Carlos A. Jaramillo

The prevalence of epilepsy and association with traumatic brain injury in veterans of the Afghanistan and Iraq wars

Objective:To examine the association of epilepsy with traumatic brain injury (TBI) in Afghanistan and Iraq (Operation Enduring Freedom [OEF]/Operation Iraqi Freedom [OIF]) Veterans. Design:Cross-sectional observational study. Participants:A total 256 284 OEF/OIF Veterans who received inpatient and outpatient care in the Veterans Health Administration in fiscal years 2009-2010. Main Outcome Measures:We used algorithms developed for use with International Classification of Diseases, Ninth Revision, Clinical Modification, codes to identify epilepsy, TBI (penetrating TBI [pTBI]/other TBI), and other risk factors for epilepsy (eg, stroke). TBI and other risk factors were identified prior to the index date (first date of seizure or October 1, 2009) for primary analyses. Results:Epilepsy prevalence was 10.6 per 1000 (N = 2719) in fiscal year 2010; age-adjusted prevalence was 6.1. Of 37 718 individuals with a diagnosis of TBI, 29 297 Veterans had a diagnosis of TBI prior to the index date. Statistically significant associations were found between epilepsy and prior TBI diagnosis (pTBI: adjusted odds ratio = 18.77 [95% confidence interval, 9.21-38.23]; other TBI: adjusted odds ratio = 1.64 [1.43–1.89]). Conclusions:Among OEF/OIF Veterans, epilepsy was associated with previous TBI diagnosis, with pTBI having the strongest association. Because war-related epilepsy in Vietnam War Veterans with TBI continued 35 years postwar, a detailed, prospective study is needed to understand the relationship between epilepsy and TBI severity in OEF/OIF Veterans.

The Lack of CuZnSOD Leads to Impaired Neurotransmitter Release, Neuromuscular Junction Destabilization and Reduced Muscle Strength in Mice

Elevated reactive oxygen species (ROS) production and ROS-dependent protein damage is a common observation in the pathogenesis of many muscle wasting disorders, including sarcopenia. However, the contribution of elevated ROS levels to –a breakdown in neuromuscular communication and muscle atrophy remains unknown. In this study, we examined a copper zinc superoxide dismutase [CuZnSOD (Sod1)] knockout mouse (Sod1 −/−), a mouse model of elevated oxidative stress that exhibits accelerated loss of muscle mass, which recapitulates many phenotypes of sarcopenia as early as 5 months of age. We found that young adult Sod1 −/− mice display a considerable reduction in hind limb skeletal muscle mass and strength when compared to age-matched wild-type mice. These changes are accompanied by gross alterations in neuromuscular junction (NMJ) morphology, including reduced occupancy of the motor endplates by axons, terminal sprouting and axon thinning and irregular swelling. Surprisingly however, the average density of acetylcholine receptors in endplates is preserved. Using in vivo electromyography and ex vivo electrophysiological studies of hind limb muscles in Sod1 −/− mice, we found that motor axons innervating the extensor digitorum longus (EDL) and gastrocnemius muscles release fewer synaptic vesicles upon nerve stimulation. Recordings from individually identified EDL NMJs show that reductions in neurotransmitter release are apparent in the Sod1 −/− mice even when endplates are close to fully innervated. However, electrophysiological properties, such as input resistance, resting membrane potential and spontaneous neurotransmitter release kinetics (but not frequency) are similar between EDL muscles of Sod1 −/− and wild-type mice. Administration of the potassium channel blocker 3,4-diaminopyridine, which broadens the presynaptic action potential, improves both neurotransmitter release and muscle strength. Together, these results suggest that ROS-associated motor nerve terminal dysfunction is a contributor to the observed muscle changes in Sod1 −/− mice.

A retrospective cohort study of comorbidity trajectories associated with traumatic brain injury in veterans of the Iraq and Afghanistan wars.

Abstract Objectives: To identify and validate trajectories of comorbidity associated with traumatic brain injury in male and female Iraq and Afghanistan war Veterans (IAV). Methods: Derivation and validation cohorts were compiled of IAV who entered the Department of Veterans Affairs (VA) care and received 3 years of VA care between 2002–2011. Chronic disease and comorbidities associated with deployment including TBI were identified using diagnosis codes. A latent class analysis (LCA) of longitudinal comorbidity data was used to identify trajectories of comorbidity. Results: LCA revealed five trajectories that were similar for women and men: (1) Healthy, (2) Chronic Disease, (3) Mental Health, (4) Pain and (5) Polytrauma Clinical Triad (PCT: pain, mental health and TBI). Two additional classes found in men were 6) Minor Chronic and 7) PCT with chronic disease. Among these gender-stratified trajectories, it was found that women were more likely to experience headache (Pain trajectory) and depression (Mental Health trajectory), while men were more likely to experience lower back pain (Pain trajectory) and substance use disorder (Mental Health trajectory). The probability of TBI was highest in the PCT-related trajectories, with significantly lower probabilities in other trajectories. Conclusions: It was found that TBI was most common in PCT-related trajectories, indicating that TBI is commonly comorbid with pain and mental health conditions for both men and women. The relatively young age of this cohort raises important questions regarding how disease burden, including the possibility of neurodegenerative sequelae, will accrue alongside normal age-related decline in individuals with TBI. Additional ‘big data’ methods and a longer observation period may allow the development of predictive models to identify individuals with TBI that are at-risk for adverse outcomes.

Dietary restriction attenuates the accelerated aging phenotype of Sod1 -/- mice

Dietary restriction is a powerful aging intervention that extends the life span of diverse biological species ranging from yeast to invertebrates to mammals, and it has been argued that the antiaging action of dietary restriction occurs through reduced oxidative stress/damage. Using Sod1(-/-) mice, which have previously been shown to have increased levels of oxidative stress associated with a shorter life span and a high incidence of neoplasia, we were able to test directly the ability of dietary restriction to reverse an aging phenotype due to increased oxidative stress/damage. We found that dietary restriction increased the life span of Sod1(-/-) mice 30%, returning it to that of wild-type, control mice fed ad libitum. Oxidative damage in Sod1(-/-) mice was markedly reduced by dietary restriction, as indicated by a reduction in liver and brain F2-isoprostanes, a marker of lipid peroxidation. Analysis of end of life pathology showed that dietary restriction significantly reduced the overall incidence of pathological lesions in the Sod1(-/-) mice fed the dietary-restricted diet compared to Sod1(-/-) mice fed ad libitum, including the incidence of lymphoma (27 vs 5%) and overall liver pathology. In addition to reduced incidence of overall and liver-specific pathology, the burden and severity of both neoplastic and nonneoplastic lesions was also significantly reduced in the Sod1(-/-) mice fed the dietary-restricted diet. These data demonstrate that dietary restriction can significantly attenuate the accelerated aging phenotype observed in Sod1(-/-) mice that arises from increased oxidative stress/damage.

Traumatic brain injury in veterans of the wars in Iraq and Afghanistan: communication disorders stratified by severity of brain injury.

Abstract Objective: To describe the prevalence of communication disorders in veterans of the wars in Iraq and Afghanistan with traumatic brain injury (TBI). Design: Retrospective study of the prevalence of aphasia, fluency and voice disorders among veterans with different severity levels of TBI. Data was obtained from the VA National repository for OEF/OIF/OND veterans who received VA care in Fiscal Years 2010 and 2011. Results: Among the 303 716 veterans in this study, 1848 were diagnosed with a communication disorder; 40% of these were also diagnosed with a TBI. Voice disorders were the most prevalent diagnosis (3.5 per 1000) followed by aphasia (1.9 per 1000) and fluency disorder (0.7 per 1000). Individuals with a TBI diagnosis were more likely to have a diagnosis of aphasia, followed by fluency and then voice disorder. The odds ratio (OR) of aphasia with TBI was 11.09–252.75 (95% CI = 8.78–441.52, p < 0.01). OR for fluency disorders with TBI was 3.58–10.41 (95% CI = 2.56–42.40, p < 0.01) and association of voice disorders with TBI was significant for all levels of TBI severity (OR = 1.5–6.61, 95% CI = 1.24–14.05, p < 0.01). Conclusions: Veterans who sustained a TBI were more likely to have a diagnosis of a communication disorder, regardless of TBI severity. Those with TBI, including mild TBI, should be screened and evaluated for communication disorders.

A cohort study examining headaches among veterans of Iraq and Afghanistan wars: Associations with traumatic brain injury, PTSD, and depression

To describe the prevalence and persistence of headache and associated conditions in an inception cohort of U.S. veterans of Iraq and Afghanistan wars.

Increasing Prevalence of Chronic Lung Disease in Veterans of the Wars in Iraq and Afghanistan

Research from the wars in Afghanistan and Iraq have focused on traumatic brain injury (TBI) and mental health conditions; however, it is becoming clear that other health concerns, such as respiratory illnesses, warrant further scientific inquiry. Early reports from theater and postdeployment health assessments suggested an association with deployment-related exposures (e.g., sand, burn pits, chemical, etc.) and new-onset respiratory symptoms. We used data from Veterans Affairs medical encounters between fiscal years 2003 and 2011 to identify trends in chronic obstructive pulmonary disease, asthma, and interstitial lung disease in veterans. We used data from Veterans Affairs and Department of Defense sources to identify sociodemographic (age, sex, race), military (e.g., service branch, multiple deployments) and clinical characteristics (TBI, smoking) of individuals with and without chronic lung diseases. Generalized estimating equations found significant increases over time for chronic obstructive pulmonary disease and asthma in both unadjusted and adjusted analyses. Trends for interstitial lung disease were significant only in adjusted analyses. Age, smoking, and TBI were also significantly associated with chronic lung diseases; however, multiple deployments were not associated. Research is needed to identify which characteristics of deployment-related exposures are linked with chronic lung disease.

The effect of mild traumatic brain injury on peripheral nervous system pathology in wild type mice and the G93A mutant mouse model of motor neuron disease

Traumatic brain injury (TBI) is associated with a risk of neurodegenerative disease. Some suggest a link between TBI and motor neuron disease (MND), including amyotrophic lateral sclerosis (ALS). To investigate the potential mechanisms linking TBI to MND, we measured motor function and neuropathology following mild-TBI in wild-type and a transgenic model of ALS, G93A mutant mice. Mild-TBI did not alter the lifespan of G93A mice or age of onset; however, rotarod performance was impaired in G93A verses wild-type mice. Grip strength was reduced only in G93A mice after mild-TBI. Increased electromyography (EMG) abnormalities and markers of denervation (AchR, Runx1) indicate that mild-TBI may result in peripheral effects that are exaggerated in G93A mice. Markers of inflammation (cell edema, astrogliosis and microgliosis) were detected at 24 and 72h in the brain and spinal cord in wild-type and G93A mice. Levels of F2-isoprostanes, a marker of oxidative stress, were increased in the spinal cord 24h post mild-TBI in wild-type mice but were not affected by TBI in G93A mice. In summary, our data demonstrate that mild-TBI induces inflammation and oxidative stress and negatively impacts muscle denervation and motor performance, suggesting mild-TBI can potentiate motor neuron pathology and influence the development of MND in mice.

Traumatic Brain Injury Severity, Comorbidity, Social Support, Family Functioning, and Community Reintegration Among Veterans of the Afghanistan and Iraq Wars

OBJECTIVE To examine the association between traumatic brain injury (TBI) severity; social, family, and community reintegration outcomes; and return to work status among post-9/11 veterans in Department of Veterans Affairs (VA) care. DESIGN Retrospective observational cohort study. SETTING Mail/online survey fielded to a national sample of veterans. PARTICIPANTS Sample of post-9/11 veterans with at least 3 years of VA care stratified according to TBI severity and comorbidities who completed and returned surveys (N=2023). INTERVENTIONS Not applicable. MAIN OUTCOME MEASURES Deployment Risk and Resilience Inventory-2 family functioning and social support subscales; Military to Civilian Questionnaire; and employment status. RESULTS Bivariate analyses revealed that veterans with every classification of TBI severity reported significantly more difficulty on social, family, and community reintegration outcomes than those with no TBI. In the fully adjusted model, veterans with unclassified and moderate/severe TBI reported significantly more difficulty with community reintegration and were less likely to be employed relative to those with no TBI; those with unclassified TBI also reported significantly more difficulty with family functioning. Veterans with mild TBI also reported significantly more difficulty with community reintegration. CONCLUSIONS This study provides insight into long-term outcomes associated with TBI in post-9/11 veterans and suggests that exposure to TBI has a negative effect on social and family functioning, community reintegration, and return to work even after controlling for comorbidity, deployment experiences, and sociodemographic characteristics. Additional research is required to explicate what appears to be complex interactions among TBI severity, psychosocial well-being, combat exposures, and socioeconomic resources in this population.

Medical Complications After Moderate to Severe Traumatic Brain Injury

Owing to the potential for prolonged length of stays, increased healthcare costs, and significantly increased risk of mortality, the secondary complications of traumatic brain injury (TBI) must be recognized early and managed appropriately. Conditions such as spasticity, venous thromboembolism, paroxysmal sympathetic hyperactivity, neuroendocrine dysfunction, heterotopic ossification, nutritional deficits, and sleep disturbances can all negatively affect functional outcomes and community reintegration. Unfortunately, for most of these secondary complications, there is a paucity of evidence for treatment protocols in this unique population. The purpose of this chapter is to shed light on the current strategies for optimal management of secondary complications in patients with TBI and to raise awareness of controversies and limitations in practice.