEF military service members from September 2005 through October 2007 to the burn ward at Brooke Army Medical Center (n=194)Inclusion: Age at least 18y, English speaking, and sustained an injury while on active military duty

      Exclusion: Duration of PTA >24h, not able to complete the manual portion of neuropsychological testing because of severe bilateral burns and/or amputations, and preexisting neurological disorder
      LOC<30min; loss of memory for events immediately before or after the accident (PTA<24 h); any alteration in mental state at the time of the injury (ie, dazed, disoriented, confused); and if available, a GCS score of ≥13

      Case definition was determined through detailed clinical interviews and review of records conducted by 2 clinical neuropsychologists
      Prognostic factors:

      Age, education, race (majority/minority), weeks postinjury, ISS, narcotic pain medications, psychiatric diagnosis, TBSA

      Outcome:

      RBANS
      Blast-injured burn subjects who sustained an MTBI were likely to perform slightly worse on measures of attention and processing speed than those who did not have MTBI in the acute phase of recovery. On average, subjects were interviewed 8wk postinjury

      Psychiatric comorbidities did not have a statistically significant effect on cognitive functioning, which was contrary to the authors' hypothesis
      Cooper et al, 2011, United States
      • Cooper D.B.
      • Kennedy J.E.
      • Cullen M.A.
      • Critchfield E.
      • Amador R.R.
      • Bowles A.O.
      Association between combat stress and post-concussive symptom reporting in OEF/OIF service members with mild traumatic brain injuries.
      Active duty service members including activated reservists and members of the National Guard, who were evaluated at a military medical treatment facility following a combat deployment to Iraq or Afghanistan (n=472)

      Analyzed: n=240
      Inclusion: Service members identified as possibly sustaining a TBI through a 3-item questionnaire

      Exclusion: Subjects withmoderate or severe TBI: GCS score of ≤ 12, LOC>30min and/or duration of PTA >24h or penetrating brain injuries. Subjects who reported 3 or more combat deployments were excluded because of difficulties in obtaining a clear clinical history of MTBI(s) and symptom onset following multiple deployments
      ACRM criteria: At least 1 of the following: LOC<30 min; PTA<24h; any alteration in mental state at the time of the injury (ie, dazed, disoriented, confused); presence of focal neurological deficits; and GCS score of ≥13Prognostic factors:

      Age, sex, military rank, blast mechanism of injury, months postinjury, and first deployment

      Outcomes:

      PCL-C, NSI
      NSI total scores were significantly higher for the high combat stress group than for the low combat stress group after controlling for the characteristics that were different between the 2 groups, which were sex, rank, and time postinjury

      All NSI item and cluster scores were also significantly higher for the high combat stress group than for the low stress group
       Phase II studies
      Kennedy et al, 2010, United States
      • Kennedy J.E.
      • Cullen M.A.
      • Amador R.R.
      • Huey J.C.
      • Leal F.O.
      Symptoms in military service members after blast mTBI with and without associated injuries.
      Military personnel who were evaluated at Brooke Army Medical Center, Fort Sam Houston, Texas, and Wilfort Hall Medical Center Lackland Air Force Base, Texas, for MTBI as a consequence of being exposed to an explosive/blast munitions

      while deployed in Iraq during the period of January 10, 2007, to April 9, 2009 (n=274)
      Inclusion: None specified

      Exclusion: Military personnel with moderate, severe, or penetrating TBI, injured while deployed during OEF, served>3 OIF deployments, female, injured through a nonblast mechanism, and evaluated>12 mo after their injury

      The authors further excluded any military personnel who had missing values in the PCL-C and the NSI
      Blast MTBI was defined as a transient change in mental status due to an explosive event including 1 or more of the following: LOC<30 min; retrograde or PTA<24h; alteration in mental state at the time of the injury (dazed, disoriented, confused); and GCS score of 13–15, if available

      Case definition was determined by an intake interview conducted by TBI coordinators who inquired about the injury history and reviewed the medical records
      Prognostic factors:

      Age, military rank, branch of military, number of deployments, AIS, ISS, weeks postinjury to evaluation

      Outcome:

      NSI, PCL-C
      The cohort was divided into 2 groups. Group 1 (n=130) MTBI only; Group 2 (n=144) MTBI + AIS code. There was no difference between the groups for length of time from injury, the number of deployments, and LOC. The ISS score was significantly higher in group 2, which was expected based on design. Group 1 was significantly older than group 2. The NSI and PCL-C scores were significantly higher for group 1 than for group 2 even after adjusting for age. This suggests that somatic symptoms are less pronounced when MTBI occurs along with another physical injury
      Abbreviations: ACRM, American Congress of Rehabilitation Medicine; AIS, Abbreviated Injury Scale; GCS, Glasgow Coma Scale; ISS, injury severity score; LOC, loss of consciousness; NSI, Neurobehavioural Symptom Inventory; OEF, Operation Enduring Freedom; OIF, Operation Iraqi Freedom; PTA, posttraumatic amnesia; RBANS, Repeatable Battery for the Assessment of Neuropsychological Status; TBSA, total body surface area burned.

      Results

      After applying the inclusion and exclusion criteria to 77,914 titles and abstracts for our entire review, 69 full-text articles related to TBI in the military were screened and 13 deemed eligible for review. Of these, only 3 (23%) were found to be at low risk of bias, as determined by modified Scottish Intercollegiate Guidelines Network criteria, and these form the basis of our findings. All 3 are retrospective cohort studies that involve U.S. military personnel who were deployed in either Iraq or Afghanistan (2 phase III
      • Cooper D.B.
      • Kennedy J.E.
      • Cullen M.A.
      • Critchfield E.
      • Amador R.R.
      • Bowles A.O.
      Association between combat stress and post-concussive symptom reporting in OEF/OIF service members with mild traumatic brain injuries.
      • Cooper D.B.
      • Mercado-Couch J.M.
      • Critchfield E.
      • et al.
      Factors influencing cognitive functioning following mild traumatic brain injury in OIF/OEF burn patients.
      and 1 phase II
      • Kennedy J.E.
      • Cullen M.A.
      • Amador R.R.
      • Huey J.C.
      • Leal F.O.
      Symptoms in military service members after blast mTBI with and without associated injuries.
      ; see table 1). These studies came from 2 different military health facilities within the state of Texas.
      Two studies
      • Cooper D.B.
      • Kennedy J.E.
      • Cullen M.A.
      • Critchfield E.
      • Amador R.R.
      • Bowles A.O.
      Association between combat stress and post-concussive symptom reporting in OEF/OIF service members with mild traumatic brain injuries.
      • Kennedy J.E.
      • Cullen M.A.
      • Amador R.R.
      • Huey J.C.
      • Leal F.O.
      Symptoms in military service members after blast mTBI with and without associated injuries.
      examined the type of symptoms military personnel may experience after an MTBI. Kennedy et al
      • Kennedy J.E.
      • Cullen M.A.
      • Amador R.R.
      • Huey J.C.
      • Leal F.O.
      Symptoms in military service members after blast mTBI with and without associated injuries.
      found that military personnel who only had blast-related MTBI, and did not sustain concurrent injuries, presented with significantly more postconcussive symptoms, as measured on the Neurobehavioural Symptom Inventory, than did military personnel who had blast-related MTBI and another Abbreviated Injury Severity scale–coded concurrent injury. The assessment occurred, on average, 13 weeks postinjury for both groups. Furthermore, the “blast-related only MTBI” group had significantly higher severity scores in each of the 4 domains of the Neurobehavioural Symptom Inventory, with the sensory domain having an average score 1.6 times higher than that of the other group. Specifically, those with sensitivity to light and noise, headache, and sleep problems had significantly higher scores in the sensory domain. Kennedy et al also examined the difference between these 2 groups at about 13 weeks postinjury with respect to posttraumatic stress symptoms as measured by the Posttraumatic Stress Disorder Check List–Civilian (PCL-C). On average, the blast-related only MTBI group reported significantly more symptoms than did those who had blast-related MTBI and concurrent injuries. In addition, scores on the 3 domains of the PCL-C were significantly higher in those who had blast-related only MTBI. The 2 groups were similar regarding the length of time since injury, rank, branch of military, loss of consciousness, and alteration of consciousness, but differed on age, with those having blast-related only MTBI being older. After adjusting for age, the blast-related only MTBI group remained significantly higher on postconcussive symptoms and posttraumatic stress than did the blast-related MTBI and concurrent injuries group.
      Cooper et al
      • Cooper D.B.
      • Kennedy J.E.
      • Cullen M.A.
      • Critchfield E.
      • Amador R.R.
      • Bowles A.O.
      Association between combat stress and post-concussive symptom reporting in OEF/OIF service members with mild traumatic brain injuries.
      examined postconcussive symptoms in a cohort of military personnel who experienced MTBI. The authors divided the MTBI cohort into 2 groups on the basis of their posttraumatic stress, as scored on the PCL-C. They hypothesized that the coexistence of stress would have an impact on postconcussive symptoms. The “high combat stress” group scored 60 or more on the PCL-C, and the “low combat stress” group scored 30 or less on the PCL-C. MTBI cohort members who scored between 31 and 59 points were excluded from the analysis. The 2 groups differed on sex, rank, and time since MTBI. The low combat stress group was examined on average 4 months postinjury, and the high combat stress group was examined on average 7 months postinjury. The authors controlled for these characteristics using multivariable analysis and found that the high combat stress group reported significantly more postconcussive symptoms, as measured by the Neurobehavioural Symptom Inventory, than did the low combat stress group. The average scores on the 4 domains were 3 to 5 times higher in the high combat stress group. Overall, the low combat stress group reported few postconcussive symptoms, and their most prevalent symptoms were sleep disturbances, headache, and memory problems.
      The final article examined neurocognitive performance in military personnel who had a blast-related MTBI or other blast-related injury.
      • Cooper D.B.
      • Mercado-Couch J.M.
      • Critchfield E.
      • et al.
      Factors influencing cognitive functioning following mild traumatic brain injury in OIF/OEF burn patients.
      The authors hypothesized that psychiatric comorbidity (in particular, PTSD) would be more highly associated with cognitive performance than with having an MTBI. They also hypothesized that narcotic pain medication usage would be more associated with cognitive performance. Cognitive performance was measured with the Repeatable Battery for the Assessment of Neuropsychological Status, which consists of 5 domains: immediate memory, visuospatial/constructional, language, attention, and delayed memory. The authors used information from medical records to define the presence/absence of psychiatric comorbid and narcotic pain medication usage. The MTBI group had significantly more women and significantly more military personnel who had a psychiatric-related comorbidity. The groups did not differ with regard to age, education, weeks since blast injury, total body surface area burned, injury severity score, and the usage of narcotic pain medication. Overall, the MTBI group had significantly lower unadjusted total cognitive function scores than did the non-MTBI group, but on average, the scores were within the normal range. Specifically, the MTBI group had significantly lower unadjusted scores in the visuospatial/constructional and attention domains. The authors found that both psychiatric-related comorbidity and narcotic pain medication usage explained little of the variance in the difference between the 2 groups for the attention domain of the Repeatable Battery for the Assessment of Neuropsychological Status.

      Discussion

      This systematic review of the prognosis of military personnel who had an MTBI identified 3 articles with a low risk of bias that were published between 2001 and February 2012. Two of the studies examined symptoms, and 1 study examined cognitive functioning after having an MTBI during deployment. There was an increased association of PTSD and having postconcussive symptoms after an MTBI if the service member did not have a concurrent injury.
      • Kennedy J.E.
      • Cullen M.A.
      • Amador R.R.
      • Huey J.C.
      • Leal F.O.
      Symptoms in military service members after blast mTBI with and without associated injuries.
      PTSD, depression, substance abuse, and chronic pain can exhibit similar symptoms as someone with postconcussive symptoms. Therefore, 1 phase III study stratified on combat stress and found that those who were classified with “high stress” had more postconcussive symptoms than did service members with “low stress.”
      • Cooper D.B.
      • Kennedy J.E.
      • Cullen M.A.
      • Critchfield E.
      • Amador R.R.
      • Bowles A.O.
      Association between combat stress and post-concussive symptom reporting in OEF/OIF service members with mild traumatic brain injuries.
      They also found that having an MTBI was associated with a decline in neurocognitive function; however, the authors were unable to confirm their hypotheses that neurocognitive decline could be explained by either coexisting psychiatric conditions or use of narcotic pain medication(s).
      • Cooper D.B.
      • Mercado-Couch J.M.
      • Critchfield E.
      • et al.
      Factors influencing cognitive functioning following mild traumatic brain injury in OIF/OEF burn patients.
      To put these findings into perspective, it should be noted that PTSD is common in military personnel. An American congressional report found that in 2003, there were slightly over 1,600 incident cases in nondeployed and 1,100 incident cases in deployed military personnel.
      • Fischer H.
      U.S. Military casualty statistics: Operation New Dawn, Operation Iraqi Freedom, and Operation Enduring Freedom.
      By 2011, there were around 2,800 incident cases in nondeployed and nearly 16,000 cases in deployed military personnel. In these data, PTSD was defined in a relatively conservative way, as having at least 2 outpatient visits or at least 1 hospitalization with the diagnosis of PTSD as recorded in the Defense Medical Surveillance System. Thus, these incidence estimates likely underestimate the frequency of PTSD. PTSD also appears to occur more frequently in deployed personnel, as suggested by the findings of a retrospective cohort study of Gulf War veterans where the adjusted odds of having PTSD were 3 times higher for those who were in combat duty versus veterans who served in noncombat duty.
      • Kang H.K.
      • Natelson B.H.
      • Mahan C.M.
      • Lee K.Y.
      • Murphy F.M.
      Post-traumatic stress disorder and chronic fatigue syndrome-like illness among Gulf War veterans: a population-based survey of 30,000 veterans.
      Our findings suggest that PTSD and postconcussive symptoms are associated with prognosis, but because of the retrospective nature of the studies included in this review, we are unable to determine whether there is a causal relation because there is some uncertainty with the timing of events. In a combat situation, it is feasible that military personnel may have had more than 1 traumatic incident within the same tour of duty.
      Some researchers have speculated that if a service member is able to visibly track the “healing” of a physical injury, whether it is a wound healing or being able to gain control of a limb, reassurance is provided that his or her body is healing, and therefore he or she develops less PTSD and/or postconcussion symptoms.
      • Kennedy J.E.
      • Cullen M.A.
      • Amador R.R.
      • Huey J.C.
      • Leal F.O.
      Symptoms in military service members after blast mTBI with and without associated injuries.
      • French L.M.
      • Lange R.T.
      • Iverson G.L.
      • Ivins B.
      • Marshall K.
      • Schwab K.
      Influence of bodily injuries on symptom reporting following uncomplicated mild traumatic brain injury in US military service members.
      Soldiers who had altered mental status did not differ significantly on postconcussive symptoms from soldiers who had another injury with no loss of consciousness and altered mental status after adjusting for PTSD, which may suggest that not having a memory of the event protects an individual from developing postconcussive symptoms. These findings are supported by another study in which civilians who remembered the traumatic event were more likely to develop PTSD at 6 months postinjury.
      • Gil S.
      • Caspi Y.
      • Ben-Ari I.Z.
      • Koren D.
      • Klein E.
      Does memory of a traumatic event increase the risk for posttraumatic stress disorder in patients with traumatic brain injury? A prospective study.
      In addition, failure to treat acute pain at the time of injury increased the likelihood of developing PTSD.
      • Black I.H.
      • McManus J.
      Pain management in current combat operations.
      There is a need for research that will identify the best way to manage MTBI and concomitant PTSD in military settings.
      Although the prognosis of injuries sustained in combat may differ from injuries sustained elsewhere,
      • Warden D.
      Military TBI during the Iraq and Afghanistan wars.
      the results of this review are similar to those reported in the past by the World Health Organization Collaborating Centre Task Force on Mild Traumatic Brain Injury.
      • Warden D.
      Military TBI during the Iraq and Afghanistan wars.
      • Carroll L.J.
      • Cassidy J.D.
      • Peloso P.M.
      • et al.
      Prognosis for mild traumatic brain injury: results of the WHO Collaborating Centre Task Force on Mild Traumatic Brain Injury.
      The task force found consistent evidence of post-MTBI deficits in cognitive function in the areas of recall, speed of information processing, and attention. They also found consistent evidence that these deficits resolve within 3 months postinjury. Because this review does not contain articles related to short- or long-term follow-up of cognitive function, we are unable to comment whether resolution of cognitive deficits would also occur in military personnel. The task force also found that acute stress disorder was a predictor for developing PTSD after a motor vehicle collision, which resulted in the reporting of more postconcussive symptoms.
      • Carroll L.J.
      • Cassidy J.D.
      • Peloso P.M.
      • et al.
      Prognosis for mild traumatic brain injury: results of the WHO Collaborating Centre Task Force on Mild Traumatic Brain Injury.
      The studies in the present review did not examine whether preexisting or concurrent psychological conditions are associated with PTSD.
      The 2 studies included in this review that examined symptoms did not have a non-TBI comparison group of deployed service members. The symptoms that are present in postconcussive cases are not unique to this condition because they can also be found in healthy people,
      • Iverson G.L.
      • Lange R.T.
      Examination of “postconcussion-like” symptoms in a healthy sample.
      individuals who have chronic pain,
      • Lange R.T.
      • Iverson G.L.
      • Franzen M.D.
      Comparability of neuropsychological test profiles in patients with chronic substance abuse and mild traumatic brain injury.
      and those with anxiety and/or depression.
      • Trahan D.E.
      • Ross C.E.
      • Trahan S.L.
      Relationships among postconcussional-type symptoms, depression, and anxiety in neurologically normal young adults and victims of mild brain injury.
      Furthermore, military personnel who were not injured in theater also report postconcussive symptoms, especially sleep disturbances, fatigue, irritability, headache, and memory problems.
      • Hoge C.W.
      • McGurk D.
      • Thomas J.L.
      • Cox A.L.
      • Engel C.C.
      • Castro C.A.
      Mild traumatic brain injury in U.S. soldiers returning from Iraq.
      As recommended by the World Health Organization Collaborating Centre Task Force on Mild Traumatic Brain Injury, when assessing for postconcussive symptoms, researchers should take into account the background prevalence of the symptoms along with other factors that may be associated with the injury such as pain, physical distress, and depression.
      • Carroll L.J.
      • Cassidy J.D.
      • Peloso P.M.
      • et al.
      Prognosis for mild traumatic brain injury: results of the WHO Collaborating Centre Task Force on Mild Traumatic Brain Injury.
      The task force also found that the long-term prevalence of postconcussive symptoms in the general population may be the result of factors other than the severity of the injury, for example, litigation and compensation-related issues. We cannot comment whether this occurred in the military population, because these characteristics were not examined in the studies we reviewed.
      One of our systematic reviews (published in the same issue as this review
      • Cassidy JD
      • Cancelliere C
      • Carroll LJ
      • et al.
      Systematic review of self-reported prognosis in adults after mild traumatic brain injury: results of the International Collaboration on Mild Traumatic Brain Injury Prognosis.
      ) examined subjective outcomes after MTBI and found that prior psychological health is an important factor in symptom recovery of MTBI. It is unclear whether this generalizes to the deployed military population, and should be studied. These personnel receive a predeployment medical examination, which provides an opportunity to gather preinjury emotional/psychological status.
      We are unable to comment on the long-term prognosis of MTBI in the military because the studies we reviewed were not prospective longitudinal studies. In a non-TBI population, it has been found that service members who present with PTSD at 7 months postinjury did not meet the diagnostic criteria of PTSD at 1 month postinjury.
      • Grieger T.A.
      • Cozza S.J.
      • Ursano R.J.
      • et al.
      Posttraumatic stress disorder and depression in battle-injured soldiers.
      These findings should encourage researchers studying TBI in the military to conduct long-term follow-up studies to determine what prognostic factors are associated with long-term postconcussive symptoms and PTSD because there may be a delay in presentation.
      The 3 reviewed studies collected data at least 2 months after MTBI. The relatively short time frame after the event may have reduced recall bias in reporting the injury-related symptoms; however, inaccurate reporting of symptoms may have occurred. PTSD and TBI have several common symptoms such as impaired concentration and insomnia; therefore, it can be difficult to accurately attribute these symptoms to either of these conditions and even diagnose them.
      • Bass C.R.
      • Panzer M.B.
      • Rafaels K.A.
      • Wood G.
      • Shridharani J.
      • Capehart B.
      Brain injuries from blast.
      Diagnosing non–life-threatening combat injuries is typically done via self-report of symptoms and with very little corroborating evidence.
      • Iverson G.L.
      • Langlois J.A.
      • McCrea M.A.
      • Kelly J.P.
      Challenges associated with post-deployment screening for mild traumatic brain injury in military personnel.
      It is possible that symptoms associated with acute MTBI are not recognized by the service member around the time of the injury and it may become apparent only later when they experience postconcussive symptoms.
      • Maruta J.
      • Lee S.W.
      • Jacobs E.F.
      • Ghajar J.
      A unified science of concussion.
      Moreover, service members may view being exposed to a blast as a normal outcome in theater, and they may not even self-report the incident.
      • Schwab K.A.
      • Ivins B.
      • Cramer G.
      • et al.
      Screening for traumatic brain injury in troops returning from deployment in Afghanistan and Iraq: initial investigation of the usefulness of a short screening tool for traumatic brain injury.
      In response, the U.S. military is screening military personnel who have been deployed for TBI at various time points.
      • Marshall K.R.
      • Holland S.L.
      • Meyer K.S.
      • Martin E.M.
      • Wilmore M.
      • Grimes J.B.
      Mild traumatic brain injury screening, diagnosis, and treatment.
      The first screening occurs right after an injury event while in theater and another screening occurs if the injured military personnel are treated at the Landstuhl Regional Medical Center in Germany. There are a couple of other screening opportunities that occur after the military personnel have returned from deployment.

      Post Deployment Health Assessment (PDHA). 2012. Available at: http://www.dtic.mil/whs/directives/infomgt/forms/eforms/dd2796.pdf. Accessed October 15, 2012.

      All the studies in this review relied mostly on self-report measures to collect both the exposure and the outcome. The PCL-C has been validated within military populations, and it can identify veterans who have PTSD (area under the receiver operator curve=.86), and it has moderate sensitivity (.56) and high specificity (.92).
      • Keen S.M.
      • Kutter C.J.
      • Niles B.L.
      • Krinsley K.E.
      Psychometric properties of PTSD Checklist in sample of male veterans.
      This means that studies using the PCL-C are unlikely to have misclassified those with PTSD as not having the disorder. However, there will be a substantial proportion of missed cases of PTSD. The Neurobehavioural Symptom Inventory has undergone factor analysis in a military population, and a 4-factor scale was found to be the best fit.
      • Meterko M.
      • Baker E.
      • Stolzmann K.L.
      • Hendricks A.M.
      • Cicerone K.D.
      • Lew H.L.
      Psychometric assessment of the Neurobehavioral Symptom Inventory-22: the structure of persistent postconcussive symptoms following deployment-related mild traumatic brain injury among veterans.
      However, to our knowledge, there have not been any studies within a military population that have determined the psychometric properties of the scale. Last, the Repeatable Battery for the Assessment of Neuropsychological Status has not undergone psychometric testing in a military population to our knowledge. Furthermore, the scale was designed as a screening measure, and therefore, may not be sensitive to various neurocognitive problems that may occur after MTBI.
      Because the 3 articles included in our review recruited service members from only 2 medical military facilities in the state of Texas (ie, Brooke Army Medical Center and Wilford Hall Medical Center), the results may not be generalizable to all military personnel who experienced in-theater MTBI. There is evidence that not all service members who screen positive for MTBI at a Veterans Affairs medical center in the United States attend a comprehensive TBI evaluation.
      • Maguen S.
      • Lau K.M.
      • Madden E.
      • Seal K.
      Factors associated with completing comprehensive traumatic brain injury evaluation.
      There are also significant differences in the characteristics of service members who attend those evaluations versus those who do not attend: men are 3 times more likely than women to attend, and Hispanics are 2.5 times more likely than whites to attend. In addition, military personnel who present with avoidance symptoms on the PTSD scale are less likely to attend. The authors posit that service members showing avoidance symptoms may not want to seek care at a Veterans Affairs facility, or even travel to one, because this may evoke memories of the traumatic event. These patients may also have feelings of fear with regard to being diagnosed with TBI, feelings of shame for the need to seek care, and survivor guilt. We are unable to determine how these differences may have affected the results found in our review because the authors did not report the number of service members who were screened at their location and how many were not included in their study for various reasons. Future studies should keep in mind these potential selection biases in their design and statistical analyses.
      This review did not find any articles that used “returned to duty” as an outcome measure. In 1 study, this outcome was impractical because the service members were deemed to have injuries or symptoms that were considered too severe to allow them to return to combat-related duty.
      • Kennedy J.E.
      • Cullen M.A.
      • Amador R.R.
      • Huey J.C.
      • Leal F.O.
      Symptoms in military service members after blast mTBI with and without associated injuries.
      Moreover, none of these articles assessed whether the military personnel returned to their prior normal vocational duties they had before they were deployed.
      We did not find any articles that examined prognosis after repeated exposures to blasts, or determined whether there was a history of prior concussions. Two studies did exclude military personnel who were deployed more than 3 times, which would have reduced the probability of service members' having had more than 1 exposure to a blast.
      • Cooper D.B.
      • Kennedy J.E.
      • Cullen M.A.
      • Critchfield E.
      • Amador R.R.
      • Bowles A.O.
      Association between combat stress and post-concussive symptom reporting in OEF/OIF service members with mild traumatic brain injuries.
      • Kennedy J.E.
      • Cullen M.A.
      • Amador R.R.
      • Huey J.C.
      • Leal F.O.
      Symptoms in military service members after blast mTBI with and without associated injuries.
      Although this has been studied in sports-related concussions, the conclusions drawn from this population cannot be applied to the military population because the environment and mechanism of injury are different.
      • Kelly J.C.
      • Amerson E.H.
      • Barth J.T.
      Mild traumatic brain injury: lessons learned from clinical, sports, and combat concussions.
      However, the U.S. military has adopted sport-related strategies to guide safe return to active duty.
      • McCrory P.
      • Meeuwisse W.
      • Johnston K.
      • et al.
      Consensus statement on concussion in sport: the 3rd International Conference on Concussion in Sport held in Zurich, November 2008.
      Military personnel who have been exposed to a blast must have a 24-hour rest period, but this can be denied if their commander determines that the service member is required for a mission. Military personnel who have been diagnosed with MTBI are to remain off duty until their symptoms have resolved, and at the minimum they must be off duty for 24 hours.

      Policy guidance for management of concussion/mild traumatic brain injury in the deployed setting. 2010. Available at: http://www.govexec.com/pdfs/062510bb1.pdf. Accessed November 6, 2012.

      Adherence to these proposed guidelines would suggest that service members should avoid situations, for example, playing sports, in which they could reinjure their heads while they are recovering, and they should avoid cognitive tasks such as playing video games. If a service member sustains 2 documented MTBIs within a 12-month period, he or she should remain off active duty for a minimum of 7 days following the resolution of symptoms.
      • McCrory P.
      • Meeuwisse W.
      • Johnston K.
      • et al.
      Consensus statement on concussion in sport: the 3rd International Conference on Concussion in Sport held in Zurich, November 2008.
      For 3 documented MTBIs within a 12-month period, the service member must undergo a recurrent concussion evaluation, which includes a comprehensive neurological examination, neuroimaging, and, if warranted, neuropsychological and functional assessment.
      Different teams of 2 ICoMP members independently reviewed the 13 articles, and we evaluated a large proportion of these articles as scientifically inadmissible. The acceptance rate for our entire systematic review was 34%,
      • Kristman VL
      • Borg J
      • Godbolt AK
      • et al.
      Methodological issues and research recommendations for prognosis after mild traumatic brain injury: results of the International Collaboration on Mild Traumatic Brain Injury Prognosis.
      which is higher than the rate for the military articles. Problems in scientifically inadmissible articles included unclear methodology, poorly defined MTBI definitions, poor control of confounding factors, and underpowered analyses. It is important to improve the methodological rigor used in the military studies.

      Policy guidance for management of concussion/mild traumatic brain injury in the deployed setting. 2010. Available at: http://www.govexec.com/pdfs/062510bb1.pdf. Accessed November 6, 2012.

      In addition, efforts should be made to ensure that the reporting of these observational studies improves and is consistent with current standards as set out, for example, by the Strengthening the Reporting of Observational Studies in Epidemiology Initiative.
      • Vandenbroucke J.P.
      • von Elm E.
      • Altman D.G.
      • et al.
      Strengthening the Reporting of Observational Studies in Epidemiology (STROBE): explanation and elaboration.

      Study limitations

      Our review may have missed prognostic studies that were classified as cross-sectional studies because they collected data only at a specific point in time; however, some of those studies may actually be retrospective cohort studies if the head injury exposure can be clearly placed before the onset of symptoms. We also excluded penetrating brain injuries or any studies not reporting findings specific to blunt trauma-related MTBI. However, it has been reported that penetrating head injuries are relatively rare in military personnel who served in Iraq or Afghanistan.
      United States Department of Defense
      Report to congress on expenditures for activities on traumatic brain injury and psychological health, including posttraumatic stress disorder, for 2010.
      As is common with all best-evidence systematic reviews, the possibility of publication bias may have occurred, as we only reviewed published articles in peer-reviewed journals and not “gray literature” or classified military reports. The time frame of the review would have included all peer-reviewed studies involving military personnel who served in Iraq or Afghanistan.
      Two ICoMP members assessed each study for eligibility and methodological quality. Although the composure of the teams changed over time, the review process still relies on scientific judgment. Thus, it is possible that one team may have accepted an article that another team might have rejected, and vice versa. However, we paired clinical scientists with methodologists to improve this process and the reviewers independently reviewed each article using the Scottish Intercollegiate Guidelines Network criteria before coming to a consensus. If a consensus could not be reached, a third reviewer was asked to review the article.

      Conclusions

      MTBI has been labeled as the signature injury for the wars in Iraq and Afghanistan. As with “shell shock,” the World War I signature injury, little is known about these injuries.
      • Jones E.
      • Fear N.T.
      • Wessely S.
      Shell shock and mild traumatic brain injury: a historical review.
      Although military populations may have different prognostic pathways than civilian populations, we are unable to determine whether the prognosis from a blast injury differs from civilian MTBI. Our conclusions need to be interpreted with caution because of the small number of studies included. We found that military personnel with MTBI exhibit significantly higher postconcussive symptoms and PTSD than do military personnel with MTBI plus another injury. In addition, we found that military personnel who are classified as having high combat stress report more postconcussive symptoms, which suggests that factors other than MTBI may affect these outcomes. Our review found a slight decline in neurocognitive function after blast injury, but the decline was within normal limits of function. As the studies collected data at one point of time, future studies should assess short-term and long-term outcome measures in a longitudinal fashion to determine the important prognostic characteristics for MTBI in the military population. The research should focus on long-term outcomes and functional outcomes such as “return to duty” or “return to work after deployment.” In addition, there should be studies that examine prognosis in military personnel who were exposed to repeated blasts while in theater.

      Acknowledgments

      We thank the other members of the ICoMP: Jean-Luc af Geijerstam, Jörgen Borg, MD, PhD, Victor G. Coronado, MD, MPH, Pierre Côté, DC, PhD, James Donovan, DC, Alison K. Godbolt, MBChB, MD, Cesar A. Hincapié, DC, MHSc, Ryan Hung, MD, MSc, Michelle Keightley, PhD, Vicki L. Kristman, PhD, Alvin Li, BHSc, Connie Marras, MD, PhD, Catharina Nygren-de Boussard, MD, PhD, Peter Rumney, MD, and Britt-Marie Stålnacke, MD, PhD. We also thank Panos Lambiris, MSc, Information Scientist, University Health Network, for assisting in developing, testing, and updating the search strategies and Meijia Zhou, BSc, for assisting with retrieving and screening articles.

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