Posts Tagged concussion

[REVIEW ARTICLE] Blood Biomarkers for Traumatic Brain Injury: A Quantitative Assessment of Diagnostic and Prognostic Accuracy – Full Text

Blood biomarkers have been explored for their potential to provide objective measures in the assessment of traumatic brain injury (TBI). However, it is not clear which biomarkers are best for diagnosis and prognosis in different severities of TBI. Here, we compare existing studies on the discriminative abilities of serum biomarkers for four commonly studied clinical situations: detecting concussion, predicting intracranial damage after mild TBI (mTBI), predicting delayed recovery after mTBI, and predicting adverse outcome after severe TBI (sTBI). We conducted a literature search of publications on biomarkers in TBI published up until July 2018. Operating characteristics were pooled for each biomarker for comparison. For detecting concussion, 4 biomarker panels and creatine kinase B type had excellent discriminative ability. For detecting intracranial injury and the need for a head CT scan after mTBI, 2 biomarker panels, and hyperphosphorylated tau had excellent operating characteristics. For predicting delayed recovery after mTBI, top candidates included calpain-derived αII-spectrin N-terminal fragment, tau A, neurofilament light, and ghrelin. For predicting adverse outcome following sTBI, no biomarker had excellent performance, but several had good performance, including markers of coagulation and inflammation, structural proteins in the brain, and proteins involved in homeostasis. The highest-performing biomarkers in each of these categories may provide insight into the pathophysiologies underlying mild and severe TBI. With further study, these biomarkers have the potential to be used alongside clinical and radiological data to improve TBI diagnostics, prognostics, and evidence-based medical management.

Introduction

Traumatic brain injury (TBI) is a common cause of disability and mortality in the US (1) and worldwide (2). Pathological responses to TBI in the CNS include structural and metabolic changes, as well as excitotoxicity, neuroinflammation, and cell death (34). Fluid biomarkers that may track these injury and inflammatory processes have been explored for their potential to provide objective measures in TBI assessment. However, at present there are limited clinical guidelines available regarding the use of biomarkers in both the diagnosis of TBI and outcome prediction following TBI. To inform future guideline formulation, it is critical to distinguish between different clinical situations for biomarker use in TBI, such as detection of concussion, prediction of positive and negative head computed tomography (CT) findings, and prediction of outcome for different TBI severities. This allows for comparisons to determine which biomarkers may be used most appropriately to characterize different aspects of TBI.

The identification of TBI severity has become a contentious issue. Currently, inclusion in TBI clinical trials is primarily based on the Glasgow Coma Scale (GCS), which stratifies patients into categories of mild, moderate, and severe TBI. The GCS assesses consciousness and provides prognostic information, but it does not inform the underlying pathologies that may be targeted for therapy (56). Furthermore, brain damage and persistent neurological symptoms can occur across the spectrum of TBI severity, limiting the use of GCS-determined injury severity to inform clinical management. Biomarkers in TBI have the potential to provide objective and quantitative information regarding the pathophysiologic mechanisms underlying observed neurological deficits. Such information may be more appropriate for guiding management than initial assessments of severity alone. Since the existing literature primarily focuses on applications of biomarkers in either suspected concussion, mild TBI (mTBI), or severe TBI (sTBI), we will discuss biomarker usage in these contexts.

Concussion is a clinical syndrome involving alteration in mental function induced by head rotational acceleration. This may be due to direct impact or unrestrained rapid head movements, such as in automotive crashes. Although there are over 30 official definitions of concussion, none include the underlying pathology. Missing from the literature have been objective measures to not only identify the underlying pathology associated with the given clinical symptoms, but also to indicate prognosis in long-term survival. Indeed, current practices in forming an opinion of concussion involve symptom reports, neurocognitive testing, and balance testing, all of which have elements of subjectivity and questionable reliability (7). While such information generally reflects functional status, it does not identify any underlying processes that may have prognostic or therapeutic consequences. Furthermore, because patients with concussion typically present with negative head CT findings, there is a potential role for blood-based biomarkers to provide objective information regarding the presence of concussion, based on an underlying pathology. This information could inform management decisions regarding resumption of activities for both athletes and non-athletes alike.

Blood-based biomarkers have utility far beyond a simple detection of concussion by elucidating specific aspects of the injury that could drive individual patient management. For example, biomarkers may aid in determining whether a mTBI patient presenting to the emergency department requires a CT scan to identify intracranial pathology. The clinical outcome for a missed epidural hematoma in which the patient is either discharged or admitted for routine observation is catastrophic; 25% are left severely impaired or dead (8). The Canadian CT Head Rule (9) and related clinical decision instruments achieve high sensitivities in predicting the need for CT scans in mild TBI cases. However, they do this at specificities of only 30–50% (10). Adding a blood biomarker to clinical evaluation may be useful to improve specificity without sacrificing sensitivity, as recently suggested (11). In addition, given concern about radiation exposure from head CT scans in concussion cases, particularly in pediatric populations, identification of patients who would be best assessed with neuroimaging is crucial. Thus, the use of both sensitive and specific biomarkers may serve as cost-effective tools to aid in acute assessment, especially in the absence of risk factors for intracranial injury (12). S-100B, an astroglial protein, has been the most extensively studied biomarker for TBI thus far and has been incorporated into some clinical guidelines for CT scans (1314). However, S-100B is not CNS-specific (1516) and has shown inconsistent predictive capacity in the outcome of mild TBI (1718). Given that several other promising biomarkers have also been investigated in this context, it is important to evaluate and compare the discriminative abilities of S-100B with other candidate blood-based biomarkers for future use.

Blood biomarkers also have the potential to help predict unfavorable outcomes across the spectrum of TBI severity. Outcome predication is difficult; in mTBI, existing prognostic models performed poorly in an external validation study (19). Identifying biomarkers that best predict delayed recovery or persistent neurological symptoms following mTBI would help with the direction of resources toward patients who may benefit most from additional rehabilitation or prolonged observation. In sTBI, poorer outcome has often been associated with a low GCS score (20). However, factors such as intoxication or endotracheal intubation may make it difficult to assess GCS reliably in the acute setting (2122). The addition of laboratory parameters to head CT and admission characteristics have improved prognostic models (23). Thus, prognostic biomarkers in sTBI could help determine whether patients are likely to benefit from intensive treatment. Several candidate biomarkers that correlate with various pathologies of mild and severe TBI have been studied (24), but their relative prognostic abilities remain unclear.

Existing reviews on biomarkers in TBI have provided valuable insight into the pathologic correlates of biomarkers, as well as how biomarkers may be used for diagnosis and prognosis (2531). However, there has been no previous quantitative comparison of the literature regarding biomarkers’ discriminative abilities in specific clinical situations. Here, we compare existing studies on the discriminative abilities of serum biomarkers for four commonly studied clinical situations: detecting concussion, predicting intracranial damage after mTBI, predicting delayed recovery after mTBI, and predicting adverse outcome after sTBI.[…]

 

Continue —-> Frontiers | Blood Biomarkers for Traumatic Brain Injury: A Quantitative Assessment of Diagnostic and Prognostic Accuracy | Neurology

Figure 2. Anatomical locations of potential TBI biomarkers. The biomarkers included in this schematic all rated as “good” (AUC=0.800.89) or better for any of the four clinical situations studied (detecting concussion, predicting intracranial damage after concussion, predicting delayed recovery after concussion, and predicting adverse outcome after severe TBI). Biomarkers with a pooled AUC <0.8 are not shown. 1Also found in adipose tissue; 2synthesized in cells of stomach and pancreas; may regulate HPA axis; 3found mostly in pons; 4also found extracellularly; 5lectin pathway of the complement system; 6also found in endothelial cells. BBB, blood brain barrier. ECM, Extracellular matrix. Image licensed under Creative Commons Attribution-ShareAlike 4.0 International license. https://creativecommons.org/licenses/by-sa/4.0/deed.en. See Supplementary Material for image credits and licensing.

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[BLOG] Lash & Associates’ Award-Winning Blog site

TBI, ABI, PTSD, Stroke, Concussion Blog Posts!

Lash & Associates’
Award-Winning Blog Site
Is Well Worth A Look

Our large variety of blog articles are keyword searchable, and offer help & encouragement.

Click here to go the our blog site!

No matter what your situation – as a survivor, a clinician, a caregiver, or a family member, our blog site provides a great reference point. Check it out – we’ve got something for most any situation regarding the greater TBI Community!

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[Abstract] Rehabilitation of Cognitive Dysfunction Following Traumatic Brain Injury – Epilepsy Society

This article outlines key principles and considerations in the rehabilitation of cognitive challenges following mild, moderate, and severe traumatic brain injuries, with a focus on the needs of the service member and veteran population. The authors highlight specific evidence-based strategies and interventions and provide functional examples to support implementation. By emphasizing the array of tools and resources that have been designed to address cognitive challenges in the service member and veteran population, they focus on optimizing cognition to support successful community reintegration and the resumption of a full and meaningful life.

 

First page of article

via Rehabilitation of Cognitive Dysfunction Following Traumatic Brain Injury – Physical Medicine and Rehabilitation Clinics

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[ARTICLE] Clinical Findings in a Multicenter MRI Study of Mild TBI

Abstract

Background: Uncertainty continues to surround mild traumatic brain injury (mTBI) diagnosis, symptoms, prognosis, and outcome due in part to a lack of objective biomarkers of injury and recovery. As mTBI gains recognition as a serious public health epidemic, there is need to identify risk factors, diagnostic tools, and imaging biomarkers to help guide diagnosis and management.

Methods: One hundred and eleven patients (15–50 years old) were enrolled acutely after mTBI and followed with up to four standardized serial assessments over 3 months. Each encounter included a clinical exam, neuropsychological assessment, and magnetic resonance imaging (MRI). Chi-square and linear mixed models were used to assess changes over time and determine potential biomarkers of mTBI severity and outcome.

Results: The symptoms most frequently endorsed after mTBI were headache (91%), not feeling right (89%), fatigue (86%), and feeling slowed down (84%). Of the 104 mTBI patients with a processed MRI scan, 28 (27%) subjects had white matter changes which were deemed unrelated to age, and 26 of these findings were deemed unrelated to acute trauma. Of the neuropsychological assessments tested, 5- and 6-Digit Backward Recall, the modified Balance Error Scoring System (BESS), and Immediate 5-Word Recall significantly improved longitudinally in mTBI subjects and differentiated between mTBI subjects and controls. Female sex was found to increase symptom severity scores (SSS) at every time point. Age ≥ 25 years was correlated with increased SSS. Subjects aged ≥ 25 also did not improve longitudinally on 5-Digit Backward Recall, Immediate 5-Word Recall, or Single-Leg Stance of the BESS, whereas subjects < 25 years improved significantly. Patients who reported personal history of depression, anxiety, or other psychiatric disorder had higher SSS at each time point.

Conclusions: The results of this study show that 5- and 6-Digit Backward Recall, the modified BESS, and Immediate 5-Word Recall should be considered useful in demonstrating cognitive and vestibular improvement during the mTBI recovery process. Clinicians should take female sex, older age, and history of psychiatric disorder into account when managing mTBI patients. Further study is necessary to determine the true prevalence of white matter changes in people with mTBI.

Introduction

Mild traumatic brain injury (mTBI) is defined as a traumatically induced physiological disruption of brain function (1). Although mTBI accounts for at least 75% of traumatic brain injuries and imposes an excessive societal burden (23), mTBI diagnosis continues to lack objective clinical and imaging biomarkers. As of now, the best marker for severity and recovery is a subjective assessment of acute symptom burden (4). Uncertainty continues to surround mTBI diagnosis, symptoms, prognosis, and outcome for physicians and patients as reliable biomarkers remain elusive. As injury rates increase and mTBI becomes a serious public health epidemic (5), there is an increasing role for identification of potential imaging biomarkers, specific neuropsychological assessments, and validated risk factors to help guide prognoses and return to play decisions.

Given the current subjective nature of symptom burden assessment, there is a role for neuropsychological assessments in evaluating the cognitive impairment of patients after injury. The sport concussion assessment tool (SCAT) has been demonstrated as an effective tool to differentiate between mTBI subjects and controls in non-athlete populations and is widely used in mTBI studies (68). Tests of memory, balance, and cognition are incorporated into the SCAT (910), but research has not demonstrated their effectiveness as longitudinal assessments (11). Separately, 3-word recall is commonly employed in patients with mTBI to assess memory function (12). This test is usually normal and is probably inadequate for assessing these patients.

The risk factors for mTBI severity are debated in the literature. Demographic factors commonly explored include sex, age, previous concussions, learning disability, psychiatric history, and migraine/headache history (13). Although each of these preinjury characteristics has been studied in numerous protocols, a consensus has not been reached. Further research is needed to establish the risk factors for mTBI severity so that they may be incorporated into clinical care.

Moreover, routine imaging techniques are limited in their value of serving as biomarkers of severity or prognosis in the mTBI population, and the extent of incidental magnetic resonance imaging (MRI) findings in mTBI patients also remains unclear. Conventional structural MR imaging is felt to be limited in its yield of disease severity or prognosis. Further research is necessary to investigate the anatomical characteristics of the mTBI population that present to medical attention. Better characterization of the specific abnormalities in anatomic imaging in this population is necessary.

The aim of this study was to incorporate patient history, clinical exams, imaging, and multiple neurological assessments into a prospective longitudinal study of patients presenting with an acute mild traumatic brain injury to provide guidance for hypothesis generation and future study design of mTBI research. Traditional neuropsychological assessments were developed to further attempt to detect abnormalities in patients with mTBI. Although MR imaging is not routinely performed for acute mTBI, recent advances in MRI based techniques have allowed researchers to incorporate imaging into mTBI trials. This study specifically investigated the presence of white matter hyperintensities on structural imaging. This combination of assessments and time points provided a more comprehensive and detailed assessment of symptoms and outcomes of mTBI patients than found in previous studies. This allows for identification of previously elusive potential risk factors which may influence outcome measures for mTBI populations.[…]

 

Continue —>  Frontiers | Clinical Findings in a Multicenter MRI Study of Mild TBI | Neurology

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[Poster] Repetitive Transcranial Magnetic Stimulation (rTMS) application in cognitive deficits after Traumatic Brain Injury (TBI)/concussion

Objective: The objective of this study is to review current literature for the efficacy of Repetitive Transcranial Magnetic Stimulation (rTMS) treatment for cognitive deficits after Traumatic Brain Injury (TBI)/concussion.

Background: TBI is a major public health problem and can cause substantial disability. TBI can lead to Post Concussive Syndrome (PCS) which consists of neuro-motor, cognitive, behavioral/affective, and emotional symptoms. Cognitive deficits can significantly impact functionality. The outcome of neuropsychopharmacological treatment is limited, with risk for side effects. TMS is a form of non-invasive neuromodulation which is FDA-approved for treatment-resistant depression. However, there is limited understanding about its application in addressing cognitive deficits after TBI. We therefore sought to examine current research pertaining to the application of TMS in post-TBI cognitive deficits.

Methods: We searched the PubMed research database with the specific terms “TMS in cognitive deficits after TBI”, “rTMS” and “post concussive syndrome.” We assessed clinical trials where cognition was measured either as a primary or secondary variable. Case studies/reports were excluded.

Results: One non-controlled, pilot study was found that assessed cognition after TMS as a secondary variable in TBI. The aim of the study was to assess safety, tolerability and efficacy of repetitive TMS for treatment of PCS after mild TBI (mTBI). Patients who had sustained mTBI over three months prior and had a PCS Symptom Scale score of over 21 were selected. Repetitive TMS (rTMS) was used as the intervention with 20 sessions of rTMS using a figure-8 coil attached to MagPro stimulator. Cognitive symptoms were assessed using subjective self-report scales and objective tests for attention and speed of processing domains. Neuropsychological tests that were used include Trails A & B, Ruff’s 2 & 7 Automatic speed test, Stroop test, Language test for phonemic, and category fluency, Rey AVLT test. The study showed a reduction in overall severity of PCS symptoms but no significant changes on the cognitive symptoms questionnaire or on the majority of neuropsychological test scores.

Conclusion: Despite the limitation in this study with the lack of a control group, there appears to be a good signal for the clinical application of TMS for post-concussive syndrome after TBI/concussion. A more robust, large well-controlled study may be very reasonable approach in the future to evaluate efficacy of rTMS.

References

1. Koski L1, Kolivakis T, Yu C, Chen JK, Delaney S, Ptito A. Noninvasive brain stimulation for persistent postconcussion symptoms in mild traumatic brain injury. J Neurotrauma. 2015 Jan 1;32(1):38-44. https://doi.org/10.1089/neu.2014.3449.

2. Bashir S1, Vernet M, Yoo WK, Mizrahi I, Theoret H, Pascual-Leone A. Changes in cortical plasticity after mild traumatic brain injury. Restor Neurol Neurosci. 2012;30(4):277-82. https://doi.org/10.3233/RNN-2012-110207.

3. Demirtas-Tatlidede A1, Vahabzadeh-Hagh AM, Bernabeu M, Tormos JM, Pascual-Leone A.Noninvasive brain stimulation in traumatic brain injury. J Head Trauma Rehabil. 2012 Jul-Aug;27(4):274-92. https://doi.org/10.1097/HTR.0b013e318217df55.

4. Neville IS, Hayashi CY, El Hajj SA, Zaninotto AL, Sabino JP, Sousa LM Jr, Nagumo MM, Brunoni AR, Shieh BD, Amorim RL, Teixeira MJ, Paiva WS. Repetitive Transcranial Magnetic Stimulation (rTMS) for the cognitive rehabilitation of traumatic brain injury (TBI) victims: study protocol for a randomized controlled trial. Trials. 2015 Oct 5;16:440. https://doi.org/10.1186/s13063-015-0944-2.

via Repetitive Transcranial Magnetic Stimulation (rTMS) application in cognitive deficits after Traumatic Brain Injury (TBI)/concussion – Brain Stimulation: Basic, Translational, and Clinical Research in Neuromodulation

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[WEB SITE] Learning stress-reducing techniques may benefit people with epilepsy

Learning techniques to help manage stress may help people with epilepsy reduce how often they have seizures, according to a study published in the February 14, 2018, online issue of Neurology®, the medical journal of the American Academy of Neurology.

“Despite all the advances we have made with new drugs for epilepsy, at least one-third of people continue to have seizures, so new options are greatly needed,” said study author Sheryl R. Haut, MD, of Montefiore Medical Center and the Albert Einstein College of Medicine in the Bronx, NY, and member of the American Academy of Neurology. “Since stress is the most common seizure trigger reported by patients, research into reducing stress could be valuable.”

The study involved people with seizures that did not respond well to medication. While all of the 66 participants were taking drugs for seizures, all continued to have at least four seizures during about two months before the study started.

During the three-month treatment period all of the participants met with a psychologist for training on a behavioral technique that they were then asked to practice twice a day, following an audio recording. If they had a day where they had signs that they were likely to have a seizure soon, they were asked to practice the technique another time that day. The participants filled out daily electronic diaries on any seizures, their stress level, and other factors such as sleep and mood.

Half of the participants learned the progressive muscle relaxation technique, a stress reduction method where each muscle set is tensed and relaxed, along with breathing techniques. The other participants were the control group-;they took part in a technique called focused attention. They did similar movements as the other group, but without the muscle relaxation, plus other tasks focusing on attention, such as writing down their activities from the day before. The study was conducted in a blinded fashion so that participants and evaluators were not aware of treatment group assignment.

Before the study, the researchers had hypothesized that the people doing the muscle relaxing exercises would show more benefits from the study than the people doing the focused attention exercises, but instead they found that both groups showed a benefit-;and the amount of benefit was the same.

The group doing the muscle relaxing exercises had 29 percent fewer seizures during the study than they did before it started, while the focused attention group had 25 percent fewer seizures, which is not a significant difference, Haut said. She added that study participants were highly motivated as was shown by the nearly 85 percent diary completion rate over a five-month period.

“It’s possible that the control group received some of the benefits of treatment in the same way as the ‘active’ group, since they both met with a psychologist and every day monitored their mood, stress levels and other factors, so they may have been better able to recognize symptoms and respond to stress,” said Haut. “Either way, the study showed that using stress-reducing techniques can be beneficial for people with difficult-to-treat epilepsy, which is good news.”

Haut said more research is needed with larger numbers of people and testing other stress reducing techniques like mindfulness based cognitive therapy to determine how these techniques could help improve quality of life for people with epilepsy.

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[BLOG POST] Study: Transcranial e-stim beneficial in mild traumatic brain injury

Researchers from the University of California San Diego and from the Veterans Affairs San Diego Healthcare System have improved neural function in a group of people with mild traumatic brain injury using low-impulse electrical stimulation to the brain, according to a study published in Brain Injury.

Although little is understood about the pathology of mild TBI, the team of researchers noted that previous work has shown that passive neuro-feedback, low-intensity pulses applied to the brain through transcranial electrical stimulation, has promise as a potential treatment.

The team’s pilot study enrolled six people with mild TBI who were experiencing post-concussion symptoms. Researchers used a form of LIP-tES combined with concurrent electroencephalography monitoring and assessed the treatment’s effect using a non-invasive functional imaging technique, magnetoencephalography, before and after treatment.

“Our previous publications have shown that MEG detection of abnormal brain slow-waves is one of the most sensitive biomarkers for mild traumatic brain injury (concussions), with about 85 percent sensitivity in detecting concussions and, essentially, no false-positives in normal patients,” senior author Dr. Roland Lee said in prepared remarks. “This makes it an ideal technique to monitor the effects of concussion treatments such as LIP-tES.”

Researchers reported that the brains in all six patients had abnormal slow-waves at the time of initial scans. After treatment, MEG scans showed reduced abnormal slow-waves and the study participants reported a significant reduction in post-concussion scores.

“For the first time, we’ve been able to document with neuroimaging the effects of LIP-tES treatment on brain functioning in mild TBI,” first author Ming-Xiong Huang added. “It’s a small study, which certainly must be expanded, but it suggests new potential for effectively speeding the healing process in mild traumatic brain injuries.”

Source: Study: Transcranial e-stim beneficial in mild traumatic brain injury – MassDevice

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[WEB SITE] TBI Basics – BrainLine

A TBI can happen to anyone, whether it happens while playing sports, at work, or just slipping on an icy sidewalk. Injuries can range from “mild” to “severe”, with a majority of cases being concussions or mild TBI. The good news is that most cases are treatable and there are several ways to help prevent injury.

What You’ll Find Here

You Are Not Alone

You Are Not Alone

See how others are navigating their post-TBI lives. Check out personal stories and “life after TBI” blogs, or join the conversation with our Facebook community.

Source: TBI Basics | BrainLine

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[WEB SITE] 9 1/2 Need-to-Know Facts About Traumatic Brain Injury

9 1/2 Need-to-Know Things About Traumatic Brian InjuryAn estimated 5.3 million Americans — about 2 percent of the U.S. population — currently have a long-term or lifelong need for help with everyday activities due to traumatic brain injury (TBI). (1) Many believe this number to be low as it only takes into account the number of reported injuries to hospital emergency rooms and by health care professionals. We’ve compiled the top 9 1/2 things to know about traumatic brain injury, it would have been 10 but the last 1/2 was left off because memory is often affected by traumatic brain injury.

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  1. A traumatic brain injury is a blow or jolt to the head or a penetrating head injury that disrupts the function of the brain. You do not need to lose consciousness to sustain a concussion.
  2. 1.7 million people sustain a TBI each year in the United States. By the numbers, every American has more than a 1:300 chance of sustaining a traumatic brain injury each year. (2)

  3. The three groups at highest risk for traumatic brain injury are children (0-4 year olds), teenagers (15-19 year olds), and adults (65 and older). (2)

  4. Estimates peg the number of sports-related traumatic brain injuries as high as 3.8 million per year. (2)

  5. Using a seatbelt and wearing a helmet are the best ways to prevent a TBI.

  6. Males are almost twice as likely as females to sustain a TBI.

  7. A concussion is a mild brain injury. The consequences of multiple concussions can be far more dangerous than those of a first TBI. (3)

  8. The area most often injured are the frontal lobes that control thinking and emotional regulation.

  9. A blow to one part of the brain can cause damage throughout.

9 1/2. Most people do make a good recovery from TBI.

If you found this useful, please share with family and friends or leave a comment below if you think we’ve left something off.

References:

  1. Centers for Disease Control. http://www.cdc.gov/traumaticbraininjury/pdf/BlueBook_factsheet-a.pdf
  2. Langlois JA, Rutland-Brown W, Thomas KE. Traumatic brain injury in the United States: emergency department visits, hospitalizations, and deaths. Atlanta (GA): Centers for Disease Control and Prevention, National Center for Injury Prevention and Control; 2006.
  3. Cifu, David, MD. eMedicine.com. www.emedicine.com/sports/TOPIC113.HTM.

Source: 9 1/2 Need-to-Know Facts About Traumatic Brain Injury

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[ARTICLE] Role of Interleukin-10 in Acute Brain Injuries – Full Text

 

Interleukin-10 (IL-10) is an important anti-inflammatory cytokine expressed in response to brain injury, where it facilitates the resolution of inflammatory cascades, which if prolonged causes secondary brain damage. Here, we comprehensively review the current knowledge regarding the role of IL-10 in modulating outcomes following acute brain injury, including traumatic brain injury (TBI) and the various stroke subtypes. The vascular endothelium is closely tied to the pathophysiology of these neurological disorders and research has demonstrated clear vascular endothelial protective properties for IL-10. In vitro and in vivo models of ischemic stroke have convincingly directly and indirectly shown IL-10-mediated neuroprotection; although clinically, the role of IL-10 in predicting risk and outcomes is less clear. Comparatively, conclusive studies investigating the contribution of IL-10 in subarachnoid hemorrhage are lacking. Weak indirect evidence supporting the protective role of IL-10 in preclinical models of intracerebral hemorrhage exists; however, in the limited number of clinical studies, higher IL-10 levels seen post-ictus have been associated with worse outcomes. Similarly, preclinical TBI models have suggested a neuroprotective role for IL-10; although, controversy exists among the several clinical studies. In summary, while IL-10 is consistently elevated following acute brain injury, the effect of IL-10 appears to be pathology dependent, and preclinical and clinical studies often paradoxically yield opposite results. The pronounced and potent effects of IL-10 in the resolution of inflammation and inconsistency in the literature regarding the contribution of IL-10 in the setting of acute brain injury warrant further rigorously controlled and targeted investigation.

Introduction

Stroke and traumatic brain injury (TBI) are devastating acute neurological disorders that can result in high mortality rates or long-lasting disability. Approximately 87% of strokes are ischemic and 13% are hemorrhagic, with 10 and 3% of the latter representing intracerebral hemorrhage (ICH) and subarachnoid hemorrhage (SAH), respectively (1). Stroke is the fourth most common cause of death in the United States, and ischemic stroke (IS) in particular is the seventh most frequent emergency department presentation (2, 3). TBI and concussions have over twice the incidence of all strokes combined (4), with more than three million people in the United States alone living with long-term disability as a result of TBI (5). Collectively, stroke and TBI have very few treatments, and despite advances in clinical management of these disorders, they are still associated with significant disability and mortality (6, 7).

Inflammation plays a central role in the pathophysiology of stroke and TBI and can have both protective and harmful effects on brain tissue (815). Although there are some distinct differences in the inflammatory cascades following the various types of acute brain injury, there are also numerous commonalities. Acute neuroinflammation is characterized by the activation of resident central nervous system (CNS) immune surveillance glial cells that release cytokines, chemokines, and other immunologic mediators, which facilitate the recruitment of peripheral cells such as monocytes, neutrophils, and lymphocytes (8, 9, 12, 15). Collectively, this initial response is helpful in the clearance of toxic entities and the restoration and repair of damaged tissue. However, during the resolution phase, with an uncontrolled and prolonged inflammatory response, secondary damage results from overactivation of this inflammatory surge and release of additional factors that led to breakdown of the blood–brain barrier (BBB), cerebral edema, cerebral hypertension, and ischemia.

Interleukin-10 is generally known as an anti-inflammatory cytokine that exerts a plethora of immunomodulatory functions during an inflammatory response and is particularly important during the resolution phase. Expression of IL-10 in the brain increases with CNS pathology, promoting neuronal and glial cell survival, and dampening of inflammatory responses via a number of signaling pathways (16). IL-10 was originally described as cytokine synthesis inhibitory factor and in addition to attenuating the synthesis of proinflammatory cytokines, IL-10 also limits inflammation by reducing cytokine receptor expression and inhibiting receptor activation (16). Furthermore, IL-10 has potent and diverse effects on essentially all hematopoetic cells that infiltrate the brain following injury. For example, IL-10 reduces the activation and effector functions of T cells, monocytes, and macrophages, ultimately ending the inflammatory response to injury (17). The structure, function, and regulation of IL-10 have been extensively reviewed elsewhere, including a review of IL-10 in the brain (1620), although not in the context of the various forms of acute brain injury. Please refer to the aforementioned reviews for additional details, including the potential cellular sources, target cells, signal transduction, and mode of action of IL-10.

Given the intriguing multifactorial role of IL-10 in the resolution of inflammatory cascades that are important for promoting neurologic recovery from acute brain injury, here we present a comprehensive literature review of preclinical and clinical studies in this area. We focus on the contribution of IL-10 in modulating various important parameters and pathophysiologic processes important for IS, SAH, ICH, and TBI outcomes, and whether IL-10 has therapeutic or biomarker potential. A better understanding of the many functions of IL-10 in the brain after injury, particularly in the resolution phase of inflammatory processes, will promote our knowledge of the pathophysiology of these debilitating disorders and guide future development of novel therapeutic approaches.[…]

Continue —> Frontiers | Role of Interleukin-10 in Acute Brain Injuries | Neurology

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