Guidelines of the International Headache Society for controlled trials of pharmacological preventive treatment for persistent post-traumatic headache attributed to mild traumatic brain injury.

BACKGROUND: Persistent headache attributed to traumatic injury to the head is divided into two subtypes, one attributed to moderate or severe traumatic injury and another attributed to mild traumatic injury (i.e., concussion). The latter is much more prevalent, in part because more than 90% of cases with traumatic brain injury are classified as mild. The pathophysiology of persistent post-traumatic headache is poorly understood and the underlying mechanisms are likely multifactorial. There is currently no approved treatment specifically for persistent post-traumatic headache, and management strategies rely on medications used for migraine or tension-type headache. Therefore, high-quality trials are urgently needed to support clinical decision-making and optimize management strategies. International guidelines can facilitate appropriate trial design and ensure the acquisition of high-quality data evaluating the efficacy, tolerability, and safety of available and novel pharmacological therapies for the preventive treatment of persistent post-traumatic headache. METHODS: The development of this guideline was based on a literature review of available studies in MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials, along with a review of previously published guidelines for controlled trials of preventive treatment for episodic and chronic migraine. The identified literature was critically appraised, and due to the scarcity of scientific evidence, recommendations were primarily based on the consensus of experts in the field. OBJECTIVE: To provide guidelines for designing state-of-the-art controlled clinical trials aimed at evaluating the effectiveness of preventive treatments for persistent post-traumatic headache attributed to mild traumatic brain injury.

Opioids and Youth Athletes.

CONTEXT: The ongoing opioid epidemic and associated adverse effects impart a large burden on our current healthcare system. The annual economic and noneconomic cost of opioid use disorder and fatal opioid overdose is currently estimated at $1 trillion. OBJECTIVE: This review presents the prevalence, frequency of use, need, and effectiveness of opioid analgesia in the youth and adolescent athlete population. It identifies current indications for opioid versus nonopioid analgesic use in the setting of acute orthopaedic injuries, postoperative management, concussion, and chronic pain. Current knowledge of youth athlete opioid use, risks related to use, misuse, diversion, and addiction are reviewed. DATA SOURCES: A PubMed, Medline, and Cochrane Library search was conducted in February 2023 to review opioid pain management strategies in the pediatric athlete population from 2000 to present. STUDY SELECTION: Searches were restricted to English language articles and human subjects. Initial reviews of titles and abstracts were performed by all authors and relevant full-text articles were selected. Priority was given to systematic and narrative reviews, meta-analyses, and prospective studies. STUDY DESIGN: Narrative review. LEVEL OF EVIDENCE: Level 3. DATA EXTRACTION: First author name, publication year, study design, study country, subject demographics, and data on the frequency, type, and duration of analgesic treatments for musculoskeletal injuries, postsurgical care, chronic pain disorders, and concussion were extracted. RESULTS: Pediatric athletes comprise a high-risk population seeking analgesic relief for injury-related pain. Participation in high school sports is associated with increased risk of opioid use. An average of 28% to 46% of high school athletes have used opioids in their lifetime. Participation in ≥1 high school sport puts adolescents at 30% greater odds of future opioid misuse. CONCLUSION: The use of opioids in the pediatric athlete population is common and associated with both short- and long-term risks of misuse and addiction.

In old anticoagulated patients with mild traumatic brain injury, a 24-h observation period should not be recommended without evidence of a clear benefit: a retrospective study of delayed hemorrhagic versus iatrogenic complications.

Mild traumatic brain injury (mTBI) is a common cause of admission to the Emergency Department (ED). Many patients are elderly on oral anticoagulant therapy (OAT) at increased risk of immediate and delayed intracranial hemorrhage (ICH). To investigate the frequency of delayed ICH (DICH) in old patients with mTBI in OAT and the occurrence of complications related to the ED stay. In this single-center retrospective study, we recruited all patients in OAT aged 65 and over, admitted for mTBI to the ED of our Hospital in Florence from March 2019 to February 2021. Clinical variables were collected and cranial computed tomography (CT) scans reviewed. The primary outcome was the frequency of DICH occurring within 30 days since the trauma after a first negative CT. Secondary outcomes included need of neurosurgical intervention and death for DICH, and hospital-related complications. Statistical analyses were conducted using IBM SPSS Statistics (version 22). Among 363 enrolled patients, there were 31 acute ICH (8.5%) at the first CT scan, while in the 316 negative included patients, 10 DICH (3.2%) were identified. Among the latter, no neurosurgical treatment, or death due to ICH occurred. Overall, 25 cases (6.9%) had iatrogenic complications during the 24-h observation period, often serious, such as respiratory failure after sedation due to restlessness, or COVID-19 infection. The low frequency of DICH and the occurrence of several iatrogenic complications suggest that the risk-benefit ratio of a 24-h ED observation is not advantageous in elderly with mTBI.

Concussion Risk and Recovery in Athletes With Psychostimulant-Treated Attention-Deficit/Hyperactivity Disorder: Findings From the NCAA-DOD CARE Consortium.

The aim of the present study was to examine the effects of attention-deficit/hyperactivity disorder (ADHD) -related psychostimulant use in the context of concussion risk and symptom recovery. Data were obtained from the National Collegiate Athletic Association Department of Defense Grand Alliance Concussion Assessment, Research, and Education (NCAA-DOD CARE) Consortium from 2014 to 2017. Relative to individuals without diagnosed ADHD (i.e., control), both ADHD diagnosis and the combination of ADHD diagnosis and psychostimulant use were associated with a greater risk of incurring a concussive injury. Following a concussive injury, ADHD diagnosis was associated with longer symptom recovery time relative to the control group. However, individuals with ADHD who use psychostimulants did not take longer to resolve symptoms than controls, suggesting that psychostimulants may have a positive influence on recovery. Regardless of time point, ADHD diagnosis was associated with an elevated number of concussion-related symptoms; however, this effect appears mitigated by having used ADHD-related psychostimulants.

Multi-centric study for development and validation of a CT head rule for mild traumatic brain injury in direct oral anticoagulants: the HERO-M nomogram.

BACKGROUND: Nomograms are easy-to-handle clinical tools which can help in estimating the risk of adverse outcome in certain population. This multi-center study aims to create and validate a simple and usable clinical prediction nomogram for individual risk of post-traumatic Intracranial Hemorrhage (ICH) after Mild Traumatic Brain Injury (MTBI) in patients treated with Direct Oral Anticoagulants (DOACs). METHODS: From January 1, 2016 to December 31, 2019, all patients on DOACs evaluated for an MTBI in five Italian Emergency Departments were enrolled. A training set to develop the nomogram and a test set for validation were identified. The predictive ability of the nomogram was assessed using AUROC, calibration plot, and decision curve analysis. RESULTS: Of the 1425 patients in DOACs in the study cohort, 934 (65.5%) were included in the training set and 491 (34.5%) in the test set. Overall, the rate of post-traumatic ICH was 6.9% (7.0% training and 6.9% test set). In a multivariate analysis, major trauma dynamic (OR: 2.73, p = 0.016), post-traumatic loss of consciousness (OR: 3.78, p = 0.001), post-traumatic amnesia (OR: 4.15, p < 0.001), GCS < 15 (OR: 3.00, p < 0.001), visible trauma above the clavicles (OR: 3. 44, p < 0.001), a post-traumatic headache (OR: 2.71, p = 0.032), a previous history of neurosurgery (OR: 7.40, p < 0.001), and post-traumatic vomiting (OR: 3.94, p = 0.008) were independent risk factors for ICH. The nomogram demonstrated a good ability to predict the risk of ICH (AUROC: 0.803; CI95% 0.721-0.884), and its clinical application showed a net clinical benefit always superior to performing CT on all patients. CONCLUSION: The Hemorrhage Estimate Risk in Oral anticoagulation for Mild head trauma (HERO-M) nomogram was able to predict post-traumatic ICH and can be easily applied in the Emergency Department (ED).

Anti-Inflammatory, Antioxidant and Neuroprotective Effects of Niacin on Mild Traumatic Brain Injury in Rats.

AIM: To study the effects of niacin, a water-soluble vitamin, on inflammation, oxidative stress and apoptotic processes observed after mild traumatic brain injury (TBI). MATERIAL AND METHODS: A total of 25 Wistar albino male rats were randomly divided into control (n=9), TBI + Placebo group (n=9), TBI + niacin (500 mg/kg; n=7) groups. Mild TBI was performed under anesthesia by dropping a 300 g weight from a height of 1 meter onto the skull. Behavioral tests were applied before and 24 hours after TBI. Luminol and lucigenin levels and tissue cytokine levels were measured. Histopathological damage was scored in brain tissue. RESULTS: After mild TBI, luminol and lucigenin levels were increased (p < 0.001), and their levels were decreased with niacin treatment (p < 0.01-p < 0.001). An increased score was obtained with trauma in the tail suspension test (p < 0.01), showing depressive behavior. The number of entries to arms in Y-maze test were decreased in TBI group compared to pre-traumatic values (p < 0.01), while discrimination (p < 0.05) and recognition indices (p < 0.05) in object recognition test were decreased with trauma, but niacin treatment did not change the outcomes in behavioral tests. Levels of the anti-inflammatory cytokine IL-10 were decreased with trauma, and increased with niacin treatment (p < 0.05). The histological damage score was increased with trauma (p < 0.001), and decreased with niacin treatment in the cortex (p < 0.05), and hippocampal dentate gyrus region (p < 0.01). CONCLUSION: Niacin treatment after mild TBI inhibited trauma-induced production of reactive oxygen derivatives and elevated the anti-inflammatory IL-10 level. Niacin treatment ameliorated the histopathologically evident damage.

MPC-n (IgG) improves long-term cognitive impairment in the mouse model of repetitive mild traumatic brain injury.

BACKGROUND: Contact sports athletes and military personnel who suffered a repetitive mild traumatic brain injury (rmTBI) are at high risk of neurodegenerative diseases such as advanced dementia and chronic traumatic encephalopathy (CTE). However, due to the lack of specific biological indicators in clinical practice, the diagnosis and treatment of rmTBI are quite limited. METHODS: We used 2-methacryloyloxyethyl phosphorylcholine (MPC)-nanocapsules to deliver immunoglobulins (IgG), which can increase the delivery efficiency and specific target of IgG while reducing the effective therapeutic dose of the drug. RESULTS: Our results demonstrated that MPC-capsuled immunoglobulins (MPC-n (IgG)) significantly alleviated cognitive impairment, hippocampal atrophy, p-Tau deposition, and myelin injury in rmTBI mice compared with free IgG. Furthermore, MPC-n (IgG) can also effectively inhibit the activation of microglia and the release of inflammatory factors. CONCLUSIONS: In the present study, we put forward an efficient strategy for the treatment of rmTBI-related cognitive impairment and provide evidence for the administration of low-dose IgG.

Current evidence for pharmacological management of pediatric concussion: a systematic review.

PURPOSE: Mild traumatic brain injury (mTBI) is a global public health problem and its current management is limited to rest and symptom management. Despite frequent use of drugs for symptom control, there is a lack of consensus on the optimal pharmacological management of post-concussive symptoms. We reviewed the relevant literature to compile the evidence about the pharmaceutical management of pediatric mTBI. METHODS: We performed a systematic review of the literature available in PubMed, Cochrane CENTRAL, and ClinicalTrials.Gov as well as through citation tracing. A modified PICO framework was used for the construction of search strategy and eligibility criteria. Risk of bias was assessed using RoB-2 tool for randomized and ROBINS-I for non-randomized studies. RESULTS: A total of 6260 articles were screened for eligibility. After exclusions, a total of 88 articles received full text review. A total of 15 reports representing 13 studies (5 randomized clinical trials, 1 prospective randomized cohort study, 1 prospective cohort study, and 6 retrospective cohort studies) met the eligibility criteria and were included in the review. We identified 16 pharmacological interventions in a total of 931 pediatric patients with mTBI. Amytriptiline (n = 4), ondansetron (n = 3), melatonin (n = 3), metoclopramide (n = 2), magnesium (n = 2), and topiramate (n = 2) were investigated in multiple studies. All RCTs were relatively of small size (n ≤ 33/group). CONCLUSION: The available evidence supporting pharmacological intervention in pediatric mild traumatic brain injury is scarce. We propose a framework to facilitate future collaborative research efforts to test and validate various pharmacological interventions for acute and persistent post-concussive symptoms in children.

Sex differences in the effects of mild traumatic brain injury and progesterone treatment on anxiety-like behavior and fear conditioning in rats.

Mild traumatic brain injuries (mild TBIs) commonly occur in young adults of both sexes, oftentimes in high-stress environments. In humans, sex differences have been observed in the development of post-concussive anxiety and PTSD-like behaviors. Progesterone, a sex steroid that has neuroprotective properties, restores cognitive function in animal models following more severe TBI, but its effectiveness in preventing the psychological symptoms associated with mild TBI has not been evaluated. Using a model of mild TBI that pairs a social stressor (social defeat) with weight drop, male and naturally estrous-cycling female rats were treated with 4 mg/kg progesterone or vehicle once daily for 5 days after injury. Behavioral measures, including elevated plus maze (EPM), contextual fear conditioning, and novel object recognition (NOR) were assessed following progesterone treatment. Anxiety-like behavior was increased by mild TBI in male rats, with a smaller effect seen in female rats in the diestrus phase at the time of EPM testing. In contrast, mild TBI impaired fear learning in female rats in estrus at the time of fear acquisition. Progesterone treatment failed to attenuate post-mild TBI anxiety-like behavior in either sex. Furthermore, progesterone increased fear conditioning and impaired NOR discrimination in male rats, independent of TBI status. Overall, both sex and estrous cycle contributed to psychological outcomes following mild TBI, which were not ameliorated by post-TBI progesterone. This suggests sex steroids play an important role as a moderator of the expression of mild TBI-induced psychological symptoms, rather than as a potential treatment for their underlying etiology.

Challenges in the pharmacological treatment of patients under suspicion of chronic traumatic encephalopathy: A review.

Chronic traumatic encephalopathy (CTE) is caused by progressive neurodegeneration associated with repetitive head impacts. This disease is more common in professionals who practice contact sports, resulting in a concussion and subconcussive trauma. CTE is characterized by the accumulation of hyperphosphorylated tau protein in neurons, astrocytes, and frontotemporal lobe degeneration. Symptoms are usually nonspecific and overlap with other neurodegenerative diseases, such as Alzheimer's disease and frontotemporal dementia, making it difficult to provide drug treatment for patients with this comorbidity. Therefore, the objective of this article is to present an updated review of the pharmacological treatment of chronic traumatic encephalopathy and its challenges.

Limited benefit of systematic head CT for mild traumatic brain injury in patients under antithrombotic therapy.

BACKGROUND AND PURPOSE: Mild traumatic brain injury (mTBI) in patients on antiplatelet (AP), anticoagulant (AC) or direct oral anticoagulant (DOAC) medication has become a systematic indication for head CT. However, the over-risk and impact of the intracranial hemorrhages (IH) detected with CT in this population remain unclear and need to be assessed. MATERIALS AND METHODS: We prospectively assessed head CTs performed in adults taking AP/AC/DOAC referred after a mTBI to our Emergency Departments between September 2016 and January 2018. Frequency, type and severity of IH were described and frequency was analyzed as a function of treatment. RESULTS: 840 patients were prospectively included. 58.9% were treated with AP, 23.7% with AC, 11.7% with DOAC and 5.7% with a combination of antithrombotic agents. The rate of IH detected with head CT was 5.8% (n...=...49), of which 81.6% (n...=...40) and 18.4% (n...=...9) with minor and intermediate severity respectively. No patient required surgical care and no death occurred. No statistically significant difference was found in treatment distribution between patients with or without IH (p...=...0.98). Among the patients who discontinued their antithrombotic treatment after mTBI, three experienced thrombotic events during the hospitalization. CONCLUSIONS: Our results showed a low frequency and severity of IH in mTBI patients indifferently treated with AP, AC or DOAC, without secondary neurological deterioration, death or need of surgical care. Our study suggests the limited benefit of systematic CT head scan as a standard practice for the management of mTBI patients under antithrombotic therapy.

Transcranial direct current stimulation combined with amantadine in repetitive mild traumatic brain injury in rats.

BACKGROUND: Balance and memory deficits are common in patients with repetitive mild traumatic brain injury (mTBI). OBJECTIVE: To investigate the combined effects of amantadine and transcranial direct current stimulation (tDCS) on balance and memory in repetitive mTBI rat models. METHODS: In this prospective animal study, 40 repetitive mTBI rats were randomly assigned to four groups: tDCS, amantadine, combination of amantadine and anodal tDCS, and control. The tDCS group received four sessions of anodal tDCS for four consecutive days. The amantadine group received four intraperitoneal injections of amantadine for four consecutive days. The combination group received four intraperitoneal injections of amantadine and anodal tDCS for four consecutive days. Motor-evoked potential (MEP), rotarod test, and novel object test results were evaluated before mTBI, before treatment, and after treatment. RESULTS: All groups showed significant improvements in the rotarod and novel object tests, particularly the combination group. The combination group showed a significant improvements in duration (p < 0.01) and maximal speed in the rotarod test (p < 0.01), as well as an improvement in novel object ratio (p = 0.05) and MEP amplitude (p = 0.05) after treatment. The combination group exhibited a significant increase in novel object ratio compared to the tDCS group (p = 0.04). The GFAP integral intensity of the left motor cortex and hippocampus was the lowest in the combination group. CONCLUSION: Combination treatment with amantadine and tDCS had positive effects on balance and memory recovery after repetitive mTBI in rats. Therefore, we expect that the combination of amantadine and tDCS may be a treatment option for patients with repetitive mTBIs.

Testosterone treatment restores vestibular function by enhancing neuronal survival in an experimental closed-head repetitive mild traumatic brain injury model.

Repetitive mild traumatic brain injury (rmTBI) results in a myriad of symptoms, including vestibular impairment. The mechanisms underlying vestibular dysfunction in rmTBI patients remain poorly understood. Concomitantly, acute hypogonadism occurs following TBI and can persist chronically in many patients. Using a repetitive mild closed-head animal model of TBI, the role of testosterone on vestibular function was tested. Male Long Evans Hooded rats were randomly divided into sham or rmTBI groups. Significant vestibular deficits were observed both acutely and chronically in the rmTBI groups. Systemic testosterone was administered after the development of chronic vestibular dysfunction. rmTBI animals given testosterone showed improved vestibular function that was sustained for 175 days post-rmTBI. Significant vestibular neuronal cell loss was, however, observed in the rmTBI animals compared to Sham animals at 175 days post-rmTBI and testosterone treatment significantly improved vestibular neuronal survival. Taken together, these data demonstrate a critical restorative role of testosterone in vestibular function following rmTBI. This study has important clinical implications because it identifies testosterone treatment as a viable therapeutic strategy for the long-term recovery of vestibular function following TBI.

A Pilot Randomized Controlled Trial of Docosahexaenoic Acid for the Treatment of Sport-Related Concussion in Adolescents.

The objective was to examine the use of docosahexaenoic acid (DHA) for the treatment of sport-related concussion (SRC) in adolescent athletes. We hypothesize that participants who intake 2 g of DHA daily will not experience differences in recovery compared with participants who take a placebo. This double-blind, randomized controlled pilot trial was performed in a tertiary pediatric sports medicine clinic from 2013 to 2017 in adolescents (14-18 years) presenting with diagnosed SRC within 4 days of injury. Forty participants were randomized into DHA or PLACEBO group and were instructed to take 2 capsules twice daily for 12 weeks. Participants in the DHA group were symptom-free earlier than the PLACEBO group (11.0 vs 16.0 days, P = .08) and were cleared to begin the Return to Sport progression (14.0 vs 19.5 days, P = .12) sooner. The use of 2 g/day of DHA was well-tolerated and did not significantly affect recovery times in adolescent athletes following SRC.Clinical Trial Registration: ClincalTrials.gov, NCT01903525.

Preclinical assessment of onabotulinumtoxinA for the treatment of mild traumatic brain injury-related acute and persistent post-traumatic headache.

OBJECTIVE: Investigation of onabotulinumtoxinA in a murine model of acute and persistent post-traumatic headache. METHODS: Mild traumatic brain injury was induced with a weight drop method. Periorbital and hindpaw cutaneous allodynia were measured for 14 days. Mice were then exposed to bright light stress and allodynia was reassessed. OnabotulinumtoxinA (0.5 U) was injected subcutaneously over the cranial sutures at different post-injury time points. RESULTS: After milt traumatic brain injury, mice exhibited periorbital and hindpaw allodynia that lasted for approximately 14 days. Allodynia could be reinstated on days 14-67 by exposure to stress only in previously injured mice. OnabotulinumtoxinA administration at 2 h after mild traumatic brain injury fully blocked both transient acute and stress-induced allodynia up to day 67. When administered 72 h post-mild traumatic brain injury, onabotulinumtoxinA reversed acute allodynia, but only partially prevented stress-induced allodynia. OnabotulinumtoxinA administration at day 12, when initial allodynia was largely resolved, produced incomplete and transient prevention of stress-induced allodynia. The degree of acute allodynia correlated positively with subsequent stress-induced allodynia. CONCLUSION: Mild traumatic brain injury induced transient headache-like pain followed by long lasting sensitization and persistent vulnerability to a normally innocuous stress stimulus, respectively modeling acute and persistent post-traumatic headache.. Administration of onabotulinumtoxinA following the resolution of acute post-traumatic headache diminished persistent post-traumatic headache but the effects were transient, suggesting that underlying persistent mild traumatic brain injury-induced maladaptations were not reversed. In contrast, early onabotulinumtoxinA administration fully blocked both acute post-traumatic headache as well as the transition to persistent post-traumatic headache suggesting prevention of neural adaptations that promote vulnerability to headache-like pain. Additionally, the degree of acute post-traumatic headache was predictive of risk of persistent post-traumatic headache.

Prophylactic zinc supplementation modulates hippocampal ionic zinc and partially remediates neurological recovery following repetitive mild head injury in mice.

Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative condition caused by repetitive mild traumatic brain injury (TBI) that leads to impaired executive functioning, emotional disturbances, and disordered memory, warranting both basic and translational research of potential therapeutic targets. One area of research concerns prophylactic zinc (Zn) supplementation; however, Zn supplementation remains poorly understood. This study explored the effects of Zn supplementation in a mouse model of repetitive mild TBI. Four-week-old male (n = 50) and female (n = 50) C57BL/6J mice consumed tap water or 10 parts per million Zn-supplemented water for eight weeks prior to injury. At 12 weeks of age, mice underwent either five sham procedures or five closed-head injuries spaced apart by 48 h after which they completed behavioral tests. Zinc-supplemented injured mice righted themselves and regained normal ambulatory function as fast as non-injured mice across four out of the five injury days. In contrast, non-supplemented injured mice exhibited impairment in normal ambulation by days 4 and 5. Injury also reduced free, ionic Zn in the dentate gyrus and CA3 region of the hippocampus and Zn supplementation partially remediated this reduction but not to the levels of non-injured mice. There were no structural differences in cortex, hippocampus, striatum, and corpus callosum, suggesting that Zn reduction was not due to macroscopic abnormalities. Overall, these results suggest that Zn may improve short-term and physical neurological recovery, but it may not be sufficient as a single pre-treatment for consequences of repetitive mild TBI such as cognitive impairment. These results further demonstrate the need for additional research documenting the underlying mechanisms of Zn in TBI-related neuropathology.

Saffron extract and crocin exert anti-inflammatory and anti-oxidative effects in a repetitive mild traumatic brain injury mouse model.

Saffron Crocus sativus L. (C. sativus) is a flower from the iridaceous family. Crocin, saffron's major constituent, and saffron have anti-oxidative and anti-inflammatory activities. In this work, the neuroprotective effects of saffron and crocin are being investigated in a repetitive mild traumatic brain injury (rmTBI) mouse model. A weight drop model setup was employed to induce mild brain injury in male albino BABL/c mice weighing 30-40 g. Saffron (50 mg/kg) and crocin (30 mg/kg) were administrated intraperitoneally 30 min before mTBI induction. Behavioral tests were conducted to assess behavioral deficits including the modified neurological severity score (NSS), Morris water maze (MWM), pole climb test, rotarod test, and adhesive test. The levels of TNF alpha (TNF-α), interferon-gamma (IFN-γ), myeloperoxidase activity (MPO), malonaldehyde (MDA), and reduced glutathione (GSH) were measured. Histological analysis of different brain parts was performed. Both saffron and crocin demonstrated marked improved neurological, cognitive, motor, and sensorimotor functions. Besides, both compounds significantly reduced the oxidative stress and inflammatory processes. No abnormal histological features were observed in any of the injured groups. Saffron extract and crocin provide a neuroprotective effect in a mouse model of rmTBI by decreasing oxidative stress, inflammatory responses, and behavioral deficits.

"Decision tree analysis for assessing the risk of post-traumatic haemorrhage after mild traumatic brain injury in patients on oral anticoagulant therapy".

BACKGROUND: The presence of oral anticoagulant therapy (OAT) alone, regardless of patient condition, is an indication for CT imaging in patients with mild traumatic brain injury (MTBI). Currently, no specific clinical decision rules are available for OAT patients. The aim of the study was to identify which clinical risk factors easily identifiable at first ED evaluation may be associated with an increased risk of post-traumatic intracranial haemorrhage (ICH) in OAT patients who suffered an MTBI. METHODS: Three thousand fifty-four patients in OAT with MTBI from four Italian centers were retrospectively considered. A decision tree analysis using the classification and regression tree (CART) method was conducted to evaluate both the pre- and post-traumatic clinical risk factors most associated with the presence of post-traumatic ICH after MTBI and their possible role in determining the patient's risk. The decision tree analysis used all clinical risk factors identified at the first ED evaluation as input predictor variables. RESULTS: ICH following MTBI was present in 9.5% of patients (290/3054). The CART model created a decision tree using 5 risk factors, post-traumatic amnesia, post-traumatic transitory loss of consciousness, greater trauma dynamic, GCS less than 15, evidence of trauma above the clavicles, capable of stratifying patients into different increasing levels of ICH risk (from 2.5 to 61.4%). The absence of concussion and neurological alteration at admission appears to significantly reduce the possible presence of ICH. CONCLUSIONS: The machine-learning-based CART model identified distinct prognostic groups of patients with distinct outcomes according to on clinical risk factors. Decision trees can be useful as guidance in patient selection and risk stratification of patients in OAT with MTBI.

Pharmacotherapy for mild traumatic brain injury: an overview of the current treatment options.

INTRODUCTION: Accounting for 90% of all traumatic brain injuries (TBIs), mild traumatic brain injury (mTBI) is currently the most frequently seen type of TBI. Although most patients can recover from mTBI, some may suffer from prolonged symptoms for months to years after injury. Growing evidence indicates that mTBI is associated with neurodegenerative diseases, including dementia and Parkinson's disease (PD). Pharmacological interventions are necessary to address the symptoms and avoid the adverse consequences of mTBI. AREAS COVERED: To provide an overview of the current treatment options, the authors herein review the potential drugs to reduce the secondary damage and symptom-targeted therapy, as well as the ongoing clinical trials of pharmacotherapy for mTBI. EXPERT OPINION: There has been no consensus on pharmacotherapy for mTBI. Several candidates, including n-3 PUFAs, melatonin, NAC, and statins show potential benefits in lessening the secondary injury and improving neurological deficits in preclinic studies, which, however, still need further investigation in clinical trials. The current pharmacotherapy for mTBI is empirical in nature and mainly targets to mitigate the symptoms. Well-designed clinical trials are now warranted to provide high-level evidence.

Mild Traumatic Brain Injury in Elderly Patients Receiving Direct Oral Anticoagulants: A Systematic Review and Meta-Analysis.

The aim of this work was to conduct a systematic review and meta-analysis of studies reporting on the risk of traumatic intracerebral hemorrhage (tICH), the course of tICH, and its treatment and mortality rates in elderly mild traumatic brain injury (mTBI) patients using direct oral anticoagulants (DOACs). We consulted PubMed and Embase for relevant cohort and case-control studies with a control group. Two authors independently selected studies, assessed methodological quality, and extracted outcome data. Estimates were pooled with the Mantel-Haenszel random-effects method. We identified 16 articles comprising 3671 elderly mTBI patients using DOACs. Use of DOACs was associated with a reduced risk of tICH compared to the use of vitamin K antagonists (VKAs; odds ratio [OR], 0.44; 95% confidence interval [CI], 0.29-0.65; I2 = 22%) and a similar risk compared to the use of antiplatelet therapy (APT; OR, 0.98; 95% CI, 0.39-2.44; I2 = 0%). Reversal agent use and neurosurgical intervention rate were lower in patients using DOACs compared to patients using VKAs (OR, 0.10; 95% CI, 0.06-0.16; I2 = 0% and OR, 0.37; 95% CI, 0.21-0.67; I2 = 0%, respectively). There was no significant difference in neurosurgical intervention rate between patients who used DOACs versus patients who used APT (OR, 0.58; 95% CI, 0.15-2.21; I2 = 41%) or no antithrombotic therapy (OR, 0.76; 95% CI, 0.20-2.86; I2 = 23%). ICH progression, risk of delayed ICH, and TBI-related in-hospital mortality were comparable among treatment groups. The present study indicates that elderly patients using DOACs have a lower risk of adverse outcome compared to patients using VKAs and a similar risk compared to patients using APT after mTBI.