Applications of supraorbital keyhole craniotomy in pediatric cranial trauma: illustrative series of two cases and systematic literature review.

Minimally invasive (MIS) approaches to neurosurgical diseases continue to increase in popularity due to their association with decreased infection risk, shorter recovery time, and improved cosmesis. Cosmesis and lower morbidity are especially important for pediatric patients. The supraorbital keyhole craniotomy (SOKC) is one MIS approach shown to be effective for both neoplastic and vascular pathologies in pediatric patients. However, it is limited data on its use in pediatric trauma patients. Two cases employing SOKC in pediatric trauma patients are presented here along with a systematic review of the literature. We queried PubMed, Scopus, and Web of Science databases from inception to August 2022 using the Boolean search term: (supraorbital OR eyebrow OR transeyebrow OR suprabrow OR superciliary OR supraciliary) AND (craniotomy OR approach OR keyhole OR procedure) AND (pediatric OR children OR child OR young) AND "trauma". Studies that discussed the use of an SOKC in a pediatric patient having sustained trauma to the frontal calvarium and/or anterior fossa/sellar region of the skull base were included. Details were extracted on patient demographics, trauma etiology, endoscope use, and surgical and cosmetic outcomes. We identified 89 unique studies, of which four met inclusion criteria. Thirteen total cases were represented. Age and sex were reported for 12 patients, 25% of whom were male; the mean age was 7.5 years (range: 3-16). Pathologies included acute epidural hematoma (9), orbital roof fracture with dural tear (1), blowout fracture of the medial wall of the frontal sinus with supraorbital rim fracture (1), and compound skull fracture (1). Twelve patients were treated with a conventional operating microscope, while one underwent endoscope-assisted surgery. Only one significant complication (recurrent epidural hematoma) was reported. There were no reported cosmetic complications. The MIS SOKC approach is a reasonable option for select anterior skull base trauma in the pediatric population. This approach has been used previously for successful frontal epidural hematoma evacuation, which is often treated by a large craniotomy. Further study is merited.

Milestones for neurosurgery sub-interns: a novel evaluation tool to quantitatively differentiate residency applicants.

OBJECTIVE: The study objective was to create a novel milestones evaluation form for neurosurgery sub-interns and assess its potential as a quantitative and standardized performance assessment to compare potential residency applicants. In this pilot study, the authors aimed to determine the form's interrater reliability, relationship to percentile assignments in the neurosurgery standardized letter of recommendation (SLOR), ability to quantitatively differentiate tiers of students, and ease of use. METHODS: Medical student milestones were either adapted from the resident Neurological Surgery Milestones or created de novo to evaluate a student's medical knowledge, procedural aptitude, professionalism, interpersonal and communication skills, and evidence-based practice and improvement. Four milestone levels were defined, corresponding to estimated 3rd-year medical student through 2nd-year resident levels. Faculty and resident evaluations as well as student self-evaluations were completed for 35 sub-interns across 8 programs. A cumulative milestone score (CMS) was computed for each student. Student CMSs were compared both within and between programs. Interrater reliability was determined with Kendall's coefficient of concordance (Kendall's W). Student CMSs were compared against their percentile assignments in the SLOR using analysis of variance with post hoc testing. CMS-derived percentile rankings were assigned to quantitatively distinguish tiers of students. Students and faculty were surveyed on the form's usefulness. RESULTS: The average faculty rating overall was 3.20, similar to the estimated competency level of an intern. Student and faculty ratings were similar, whereas resident ratings were lower (p < 0.001). Students were rated most highly in coachability and feedback (3.49 and 3.67, respectively) and lowest in bedside procedural aptitude (2.90 and 2.85, respectively) in both faculty and self-evaluations. The median CMS was 26.5 (IQR 21.75-29.75, range 14-32) with only 2 students (5.7%) achieving the highest rating of 32. Programs that evaluated the most students differentiated the highest-performing students from the lowest by at least 13 points. A program with 3 faculty raters demonstrated scoring agreement across 5 students (p = 0.024). The CMS differed significantly between SLOR percentile assignments, despite 25% of students being assigned to the top fifth percentile. CMS-driven percentile assignment significantly differentiated the bottom, middle, and top third of students (p < 0.001). Faculty and students strongly endorsed the milestones form. CONCLUSIONS: The medical student milestones form was well received and differentiated neurosurgery sub-interns both within and across programs. This form has potential as a replacement for numerical Step 1 scoring as a standardized, quantitative performance assessment for neurosurgery residency applicants.

Effects of 24-hour versus night-float call schedules on the clinical and operative experiences of postgraduate year 2 and 3 neurosurgical residents.

OBJECTIVE: To comply with the removal of the 88-hour week exemption and to support additional operative experience during junior residency, Oregon Health & Science University (OHSU) switched from a night-float call schedule to a modified 24-hour call schedule on July 1, 2019. This study compared the volumes of clinical, procedural, and operative cases experienced by postgraduate year 2 (PGY-2) and PGY-3 residents under these systems. METHODS: The authors retrospectively studied billing and related clinical records, call schedules, and Accreditation Council for Graduate Medical Education case logs for PGY-2 and PGY-3 residents at OHSU, a tertiary academic health center, for the first 4 months of the academic years from 2017 to 2020. The authors analyzed the volumes of new patient consultations, bedside procedures, and operative procedures performed by each PGY-2 and PGY-3 resident during these years, comparing the volumes experienced under each call system. RESULTS: Changing from a PGY-2 resident-focused night-float call system to a 24-hour call system that was more evenly distributed between PGY-2 and PGY-3 residents resulted in decreased volume of new patient consultations, increased volume of operative procedures, and no change in volume of bedside procedures for PGY-2 residents. PGY-3 residents experienced a decrease in operative procedure volume under the 24-hour call system. CONCLUSIONS: Transition from a night-float system to a 24-hour call system altered the distribution of clinical and procedural experiences between PGY-2 and PGY-3 residents. Further research is necessary to understand the impact of these changes on educational outcomes, quality and safety of patient care, and resident satisfaction.

Neonatal administration of erythropoietin attenuates cognitive deficits in adult rats following placental insufficiency.

Preterm birth is a principal cause of neurological disability later in life, including cognitive and behavioral deficits. Notably, cognitive impairment has greater impact on quality of life than physical disability. Survivors of preterm birth commonly have deficits of executive function. Difficulties with tasks and planning complexity correlate positively with increasing disability. To overcome these barriers for children born preterm, preclinical and clinical studies have emphasized the importance of neurorestoration. Erythropoietin (EPO) is a endogenous cytokine with multiple beneficial mechanisms of action following perinatal brain injury. While most preclinical investigations have focused on pathology and molecular mechanisms, translational studies of repair using clinically viable biobehavioral biomarkers are still lacking. Here, using an established model of encephalopathy of prematurity secondary to placental insufficiency, we tested the hypothesis that administration of EPO in the neonatal period would attenuate deficits in recognition memory and cognitive flexibility in adult rats of both sexes. We assessed cognition and executive function in two ways. First, using the classic test of novel object recognition and second, using a touchscreen platform. Touchscreen testing allows for rigorous testing of cognition and executive function in preclinical and clinical scenarios. Data show that adult rats exhibit deficits in recognition memory and cognitive flexibility following in utero placental insufficiency. Notably, neonatal treatment of EPO attenuates these deficits in adulthood and facilitates functional repair. Together, these data validate EPO neurorestoration using a clinically relevant outcome measure and support the concept that postnatal treatment following in utero injury can improve cognition and executive function through adulthood.

Extended Erythropoietin Treatment Prevents Chronic Executive Functional and Microstructural Deficits Following Early Severe Traumatic Brain Injury in Rats.

Survivors of infant traumatic brain injury (TBI) are prone to chronic neurological deficits that impose lifelong individual and societal burdens. Translation of novel interventions to clinical trials is hampered in part by the lack of truly representative preclinical tests of cognition and corresponding biomarkers of functional outcomes. To address this gap, the ability of a high-dose, extended, post-injury regimen of erythropoietin (EPO, 3000U/kg/dose × 6d) to prevent chronic cognitive and imaging deficits was tested in a postnatal day 12 (P12) controlled-cortical impact (CCI) model in rats, using touchscreen operant chambers and regional analysis of diffusion tensor imaging (DTI). Results indicate that EPO prevents functional injury and MRI injury after infant TBI. Specifically, subacute DTI at P30 revealed widespread microstructural damage that is prevented by EPO. Assessment of visual discrimination on a touchscreen operant chamber platform demonstrated that all groups can perform visual discrimination. However, CCI rats treated with vehicle failed to pass reversal learning, and perseverated, in contrast to sham and CCI-EPO rats. Chronic DTI at P90 showed EPO treatment prevented contralateral white matter and ipsilateral lateral prefrontal cortex damage. This DTI improvement correlated with cognitive performance. Taken together, extended EPO treatment restores executive function and prevents microstructural brain abnormalities in adult rats with cognitive deficits in a translational preclinical model of infant TBI. Sophisticated testing with touchscreen operant chambers and regional DTI analyses may expedite translation and effective yield of interventions from preclinical studies to clinical trials. Collectively, these data support the use of EPO in clinical trials for human infants with TBI.

Secondary overtriage of pediatric neurosurgical trauma at a Level I pediatric trauma center.

The authors looked at all of the pediatric patients with a head injury who were transferred from other hospitals to their own over 12 years and tried to identify factors that would allow patients to stay closer to home at their local hospitals and not be transferred. Many patients with isolated, nondisplaced skull fractures or negative CT imaging likely could have avoided transfer. While hospitals should be cautious, this may help families stay closer to home.

Neonatal erythropoietin mitigates impaired gait, social interaction and diffusion tensor imaging abnormalities in a rat model of prenatal brain injury.

Children who are born preterm are at risk for encephalopathy of prematurity, a leading cause of cerebral palsy, cognitive delay and behavioral disorders. Current interventions are limited and none have been shown to reverse cognitive and behavioral impairments, a primary determinant of poor quality of life for these children. Moreover, the mechanisms of perinatal brain injury that result in functional deficits and imaging abnormalities in the mature brain are poorly defined, limiting the potential to target interventions to those who may benefit most. To determine whether impairments are reversible after a prenatal insult, we investigated a spectrum of functional deficits and diffusion tensor imaging (DTI) abnormalities in young adult animals. We hypothesized that prenatal transient systemic hypoxia-ischemia (TSHI) would induce multiple functional deficits concomitant with reduced microstructural white and gray matter integrity, and tested whether these abnormalities could be ameliorated using postnatal erythropoietin (EPO), an emerging neurorestorative intervention. On embryonic day 18 uterine arteries were transiently occluded for 60min via laparotomy. Shams underwent anesthesia and laparotomy for 60min. Pups were born and TSHI pups were randomized to receive EPO or vehicle via intraperitoneal injection on postnatal days 1 to 5. Gait, social interaction, olfaction and open field testing was performed from postnatal day 25-35 before brains underwent ex vivo DTI to measure fractional anisotropy, axial diffusivity and radial diffusivity. Prenatal TSHI injury causes hyperactivity, impaired gait and poor social interaction in young adult rats that mimic the spectrum of deficits observed in children born preterm. Collectively, these data show for the first time in a model of encephalopathy of prematurity that postnatal EPO treatment mitigates impairments in social interaction, in addition to gait deficits. EPO also normalizes TSHI-induced microstructural abnormalities in fractional anisotropy and radial diffusivity in multiple regions, consistent with improved structural integrity and recovery of myelination. Taken together, these results show behavioral and memory deficits from perinatal brain injury are reversible. Furthermore, resolution of DTI abnormalities may predict responsiveness to emerging interventions, and serve as a biomarker of CNS injury and recovery.

Microstructural and microglial changes after repetitive mild traumatic brain injury in mice.

Traumatic brain injury (TBI) is a major public health issue, with recently increased awareness of the potential long-term sequelae of repetitive injury. Although TBI is common, objective diagnostic tools with sound neurobiological predictors of outcome are lacking. Indeed, such tools could help to identify those at risk for more severe outcomes after repetitive injury and improve understanding of biological underpinnings to provide important mechanistic insights. We tested the hypothesis that acute and subacute pathological injury, including the microgliosis that results from repeated mild closed head injury (rmCHI), is reflected in susceptibility-weighted magnetic resonance imaging and diffusion-tensor imaging microstructural abnormalities. Using a combination of high-resolution magnetic resonance imaging, stereology, and quantitative PCR, we studied the pathophysiology of male mice that sustained seven consecutive mild traumatic brain injuries over 9 days in acute (24 hr) and subacute (1 week) time periods. rmCHI induced focal cortical microhemorrhages and impaired axial diffusivity at 1 week postinjury. These microstructural abnormalities were associated with a significant increase in microglia. Notably, microgliosis was accompanied by a change in inflammatory microenvironment defined by robust spatiotemporal alterations in tumor necrosis factor-α receptor mRNA. Together these data contribute novel insight into the fundamental biological processes associated with repeated mild brain injury concomitant with subacute imaging abnormalities in a clinically relevant animal model of repeated mild TBI. These findings suggest new diagnostic techniques that can be used as biomarkers to guide the use of future protective or reparative interventions. © 2016 Wiley Periodicals, Inc.

Imaging and serum biomarkers reflecting the functional efficacy of extended erythropoietin treatment in rats following infantile traumatic brain injury.

OBJECTIVE Traumatic brain injury (TBI) is a leading cause of death and severe morbidity for otherwise healthy full-term infants around the world. Currently, the primary treatment for infant TBI is supportive, as no targeted therapies exist to actively promote recovery. The developing infant brain, in particular, has a unique response to injury and the potential for repair, both of which vary with maturation. Targeted interventions and objective measures of therapeutic efficacy are needed in this special population. The authors hypothesized that MRI and serum biomarkers can be used to quantify outcomes following infantile TBI in a preclinical rat model and that the potential efficacy of the neuro-reparative agent erythropoietin (EPO) in promoting recovery can be tested using these biomarkers as surrogates for functional outcomes. METHODS With institutional approval, a controlled cortical impact (CCI) was delivered to postnatal Day (P)12 rats of both sexes (76 rats). On postinjury Day (PID)1, the 49 CCI rats designated for chronic studies were randomized to EPO (3000 U/kg/dose, CCI-EPO, 24 rats) or vehicle (CCI-veh, 25 rats) administered intraperitoneally on PID1-4, 6, and 8. Acute injury (PID3) was evaluated with an immunoassay of injured cortex and serum, and chronic injury (PID13-28) was evaluated with digitized gait analyses, MRI, and serum immunoassay. The CCI-veh and CCI-EPO rats were compared with shams (49 rats) primarily using 2-way ANOVA with Bonferroni post hoc correction. RESULTS Following CCI, there was 4.8% mortality and 55% of injured rats exhibited convulsions. Of the injured rats designated for chronic analyses, 8.1% developed leptomeningeal cyst-like lesions verified with MRI and were excluded from further study. On PID3, Western blot showed that EPO receptor expression was increased in the injured cortex (p = 0.008). These Western blots also showed elevated ipsilateral cortex calpain degradation products for αII-spectrin (αII-SDPs; p < 0.001), potassium chloride cotransporter 2 (KCC2-DPs; p = 0.037), and glial fibrillary acidic protein (GFAP-DPs; p = 0.002), as well as serum GFAP (serum GFAP-DPs; p = 0.001). In injured rats multiplex electrochemiluminescence analyses on PID3 revealed elevated serum tumor necrosis factor alpha (TNFα p = 0.01) and chemokine (CXC) ligand 1 (CXCL1). Chronically, that is, in PID13-16 CCI-veh rats, as compared with sham rats, gait deficits were demonstrated (p = 0.033) but then were reversed (p = 0.022) with EPO treatment. Diffusion tensor MRI of the ipsilateral and contralateral cortex and white matter in PID16-23 CCI-veh rats showed widespread injury and significant abnormalities of functional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD); MD, AD, and RD improved after EPO treatment. Chronically, P13-P28 CCI-veh rats also had elevated serum CXCL1 levels, which normalized in CCI-EPO rats. CONCLUSIONS Efficient translation of emerging neuro-reparative interventions dictates the use of age-appropriate preclinical models with human clinical trial-compatible biomarkers. In the present study, the authors showed that CCI produced chronic gait deficits in P12 rats that resolved with EPO treatment and that chronic imaging and serum biomarkers correlated with this improvement.

Erythropoietin Modulates Cerebral and Serum Degradation Products from Excess Calpain Activation following Prenatal Hypoxia-Ischemia.

Preterm infants suffer central nervous system (CNS) injury from hypoxia-ischemia and inflammation - termed encephalopathy of prematurity. Mature CNS injury activates caspase and calpain proteases. Erythropoietin (EPO) limits apoptosis mediated by activated caspases, but its role in modulating calpain activation has not yet been investigated extensively following injury to the developing CNS. We hypothesized that excess calpain activation degrades developmentally regulated molecules essential for CNS circuit formation, myelination and axon integrity, including neuronal potassium-chloride co-transporter (KCC2), myelin basic protein (MBP) and phosphorylated neurofilament (pNF), respectively. Further, we predicted that post-injury EPO treatment could mitigate CNS calpain-mediated degradation. Using prenatal transient systemic hypoxia-ischemia (TSHI) in rats to mimic CNS injury from extreme preterm birth, and postnatal EPO treatment with a clinically relevant dosing regimen, we found sustained postnatal excess cortical calpain activation following prenatal TSHI, as shown by the cleavage of alpha II-spectrin (αII-spectrin) into 145-kDa αII-spectrin degradation products (αII-SDPs) and p35 into p25. Postnatal expression of the endogenous calpain inhibitor calpastatin was also reduced following prenatal TSHI. Calpain substrate expression following TSHI, including cortical KCC2, MBP and NF, was modulated by postnatal EPO treatment. Calpain activation was reflected in serum levels of αII-SDPs and KCC2 fragments, and notably, EPO treatment also modulated KCC2 fragment levels. Together, these data indicate that excess calpain activity contributes to the pathogenesis of encephalopathy of prematurity. Serum biomarkers of calpain activation may detect ongoing cerebral injury and responsiveness to EPO or similar neuroprotective strategies.

Modeling Encephalopathy of Prematurity Using Prenatal Hypoxia-ischemia with Intra-amniotic Lipopolysaccharide in Rats.

Encephalopathy of prematurity (EoP) is a term that encompasses the central nervous system (CNS) abnormalities associated with preterm birth. To best advance translational objectives and uncover new therapeutic strategies for brain injury associated with preterm birth, preclinical models of EoP must include similar mechanisms of prenatal global injury observed in humans and involve multiple components of the maternal-placental-fetal system. Ideally, models should produce a similar spectrum of functional deficits in the mature animal and recapitulate multiple aspects of the pathophysiology. To mimic human systemic placental perfusion defects, placental underperfusion and/or chorioamnionitis associated with pathogen-induced inflammation in early preterm birth, we developed a model of prenatal transient systemic hypoxia-ischemia (TSHI) combined with intra-amniotic lipopolysaccharide (LPS). In pregnant Sprague Dawley rats, TSHI via uterine artery occlusion on embryonic day 18 (E18) induces a graded placental underperfusion defect associated with increasing CNS damage in the fetus. When combined with intra-amniotic LPS injections, placental inflammation is increased and CNS damage is compounded with associated white matter, gait and imaging abnormalities. Prenatal TSHI and TSHI+LPS prenatal insults meet several of the criteria of an EoP model including recapitulating the intrauterine insult, causing loss of neurons, oligodendrocytes and axons, loss of subplate, and functional deficits in adult animals that mimic those observed in children born extremely preterm. Moreover, this model allows for the dissection of inflammation induced by divergent injury types.

Cerebrospinal fluid reconstitution via a perfusion-based cadaveric model: feasibility study demonstrating surgical simulation of neuroendoscopic procedures.

Cadaveric surgical simulation carries the advantage of realistic anatomy and haptic feedback but has been historically difficult to model for intraventricular approaches given the need for active flow of CSF. This feasibility study was designed to simulate intraventricular neuroendoscopic approaches and techniques by reconstituting natural CSF flow in a cadaveric model. In 10 fresh human cadavers, a simple cervical laminectomy and dural opening were made, and a 12-gauge arterial catheter was introduced. Saline was continuously perfused at physiological CSF pressures to reconstitute the subarachnoid space and ventricles. A neuroendoscope was subsequently inserted via a standard right frontal bur hole. In 8 of the 10 cadavers, adequate reconstitution and endoscopic access of the lateral and third ventricles were achieved. In 2 cadavers, ventricular access was not feasible, perhaps because of a small ventricle size and/or deteriorated tissue quality. In all 8 cadavers with successful CSF flow reconstitution and endoscopic access, identifying the foramen of Monro was possible, as was performing septum pellucidotomy and endoscopic third ventriculostomy. Furthermore, navigation of the cerebral aqueduct, fourth ventricle, prepontine cistern, and suprasellar cistern via the lamina terminalis was possible, providing a complementary educational paradigm for resident education that cannot typically be performed in live surgery. Surgical simulation plays a critical and increasingly prominent role in surgical education, particularly for techniques with steep learning curves including intraventricular neuroendoscopic procedures. This novel model provides feasible and realistic surgical simulation of neuroendoscopic intraventricular procedures and approaches.

Cerebral vasospasm in traumatic brain injury.

Vasospasm following traumatic brain injury (TBI) may dramatically affect the neurological and functional recovery of a vulnerable patient population. While the reported incidence of traumatic vasospasm ranges from 19%-68%, the true incidence remains unknown due to variability in protocols for its detection. Only 3.9%-16.6% of patients exhibit clinical deficits. Compared to vasospasm resulting from aneurysmal SAH (aSAH), the onset occurs earlier and the duration is shorter. Overall, the clinical course tends to be milder, although extreme cases may occur. Traumatic vasospasm can occur in the absence of subarachnoid hemorrhage. Surveillance transcranial Doppler ultrasonography (TCD) has been utilized to monitor for radiographic vasospasm following TBI. However, effective treatment modalities remain limited. Hypertension and hypervolemia, the mainstays of treatment of vasospasm associated with aSAH, must be used judiciously in TBI patients, and calcium-channel blockers have offered mixed clinical results. Currently, the paucity of large prospective cohort studies and level-one data limits the ability to form evidence-based recommendations regarding the diagnosis and management of vasospasm associated with TBI.

The use of nanoparticles as contrast media in neuroimaging: a statement on toxicity.

The use of nanoparticles in diagnostic imaging is rapidly gaining utility and acceptance. A handful of iron oxide nanoparticle compounds have already been approved by the U.S. Food and Drug Administration for clinical use with a favorable acute safety profile. However, because use of these agents is still in its early stages, long-term clinical data has yet to become readily available. The ability of these particles to interact with cellular biology at a molecular level does have theoretical injurious potential. As with any medical intervention, its relative risks must be clearly understood. This article discusses the safety profile and potential toxicities of nanoparticles as used in diagnostic imaging, and serves to inform the prescribing physician of relative and potential risk to the patient.

Visualizing the future: enhancing neuroimaging with nanotechnology.

Advancements in imaging of the central nervous system have paralleled and propelled neurosurgical practice. These technologic innovations have expanded our understanding of neuroanatomy and neuropathology, helping to refine neurosurgical techniques to be more precise and less invasive. Nanotechnology will play a significant role in the next wave of technology that will continue to improve neurosurgical practice. With specific regard to neuroimaging, nanotechnology has the potential to provide more precise resolution when imaging nervous system malignancies. Nanoparticles may be engineered to noninvasively visualize pathology once found only under a microscope. They will enhance our ability to target new disease processes and thus develop more precise surgical and nonsurgical treatments. This article will discuss the background of nanotechnology's use in imaging of the nervous system, its current status, and future potentials.

Conditional associative learning of spatial and object information in children with attention deficit/hyperactivity disorder.

The present study assessed frontostriatal mediated memory functions in children with ADHD (N=12) and healthy control participants (N=12) using two tests of conditional associative learning (i.e., object and spatial) that shared similar stimulus-response association structures but that differed in terms of the demands placed upon strategic processes. Children with ADHD displayed normal performance on the object learning task but were impaired on the spatial learning task that placed greater demands on internally derived strategic processes. Secondary analyses further indicated that this strategic processing impairment cannot be attributed specifically to perseverative or working memory errors but rather appears to be related to a more general inability to maintain a high degree of consistency in responding across trials. Although the results of this study must be interpreted in light of the small sample sizes, they suggest that ADHD does not produce a basic deficit in acquiring stimulus-response associations previously shown to be associated with basal ganglia dysfunction. Rather, these findings suggest that the impaired conditional associative learning performance of children with ADHD is attributable to deficits in strategic processes previously been found to be dependent upon the integrity of the prefrontal cortex.