Initial clinical evidence on biperiden as antiepileptogenic after traumatic brain injury-a randomized clinical trial.

There is currently no efficacious intervention for preventing post-traumatic epilepsy (PTE). Preclinical studies support the potential use of anticholinergics for this condition. The purpose of this study was to evaluate the effects of biperiden as an intervention for preventing PTE. A randomized, double-blinded clinical trial was conducted at HC/FMUSP between 2018-2022. Adults with acute traumatic brain injury (TBI) were randomly assigned to receive biperiden or placebo, for 10 days. The primary outcome was the incidence of PTE while the secondary outcomes included the frequency of seizures, the frequency of any adverse events and mortality after 24 months. The study was powered at a planned enrolment of 132 patients. The trial began in January 2018 and was halted by researchers on March 2020 (and terminated in December 2022) in the face of the global COVID-19 pandemic. Overall, 123 participants were randomized and 112 contributed with data for modified mITT analysis, being that 61 (49.5%) participants completed the 24-month follow-up consult. Data analysis indicated lack of evidence of biperiden for either, the incidence of post-traumatic epilepsy (2.6, 95%CI, 0.65-10.57; p = 0.170) or the mortality rate (1.57, 95%CI, 0.73-3.38; p = 0.248). The frequency of late post-traumatic seizures was higher for biperiden group (2.03, 95%CI = 0.912-3.1597; p <0.001). The present study suggests that there was insufficient evidence regarding the effect of biperiden in preventing PTE after TBI, which underpins the need for larger studies. Clinical trial registration: ClinicalTrials.gov, identifier: NCT01048138.

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.

Evaluation of cerebral hemodynamics by transcranial Doppler ultrasonography and its correlation with intracranial pressure in an animal model of intracranial hypertension / Avaliação da hemodinâmica encefálica utilizando Doppler transcraniano e sua correlação com a pressão intracraniana em um modelo animal de hipertensão intracraniana

ABSTRACT Background: Transcranial Doppler has been tested in the evaluation of cerebral hemodynamics as a non-invasive assessment of intracranial pressure (ICP), but there is controversy in the literature about its actual benefit and usefulness in this situation. Objective: To investigate cerebral blood flow assessed by Doppler technique and correlate with the variations of the ICP in the acute phase of intracranial hypertension in an animal model. Methods: An experimental animal model of intracranial hypertension was used. The experiment consisted of two groups of animals in which intracranial balloons were implanted and inflated with 4 mL (A) and 7 mL (B) for controlled simulation of different volumes of hematoma. The values of ICP and Doppler parameters (systolic [FVs], diastolic [FVd], and mean [FVm] cerebral blood flow velocities and pulsatility index [PI]) were collected during the entire procedure (before and during hematoma simulations and venous hypertonic saline infusion intervention). Comparisons between Doppler parameters and ICP monitoring were performed. Results: Twenty pigs were studied, 10 in group A and 10 in group B. A significant correlation between PI and ICP was obtained, especially shortly after abrupt elevation of ICP. There was no correlation between ICP and FVs, FVd or FVm separately. There was also no significant change in ICP after intravenous infusion of hypertonic saline solution. Conclusions: These results demonstrate the potential of PI as a parameter for the evaluation of patients with suspected ICP elevation.

RESUMO Antecedentes: O Doppler transcraniano (DTC) é uma técnica não invasiva para a avaliação da hemodinâmica cerebral, porém existem controvérsias na literatura sobre sua aplicabilidade preditiva em situações de elevada pressão intracraniana (PIC). Objetivo: Investigar o fluxo sanguíneo cerebral pelo DTC e correlacioná-lo com as variações da PIC na fase aguda da hipertensão intracraniana em modelo animal. Métodos: Dois grupos de animais (suínos) foram submetidos a hipertensão intracraniana secundária à indução de diferentes volumes de hematoma, por meio da insuflação de balão intracraniano controlado com 4 e 7 mL de solução salina fisiológica (grupos A e B, respectivamente). Em seguida, administrou-se infusão venosa de solução salina hipertônica (SSH 3%). Foram coletados os valores dos parâmetros de PIC e DTC (velocidade sistólica [FVs], diastólica [FVd] e média [FVm] do fluxo sanguíneo cerebral), bem como o índice de pulsatilidade (IP). Comparações entre os parâmetros do DTC e o monitoramento da PIC foram realizadas. Resultados: Vinte porcos foram estudados, dez no grupo A e dez no grupo B. Correlação significativa entre IP e PIC foi obtida, principalmente logo após a elevação abrupta da PIC. Não houve correlação entre PIC e FVs, FVd ou FVm separadamente. Também não houve alteração significativa na PIC após a infusão de SSH. Conclusões: Esses resultados demonstram o potencial do IP como um bom parâmetro para a avaliação de pacientes com suspeita de elevação da PIC.

Evaluation of cerebral hemodynamics by transcranial Doppler ultrasonography and its correlation with intracranial pressure in an animal model of intracranial hypertension.

BACKGROUND: Transcranial Doppler has been tested in the evaluation of cerebral hemodynamics as a non-invasive assessment of intracranial pressure (ICP), but there is controversy in the literature about its actual benefit and usefulness in this situation. OBJECTIVE: To investigate cerebral blood flow assessed by Doppler technique and correlate with the variations of the ICP in the acute phase of intracranial hypertension in an animal model. METHODS: An experimental animal model of intracranial hypertension was used. The experiment consisted of two groups of animals in which intracranial balloons were implanted and inflated with 4 mL (A) and 7 mL (B) for controlled simulation of different volumes of hematoma. The values of ICP and Doppler parameters (systolic [FVs], diastolic [FVd], and mean [FVm] cerebral blood flow velocities and pulsatility index [PI]) were collected during the entire procedure (before and during hematoma simulations and venous hypertonic saline infusion intervention). Comparisons between Doppler parameters and ICP monitoring were performed. RESULTS: Twenty pigs were studied, 10 in group A and 10 in group B. A significant correlation between PI and ICP was obtained, especially shortly after abrupt elevation of ICP. There was no correlation between ICP and FVs, FVd or FVm separately. There was also no significant change in ICP after intravenous infusion of hypertonic saline solution. CONCLUSIONS: These results demonstrate the potential of PI as a parameter for the evaluation of patients with suspected ICP elevation.

Decompressive hinge craniectomy with linear durotomies for ischemic stroke: a pilot study.

OBJECTIVE: Decompressive craniectomy may be a life-saving measure in ischemic stroke patients, who still have several associated complications. The objective of this study is to evaluate a novel decompressive surgery technique for severe hemispheric ischemic stroke. METHODS: For the hinge decompressive craniectomy (HDC), linear durotomies were performed. Vertical (one or two frontal and two parietal), and two horizontal (temporal), with approximately 5 cm long, linear durotomies were carried out. Duroplasty was performed using an autologous subgaleal tissue graft fixed with separate sutures to avoid CSF leak and direct contact of the cortex with the bone flap. The bone flap was fixed in three parietal locations. We compared 10 patients who underwent our modified HDC with 9 patients submitted to classical decompressive craniectomy (CDC). The primary outcome of this study was mortality. RESULTS: Nineteen patients were included, with a mean age of 52.3 years (±8.2). Four (44%) patients from the HDC group had to be reoperated to remove the bone flap because of brain swelling worsening, but none of them died. The average time of HDC was 90 minutes. Overall 14-days mortality was 21.1% (n=4), and cumulative six-months mortality was 42.1% (n=8). Five (50%) patients submitted to CDC died, while 3 (33.3%) submitted to HDC died (χ2=0.07, p=0.79). The mean length of stay was 46.7 days (±32.1) for HDC and 38.7 (±27.1) for CDC (p=0.60). CONCLUSIONS: We present a modified technique of hinge craniectomy with linear vertical and horizontal durotomies, which seems to have reduced operative time and mortality compared to classical decompressive craniotomy, although the difference was not statistically significant.

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.

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.

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.

Pterional, Pretemporal, and Orbitozygomatic Approaches: Anatomic and Comparative Study.

OBJECTIVE: Although pterional craniotomy and its variants are the most used approaches in neurosurgery, few studies have evaluated their precise indications. We evaluate the pterional (PT), pretemporal (PreT), and orbitozygomatic (OZ) approaches through quantitative measurements of area, linear, and angular exposures of the major intracranial vascular structures. METHODS: Eight fresh, adult cadavers were operated with the PT, followed by the PreT, and ending with the OZ approach. The working area, angular exposure of vascular structures and linear exposure of the basilar artery were measured. RESULTS: The OZ approach presented a wider area (1301.3 ± 215.9 mm2) with an increase of 456.7 mm2 compared with the PT and of 167.4 mm2 to the PreT (P = 0.011). The extension from PT to PreT and OZ increases linear exposure of the basilar artery. When comparing the PreT and OZ, we found an increase in the horizontal and vertical angle to the bifurcation of the ipsilateral middle cerebral artery (P = 0.005 and P = 0.032, respectively), horizontal angle to the basilar artery tip (P = 0.02), and horizontal angle to the contralateral ICA bifurcation (P = 0.048). CONCLUSIONS: The OZ approach offered notable surgical advantages compared with the traditional PT and PreT regarding to the area of exposure and linear exposure to basilar artery. Regarding angle of attack, the orbital rim and zygomatic arch removal provided quantitatively wider exposure and increased surgical freedom. A detailed anatomic study for each patient and surgeon experience must be considered for individualized surgical approach indication.