Provider Training in the Management of Headache Following Concussion Clinical Recommendation: Promoting a Standardized Means for Efficient Patient Recovery and Timely Return to Duty.

Background: Headache is a common symptom reported following concussion/mild traumatic brain injury. The Department of Defense's clinical recommendation (CR) describes guidance for primary care providers for the management of post-traumatic headache (PTH) in Service members. Objective: The objective of this study is to examine the association between training on the CR with provider clinical practice, patient behaviors, and symptom recovery. Methods: Participants were healthcare providers and two patient groups (one receiving care as usual [CAU] and another receiving care after provider training on PTH CR [CR+]). Providers were interviewed at three time points: (1) prior to CAU enrollment; (2) after CAU enrollment, but prior to training; and (3) after CR+ follow-up. Data from the second and third provider interview were used to evaluate a potential difference between provider practices pre- and post-training (n = 13). Patients were enrolled within 6 months of concussion. Patient outcomes (including neurobehavioral and headache symptoms) were assessed at three time-points: within 72 h (n = 35), at 1-week (n = 34) and at 1-month post-enrollment (n = 27). Results: Most follow-up care reported by providers were recommended within 72 h of initial visit post-training vs. >1 week pre-training. Additionally, providers reported a greater number of visits based on patient symptoms after training than before. Post-training, most providers reported referring patients to higher level of care "as needed," if not "very rarely," compared to 25% reported referrals prior to training. At 1-week post-enrollment the CR+ patient group reported more frequent medical provider visits compared to the CAU group. This trend was reversed at the 1-month follow-up whereby more CAU reported seeing a medical provider compared to CR+. By 1-week post-enrollment, fewer patients in the CR+ group reported being referred to any other providers or specialists compared to the CAU group. No differences in patient outcomes by provider training was found. Conclusion: The study results demonstrate the feasibility of training on the Management of Headache Following Concussion CR in order to change provider practices by promoting timely care, and promoting patient compliance as shown through improvement in follow-up visits and more monitoring within the primary care clinic.

Current patterns of primary care provider practices for the treatment of post-traumatic headache in active duty military settings.

OBJECTIVE: To provide a preliminary assessment of the current clinical practice for the treatment of post-traumatic headache following concussion in military primary health care settings. BACKGROUND: Headache is one of the most common symptoms post-concussion; however, little is known of the current clinical practices of primary care providers (on the treatment of post-traumatic headache), particularly in military settings. METHODS: Study participants were primary care providers (n = 65) who treated active duty Service members suffering from post-traumatic headache at two military installations. Qualitative data gathered via semi-structured interviews were used to describe provider practices and experience in treating patients with post-traumatic headache. RESULTS: Some patterns of care across primary care providers treating post-traumatic headache were consistent with the Department of Defense-recommended clinical recommendation (e.g., recommendation of both pharmacological and non-pharmacological treatment [89.4%]; engaging in follow-up care [100%]). Differences existed in timing of follow-up from initial visit [16.9% reporting within 24 hours; 21.5% reporting within 48-72 hours; and 26.2% reporting more than 1 week], the factors contributing to the type of care given (e.g., symptomatology [33.0%], injury characteristic [24.2%], patient characteristic [13.2%]) and the need for referral to higher level of care (e.g., symptomatology [44.6%], treatment failure [25.0%]). These variations may be indicative of individualized treatment which would be compliant with best clinical practice. CONCLUSION: The results of this study demonstrate the current clinical practice in military primary care settings for the treatment of post-traumatic headache which can potentially inform and improve implementation of provider training and education.

Use of the Progressive Return to Activity Guidelines May Expedite Symptom Resolution After Concussion for Active Duty Military.

BACKGROUND: Clinical recommendations for concussion management encourage reduced cognitive and physical activities immediately after injury, with graded increases in activity as symptoms resolve. Empirical support for the effectiveness of such recommendations is needed. PURPOSE: To examine whether training medical providers on the Defense and Veterans Brain Injury Center's Progressive Return to Activity Clinical Recommendation (PRA-CR) for acute concussion improves patient outcomes. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: This study was conducted from 2016 to 2018 and compared patient outcomes before and after medical providers received an educational intervention (ie, provider training). Patients, recruited either before or after intervention, were assessed at ≤72 hours, 1 week, 1 month, 3 months, and 6 months after a concussion. The participant population included 38 military medical providers and 106 military servicemembers with a diagnosed concussion and treated by one of the military medical providers: 58 patient participants received care before the intervention (ie, provider training) and 48 received care after intervention. The primary outcome measure was the Neurobehavioral Symptom Inventory. RESULTS: The patients seen before and after the intervention were predominantly male (89.7% and 93.8%, respectively) of military age (mean ± SD, 26.62 ± 6.29 years and 25.08 ± 6.85 years, respectively) and a mean ± SD of 1.92 ± 0.88 days from injury. Compared with patients receiving care before intervention, patients receiving care after intervention had smaller increases in physical activities (difference in mean change; 95% CI, 0.39 to 6.79) and vestibular/balance activities (95% CI, 0.79 to 7.5) during the first week of recovery. Although groups did not differ in symptoms at ≤72 hours of injury (d = 0.22; 95% CI, -2.21 to 8.07), the postintervention group reported fewer symptoms at 1 week (d = 0.61; 95% CI, 0.52 to 10.92). Postintervention patients who completed the 6-month study had improved recovery both at 1 month (d = 1.55; 95% CI, 5.33 to 15.39) and 3 months after injury (d = 1.10; 95% CI, 2.36 to 11.55), but not at 6 months (d = 0.35; 95% CI, 5.34 to 7.59). CONCLUSION: Training medical providers on the PRA-CR for management of concussion resulted in expedited recovery of patients.

The "Top 10" research and development priorities for battlefield surgical care: Results from the Committee on Surgical Combat Casualty Care research gap analysis.

BACKGROUND: The US Military has achieved the highest casualty survival rates in its history. However, there remain multiple areas in combat trauma that present challenges to the delivery of high-quality and effective trauma care. Previous work has identified research priorities for pre-hospital care, but there has been no similar analysis for forward surgical care. METHODS: A list of critical "focus areas" was developed by the Committee on Surgical Combat Casualty Care (CoSCCC). Individual topics were solicited and mapped to appropriate focus areas by group consensus and review of Eastern Association for the Surgery of Trauma (EAST) and Joint Trauma System guidelines. A web-based survey was distributed to the CoSCCC and the military committees of EAST and the American Association for the Surgery of Trauma. Topics were rated on a Likert scale from 1 (low) to 10 (high priority). Descriptives, univariate statistics, and inter-rater correlation analysis was performed. RESULTS: 13 research focus areas were identified (eight clinical and five adjunctive categories). Ninety individual topics were solicited. The survey received 64 responses. The majority of respondents were military (90%) versus civilians (10%). There was moderate to high agreement (inter-rater correlation coefficient = 0.93, p < 0.01) for 10 focus areas. The top five focus areas were Personnel/Staffing (mean, 8.03), Resuscitation and Hemorrhage Management (7.49), Pain/Sedation/Anxiety Management (6.96), Operative Interventions (6.9), and Initial Evaluation (6.9). The "Top 10" research priorities included four in Personnel/Staffing, four in Resuscitation/Hemorrhage Management, and three in Operative Interventions. A complete list of the topics/scores will be presented. CONCLUSIONS: This is the first objective ranking of research priorities for combat trauma care. The "Top 10" priorities were all from three focus areas, supporting prioritization of personnel/staffing of austere teams, resuscitation/hemorrhage control, and damage-control interventions. This data will help guide Department of Defense research programs and new areas for prioritized funding of both military and civilian researchers. LEVEL OF EVIDENCE: Study design, level IV.

Continuum of the United States military's traumatic brain injury care: adjusting to the changing battlefield.

Over the past 8 years, advances in the US Military Health System (MHS) have led to extensive changes in the way combat casualty care is provided to deployed service members with a traumatic brain injury (TBI). Changes include the application of cutting-edge Clinical Practice Guidelines, use of pioneering technologies, and advances in evacuation procedures. Compared with previous engagements, current operations occur on a much smaller scale, and more frequently in austere environments, such that effective medical support is increasingly challenging. In this paper, the authors describe key aspects of the current continuum of TBI care in the US military, from the point of injury through rehabilitation, with an emphasis on how emerging technologies and evidence-based Clinical Practice Guidelines assist MHS clinicians with providing the best clinical care possible in the changing battlefield.

Role of Department of Defense Policies in Identifying Traumatic Brain Injuries Among Deployed US Service Members, 2001-2016.

OBJECTIVES: To examine the role of Department of Defense policies in identifying theater-sustained traumatic brain injuries (TBIs). METHODS: We conducted a retrospective study of 48 172 US military service members who sustained their first lifetime TBIs between 2001 and 2016 while deployed to Afghanistan or Iraq. We used multivariable negative binomial models to examine the changes in TBI incidence rates following the introduction of Department of Defense policies. RESULTS: Two Army policies encouraging TBI reporting were associated with an increase of 251% and 97% in TBIs identified following their implementation, respectively. Among airmen, the introduction of TBI-specific screening questions to the Post-Deployment Health Assessment was associated with a 78% increase in reported TBIs. The 2010 Department of Defense Directive Type Memorandum 09-033 was associated with another increase of 80% in the likelihood of being identified with a TBI among soldiers, a 51% increase among sailors, and a 124% increase among Marines. CONCLUSIONS: Department of Defense and service-specific policies introduced between 2006 and 2013 significantly increased the number of battlefield TBIs identified, successfully improving the longstanding problem of underreporting of TBIs.

Traumatic brain injury in the US military: epidemiology and key clinical and research programs.

Traumatic brain injury (TBI), and particularly concussion, is a major concern for the U.S. Military because of the associated short term disability, long term cognitive and pain symptoms suffered by some, and risk of prolonged or permanent neurologic injury if the Service member incurs a second TBI before full recovery from the first. Concussions were seen more often during the recent conflicts in Afghanistan and Iraq than in prior conflicts, such as the Vietnam War, because of the use of improvised explosive devices that typically caused non-penetrating closed head injury. Since 2000 more than 300,000 Service members were diagnosed with TBI, of which more than 80 % were concussions. Improved TBI screening tools also have identified a higher than expected incidence of concussions occurring in garrison. In this review we summarize current epidemiologic data for TBI in the Military, and describe contemporary Military procedures and strategies for TBI prevention, identification, evaluation, and acute and chronic care. Key TBI clinical research priorities and programs are described, and innovative organizational plans to address future TBI needs are summarized.

Identification of the rostral migratory stream in the canine and feline brain.

In the adult rodent brain, neural progenitor cells migrate from the subventricular zone of the lateral ventricle towards the olfactory bulb in a track known as the rostral migratory stream (RMS). To facilitate the study of neural progenitor cells and stem cell therapy in large animal models of CNS disease, we now report the location and characteristics of the normal canine and feline RMS. The RMS was found in Nissl-stained sagittal sections of adult canine and feline brains as a prominent, dense, continuous cellular track beginning at the base of the anterior horn of the lateral ventricle, curving around the head of the caudate nucleus and continuing laterally and ventrally to the olfactory peduncle before entering the olfactory tract and bulb. To determine if cells in the RMS were proliferating, the thymidine analog 5-bromo-2-deoxyuridine (BrdU) was administered and detected by immunostaining. BrdU-immunoreactive cells were present throughout this track. The RMS was also immunoreactive for markers of proliferating cells, progenitor cells and immature neurons (Ki-67 and doublecortin), but not for NeuN, a marker of mature neurons. Luxol fast blue and CNPase staining indicated that myelin is closely apposed to the RMS along much of its length and may provide guidance cues for the migrating cells. Identification and characterization of the RMS in canine and feline brain will facilitate studies of neural progenitor cell biology and migration in large animal models of neurologic disease.

The use of specific AAV serotypes to stably transduce primary CNS neuron cultures.

Although primary neuronal cell cultures are a valuable source of in vitro insight for many neurobiologists, all current gene expression technologies for these cells have significant drawbacks. Some of these limitations of current gene expression protocols include toxicity, transient expression, a requirement for postnatal neurons, and/or low efficiency. To date, many types of experiments were not possible because of these limitations. Here, we outline a methodology by which primary cultured neurons can be transduced at any age, after plating, with virtually no toxicity and continued gene expression for the lifetime of the culture. This method involves the use of adeno-associated viral vectors, which have the potential to be highly useful for either upregulation or downregulation of single or multiple genes, including neurotrophins, other neuroprotective genes, and neurotoxins.

Identification of potentially neuroprotective genes upregulated by neurotrophin treatment of CA3 neurons in the injured brain.

Specific neurotrophic factors mediate histological and/or functional improvement in animal models of traumatic brain injury (TBI). In previous work, several lines of evidence indicated that the mammalian neurotrophin NT-4/5 is neuroprotective for hippocampal CA3 pyramidal neurons after experimental TBI. We hypothesized that NT-4/5 neuroprotection is mediated by changes in the expression of specific sets of genes, and that NT-4/5-regulated genes are potential therapeutic targets for blocking delayed neuronal death after TBI. In this study, we performed transcription profiling analysis of CA3 neurons to identify genes regulated by lateral fluid percussion injury, or by treatment with the trkB ligands NT-4/5 or brain-derived neurotrophic factor (BDNF). The results indicate extensive overlap between genes upregulated by neurotrophins and genes upregulated by injury, suggesting that the mechanism behind neurotrophin neuroprotection may mimic the brain's endogenous protective response. A subset of genes selected for further study in vitro exhibited neuroprotection against glutamate excitotoxicity. The neuroprotective genes identified in this study were upregulated at 30 h post-injury, and are thus expected to act during a clinically useful time frame of hours to days after injury. Modulation of these factors and pathways by genetic manipulation or small molecules may confer hippocampal neuroprotection in vivo in preclinical models of TBI.

Role of monocyte chemoattractant protein-1 (MCP-1/CCL2) in migration of neural progenitor cells toward glial tumors.

Neural progenitor cells (NPCs) have been investigated as potential vehicles for brain tumor therapy because they have been shown to migrate toward central nervous system gliomas and can be genetically engineered to deliver cytotoxic agents to tumors. The mechanisms that regulate migration of NPCs to tumors are not fully understood. By means of microarray analysis, polymerase chain reaction, enzyme-linked immunosorbent assay, and immunohistochemistry, we found that monocyte chemoattractant protein-1 (MCP-1/CCL-2) was expressed in experimental brain tumor cells in vivo and in vitro. CCR2, the receptor for MCP-1, was expressed on C17.2 NPCs. We used a modified Boyden chamber assay and found increased migration of NPCs in vitro in response to MCP-1. By means of an in vivo model for NPC migration, we found evidence of NPC migration toward areas of MCP-1 infusion in rat brains. An understanding of NPC migration mechanisms may be used to enhance delivery of cytotoxic agents to brain tumor cells.

Sertoli cells improve survival of motor neurons in SOD1 transgenic mice, a model of amyotrophic lateral sclerosis.

Cell replacement therapy has been widely suggested as a treatment for multiple diseases including motor neuron disease. A variety of donor cells have been tested for treatment including isolated preparations from bone marrow and embryonic spinal cord. Another cell source, Sertoli cells, have been successfully used in models of diabetes, Parkinson's disease and Huntington's disease. The ability of these cells to secrete cytoprotective proteins and their role as 'nurse cells' supporting the function of other cell types in the testes suggest their potential use as neuroprotective cells. The current study examines the ability of Sertoli cells injected into the parenchyma of the spinal cord to protect motor neurons in a mouse model for amyotrophic lateral sclerosis. Seventy transgenic mice expressing the mutant (G93A) human Cu-Zn superoxide dismutase (SOD1) received a unilateral spinal injection of Sertoli-enriched testicular cells into the L4-L5 ventral horn (1 x 10(5) cells total) prior to the onset of clinical symptoms. The animals were euthanized at the end stage of the disease. Histological and morphometric analyses of the transplant site were performed. A significant increase in the number of surviving ChAT positive motor neurons was found ipsilateral to the injection compared with contralateral and uninjected spinal cord. The ipsilateral increase in motor neuron density was dependent upon proximity to the injection site. Sections rostral or caudal to the injection site did not display a similar difference in motor neuron density. Implantation of a Sertoli-cell-enriched preparation has a significant neuroprotective benefit to vulnerable motor neurons in the SOD1 transgenic model. The therapeutic benefit may be the result of secreted neurotrophic factors present at a critical stage of motor neuron degeneration in this model.