Closed Head Injury Research Articles

Evaluation and Management of Blunt Head Trauma in the Pediatric Clinic.

Head injuries, and specifically blunt head trauma, are common among pediatric patients of all ages. Patients may present to their primary care provider, to urgent care, or to the emergency department after head trauma. Such injuries may occur as a result of a variety of mechanisms, including falls, motor vehicle collisions, or sports injuries. Clinical decision rules exist to help guide the clinician in the initial evaluation of head injury and in determining when head imaging may be indicated. One such guideline that is widely used in the United States is known as the PECARN (Pediatric Emergency Care Applied Research Network) criteria. Pediatricians should also evaluate for the presence of symptoms consistent with concussion that may occur as a result of blunt head trauma and be familiar with the management and sequelae of concussion and head injuries. [Pediatr Ann. 2023;52(8):e279-e281.].

Glasgow Coma Scale Intubation Thresholds and Outcomes of Patients With Traumatic Brain Injury: The Need for Tailored Practice Management Guidelines.

This study aims to re-evaluate the GCS threshold for intubation in patients presenting to the ED with a traumatic brain injury to optimize outcomes and provide evidence for future practice management guidelines. We retrospectively reviewed the ACS-TQIP-Participant Use File (PUF) 2015-2019 for adult trauma patients 18years and older who experienced a blunt traumatic head injury and received computerized tomography. Multivariable regressions were performed to assess associations between outcomes and GCS intubation thresholds of 5, 8, and 10. In patients with a GCS ≤5, there were no differences in mortality (GCS ≤5: 26.3% vs GCS >5: 28.3%, adjusted P = .08), complication rates (GCS ≤5: 9.1% vs GCS >5: 10.3%, adjusted P = .91), or ICU length of stay (GCS ≤5: 5.4 vs GCS >5: 4.7, adjusted P = .36) between intubated and non-intubated patients. Intubated patients at GCS thresholds ≤8 (26.2% vs 19.1%, adjusted P < .0001) and ≤10 (25.6% vs 15.8%, adjusted P < .0001) had significantly higher mortality rates than non-intubated patients. Intubation at all GCS thresholds >5 resulted in higher rates of complications, H-LOS, and ICU-LOS when compared to non-intubated patients with the same GCS score. A GCS ≤5 was the threshold at which intubation in TBI patients conferred an additional benefit in disposition without worsened outcomes of mortality, H-LOS, or ICU-LOS. Trauma societies and hospital institutions should consider revisiting existing guidelines and protocols concerning the appropriate GCS threshold for safer intubation and better outcomes among these patient population.

Repeated mild closed head injury in neonatal rats results in sustained cognitive deficits associated with chronic microglial activation and neurodegeneration.

Abusive head trauma in infants is a consequence of multiple episodes of abuse and results in axonal injury, brain atrophy, and chronic cognitive deficits. Anesthetized 11-day-old rats, neurologically equivalent to infants, were subjected to 1 impact/day to the intact skull for 3 successive days. Repeated, but not single impact(s) resulted in spatial learning deficits (p < 0.05 compared to sham-injured animals) up to 5 weeks postinjury. In the first week following single or repetitive brain injury, axonal and neuronal degeneration, and microglial activation were observed in the cortex, white matter, thalamus, and subiculum; the extent of the histopathologic damage was significantly greater in the repetitive-injured animals compared to single-injured animals. At 40 days postinjury, loss of cortical, white matter and hippocampal tissue was evident only in the repetitive-injured animals, along with evidence of microglial activation in the white matter tracts and thalamus. Axonal injury and neurodegeneration were evident in the thalamus up to 40 days postinjury in the repetitive-injured rats. These data demonstrate that while single closed head injury in the neonate rat is associated with pathologic alterations in the acute post-traumatic period, repetitive closed head injury results in sustained behavioral and pathologic deficits reminiscent of infants with abusive head trauma.

Modified mouse model of repeated mild traumatic brain injury through a thinned-skull window and fluid percussion.

Mild traumatic brain injury (mTBI) is a clinically highly heterogeneous neurological disorder, none of the existing animal models can replicate the entire sequelae. This study aimed to develop a modified closed head injury (CHI) model of repeated mTBI (rmTBI) for investigating Ca2+ fluctuations of the affected neural network, the alternations of electrophysiology, and behavioral dysfunctions. The transcranial Ca2+ study protocol includes AAV-GCaMP6s infection in the right motor cortex, thinned-skull preparation, and two-photon laser scanning microscopy (TPLSM) imaging. The CHI rmTBI model is fabricated using the thinned-skull site and applying 2.0 atm fluid percussion with 48-h interval. The neurological dysfunction, minor motor performance, evident mood, spatial working, and reference deficits we found in this study mimic the clinically relevant syndromes after mTBI. Besides, our study revealed that there was a trend of transition from Ca2+ singlepeak to multipeak and plateau, and the total Ca2+ activities of multipeaks and plateaus (p < .001 vs. pre-rmTBI value) were significantly increased in ipsilateral layer 2/3 motor neurons after rm TBI. In parallel, there is a low-frequency power shift from delta to theta band (p < .01 vs. control) in the ipsilateral layer 2/3 of motor cortex of the rmTBI mice, and the overall firing rates significantly increased (p < .01 vs. control). Moreover, rmTBI causes slight cortical and hippocampal neuron damage and possibly induces neurogenesis in the dentate gyrus (DG). The alternations of Ca2+ and electrophysiological characteristics in layer 2/3 neuronal network, histopathological changes, and possible neurogenesis may play concertedly and partially contribute to the functional outcome post-rmTBI.

Enlarging traumatic superficial temporal artery pseudoaneurysm from a lacrosse ball injury: illustrative case.

The development of a mobile, growing, pulsatile mass after blunt head trauma to the forehead area, resulting in a superficial temporal artery pseudoaneurysm, is a very rare outcome. Most pseudoaneurysms are diagnosed with ultrasound, computed tomography (CT), and/or magnetic resonance imaging and treated via resection or, occasionally, embolization. The authors describe a case of a young male lacrosse player who presented with a bulging, partially pulsatile mass in the right forehead region 2 months after trauma from a high-velocity ball striking his head while helmeted. The authors reviewed 12 patients in the literature and describe each patient's epidemiological features, nature of the trauma, and onset of the lesion after the trauma, as well as the diagnostic methods and treatments for each case. Overall, CT and ultrasound appear to be the easiest and most used methods of diagnosis, and resection under general anesthesia is the most common treatment method.

Fracture of the Petrous Carotid Canal

A 23-year-old male motorcyclist experienced blunt head trauma with loss of consciousness, headache and vomiting, epistaxis and right otorrhagia after a collision with a motor vehicle. Fractures involving the right parietal and temporal bones, as well as acute subdural and subarachnoid hemorrhage were identified on a cranial and facial CT scan. On independent evaluation of the imaging study, a subtle but distinct fracture line in the skull base involving the petrous carotid canal was identified. (Figure 1) The patient subsequently underwent CT angiography to evaluate for any injury to the internal carotid artery. In this examination, good opacification of the internal carotid arteries and their branches was noted, with no evident aneurysm, arteriovenous malformation or arteriovenous fistula formation.&#x0D; In patients with temporal bone fractures, the most commonly encountered complications are: tympano-ossicular injury causing conductive hearing loss, cochlear or vestibular injury causing sensorineural hearing loss or vertigo, facial nerve trauma causing facial paralysis, and fractures of the tegmen or posterior cranial fossa plate causing cerebrospinal fluid leaks.1 On the other hand, injury to the intratemporal portion of the internal carotid artery has been described as a rare complication and as such may be overlooked.1 However, its potentially devastating and life-threatening sequelae necessitates a purposeful and intentional evaluation for its presence. These sequelae include brain ischemia from arterial dissection or complete vascular occlusion, exsanguinating epistaxis or otorrhagia from carotid pseudoaneurysms, and the formation of carotid-cavernous fistulas.2 The incidence of involvement of the carotid canal in skull base fractures has been reported to be around 24%, with around 11% of this group developing internal carotid artery injuries.3 As such, the presence of fractures involving the petrous carotid canal is an indication for CT or MR angiography to further evaluate the internal carotid artery.4

Repetitive mild traumatic brain injury induces hippocampal neural immune signaling linked to astrocyte reactivity

AbstractBackgroundRepeated mild traumatic brain injuries (mTBIs) sustained within a “window of vulnerability” can lead to a cumulative severity of outcomes such as memory impairment, depression, and long‐term development of amyloid beta (Aβ) pathology and neurofibrillary tangles. We previously reported that acute increases in neural immune signaling within the MAPK pathway and expression of pro‐inflammatory cytokines were associated with low cerebral blood flow (CBF) and worse long‐term spatial learning and memory in a weight‐drop mouse model of repetitive mTBI. We hypothesized that an increasing number of injuries would lead to an increase in neural immune signaling, pathological markers, and glial activation in the hippocampus.MethodFemale 3xTg mice at 3‐4mo of age were subjected to 1x, 3x, or 5x weight‐drop closed head injuries (CHI) spaced once‐daily. Animals were sacrificed and brains harvested at 30min, 4h, 24h, or 1‐month after the final CHI (n = 7‐10/time point/injury group). 32 cytokines, 10 MAPK phospho‐proteins, Aβ42, Aβ40, phospho‐tau (pThr181), and total tau were measured by Luminex in hippocampal tissues. GFAP was measured by ELISA. CBF was non‐invasively measured immediately prior to sacrifice.ResultWe observed a steady increase in both total tau and phospho‐tau and a trend of increased GFAP in the hippocampus after repeated injuries. We then identified groups of cytokines and MAPK phospho‐proteins which co‐vary with either GFAP or phospho‐tau. GFAP‐associated cytokines showed a rapid acute increase after injury then a return to basal levels by 24h, while GFAP‐associated MAPK dynamics changed with repeated injury. Cytokines and MAPK phospho‐proteins showed a notably high degree of cross‐correlation 4h after repeated injury, when GFAP levels were at their highest. Multivariate analysis revealed that high levels of GFAP were associated with low CBF while increased phospho‐tau in the frontal cortex was associated with high CBF.ConclusionTogether, our data indicate an increase in hippocampal neural immune signaling and astrocyte reactivity after repetitive brain injury. Immune signaling changes may be causally linked to spatial learning and memory deficits after repetitive mTBI.

Редкий случай развития каротидно-кавернозного соустья в офтальмологической практике

Purpose. Demonstration of a clinical case of the formation of carotid-cavernous fistula (CCF), which we observed in our ophthalmological practice. Material and methods. A 52-year-old patient who was urgently referred for surgical treatment of orbital phlegmon, accompanied by a decrease in vision to 0.02, reactive eyelid edema, secondary glaucoma, and rather mild exophthalmos of the left eye. On the same day, she was admitted to the hospital, where she underwent an opening and drainage of the orbit. However, after 5 days, against the background of further anti-inflammatory therapy, the patient began to be disturbed by a noise in the head, reminiscent of the «noise of a steam locomotive», and pain in the left eye appeared. Conducted selective computed tomography with angiography made it possible to establish the final diagnosis: cerebrovascular disease, arteriovenous malformation in the projection of the supraclinoid section of the left internal carotid artery, post-traumatic CCF on the left side. First, the patient underwent a course of vascular, decongestant, and symptomatic therapy, and then endovascular embolization CCF of the left side was successfully performed. Results. After that, headaches and noise in the head disappeared, exophthalmos and congestion in the form of edema of the eyelids and bulbar conjunctiva gradually regressed. However, the visual acuity of the left eye remained reduced (0.03) due to atrophy of the optic nerve. Conclusion. The rare occurrence of this pathology in ophthalmic practice may cause the lack of alertness of doctors of this specialty in terms of timely diagnosis of CCF. At the same time, it should be taken into account that neuroophthalmic symptoms are of decisive importance in clarifying the indications for the accelerated conduct of the only effective surgical endovascular treatment of this pathology. Particular care should be taken in cases where the patient has unilateral exophthalmos with a pulsating noise in the head and a history of blunt head trauma from several days to 2 months before their onset. Keywords: traumatic brain injury, carotid-cavernous fistula, diagnosis, carotid angiography, endovascular surgical treatment

Altered Tau Kinase Activity in rTg4510 Mice after a Single Interfaced CHIMERA Traumatic Brain Injury.

Traumatic brain injury (TBI) is an established risk factor for neurodegenerative diseases. In this study, we used the Closed Head Injury Model of Engineered Rotational Acceleration (CHIMERA) to investigate the effects of a single high-energy TBI in rTg4510 mice, a mouse model of tauopathy. Fifteen male rTg4510 mice (4 mo) were impacted at 4.0 J using interfaced CHIMERA and were compared to sham controls. Immediately after injury, the TBI mice showed significant mortality (7/15; 47%) and a prolonged duration of loss of the righting reflex. At 2 mo post-injury, surviving mice displayed significant microgliosis (Iba1) and axonal injury (Neurosilver). Western blotting indicated a reduced p-GSK-3β (S9):GSK-3β ratio in TBI mice, suggesting chronic activation of tau kinase. Although longitudinal analysis of plasma total tau suggested that TBI accelerates the appearance of tau in the circulation, there were no significant differences in brain total or p-tau levels, nor did we observe evidence of enhanced neurodegeneration in TBI mice compared to sham mice. In summary, we showed that a single high-energy head impact induces chronic white matter injury and altered GSK-3β activity without an apparent change in post-injury tauopathy in rTg4510 mice.

Should Infants with Blunt Traumatic Brain Injuries and Intracranial Hemorrhage Have Routine Repeat Imaging?

The practice of repeat head CT imaging in infants as a distinct population is poorly studied. The purpose of this study was to evaluate the incidence and utility of repeat head CT in the infant population. A 10-year retrospective review was conducted of infants with blunt traumatic head injuries (N = 50) that presented to a trauma center. Information from the hospital trauma registry and patient medical records were extracted regarding the size and type of injury, number and results of computed tomography (CT) imaging, changes in neurological exams, and any interventions that were required. Most patients (68%) had at least one repeat CT, with 26% showing progression of hemorrhage. Decreased Glasgow Coma Scale was associated with having repeat CT scans. Nearly one in four infants had a change in management associated with repeat imaging. Repeat CT scans resulted in operative interventions in 11.8% of cases and longer intensive care unit (ICU) stays in 8.8% of cases. Repeat CT scans were associated with increased hospital length of stay, but not with increased ventilator days, ICU length of stay, or mortality. Worsening bleeds were associated with mortality, but not with other hospital outcomes. Changes in management following repeat CT appeared to be more common in this population than in older children or adults. Findings from this study supported repeat CT imaging in infants, however, further research is needed to validate results of this study.

Injury trends aboard US Navy vessels: A 50-year analysis of mishaps at sea.

Maritime activities have been associated with unique dangers to civilian and military sailors. We performed a retrospective cohort study analyzing injury mechanisms and clinical outcomes of casualties onboard US naval ships to determine common injury mechanisms, trends, and outcomes. We hypothesized there would be a downward trend of injuries and fatalities on US naval ships during the study period. All mishaps recorded by the Naval Safety Command aboard active service US naval ships from 1970 through 2020 were reviewed. Only mishaps resulting in injury or fatality were included. Over time, injury mechanisms and casualty incidence rates were trended and compared based on medical capabilities. Ships without surgical capabilities were categorized as Role 1, and those with surgical capabilities as Role 2. There were a total of 3,127 casualties identified and analyzed, with 1,048 fatalities and 2,079 injuries. The injury mechanisms associated with the highest mortality included electrocution, blunt head trauma, fall from height, man overboard, and explosion. There was a decrease in the trend of mishaps resulting in casualties, fatalities, and injuries over the 50-year study period. The mortality rate for select severe injury mechanisms was higher on Role 1 capable platforms, compared with Role 2 (0.334 vs. 0.250, p < 0.05). Casualty incidences decreased over 50 years. However, mortality still remains high for certain mechanisms no matter the operational platform. Furthermore, Role 1 capable vessels have a higher overall mortality rate for severe injuries compared with Role 2. The authors propose training, process improvement, and technology-related solutions to improve outcomes on Role 1 capable naval vessels. Prognostic and Epidemiological; Level IV.

Ultrasound, photoacoustic, and magnetic resonance imaging to study hyperacute pathophysiology of traumatic and vascular brain injury.

Cerebrovascular dynamics and pathomechanisms that evolve in the minutes and hours following traumatic vascular injury in the brain remain largely unknown. We investigated the pathophysiology evolution in mice within the first 3hours after closed-head traumatic brain injury (TBI) and subarachnoid hemorrhage (SAH), two significant traumatic vascular injuries. We took a multimodal imaging approach using photoacoustic imaging, color Doppler ultrasound, and MRI to track injury outcomes using a variety of metrics. Brain oxygenation and velocity-weighted volume of blood flow (VVF) values significantly decreased from baseline to 15minutes after both TBI and SAH. TBI resulted in 19.2% and 41.0% ipsilateral oxygenation and VVF reductions 15minutes postinjury, while SAH resulted in 43.9% and 85.0% ipsilateral oxygenation and VVF reduction (p<.001). We found partial recovery of oxygenation from 15minutes to 3hours after injury for TBI but not SAH. Hemorrhage, edema, reduced perfusion, and altered diffusivity were evident from MRI scans acquired 90-150minutes after injury in both injury models, although the spatial distribution was mostly focal for TBI and diffuse for SAH. The results reveal that the cerebral oxygenation deficits immediately following injuries are reversible for TBI and irreversible for SAH. Our findings can inform future studies on mitigating these early responses to improve long-term recovery.

Neuroprotective Effect of Sub-lethal Hyperthermia Preconditioning in a Rat Model of Repeated Closed Head Injury

Repeated mild traumatic brain injury (rTBI), one of the most common forms of traumatic brain injury, is a worldwide severe public health concern. rTBI induces cumulative neuronal injury, neurological dysfunction, and cognitive deficits. Although there are clinical treatment methods, there is still an urgent need to develop preventive approaches for susceptible populations. Using a repeated closed head injury (rCHI) rat model, we interrogate the effect of sub-lethal hyperthermia preconditioning (SHP) on rCHI-induced neuronal injury and behavioral changes. Our study applied the repeated weight-drop model to induce the rCHI. According to the changes of heat shock protein 70 (HSP 70) in the cortex and hippocampus following a single SHP treatment in normal rats, the SHP was delivered to the rats 18 h before rCHI. We found that HSP significantly alleviated rCHI-induced anxiety-like behaviors and impairments in motor abilities and spatial memory. SHP exerts significant neuroprotection against rCHI-induced neuronal damage, apoptosis, and neuroinflammation. Our findings support the potential use of SHP as a preventative approach for alleviating rCHI-induced brain damage.

Salt diet Induces Neuroinflammatory Response, Microbiome Dysregulation and Associated with Long-term Anxiety Following Repetitive Closed Head Injury. (S28.003)

<h3>Objective:</h3> Investigate the effects of salt diet on neuroinflammatory response, behavior, and microbiome dysregulation following repetitive closed head injury model. <h3>Background:</h3> Concussions continue to be a prominent public health concern, with an estimated 1.6–3.8 million incidences annually in the United States. Younger populations are experiencing the highest rates of concussion and nearly all athletic endeavors have some risk of concussive injury. Concerns surrounding the potential risks of long-term cognitive and medical outcomes made adolescent traumatic brain injury (TBI) a central focus of public attention. Coupled to these events, recent clinical studies have shown that lifestyle factors, including salt diet, constitute additional risk affecting TBI consequences and neuropathophysiological outcomes. However, the impact of salt diet on the pathophysiology of TBI and whether it exacerbates post-injury outcomes is still largely unknown. <h3>Design/Methods:</h3> We investigated if the exposure to a high salt diet (HSD) would alter hemodynamics, behavior, innate immune response and microbiome diversity after repetitive mild closed head injury in adolescent mice. Mice were injured with a three hit model (3HD) and then maintained on a HSD or standard diet (STD) for 12 weeks. <h3>Results:</h3> We found that HSD didn’t change systolic and diastolic blood pressure, and heart rate compared with STD group. HSD group was associated with worsening anxiety-like behavior at 12 weeks post diet administration. HSD induced microgliosis and proinflammatory microglial transcriptomic signature including upregulation in interferon gamma, Interferon beta, T cells proliferation pathways. Consistently, we found upregulation of proinflammatory Tumor necrotic factor (TNF) in brain compared to Sham-HSD and TBI-STD groups. HSD was the main driver of microbiome dysregulation in both TBI and Sham groups. We found that Eubacterium xylanophilum and Lachnospiraceae bacterium associated with an anxiety phenotype following injury at 12 weeks post diet administration. <h3>Conclusions:</h3> Salt diet associated with increasing risk of worsening anxiety and exacerbating chronic neuroinflammation post repetitive head injury. <b>Disclosure:</b> Dr. Izzy has received publishing royalties from a publication relating to health care. Taha Yahya has nothing to disclose. Dr. Cao has nothing to disclose. Mr. Albastaki has nothing to disclose. Dr. Waed has nothing to disclose. Ms. Chopra has nothing to disclose. Miss EKWUDO has nothing to disclose. Miss Kurdeikaite has nothing to disclose. Ms. Moraes Verissimo has received personal compensation for serving as an employee of Brigham and Women’s Hospital. Ms. Moraes Verissimo has received personal compensation for serving as an employee of Brigham and Women’s Hospital and Harvard Medical School. Ms. Moraes Verissimo has received personal compensation for serving as an employee of Von Medical, Inc.. Ms. Moraes Verissimo has received personal compensation for serving as an employee of Nova Southeastern University. Ms. Moraes Verissimo has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Montachem Company. Dr. Cox has received personal compensation for serving as an employee of Anaerobe Systems. The institution of Dr. Cox has received research support from Infectious Disease Society. The institution of Dr. Cox has received research support from BrightFocus Foundation. Dr. Cox has received intellectual property interests from a discovery or technology relating to health care. Dr. Zafonte has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for MYOMO. Dr. Zafonte has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Kisbee. Dr. Zafonte has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Frontiers in Neurology. The institution of Dr. Zafonte has received research support from NIDILRR. The institution of Dr. Zafonte has received research support from NIH. The institution of Dr. Zafonte has received research support from FPHS study. Dr. Zafonte has received publishing royalties from a publication relating to health care. Michael J. Whalen has nothing to disclose.

Human amnionic progenitor cell secretome mitigates the consequence of traumatic optic neuropathy in a mouse model

Traumatic optic neuropathy (TON) is a condition in which acute injury to the optic nerve from direct or indirect trauma results in vision loss. The most common cause of TON is indirect injury to the optic nerve caused by concussive forces that are transmitted to the optic nerve. TON occurs in up to 5% of closed-head trauma patients and there is currently no known effective treatment. One potential treatment option for TON is ST266, a cell-free biological solution containing the secretome of amnion-derived multipotent progenitor (AMP) cells. We investigated the efficacy of intranasal ST266 in a mouse model of TON induced by blunt head trauma. Injured mice treated with a 10-day regimen of ST266 showed an improvement in spatial memory and learning, a significant preservation of retinal ganglion cells, and a decrease in neuropathological markers in the optic nerve, optic tract, and dorsal lateral geniculate nucleus. ST266 treatment effectively downregulated the NLRP3 inflammasome-mediated neuroinflammation pathway after blunt trauma. Overall, treatment with ST266 was shown to improve functional and pathological outcomes in a mouse model of TON, warranting future exploration of ST266 as a cell-free therapeutic candidate for testing in all optic neuropathies.

Teaching Video NeuroImages: Pulsatile proptosis and wall-eyed bilateral internuclear ophthalmoplegia

A 65-year-old man with a history of hypertension presented with double vision. Examination revealed wall-eyed bilateral internuclear ophthalmoplegia (WEBINO) (figure 1) and nonsymptomatic, pulse-synchronous, pulsatile proptosis of the left eye (video 1). According to the patient, there was a history of blunt head trauma in childhood and the pulsatile eye was present since then. CT revealed a meningocele into the left orbit due to a bony defect in the orbital roof (figure 2A). CT angiography ruled out a carotid-cavernous fistula. MRI showed an acute infarction at the midline of the midbrain tegmentum, which involved the medial longitudinal fasciculus bilaterally and caused the WEBINO (figure 2B).1 The pulsatile proptosis was attributed to the childhood head injury and due to the orbital roof fracture and associated meningocele pulsation of the brain vessels passed onto the CSF.2

Chronic traumatic encephalopathy (CTE)—features and forensic considerations

Chronic traumatic encephalopathy (CTE) is a neurodegenerative condition, in which the only known cause is exposure to repeated episodes of blunt head trauma. It most often occurs in professional and amateur athletes who have had frequent and repetitive cranial impacts during contact sports, but may also be found in victims of domestic violence, military personnel exposed to explosive devices and in individuals with severe epilepsy. The pathognomonic pathological findings are of neurofibrillary tangles and pretangles in the depths of the cerebral sulci caused by perivascular accumulation of phosphorylated Tau (pTau). Cases may be high profile requiring an evaluation of whether the neuropathological findings of CTE can be related to injuries previously sustained on the sporting field. Failure to examine the brain or to adequately sample appropriate areas at autopsy may lead to cases being overlooked and to an underestimation of the incidence of this condition in the community. Performing immunohistochemical staining for pTau in three areas from the neocortex has been found to be a useful screening tool for CTE. Ascertaining whether there is a history of head trauma, including exposure to contact sports, as a standard part of forensic clinical history protocols will help identify at-risk individuals so that Coronial consideration of the need for brain examination can be appropriately informed. Repetitive head trauma, particularly from contact sport, is being increasingly recognized as a cause of significant preventable neurodegeneration.

SON-Related Zhu-Tokita-Takenouchi-Kim Syndrome With Recurrent Hemiplegic Migraine: Putative Role of PRRT2.

Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome (OMIM 617140) is a recently identified neurodevelopmental disorder caused by heterozygous loss-of-function (LoF) variants in SON. Because the SON protein functions as an RNA-splicing regulator, it has been shown that some clinical features of ZTTK syndrome can be attributed to abnormal RNA splicing. Several neurologic features have been observed in patients with ZTTK syndrome, including seizure/epilepsy and other EEG abnormalities. However, a relationship between SON LoF in ZTTK syndrome and hemiplegic migraine remains unknown. We identified a patient with a pathogenic variant in SON who shows typical clinical features of ZTTK syndrome and experienced recurrent episodes of hemiplegic migraine. To define clinical features, brain MRI and EEG during and after episodes of hemiplegic migraine were characterized. To identify molecular mechanisms for this clinical presentation, we investigated the impact of small interfering RNA (siRNA)-mediated SON knockdown on mRNA expression of the CACNA1A, ATP1A2, SCN1A, and PRRT2 genes, known to be associated with hemiplegic migraine, by quantitative RT-PCR. Pre-mRNA splicing of PRRT2 on SON knockdown was further examined by RT-PCR using primers targeting specific exons. Recurrent episodes of hemiplegic migraine in our patient typically followed modest closed head injuries, and recurrent seizures occurred during the most severe of these episodes. Transient hemispheric cortical interstitial edema and asymmetric EEG slowing were identified during episodes. Our siRNA experiments revealed that SON knockdown significantly reduces PRRT2 mRNA levels in U87MG and SH-SY5Y cell lines, although a reduction in CACNA1A, ATP1A2, and SCN1A mRNA expression was not observed. We further identified that SON knockdown leads to failure in intron 2 removal from PRRT2 pre-mRNA, resulting in a premature termination codon that blocks the generation of functionally intact full-length PRRT2. This report identifies recurrent hemiplegic migraine as a novel clinical manifestation of ZTTK syndrome, further characterizes this clinical feature, and provides evidence for downregulation of PRRT2 caused by SON LoF as a mechanism causing hemiplegic migraine. Examination of the SON gene may be indicated in individuals with recurrent hemiplegic migraine.

Characteristics of paediatric pre-hospital intubation by Intensive Care Paramedics.

Emergency intubation in children is an infrequent procedure both in the pre-hospital and hospital setting. The anatomical, physiological and situational challenges together with limited clinician exposure can make this a difficult procedure with high risk of adverse events. The aim of this collaborative study between a state-wide ambulance service and a tertiary children's hospital was to describe the characteristics of pre-hospital paediatric intubations by Intensive Care Paramedics. We conducted a retrospective review of state-wide ambulance service electronic patient care records (ePCRs) in Victoria, Australia, population: 6.5 million. Children aged 0-18 years who were attended by paramedics over a 12-month period that required advanced airway management were analysed for demographics and first-pass success rate. Paramedics attended 2674 cases aged 0-18 years over the 12-month study period who received basic or advanced airway management. A total of 78 cases required advanced airway management. The median age of patients was 12 years (interquartile range 3-16) and most were male (60.2%). Sixty-eight patients (87.5%) were intubated successfully on the first attempt, first-pass success was lowest in children <1 year of age. The most common indications for pre-hospital intubation were closed head injury and cardiac arrest. It was not possible to report complication rates because of incomplete documentation. Pre-hospital intubation in children is performed infrequently in an extremely unwell patient group. Continued high-level paramedic training is required to prevent adverse events and ensure patient safety.

190 Prion Protein Knockout Leads to Differential RNA Expression Following Head Injury

INTRODUCTION: It is not well understood why repetitive head injury causes the behavioral and pathologic sequelae associated with Chronic Traumatic Encephalopathy. Cellular prion protein (PrPC) is associated with several neurodegenerative diseases including Alzheimer’s disease and Creutzfeldt-Jakob disease and we have previously demonstrated that PrPC is required for the pathology and behavior associated with CTE after TBI. We show that Prpc knockout leads to differential mice cortex gene expression in a murine repetitive head injury model. METHODS: Experimental groups consisted of PrPC-knockout (Prnp-/-) and PrPC wild type (WT) mice. Bilateral close head injury consisted of daily impactions over 10 days with appropriate unimpacted control. All animals were allowed to recover for 6 weeks. Mice were sacrificed and brain cortexes rapidly dissected and flash frozen for RNA extraction, sequencing, and quantification. RESULTS: We identified 52 upregulated and 134 downregulated genes in WT impacted compared to unimpacted WT mice. 301 genes were upregulated and 85 downregulated in Prnp-/- impacted mice compared to Prnp-/- mice without impactions. We identified 85 upregulated and 86 downregulated genes in Prnp-/- impacted mice compared to WT impacted mice. RNA expression of KLK6 is upregulated by a factor of 2.3 and KChip3 is downregulated by a factor of 1.3 in Prnp-/- impacted mice compared to WT impacted mice. CONCLUSIONS: Deletion of PrPc in a murine model of CTE leads to differential expression of multiple gene clusters. Deletion of Prpc in impacted mice upregulates KLK6 and downregulates KCHip3 which have been implicated in neurodegenerative processes and neuroinflammation including Alzheimer’s disease. We have previously demonstrated that Prpc is required for cognitive deficits and standard histologic pathology following head injury who's biochemical mechanism may implicate KLK6 and KCHip3.