Adherence to international guidelines in neurocritical care of cervical traumatic spinal cord injury-a retrospective study.

Introduction: The American Association of Neurologic Surgeons guidelines on the management of traumatic spinal cord injury (SCI), updated in 2013, focus on spinal cord perfusion, early decompressive surgery, and venous thromboembolism (VTE) prophylaxis to improve neurological outcome. Research question: How neurocritical care and initial management have changed with the implementation of updated management guidelines, focusing on guidelines adherence and neurological outcome. Material and methods: Systemic physiological variables, time to neurosurgical treatment and VTE prophylaxis, and neurological outcome, were retrospectively collected from adult patients treated for cervical SCI 2001-2021. Results: Fifty-two patients were included. Mean arterial blood pressure (MAP) was significantly higher after 2013 (86±9.9 mmHg) when compared to before 2013 (79±9.9 mmHg), p = 0.041. Median time to surgery was 41 h before, and 20 h after 2013 (p = 0.029). Time to VTE prophylaxis was six days before and four days after 2013. Most neurocritical care complications were less commonly observed after 2013. Despite improved adherence to treatment goals, 44 % of MAP levels were below target, and 33% of patients were operated beyond 24h post-injury. Neurological outcome was not improved after implementation of the revised guidelines. Discussion and conclusion: While implementation of the revised 2013 guidelines improved most aspects of the acute SCI management, many guideline targets were not met in a large subset of patients. Strict adherence to the acute neurocritical management goals, and early surgical treatment, is likely crucial when aiming to improve SCI outcome.

Prolonged and intense neuroinflammation after severe traumatic brain injury assessed by cerebral microdialysis with 300 kDa membranes.

BACKGROUND: A neuroinflammatory response that may lead to edema and secondary brain damage is elicited in severe traumatic brain injury (TBI). Previous studies using microdialysis (MD) membranes with 100 k Dalton (kDa) cut-off found a transient intracerebral release of cytokines and chemokines without significant correlations to clinical course, intracranial pressure (ICP) or metabolites. In this study, a (300 kDa) MD probe was used to measure the levels of cytokines and chemokines in relation to ICP and metabolites. METHODS: Seven patients with severe TBI received 2 MD catheters. In four patients sufficient dialysate could be retrieved for analysis from both catheters. MD samples were analyzed bedside, then frozen and analyzed for chemokines and cytokines using a multiplex assay (Mesoscale Discovery). RESULTS: MD sampling was performed from 9 to 350 h. In total, 17 chemokines and cytokines were detected. Of these, IL-6, IL-8, IP-10, MCP-1 and MIP-1ß were consistently elevated, and investigated further in relation to metabolites, and ICP. Levels of chemokines and cytokines were higher than previously reported from TBI patients, and partially higher than those reported in patients with cytokine release syndrome. There were no significant differences between the two catheters regarding cytokine/chemokine concentrations, except for IL-6 which was higher in the peri-contusional area. No correlation with metabolites and ICP was observed. No significant increase or decline of chemokine or cytokine secretion was observed during the study period. CONCLUSION: Our data suggest that cytokine and chemokine levels reflect a perpetual, potent and pan-cerebebral inflammatory response that persists beyond 15 days following TBI.

Effect of Irrigation Fluid Temperature on Recurrence in the Evacuation of Chronic Subdural Hematoma: A Randomized Clinical Trial.

Importance: The effect of a physical property of irrigation fluid (at body vs room temperature) on recurrence rate in the evacuation of chronic subdural hematoma (cSDH) needs further study. Objective: To explore whether irrigation fluid temperature has an influence on cSDH recurrence. Design, Setting, and Participants: This was a multicenter randomized clinical trial performed between March 16, 2016, and May 30, 2020. The follow-up period was 6 months. The study was conducted at 3 neurosurgical departments in Sweden. All patients older than 18 years undergoing cSDH evacuation during the study period were screened for eligibility in the study. Interventions: The study participants were randomly assigned by 1:1 block randomization to the cSDH evacuation procedure with irrigation fluid at room temperature (RT group) or at body temperature (BT group). Main Outcomes and Measures: The primary end point was recurrence requiring reoperation within 6 months. Secondary end points were mortality, health-related quality of life, and complication frequency. Results: At 6 months after surgery, 541 patients (mean [SD] age, 75.8 [9.8] years; 395 men [73%]) had a complete follow-up according to protocol. There were 39 of 277 recurrences (14%) requiring reoperation in the RT group, compared with 16 of 264 recurrences (6%) in the BT group (odds ratio, 2.56; 95% CI, 1.38-4.66; P < .001). There were no significant differences in mortality, health-related quality of life, or complication frequency. Conclusions and Relevance: In this study, irrigation at body temperature was superior to irrigation at room temperature in terms of fewer recurrences. This is a simple, safe, and readily available technique to optimize outcome in patients with cSDH. When irrigation is used in cSDH surgery, irrigation fluid at body temperature should be considered standard of care. Trial Registration: ClincalTrials.gov Identifier: NCT02757235.

Swedish trial on embolization of middle meningeal artery versus surgical evacuation in chronic subdural hematoma (SWEMMA)-a national 12-month multi-center randomized controlled superiority trial with parallel group assignment, open treatment allocation and blinded clinical outcome assessment.

BACKGROUND: Chronic subdural hematoma (cSDH) is one of the most common neurosurgical disorders and the incidence is rising. The routine treatment is neurosurgical hematoma evacuation, which is associated with recurrence rates up to 10-25%. In recent years, endovascular embolization of the middle meningeal artery (eMMA) has garnered much attention due to recurrence rates as low as < 5%. Several randomized controlled trials are planned or ongoing. In most of these trials, conventional neurosurgical treatment with or without adjunctive endovascular embolization is compared. The proposed trial aims to conduct a head-to-head comparison between neurosurgical and endovascular treatment as stand-alone treatments. METHODS: The trial is academically driven and funded within existing public healthcare systems and infrastructure. Patients with uni- or bilateral cSDH, presenting with mild-to moderate symptoms, and admitted to neurosurgery on clinical grounds will be offered participation. Subjects are randomized 1:1 between conventional neurosurgical treatment (control) and endovascular embolization of the middle meningeal artery (intervention). Primary endpoint is reoperation due to clinically and/or radiologically significant recurrence within 3 months. Secondary endpoints include safety, technical success rate, neurological disability, and quality of life. DISCUSSION: There are mounting retrospective data suggesting eMMA, as sole treatment or as an adjunctive to neurosurgery for cSDH, is safe and effective with a reoperation rate lower than neurosurgical hematoma evacuation alone. If randomized controlled trials confirm these findings, there is a potential for a paradigm shift in the treatment of cSDH where a minimally invasive procedure can replace open surgery in a large and oftentimes old and fragile patient cohort. TRIAL REGISTRATION: ClinicalTrials.gov, ClinicalTrials.gov Identifier NCT05267184 . Registered March 4, 2022.

Cerebrospinal fluid biomarkers of white matter injury and astrogliosis are associated with the severity and surgical outcome of degenerative cervical spondylotic myelopathy.

BACKGROUND CONTEXT: Degenerative cervical spondylotic myelopathy (DCM) is the commonest form of spinal cord injury in adults. However, a limited number of clinical reports have assessed the role of biomarkers in DCM. PURPOSE: We evaluated cerebrospinal fluid (CSF) biomarkers in patients scheduled for DCM surgery and hypothesized that CSF biomarkers levels (1) would reflect the severity of preoperative neurological status; and (2) correlate with radiological appearance; and (3) correlate with clinical outcome. STUDY DESIGN/SETTING: Prospective clinical and laboratory study. PATIENT SAMPLE: Twenty-three DCM patients, aged 66.4±12.8 years and seven controls aged 45.4±5.3 years were included. OUTCOME MEASURES: The American Spinal Injury Association Impairment Scale, the Japanese Orthopaedic Association Cervical Myelopathy Evaluation Questionnaire and EuroQol 5-dimensions were assessed preoperatively and at 3 months post-surgery. METHODS: We measured preoperative biomarkers (glial fibrillary acidic protein [GFAP], neurofilament light [NFL], phosphorylated neurofilament-H [pNF-H] and Ubiquitin C-terminal hydrolase L1) in CSF samples collected from patients with progressive clinical DCM who underwent surgical treatment. Biomarker concentrations in DCM patients were compared with those of cervical radiculopathy controls. RESULTS: The median symptom duration was 10 (interquartile range 6) months. The levels of GFAP, NFL, pNF-H, Ubiquitin C-terminal hydrolase L1 were significantly higher in the DCM group compared to controls (p=.044, p=.002, p=.016, and p=.006, respectively). Higher pNF-H levels were found in patients with low signal on T1 Magnetic Resonance Imaging sequence compared to those without (p=.022, area under the receiver operating characteristic curve [AUC] 0.780, 95% Confidence Interval: 0.59-0.98). Clinical improvement following surgery correlated mainly with NFL and GFAP levels (p<.05). CONCLUSIONS: Our results suggest that CSF biomarkers of white matter injury and astrogliosis may be a useful tool to assess myelopathy severity and predict outcome after surgery, while providing valuable information on the underlying pathophysiology.

Intracerebral Proinflammatory Cytokine Increase in Surgically Evacuated Intracerebral Hemorrhage: A Microdialysis Study.

BACKGROUND: Treatment options for spontaneous intracerebral hemorrhage (ICH) are limited. A possible inflammatory response in the brain tissue surrounding an ICH may exacerbate the initial injury and could be a target for treatment of subsequent secondary brain injury. The study objective was to compare levels of inflammatory mediators in the interstitial fluid of the perihemorrhagic zone (PHZ) and in seemingly normal cortex (SNX) in the acute phase after surgical evacuation of ICH, with the hypothesis being that a difference could be demonstrated between the PHZ and the SNX. METHODS: In this observational study, ten patients needing surgical evacuation of supratentorial ICH received two cerebral microdialysis catheters: one in the PHZ and one in the SNX that is remote from the ICH. The microdialysate was analyzed for energy metabolites (including lactate pyruvate ratio and glucose) and for inflammatory mediators by using a multiplex immunoassay of 27 cytokines and chemokines at 6-10 h, 20-26 h, and 44-50 h after surgery. RESULTS: A metabolic crisis, indicated by altered energy metabolic markers, that persisted throughout the observation period was observed in the PHZ when compared with the SNX. Proinflammatory cytokines interleukin (IL) 8, tumor necrosis factor α, IL-2, IL-1ß, IL-6 and interferon γ, anti-inflammatory cytokine IL-13, IL-4, and vascular endothelial growth factor A were significantly higher in PHZ compared with SNX and were most prominent at 20-26 h following ICH evacuation. CONCLUSIONS: Higher levels of both proinflammatory and anti-inflammatory cytokines in the perihemorrhagic brain tissue implies a complex role for inflammatory mediators in the secondary injury cascades following ICH surgery, suggesting a need for targeted pharmacological interventions.

Dynamics of Selected Biomarkers in Cerebrospinal Fluid During Complex Endovascular Aortic Repair - A Pilot Study.

INTRODUCTION: Ischemic spinal cord injury (SCI) is a serious complication of complex aortic repair. Prophylactic cerebrospinal fluid (CSF) drainage, used to decrease lumbar cerebrospinal fluid (CSF) pressure, enables monitoring of CSF biomarkers that may aid in detecting impending SCI. We hypothesized that biomarkers, previously evaluated in traumatic SCI and brain injury, would be altered in CSF over time following complex endovascular aortic repair (cEVAR). OBJECTIVES: To examine if a chosen cohort of CSF biomarker correlates to SCI and warrants further research. METHODS: A prospective observational study on patients undergoing cEVAR with extensive aortic coverage. Vital parameters and CSF samples were collected on ten occasions during 72 hours post-surgery. A panel of ten biomarkers were analyzed (Neurofilament Light Polypeptide (NFL), Tau, Glial Fibrillary Acidic Protein (GFAP), Soluble Amyloid Precursos Protein (APP) α and ß, Amyloid ß 38, 40 and 42 (Aß38, 40 and 42), Chitinase-3-like protein 1 (CHI3LI or YKL-40), Heart-type fatty acid binding protein (H-FABP).). RESULTS: Nine patients (mean age 69, 7 males) were included. Median total aortic coverage was 68% [33, 98]. One patient died during the 30-day post-operative period. After an initial stable phase for the first few postoperative hours, most biomarkers showed an upward trend compared with baseline in all patients with >50% increase in value for NFL in 5/9 patients, in 7/9 patients for Tau and in 5/9 patients for GFAP. One patient developed spinal cord and supratentorial brain ischemia, confirmed with MRI. In this case, NF-L, GFAP and tau were markedly elevated compared with non-SCI patients (maximum increase compared with baseline in the SCI patient versus mean value of the maximal increase for all other patients: NF-L 367% vs 79%%, GFAP 95608% versus 3433%, tau 1020% vs 192%). CONCLUSION: This study suggests an increase in all ten studied CSF biomarkers after coverage of spinal arteries during endovascular aortic repair. However, the pilot study was not able to establish a specific correlation between spinal fluid biomarker elevation and clinical symptoms of SCI due to small sample size and event rate.

Extracellular fluid, cerebrospinal fluid and plasma biomarkers of axonal and neuronal injury following intracerebral hemorrhage.

Spontaneous intracerebral hemorrhage (ICH) is the most devastating form of stroke. To refine treatments, improved understanding of the secondary injury processes is needed. We compared energy metabolic, amyloid and neuroaxonal injury biomarkers in extracellular fluid (ECF) from the perihemorrhagic zone (PHZ) and non-injured (NCX) brain tissue, cerebrospinal fluid (CSF) and plasma. Patients (n = 11; age 61 ± 10 years) undergoing ICH surgery received two microdialysis (MD) catheters, one in PHZ, and one in NCX. ECF was analysed at three time intervals within the first 60 h post- surgery, as were CSF and plasma samples. Amyloid-beta (Aß) 40 and 42, microtubule associated protein tau (tau), and neurofilament-light (NF-L) were analysed using Single molecule array (Simoa) technology. Median biomarker concentrations were lowest in plasma, higher in ECF and highest in CSF. Biomarker levels varied over time, with different dynamics in the three fluid compartments. In the PHZ, ECF levels of Aß40 were lower, and tau higher when compared to the NCX. Altered levels of Aß peptides, NF-L and tau may reflect brain tissue injury following ICH surgery. However, the dynamics of biomarker levels in the different fluid compartments should be considered in the study of pathophysiology or biomarkers in ICH patients.

Decompression of the greater occipital nerve improves outcome in patients with chronic headache and neck pain - a retrospective cohort study.

BACKGROUND: Compression of the greater occipital nerve (GON) may contribute to chronic headache, neck pain, and migraine in a subset of patients. We aimed to evaluate whether GON decompression could reduce pain and improve quality of life in patients with occipital neuralgia and chronic headache and neck pain. METHODS: In this retrospective cohort study, selected patients with neck pain and headache referred to a single neurosurgical center were analyzed. Patients (n = 22) with suspected GON neuralgia based on nerve block or clinical criteria were included. All patients presented with occipital pain spreading frontally and to the neck in various degree. Surgical decompression was performed under local anesthesia. Follow-up was made by an assessor not involved in the treatment of the patients, by telephone 2-5 years after the surgical procedure and an interview protocol was used to collect information. The data from the follow-up protocols were then analyzed and reported. RESULTS: When analyzing the follow-up protocols, decreased headache/migraine was reported in 77% and neck pain was reduced in 55% of the patients. CONCLUSIONS: Decompression of GON(s) may reduce neck pain and headache in selected patients with persistent headache, neck pain, and clinical signs of GON neuralgia. Based on the limitations of the present retrospective study, the results should be considered with caution.

Cerebrospinal fluid biomarkers of glial and axonal injury in cervical spondylotic myelopathy.

OBJECTIVE: Degenerative cervical spondylotic myelopathy (CSM) is a major cause of spinal cord dysfunction with an unpredictable prognosis. Βiomarkers reflecting pathophysiological processes in CSM have been insufficiently investigated. It was hypothesized that preoperative cerebrospinal fluid (CSF) biomarker levels are altered in patients with CSM and correlate with neurological status and outcome. METHODS: CSF biomarkers from patients with CSM and controls were analyzed with immunoassays. Spinal cord changes were evaluated with MRI. The American Spinal Cord Injury Association Impairment Scale, the Japanese Orthopaedic Association Cervical Myelopathy Evaluation Questionnaire (JOACMEQ), and the EQ-5D questionnaire were applied prior to and 3 months after surgery. A p value < 0.05 was considered statistically significant. RESULTS: Twenty consecutive CSM patients with a mean age of 67.7 ± 13 years and 63 controls with a mean age of 65.2 ± 14.5 years (p > 0.05) were included in the study. In the CSM subjects, CSF neurofilament light subunit (NF-L) and glial fibrillary acidic protein (GFAP) concentrations were higher (p < 0.05), whereas fatty acid-binding protein 3 (FABP3), soluble amyloid precursor proteins (sAPPα and sAPPß), and amyloid ß (Aß) peptide (Aß38, Aß40, and Aß42) concentrations were lower than in controls (p < 0.05). Aß peptide levels correlated positively with symptom duration. Preoperative JOACMEQ lower extremity function and CSF NF-L levels correlated positively, and the JOACMEQ bladder function correlated negatively with sAPPα and sAPPß (p < 0.05). CSF NF-L and FABP3 levels were higher in patients with improved outcome (EQ-5D visual analog scale difference > 20). CONCLUSIONS: CSF biomarkers of glial and axonal damage, inflammation, and synaptic changes are altered in symptomatic CSM patients, indicating that axonal injury, astroglial activation, and Aß dysmetabolism may be present in these individuals. These findings reflect CSM pathophysiology and may aid in prognostication. However, future studies including larger patient cohorts, postoperative biomarker data and imaging, and longer follow-up times are required to validate the present findings.

Differential DNA Methylation of the Genes for Amyloid Precursor Protein, Tau, and Neurofilaments in Human Traumatic Brain Injury.

Traumatic brain injury (TBI) is an established risk factor for neurodegenerative disorders and dementias. Epigenetic modifications, such as DNA methylation, may alter the expression of genes without altering the DNA sequence in response to environmental factors. We hypothesized that DNA methylation changes may occur in the injured human brain and be implicated in the neurodegenerative aftermath of TBI. The DNA methylation status of genes related to neurodegeneration; for example, amyloid beta precursor protein (APP), microtubule associated protein tau (MAPT), neurofilament heavy (NEFH), neurofilament medium (NEFM), and neurofilament light (NEFL), was analyzed in fresh, surgically resected human brain tissue from 17 severe TBI patients and compared with brain biopsy samples from 19 patients with idiopathic normal pressure hydrocephalus (iNPH). We also performed an epigenome-wide association study (EWAS) comparing TBI patients with iNPH controls. Thirty-eight CpG sites in the APP, MAPT, NEFH, and NEFL genes were differentially methylated by TBI. Among the top 20 differentially methylated CpG sites, 11 were in the APP gene. In addition, the EWAS evaluating 828,888 CpG sites revealed 308 differentially methylated CpG sites in genes related to cellular/anatomical structure development, cell differentiation, and anatomical morphogenesis. These preliminary findings provide the first evidence of an altered DNA methylome in the injured human brain, and may have implications for the neurodegenerative disorders associated with TBI.

Cerebrospinal fluid levels of GFAP and pNF-H are elevated in patients with chronic spinal cord injury and neurological deterioration.

BACKGROUND: Years after a traumatic spinal cord injury (SCI), a subset of patients may develop progressive clinical deterioration due to intradural scar formation and spinal cord tethering, with or without an associated syringomyelia. Meningitis, intradural hemorrhages, or intradural tumor surgery may also trigger glial scar formation and spinal cord tethering, leading to neurological worsening. Surgery is the treatment of choice in these chronic SCI patients. OBJECTIVE: We hypothesized that cerebrospinal fluid (CSF) and plasma biomarkers could track ongoing neuronal loss and scar formation in patients with spinal cord tethering and are associated with clinical symptoms. METHODS: We prospectively enrolled 12 patients with spinal cord tethering and measured glial fibrillary acidic protein (GFAP), ubiquitin C-terminal hydrolase L1 (UCH-L1), and phosphorylated Neurofilament-heavy (pNF-H) in CSF and blood. Seven patients with benign lumbar intradural tumors and 7 patients with cervical radiculopathy without spinal cord involvement served as controls. RESULTS: All evaluated biomarker levels were markedly higher in CSF than in plasma, without any correlation between the two compartments. When compared with radiculopathy controls, CSF GFAP and pNF-H levels were higher in patients with spinal cord tethering (p ≤ 0.05). In contrast, CSF UCH-L1 levels were not altered in chronic SCI patients when compared with either control groups. CONCLUSIONS: The present findings suggest that in patients with spinal cord tethering, CSF GFAP and pNF-H levels might reflect ongoing scar formation and neuronal injury potentially responsible for progressive neurological deterioration.

Management and outcomes following emergency surgery for traumatic brain injury - A multi-centre, international, prospective cohort study (the Global Neurotrauma Outcomes Study).

INTRODUCTION: Traumatic brain injury (TBI) accounts for a significant amount of death and disability worldwide and the majority of this burden affects individuals in low-and-middle income countries. Despite this, considerable geographical differences have been reported in the care of TBI patients. On this background, we aim to provide a comprehensive international picture of the epidemiological characteristics, management and outcomes of patients undergoing emergency surgery for traumatic brain injury (TBI) worldwide. METHODS AND ANALYSIS: The Global Neurotrauma Outcomes Study (GNOS) is a multi-centre, international, prospective observational cohort study. Any unit performing emergency surgery for TBI worldwide will be eligible to participate. All TBI patients who receive emergency surgery in any given consecutive 30-day period beginning between 1st of November 2018 and 31st of December 2019 in a given participating unit will be included. Data will be collected via a secure online platform in anonymised form. The primary outcome measures for the study will be 14-day mortality (or survival to hospital discharge, whichever comes first). Final day of data collection for the primary outcome measure is February 13th. Secondary outcome measures include return to theatre and surgical site infection. ETHICS AND DISSEMINATION: This project will not affect clinical practice and has been classified as clinical audit following research ethics review. Access to source data will be made available to collaborators through national or international anonymised datasets on request and after review of the scientific validity of the proposed analysis by the central study team.

Extreme intracranial pressure elevation > 90 mmHg in an awake patient with primary CNS lymphoma-case report.

We describe a patient with primary CNS lymphomas, awake despite an extreme ICP elevation. A 48-year-old woman presented with headache since 1 month, and bilateral papillary edema was observed. Magnetic resonance imaging revealed diffuse infiltration around the petrous bone. Following external ventricular drainage (EVD) placement, ICP levels of > 90 mmHg were recorded while the patient was fully awake. Cytology revealed an aggressive primary CNS lymphoma. Cerebrospinal fluid (CSF) drainage at high opening pressure levels was required. We conclude that extreme ICP elevations, treatable by CSF drainage, can be observed without a reduced level of consciousness.

Differences in neurosurgical treatment of intracerebral haemorrhage: a nation-wide observational study of 578 consecutive patients.

BACKGROUND: Supratentorial intracerebral haemorrhage (ICH) carries an excessive mortality and morbidity. Although surgical ICH treatment can be life-saving, the indications for surgery in larger cohorts of ICH patients are controversial and not well defined. We hypothesised that surgical indications vary substantially among neurosurgical centres in Sweden. OBJECTIVE: In this nation-wide retrospective observational study, differences in treatment strategies among all neurosurgical departments in Sweden were evaluated. METHODS: Patient records, neuroimaging and clinical outcome focused on 30-day mortality were collected on each operated ICH patient treated at any of the six neurosurgical centres in Sweden from 1 January 2011 to 31 December 2015. RESULTS: In total, 578 consecutive surgically treated ICH patients were evaluated. There was a similar incidence of surgical treatment among different neurosurgical catchment areas. Patient selection for surgery was similar among the centres in terms of patient age, pre-operative level of consciousness and co-morbidities, but differed in ICH volume, proportion of deep-seated vs. lobar ICH and pre-operative signs of herniation (p < .05). Post-operative patient management strategies, including the use of ICP-monitoring, CSF-drainage and mechanical ventilation, varied among centres (p < .05). The 30-day mortality ranged between 10 and 28%. CONCLUSIONS: Although indications for surgical treatment of ICH in the six Swedish neurosurgical centres were homogenous with regard to age and pre-operative level of consciousness, important differences in ICH volume, proportion of deep-seated haemorrhages and pre-operative signs of herniation were observed, and there was a substantial variability in post-operative management. The present results reflect the need for refined evidence-based guidelines for surgical management of ICH.

Focal traumatic brain injury induces neuroplastic molecular responses in lumbar spinal cord.

BACKGROUND/OBJECTIVES: Motor impairment induced by traumatic brain injury (TBI) may be mediated through changes in spinal molecular systems regulating neuronal plasticity. We assessed whether a focal controlled cortical impact (CCI) TBI in the rat alters expression of the Tgfb1, c-Fos, Bdnf, and Gap43 neuroplasticity genes in lumbar spinal cord.Approach/Methods:Adult male Sprague-Dawley rats (n = 8) were subjected to a right-side CCI over the anterior sensorimotor hindlimb representation area or sham-injury (n = 8). Absolute expression levels of Tgfb1, c-Fos, Bdnf, and Gapd43 genes were measured by droplet digital PCR in ipsi-and contralesional, dorsal and ventral quadrants of the L4 and L5 spinal cord. The neuronal activity marker c-Fos was analysed by immunohistochemistry in the dorsal L4 and L5 segments. The contra- vs. ipsilesional expression pattern was examined as the asymmetry index, AI. RESULTS: The Tgfb1 mRNA levels were significantly higher in the CCI vs. sham-injured rats, and in the contra- vs. ipsilesional dorsal domains in the CCI group. The number of c-Fos-positive cells was elevated in the L4 and L5 segments; and on the contralesional compared to the ipsilesional side in the CCI group. The c-Fos AI in the dorsal laminae was significantly increased by CCI. CONCLUSIONS: The results support the hypothesis that focal TBI induces plastic alterations in the lumbar spinal cord that may contribute to either motor recovery or maladaptive motor responses.

Dynamic protein changes in the perihaemorrhagic zone of Surgically Treated Intracerebral Haemorrhage Patients.

The secondary injury cascades exacerbating the initial brain injury following intracerebral haemorrhage (ICH) are incompletely understood. We used dual microdialysis (MD) catheters placed in the perihaemorrhagic zone (PHZ) and in seemingly normal cortex (SNX) at time of surgical ICH evacuation in ten patients (range 26-70 years). Routine interstitial MD markers (including glucose and the lactate/pyruvate ratio) were analysed and remaining microdialysate was analysed by two-dimensional gel electrophoresis (2-DE) and nano-liquid chromatography tandem mass spectrometry (nLC-MS/MS). Two time intervals were analysed; median 2-10 hours post-surgery (time A) and median 68-76 hours post-ICH onset (time B). Using 2-DE, we quantified 232 ± 31 different protein spots. Two proteins differed between the MD catheters at time A, and 12 proteins at time B (p < 0.05). Thirteen proteins were significantly altered between time A and time B in the SNX and seven proteins in the PHZ, respectively. Using nLC-MS/MS ca 800 proteins were identified out of which 76 were present in all samples. At time A one protein was upregulated and two downregulated, and at time B, seven proteins were upregulated, and four downregulated in the PHZ compared to the SNX. Microdialysis-based proteomics is feasible for study of secondary injury mechanisms and discovery of biomarkers after ICH.

Persistent Metabolic Disturbance in the Perihemorrhagic Zone Despite a Normalized Cerebral Blood Flow Following Surgery for Intracerebral Hemorrhage.

BACKGROUND: We hypothesized that reduced cerebral blood flow (CBF) and/or energy metabolic disturbances exist in the tissue surrounding a surgically evacuated intracerebral hemorrhage (ICH). If present, such CBF and/or metabolic impairments may contribute to ongoing tissue injury and the modest clinical efficacy of ICH surgery. OBJECTIVE: To conduct an observational study of CBF and the energy metabolic state in the perihemorrhagic zone (PHZ) tissue and in seemingly normal cortex (SNX) by microdialysis (MD) following surgical ICH evacuation. METHODS: We evaluated 12 patients (median age 64; range 26-71 yr) for changes in CBF and energy metabolism following surgical ICH evacuation using Xenon-enhanced computed tomography (n = 10) or computed tomography perfusion (n = 2) for CBF and dual MD catheters, placed in the PHZ and the SNX at ICH surgery. RESULTS: CBF was evaluated at a mean of 21 and 58 h postsurgery. In the hemisphere ipsilateral to the ICH, CBF improved between the investigations (36.6 ± 20 vs 40.6 ± 20 mL/100 g/min; P < .05). In total, 1026 MD samples were analyzed for energy metabolic alterations including glucose and the lactate/pyruvate ratio (LPR). The LPR was persistently elevated in the PHZ compared to the SNX region (P < .05). LPR elevations in the PHZ were predominately type II (pyruvate normal-high; indicating mitochondrial dysfunction) as opposed to type I (pyruvate low; indicating ischemia) at 4 to 48 h (70% vs 30%) and at 49 to 84 h (79% vs 21%; P < .05) postsurgery. CONCLUSION: Despite normalization of CBF following ICH evacuation, an energy metabolic disturbance suggestive of mitochondrial dysfunction persists in the perihemorrhagic zone.

Acute Inflammatory Biomarker Responses to Diffuse Traumatic Brain Injury in the Rat Monitored by a Novel Microdialysis Technique.

Neuroinflammation is a major contributor to the progressive brain injury process induced by traumatic brain injury (TBI), and may play an important role in the pathophysiology of axonal injury. The immediate neuroinflammatory cascade cannot be characterized in the human setting. Therefore, we used the midline fluid percussion injury model of diffuse TBI in rats and a novel microdialysis (MD) method providing stable diffusion-driven biomarker sampling. Immediately post-injury, bilateral amphiphilic tri-block polymer coated MD probes (100 kDa cut off membrane) were inserted and perfused with Dextran 500 kDa-supplemented artificial cerebrospinal fluid (CSF) to optimize protein capture. Six hourly samples were analyzed for 27 inflammatory biomarkers (9 chemokines, 13 cytokines, and 5 growth factors) using a commercial multiplex biomarker kit. TBI (n = 6) resulted in a significant increase compared with sham-injured controls (n = 6) for five chemokines (eotaxin/CCL11, fractalkine/CX3CL1, LIX/CXCL5, monocyte chemoattractant protein [MCP]1α/CCL2, macrophage inflammatory protein [MIP]1α /CCL3), 10 cytokines (interleukin [IL]-1α, IL-1ß, IL-4, IL-6, IL-10, IL-13, IL-17α, IL-18, interferon [IFN]-γ, tumor necrosis factor [TNF]-α), and four growth factors (epidermal growth factor [EGF], granulocyte-macrophage colony-stimulating factor [GM-CSF], leptin, vascular endothelial growth factor [VEGF]). Therefore, diffuse TBI was associated with an increased level of 18 of the 27 inflammatory biomarkers at one through six time points, during the observation period whereas the remaining 9 biomarkers were unaltered. The study shows that diffuse TBI induces an acute increase in a number of inflammatory biomarkers. The novel MD technique provides stable MD sampling suitable for further studies on the early neuroinflammatory cascade in TBI.