Association Between 5-Year Clinical Outcome in Patients With Nonmedically Evacuated Mild Blast Traumatic Brain Injury and Clinical Measures Collected Within 7 Days Postinjury in Combat

Key Points Question What clinical measures collected acutely in combat are associated with 5-year outcome in patients with concussive blast injury? Findings In this longitudinal cohort study, nonmedically evacuated blast concussion patients had significant and sustained symptoms of neurobehavioral impairment, mental health and global disability, whereas cognitive changes were unremarkable compared with combat-deployed nonconcussed controls. Assessments collected in theater were associated with multiple domains of outcome. Meaning Nonmedically evacuated patients with concussive blast injury, considered the mildest of the mild combat casualties fared poorly 5 years later compared with combat-deployed controls.


Participant Compensation
Active duty military subjects were not paid for follow up participation, though travel expenses to University of Washington in Seattle were covered. Subjects who had subsequently separated from the service at the time of follow-up were paid $250 for participation in addition to having their travel expenses covered.

Safety and Data Monitoring
Subjects were assigned a random 5-digit code number to protect confidentiality and all research data was identified by code number only. A board-certified psychiatrist (J. Fann) was immediately available in case an evaluation exacerbated mental health symptoms. No exacerbations requiring medical intervention occurred, though additional support from study staff was required on several occasions.
For clinical evaluations, the principal investigator audited 1 in 10 randomly selected subjects' data sets to ensure that data was scored and entered correctly. These audits revealed only minor discrepancies in scoring criteria which were then corrected across the entire cohort of subjects.

Acute Evaluation Assessments
The severity of post-concussive symptoms was measured by the Rivermead Post-Concussion Symptom Questionnaire (RPCSQ) 1 , a self-administered questionnaire assessing 16 post-concussive symptoms on a scale of 0 (none) to 4 (severe) covering three domains: cognitive (memory and concentration difficulties), emotional (anxiety, restlessness and depression) and somatic (fatigue, headache, dizziness, nausea, sleep disturbance and changes in vision). Symptoms of post-traumatic stress disorder (PTSD), anxiety and mood changes were assessed using the Post-traumatic Stress Disorder Check List-Military (PCL-M) 2 and Beck Depression Inventory (BDI) 3 . The PCL-M is a 17 item self-administered questionnaire tying symptom ratings to events experienced during military service, using a scale of 1 (not at all) to 5 (extremely). The BDI is a self-administered 21 item questionnaire corresponding to symptoms of depression rated on a severity scale of 0 (no symptoms) to 3 (severe symptoms). Reports of wartime stressors experienced by combatants were measured using the Combat Exposure Scale (CES) 4 , a 7-item scale with 5-response points (1 is "no", 2 is "1 to 3 times", 3 is "4 to 12 times", 4 is "13 to 50 times", and 5 is "51+ times"), each item being weighted differently based on the severity of the experience, the total scores ranging from 0−41. Severity of balance impairment was tested using the Balance Error Scoring System (BESS) 5 . The BESS is a clinician administered balance test which includes single, double and tandem stance assessment on firm and foam (unstable) surfaces, each held for 20 seconds, with the participant's hands on the hips and eyes closed. The final score is a representation of cumulative errors. The Automated Neurocognitive Assessment Metrics -Traumatic Brain Injury Military Version 4 (ANAM) 6 is sanctioned by the Department of Defense for baseline neurocognitive assessment in all deploying troops and it is also available in the deployed setting. The ANAM includes a collection of cognitive modules including simple reaction time (SRT) and repeat simple reaction time (SRTR) for basic neural processing, Code substitution learning (CSL) for associative learning, procedural reaction time (PRT) for processing speed, mathematical processing (MTP) for working memory, matching to sample (MTS) for visual spatial memory and code substitution delayed (CSD) for delayed memory. The cognitive modules are preceded by sleepiness and mood scales. Level of examination effort was measured using the Test of Memory Malingering (TOMM) 7 , which is a clinician administered tool designed to assist in determining effort 7 . The testing paradigm involved a single TOMM trial for subjects with a score higher or equal to 45 and a second trial for subjects with a first TOMM score lower than 45. Subjects with TOMM score lower than 45 on both consecutive TOMM trials were excluded from analysis for possible poor effort during testing.

Glasgow Outcome Scale Extended
The GOS-E is scored from 1-8: 1=dead, 2=vegetative, 3-4=severe disability, 5-6=moderate disability, 7-8=good recovery. Moderate disability (GOS-E = 5-6) is defined as one or more of the following: 1) inability to work to previous capacity 2) inability to resume much of regular social and leisure activities outside the home 3) psychological problems which have frequently resulted in ongoing family disruption or disruption of friendships. Severe disability (GOS-E = 3-4) is defined as one or more of the following: 1) inability to drive and/or travel locally without assistance 2) inability to shop or run errands without assistance 3) support required for activities of daily living. Standardized, structured interviews were performed per published guidelines. 8 Participants were instructed to consider deployment as the reference point for this interview.

Neuropsychological Test Battery
The neuropsychological test battery consisted of the following: Conner's Continuous Performance Test II 9 , a computerbased assessment of attention, impulsivity, reaction time, and vigilance; the California Verbal Learning Test II 10 , an assessment of verbal declarative memory; the 25 hole grooved pegboard test 11 , an assessment of upper extremity motor speed and coordination; a timed 25 foot walk, an assessment for motor strength, balance, and coordination; the Trail Making test 12 , an assessment of visual scanning and mental flexibility; the Controlled Oral Word Association test 13 , an assessment of verbal fluency; the Wechsler Test of Adult Reading 14 as an estimate of pre-injury verbal intelligence; the Iowa Gambling Test 15 , a computer-based assessment of impulsivity and decision making; the D-KEFS Color-Word Interference Test 16 , a multi-domain assessment of executive function similar to the Stroop test; and the Ruff-Light Trail Learning Test 17 , an assessment of visual-spatial memory. A relatively easy forced choice test embedded in the California Verbal Learning Test was used to assess adequacy of effort.  Dev.

eTable 9 is provided in Panels A, B, and C for clarity given the large number of parameters for each optimization analysis.
Multivariate models selected using a stepwise algorithm (p<.05 to enter, >.10 to exit). Education was not always available in theatre so officer vs. enlisted was used as a surrogate. Given that 5-year impairment was primarily observed in domains of neurobehavior and mental health and not cognitive dysfunction, acute assessments for these domains were focused on for this optimization process. This included the RPCSQ for Concussion Symptoms, PCL-M for PTSD symptoms, BDI for depression symptoms. While all 3 measures provided comparable predictive ability, the PCL-M edged out slightly from the others as best predicting all three primary domains of long-term outcome (global disability, neurobehavioral impairment, PTSD symptom severity. For each Table B