New perspectives on assessment and understanding of the patient with cranial bone defect: a morphometric and cerebral radiodensity assessment.

Background: Skull defects after decompressive craniectomy (DC) cause physiological changes in brain function and patients can have neurologic symptoms after the surgery. The objective of this study is to evaluate whether there are morphometric changes in the cortical surface and radiodensity of brain tissue in patients undergoing cranioplasty and whether those variables are correlated with neurological prognosis. Methods: This is a prospective cohort with 30 patients who were submitted to cranioplasty and followed for 6 months. Patients underwent simple head CT before and after cranioplasty for morphometric and cerebral radiodensity assessment. A complete neurological exam with Mini-Mental State Examination (MMSE), modified Rankin Scale, and the Barthel Index was performed to assess neurological prognosis. Results: There was an improvement in all symptoms of the syndrome of the trephined, specifically for headache (p = 0.004) and intolerance changing head position (p = 0.016). Muscle strength contralateral to bone defect side also improved (p = 0.02). Midline shift of intracranial structures decreased after surgery (p = 0.004). The Anterior Distance Difference (ADif) and Posterior Distance Difference (PDif) were used to assess morphometric changes and varied significantly after surgery. PDif was weakly correlated with MMSE (p = 0.03; r = -0.4) and Barthel index (p = 0.035; r = -0.39). The ratio between the radiodensities of gray matter and white matter (GWR) was used to assess cerebral radiodensity and was also correlated with MMSE (p = 0.041; r = -0.37). Conclusion: Morphological anatomy and radiodensity of the cerebral cortex can be used as a tool to assess neurological prognosis after DC.

Animal models for the study of intracranial hematomas (Review).

Intracranial hematomas (ICH) are a frequent condition in neurosurgical and neurological practices, with several mechanisms of primary and secondary injury. Experimental research has been fundamental for the understanding of the pathophysiology implicated with ICH and the development of therapeutic interventions. To date, a variety of different animal approaches have been described that consider, for example, the ICH evolutive phase, molecular implications and hemodynamic changes. Therefore, choosing a test protocol should consider the scope of each particular study. The present review summarized investigational protocols in experimental research on the subject of ICH. With this subject, injection of autologous blood or bacterial collagenase, inflation of intracranial balloon and avulsion of cerebral vessels were the models identified. Rodents (mice) and swine were the most frequent species used. These different models allowed improvements on the understanding of intracranial hypertension establishment, neuroinflammation, immunology, brain hemodynamics and served to the development of therapeutic strategies.

Improvement in neurological outcome and brain hemodynamics after late cranioplasty.

BACKGROUND: Early cranioplasty has been encouraged after decompressive craniectomy (DC), aiming to reduce consequences of atmospheric pressure over the opened skull. However, this practice may not be often available in low-middle-income countries (LMICs). We evaluated clinical improvement, hemodynamic changes in each hemisphere, and the hemodynamic balance between hemispheres after late cranioplasty in a LMIC, as the institution's routine resources allowed. METHODS: Prospective cohort study included patients with bone defects after DC evaluated with perfusion tomography (PCT) and transcranial Doppler (TCD) and performed neurological examinations with prognostic scales (mRS, MMSE, and Barthel Index) before and 6 months after surgery. RESULTS: A final sample of 26 patients was analyzed. Satisfactory improvement of neurological outcome was observed, as well as significant improvement in the mRS (p = 0.005), MMSE (p < 0.001), and Barthel Index (p = 0.002). Outpatient waiting time for cranioplasty was 15.23 (SD 17.66) months. PCT showed a significant decrease in the mean transit time (MTT) and cerebral blood volume (CBV) only on the operated side. Although most previous studies have shown an increase in cerebral blood flow (CBF), we noticed a slight and nonsignificant decrease, despite a significant increase in the middle cerebral artery flow velocity in both hemispheres on TCD. There was a moderate correlation between the MTT and contralateral muscle strength (r = - 0.4; p = 0.034), as well as between TCD and neurological outcomes ipsilateral (MMSE; r = 0.54, p = 0.03) and contralateral (MRS; p = 0.031, r = - 0.48) to the operated side. CONCLUSION: Even 1 year after DC, cranioplasty may improve cerebral perfusion and neurological outcomes and should be encouraged.

Inflammatory markers assessment in an animal model of intracranial hypertension: a randomized trial.

BACKGROUND: Intracranial hypertension (ICH) is a common final pathway of most neurosurgical pathologies and leads to poor prognosis if not detected and treated properly. Inflammatory markers have been assessed in clinical scenarios of neurological injuries, in which systemic and brain tissue aggressions may introduce bias. There is a lack of studies under controlled settings to isolate the ICH effect on inflammation. This study aims to evaluate the effects of ICH on the serum concentration of cytokines as biomarkers of neuroinflammation in an experimental model which isolates ICH from potential confounding variables. METHODS: An established model of ICH using an intracerebral pediatric bladder catheter and a multisensor intraparenchymal catheter was used in adult pigs (Sus domesticus). The animals were randomly allocated to 2 groups based on the catheter balloon volume used to simulate the ICP increase (4 ml or 7 ml). Cytokines were measured in 4 timepoints during the experiment: (1) 15 min before balloon insufflation; (2) 5 min after insufflation; (3) 125 min after insufflation; (4) 60 min after deflation. The following cytokines were measured IL-1α; IL-1ß; IL-1ra; IL-2; IL-4; IL-6; IL-8; IL-10; IL-12; IL-18; TNFα. Generalized estimating equations were modeled to compare the ICP and cytokines values between the groups along the experiment. The study sample size was powered to detect interactions between the groups and the study moments with an effect size (f) of at least 0.3. The ARRIVE checklist was followed. RESULTS: A total of 20 animals were studied (10 in each group, 4 ml or 7 ml balloon volume insufflation). The animal model was successful in increasing the ICP along the moments of the experiment (p < 0,001) and in creating an ICP gradient between the groups (p = 0,004). The interaction term (moment × group) was also significant (p < 0,001). There was a significant association between ICP elevation and most cytokines variation. The cytokines IL-1α, IL-1ß, IL1-ra, IL-6, IL-12, and IL-18 increased, whereas IL-2, IL-4, and TNF-α decreased. IL-10 did not vary significantly in response to the ICP elevation. CONCLUSION: The serum concentration of cytokines varied in response to intracranial hypertension. The study demonstrated the specific changes in each cytokine after intracranial hypertension and provides key information to guide neuroinflammation clinical research. The proposed experiment was successful as an animal model to the study of neuroinflammation biomarkers.

Estimation of intracranial pressure by ultrasound of the optic nerve sheath in an animal model of intracranial hypertension.

BACKGROUND: Ultrasound of the optic nerve sheath diameter (ONSD) has been used as a non-invasive and cost-effective bedside alternative to invasive intracranial pressure (ICP) monitoring. However, ONSD time-lapse behavior in intracranial hypertension (ICH) and its relief by means of either saline infusion or surgery are still unknown. The objective of this study was to correlate intracranial pressure (ICP) and ultrasonography of the optic nerve sheath (ONS) in an experimental animal model of ICH and determine the interval needed for ONSD to return to baseline levels. METHODS: An experimental study was conducted on 30 pigs. ONSD was evaluated by ultrasound at different ICPs generated by intracranial balloon inflation, saline infusion, and balloon deflation, and measured using an intraventricular catheter. RESULTS: All variables obtained by ONS ultrasonography such as left, right, and average ONSD (AON) were statistically significant to estimate the ICP value. ONSD changed immediately after balloon inflation and returned to baseline after an average delay of 30 min after balloon deflation (p = 0.016). No statistical significance was observed in the ICP and ONSD values with hypertonic saline infusion. In this swine model, ICP and ONSD showed linear correlation and ICP could be estimated using the formula: -80.5 + 238.2 × AON. CONCLUSION: In the present study, ultrasound to measure ONSD showed a linear correlation with ICP, although a short delay in returning to baseline levels was observed in the case of sudden ICH relief.

Two decades of research towards a potential first anti-epileptic drug.

The basic mechanisms by which brain insults, such as trauma, stroke or status epilepticus produce epilepsy are not completely understood, and effective preventive measures and treatment are still not available in the clinical setting. Over the last 2 decades we have conducted several studies with animal models of epilepsy (rodents and non-human primates) and demonstrated that drugs that modify neuronal plastic processes, such as anticholinergic agents (e.g., antimuscarinic compounds), if administered soon after brain injury and over a period of 10-20 days, have the potential to modify the natural course of post-traumatic epilepsy. To that end treatment with scopolamine showed promising results as a candidate agent in both the pilocarpine and kainate models. We then showed that biperiden, yet another cholinergic antagonist acting in the muscarinic receptor, that is widely used to treat Parkinson's disease, also decreased the incidence and intensity of spontaneous epileptic seizures, delaying their appearance in the pilocarpine model of epilepsy. In other words, biperiden showed to be a potential candidate to be further investigated as an antiepileptogenic agent. Accordingly, we tested the safety of biperiden in a small group of patients (as a small phase II safety assessment) and confirmed its safety in the context of traumatic brain injury (TBI). Now, we provide information on our ongoing project to evaluate the efficacy of biperiden in preventing the development of epilepsy in patients that suffered TBI, in a double blind, randomized, placebo-controlled trial.

Incremental Prognostic Value of Coagulopathy in Addition to the Crash Score in Traumatic Brain Injury Patients.

BACKGROUND/OBJECTIVE: Multivariable prognostic scores play an important role for clinical decision-making, information giving to patients/relatives, benchmarking and guiding clinical trial design. Coagulopathy has been implicated on trauma and critical care outcomes, but few studies have evaluated its role on traumatic brain injury (TBI) outcomes. Our objective was to verify the incremental prognostic value of routine coagulopathy parameters in addition to the CRASH-CT score to predict 14-day mortality in TBI patients. METHODS: This is a prospective cohort of consecutive TBI patients admitted to a tertiary university hospital Trauma intensive care unit (ICU) from March/2012 to January/2015. The prognostic performance of the coagulation parameters platelet count, prothrombin time (international normalized ratio, INR) and activated partial thromboplastin time (aPTT) ratio was assessed through logistic regression adjusted for the original CRASH-CT score. A new model, CRASH-CT-Coag, was created and its calibration (Brier scores and Hosmer-Lemeshow (H-L) test), discrimination [area under the receiver operating characteristic curve (AUC-ROC) and the integrated discrimination improvement (IDI)] and clinical utility (net reclassification index) were compared to the original CRASH-CT score. RESULTS: A total 517 patients were included (median age 39 years, 85.1% male, median admission glasgow coma scale 8, neurosurgery on 44.9%). The 14-day mortality observed and predicted by the original CRASH-CT was 22.8% and 26.2%, respectively. Platelet count < 100,000/mm3, INR > 1.2 and aPTT ratio > 1.2 were present on 11.3%, 65.0% and 27.2%, respectively, (at least one of these was altered on 70.6%). All three variables maintained statistical significance after adjustment for the CRASH-CT score. The CRASH-CT-Coag score outperformed the original score on calibration (brier scores 0.122 ± 0.216 vs 0.132 ± 0.202, mean difference 0.010, 95% CI 0.005-0.019, p = 0.036, respectively) and discrimination (AUC-ROC 0.854 ± 0.020 vs 0.813 ± 0.024, p = 0.014; IDI 5.0%, 95% CI 1.3-11.0%). Both scores showed the satisfactory H-L test results. The net reclassification index favored the new model. Considering the strata of low (< 10%), moderate (10-30%) and high (> 30%) risk of death, the CRASH-CT-Coag model yielded a global net correct reclassification of 22.9% (95% CI 3.8-43.4%). CONCLUSIONS: The addition of early markers of coagulopathy-platelet count, INR and aPTT ratio-to the CRASH-CT score increased its accuracy. Additional studies are required to externally validate this finding and further investigate the coagulopathy role on TBI outcomes.

New technique for surgical decompression in traumatic brain injury: merging two concepts to prevent early and late complications of unilateral decompressive craniectomy with dural expansion.

INTRODUCTION: Decompressive craniectomy (DC) in severe traumatic brain injury (TBI) is associated with acute and late complications. To avoid these complications, we proposed a technical modification in DC. In this paper analyze a series of patients underwent to surgical treatment for acute subdural hematoma (ASDH). METHODS: We perform a prospective cohort with TBI patients undergoing DC for treatment of diffuse hemispheric brain swelling and ASDH. The effect of modified craniectomy was assessed using postoperative CT. Clinical outcome was evaluated at ICU mortality in 2 weeks. RESULTS: Comparing the CT scans before and after surgery, the midline shift decreases from median of 11 mm to 5.5 mm (P<0.001). Only one patient had presented uncontrolled intracranial hypertension after surgery. Postoperative mortality in the intensive care unit within 14 days was 48.8%. CONCLUSION: this is an interesting technical modification. In this pilot study, we observed ICP control, avoiding the complications of classical decompression.

Prediction of Early TBI Mortality Using a Machine Learning Approach in a LMIC Population.

Background: In a time when the incidence of severe traumatic brain injury (TBI) is increasing in low- to middle-income countries (LMICs), it is important to understand the behavior of predictive variables in an LMIC's population. There are few previous attempts to generate prediction models for TBI outcomes from local data in LMICs. Our study aim is to design and compare a series of predictive models for mortality on a new cohort in TBI patients in Brazil using Machine Learning. Methods: A prospective registry was set in São Paulo, Brazil, enrolling all patients with a diagnosis of TBI that require admission to the intensive care unit. We evaluated the following predictors: gender, age, pupil reactivity at admission, Glasgow Coma Scale (GCS), presence of hypoxia and hypotension, computed tomography findings, trauma severity score, and laboratory results. Results: Overall mortality at 14 days was 22.8%. Models had a high prediction performance, with the best prediction for overall mortality achieved through Naive Bayes (area under the curve = 0.906). The most significant predictors were the GCS at admission and prehospital GCS, age, and pupil reaction. When predicting the length of stay at the intensive care unit, the Conditional Inference Tree model had the best performance (root mean square error = 1.011), with the most important variable across all models being the GCS at scene. Conclusions: Models for early mortality and hospital length of stay using Machine Learning can achieve high performance when based on registry data even in LMICs. These models have the potential to inform treatment decisions and counsel family members. Level of evidence: This observational study provides a level IV evidence on prognosis after TBI.

Traumatic Lumbosacral Spondyloptosis in a Pediatric Patient: Case Report and Literature Review.

A 4-year-old girl was admitted to the emergency department after having been buried beneath a wall. A computed tomography scan revealed anterior grade V L5-S1 spondylolisthesis, and magnetic resonance imaging showed a traumatic rupture of the fibrous annulus of the L5-S1 intervertebral disc and lesion of the anterior longitudinal and yellow ligaments. The patient underwent anterior and posterior fixation. Four months later she was able to walk independently, despite a persistent left foot drop. Additionally, we conducted a literature review on lumbosacral spondyloptosis in the pediatric population published between 1990 and 2017. We found 16 cases, 86.6% of which were male, with a mean patient age of 16 ± 5.05 years. Most patients underwent spine instrumentation. Based on the data reviewed, the neurological status at admission might be a valid predictor of outcome. Pedicle screws are a safe and reliable procedure for stable fixation of the spine in these cases. The removal of screws is discouraged.

Effects of transcranial LED therapy on the cognitive rehabilitation for diffuse axonal injury due to severe acute traumatic brain injury: study protocol for a randomized controlled trial.

BACKGROUND: Photobiomodulation describes the use of red or near-infrared light to stimulate or regenerate tissue. It was discovered that near-infrared wavelengths (800-900 nm) and red (600 nm) light-emitting diodes (LED) are able to penetrate through the scalp and skull and have the potential to improve the subnormal cellular activity of compromised brain tissue. Different experimental and clinical studies were performed to test LED therapy for traumatic brain injury (TBI) with promising results. One of the proposals of this present study is to develop different approaches to maximize the positive effects of this therapy and improve the quality of life of TBI patients. METHODS/DESIGN: This is a double-blinded, randomized, controlled trial of patients with diffuse axonal injury (DAI) due to a severe TBI in an acute stage (less than 8 h). Thirty two patients will be randomized to active coil helmet and inactive coil (sham) groups in a 1:1 ratio. The protocol includes 18 sessions of transcranial LED stimulation (627 nm, 70 mW/cm2, 10 J/cm2) at four points of the frontal and parietal regions for 30 s each, totaling 120 s, three times per week for 6 weeks, lasting 30 min. Patients will be evaluated with the Glasgow Outcome Scale Extended (GOSE) before stimulation and 1, 3, and 6 months after the first stimulation. The study hypotheses are as follows: (1) transcranial LED therapy (TCLT) will improve the cognitive function of DAI patients and (2) TCLT will promote beneficial hemodynamic changes in cerebral circulation. DISCUSSION: This study evaluates early and delayed effects of TCLT on the cognitive rehabilitation for DAI following severe acute TBI. There is a paucity of studies regarding the use of this therapy for cognitive improvement in TBI. There are some experimental studies and case series presenting interesting results for TBI cognitive improvement but no clinical trials. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03281759 . Registered on 13 September 2017.

Photobiomodulation using low-level laser therapy (LLLT) for patients with chronic traumatic brain injury: a randomized controlled trial study protocol.

BACKGROUND: Photobiomodulation using low-level laser therapy (LLLT) has been tested as a new technique to optimize recovery of patients with traumatic brain injury (TBI). The aim of this study is to evaluate inhibitory attentional control after 18 sessions of active LLLT and compare with the placebo group (sham LLLT). Our exploratory analysis will evaluate the efficacy of the active LLLT on verbal and visuospatial episodic memory, executive functions (working memory, verbal and visuospatial fluency, attentional processes), and anxiety and depressive symptoms compared to the sham group. METHODS/DESIGN: A randomized double-blinded trial will be made in 36 patients with moderate and severe TBI. The active LLLT will use an optical device composed of LEDs emitting 632 nm of radiation at the site with full potency of 830 mW. The cranial region with an area of 400 cm2 will be irradiated for 30 min, giving a total dose per session of 3.74 J/cm2. The sham LLLT group contains only an LED device with power < 1 mW, only serving to simulate the irradiation. Each patient will be irradiated three times per week for six weeks, totaling 18 sessions. Neuropsychological assessments will be held one week before the beginning of the sessions, after one week, and three months after the end of LLLT sessions. Memory domain, attention, executive functioning, and visual construction will be evaluated, in addition to symptoms of depression, anxiety, and social demographics. DISCUSSION: LLLT has been demonstrated as a safe and effective technique in significantly improving the memory, attention, and mood performance in healthy and neurologic patients. We expect that our trial can complement previous finds, as an effective low-cost therapy to improve cognitive sequel after TBI. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02393079 . Registered on 20 February 2015.

Transcranial Direct Current Stimulation for Post-Concussion Syndrome: Study Protocol for a Randomized Crossover Trial.

BACKGROUND: Mild traumatic brain injury (MTBI) represents 70-80% of all treated brain injuries. A considerable proportion of MTBI patients experience post-concussion symptoms for a prolonged period after MTBI, and these symptoms are diagnosed as persistent post-concussion syndrome (PPCS). PPCS is defined as a range of physical, cognitive, and emotional symptoms. However, memory and executive dysfunction seems to be one of the most debilitating symptoms. Recently, non-invasive brain stimulation has been studied as a potential treatment method for traumatic brain injury (TBI) patients. Therefore, our primary goal is to verify the effects of transcranial direct current stimulation (tDCS) in patients with PPCS who demonstrate cognitive deficits in long-term episodic memory, working memory, and executive function following MTBI. METHODS/DESIGN: This is a randomized crossover trial of patients with a history of MTBI with cognitive deficits in memory and executive function. Thirty adult patients will be randomized in a crossover manner to receive three weekly sessions of anodal tDCS (2 mA) at left dorsolateral prefrontal cortex, left temporal cortex, and sham stimulation that will be performed at 7-day intervals (washout period). The clinical diagnosis of PPCS will be determined using the Rivermead Post-Concussion Symptoms Questionnaire. Patients who meet the inclusion criteria will be assessed with a neuropsychological evaluation. A new battery of computerized neuropsychological tests will be performed before and immediately after each stimulation. Statistical analysis will be performed to determine trends of cognitive improvement. DISCUSSION: There is paucity of studies regarding the use of tDCS in TBI patients, and although recent results showed controversial data regarding the effects of tDCS in such patients, we will address specifically patients with PPCS and MTBI and no brain abnormalities on CT scan other than subarachnoid hemorrhage. Moreover, due to the missing information on literature regarding the best brain region to be studied, we will evaluate two different regions to find immediate effects of tDCS on memory and executive dysfunction. CLINICAL TRIAL REGISTRATION: www.ClinicalTrials.gov, identifier NCT02292589 (https://register.clinicaltrials.gov).

Prognostic model for patients with traumatic brain injuries and abnormal computed tomography scans.

Traumatic brain injury (TBI) is an important cause of death and disability worldwide. The prognosis evaluation is a challenge when many variables are involved. The authors aimed to develop prognostic model for assessment of survival chances after TBI based on admission characteristics, including extracranial injuries, which would allow application of the model before in-hospital therapeutic interventions. A cohort study evaluated 1275 patients with TBI and abnormal CT scans upon admission to the emergency unit of Hospital das Clinicas of University of Sao Paulo and analyzed the final outcome on mortality. A logistic regression analysis was undertaken to determine the adjusted weigh of each independent variable in the outcome. Four variables were found to be significant in the model: age (years), Glasgow Coma Scale (3-15), Marshall Scale (MS, stratified into 2,3 or 4,5,6; according to the best group positive predictive value) and anysochoria (yes/no). The following formula is in a logistic model (USP index to head injury) estimates the probability of death of patients according to characteristics that influence on mortality. We consider that our mathematical probability model (USP Index) may be applied to clinical prognosis in patients with abnormal CT scans after severe traumatic brain injury.

Diffuse Axonal Injury: Epidemiology, Outcome and Associated Risk Factors.

Diffuse axonal injury (DAI), a type of traumatic injury, is known for its severe consequences. However, there are few studies describing the outcomes of DAI and the risk factors associated with it. This study aimed to describe the outcome for patients with a primary diagnosis of DAI 6 months after trauma and to identify sociodemographic and clinical factors associated with mortality and dependence at this time point. Seventy-eight patients with DAI were recruited from July 2013 to February 2014 in a prospective cohort study. Patient outcome was analyzed using the Extended Glasgow Outcome Scale (GOS-E) within 6 months of the traumatic injury. The mean Injury Severity Score was 35.0 (SD = 11.9), and the mean New Injury Severity Score (NISS) was 46.2 (SD = 15.9). Mild DAI was observed in 44.9% of the patients and severe DAI in 35.9%. Six months after trauma, 30.8% of the patients had died, and 45.1% had shown full recovery according to the GOS-E. In the logistic regression model, the severity variables - DAI with hypoxia, as measured by peripheral oxygen saturation, and hypotension with NISS value - had a statistically significant association with patient mortality; on the other hand, severity of DAI and length of hospital stay were the only significant predictors for dependence. Therefore, severity of DAI emerged as a risk factor for both mortality and dependence.