Faculty Bibliography

BACKGROUND AND OBJECTIVES/OBJECTIVE:Instrumented spinal fusion constructs sometimes fail because of fatigue loading, frequently necessitating open revision surgery. Favorable outcomes after percutaneous juxtapedicular cement salvage (perc-cement salvage) of failing instrumentation have been described; however, this approach is not widely known among spine surgeons , and its biomechanical properties have not been evaluated. We report our institutional experience with perc-cement salvage and investigate the relative biomechanical strength of this technique as compared with 3 other common open revision techniques. METHODS:A retrospective chart review of patients who underwent perc-cement salvage was conducted. Biomechanical characterization of revision techniques was performed in a cadaveric model of critical pedicle screw failure. Three revision cohorts involved removal and replacement of hardware: (1) screw upsizing, (2) vertebroplasty, and (3) fenestrated screw with cement augmentation. These were compared with a cohort with perc-cement salvage performed using a juxtapedicular trajectory with the failed primary screw remaining engaged in the vertebral body. RESULTS:Ten patients underwent perc-cement salvage from 2018 to 2022 to address screw haloing and/or endplate fracture threatening construct integrity. Pain palliation was reported by 8/10 patients. Open revision surgery was required in 4/10 patients, an average of 8.9 months after the salvage procedure (range 6.2-14.7 months). Only one revision was due to progressive hardware dislodgement. The remainder avoided open revision surgery through an average of 1.9 years of follow-up. In the cadaveric study, there were no significant differences in pedicle screw pullout strength among any of the revision cohorts. CONCLUSION/CONCLUSIONS:Perc-cement salvage of failing instrumentation is reasonably efficacious. The technique is biomechanically noninferior to other revision strategies that require open surgery for removal and replacement of hardware. Open revision surgery may be avoided by perc-cement salvage in select cases.

Dysregulated cholesterol metabolism represents an increasingly recognized feature of autism spectrum disorder (ASD). Children with fetal valproate syndrome caused by prenatal exposure to valproic acid (VPA), an anti-epileptic and mood-stabilizing drug, have a higher incidence of developing ASD. However, the role of VPA in cholesterol homeostasis in neurons and microglial cells remains unclear. Therefore, we examined the effect of VPA exposure on regulation of cholesterol homeostasis in the human microglial clone 3 (HMC3) cell line and the human neuroblastoma cell line SH-SY5Y. HMC3 and SH-SY5Y cells were each incubated in increasing concentrations of VPA, followed by quantification of mRNA and protein expression of cholesterol transporters and cholesterol metabolizing enzymes. Cholesterol efflux was evaluated using colorimetric assays. We found that VPA treatment in HMC3 cells significantly reduced ABCA1 mRNA, but increased ABCG1 and CD36 mRNA levels in a dose-dependent manner. However, ABCA1 and ABCG1 protein levels were reduced by VPA in HMC3. Furthermore, similar experiments in SH-SY5Y cells showed increased mRNA levels for ABCA1, ABCG1, CD36, and 27-hydroxylase with VPA treatment. VPA exposure significantly reduced protein levels of ABCA1 in a dose-dependent manner, but increased the ABCG1 protein level at the highest dose in SH-SY5Y cells. In addition, VPA treatment significantly increased cholesterol efflux in SH-SY5Y, but had no impact on efflux in HMC3. VPA differentially controls the expression of ABCA1 and ABCG1, but regulation at the transcriptional and translational levels are not consistent and changes in the expression of these genes do not correlate with cholesterol efflux in vitro.

OBJECTIVES/OBJECTIVE:Critically ill patients eliminate levetiracetam (LEV) more rapidly than healthy controls, yet low doses are commonly used for seizure prophylaxis in the ICU setting. We compared the rates of achievement of target serum levels and new onset seizure (clinical and/or electrographic) among patients who received low (500 mg bid) versus high (750-1,000 mg bid) dose LEV. DESIGN/METHODS:Prospective, observational study. SETTING/METHODS:Tertiary care, academic center. PATIENTS/METHODS:We included patients who received prophylactic LEV following traumatic brain injury, intracerebral hemorrhage, spontaneous subarachnoid hemorrhage, or supratentorial neurosurgery between 2019 and 2021. Patients with a history of seizure, antiseizure medication use, or renal failure requiring dialysis were excluded. INTERVENTIONS/METHODS:None. MEASUREMENTS/METHODS:LEV levels were obtained at steady state. The impact of low-dose versus high-dose LEV on the primary outcome of target LEV levels (12-46 μg/mL), and the secondary outcome of clinical and/or electrographic seizure, were assessed using multivariable logistic regression analyses adjusting for age, LEV loading dose, BMI, primary diagnosis and creatinine clearance (CrCl). MAIN RESULTS/RESULTS:Of the 205 subjects included in analyses, n = 106 (52%) received LEV 500 mg bid (median 13 mg/kg/d), and n = 99 (48%) received LEV 750-1,000 mg bid (median 25 mg/kg/d). Overall, 111 of 205 patients (54%) achieved target levels: 48 (45%) from the low-dose group versus 63 (64%) from the high-dose group (odds ratio [OR] 2.1; 95% CI, 1.1-3.7; p = 0.009). In multivariable analyses, high-dose LEV predicted target levels (adjusted OR [aOR] 2.23; 95% CI, 1.16-4.27; p = 0.016), and was associated with lower seizure odds (aOR 0.32; 95% CI, 0.13-0.82; p = 0.018) after adjusting for age, loading dose, BMI, diagnosis, and CrCl. CONCLUSIONS:Underdosing of LEV was common, with only 54% of patients achieving target serum levels. Higher doses (750-1,000 mg bid) were more than twice as likely to lead to optimal drug levels and reduced the odds of seizure by 68% compared with low-dose regimens (500 mg bid).

Substantial efforts are underway towards optimizing the diagnosis, monitoring, and treatment of seizures and epilepsy. We describe preclinical programs in place for screening investigational therapeutic candidates in animal models, with particular attention to identifying and eliminating drugs that might paradoxically aggravate seizure burden. After preclinical development, we discuss challenges and solutions in the design and regulatory logistics of clinical trials execution, and efforts to develop disease biomarkers and interventions that may be not only seizure-suppressing, but also disease-modifying. As disease-modifying treatments are designed, there is clear recognition that, while seizures represent one critical therapeutic target, targeting non-seizure outcomes like cognitive development or functional outcomes requires changes to traditional designs. This reflects our increasing understanding that epilepsy is a disease with profound impact on quality of life for the patient and caregivers due to both seizures themselves as well as other non-seizure factors. This review examines selected key challenges and future directions in epilepsy diagnostics and therapeutics from drug discovery to translational application.

BACKGROUND:We sought to identify patient and provider factors associated with low completion of genetic testing, specifically chromosomal microarray (CMA), for autism spectrum disorder (ASD). METHODS:Medical record review was conducted of children newly diagnosed with ASD without prior genetic testing at a single academic medical center from February 2015 through January 2016. RESULTS:Only 41.9% of individuals with ASD completed CMA testing over at least 18 months from diagnosis (n = 140 of 334). Time to CMA completion varied, with a median of 86.5 days (interquartile range 2 to 214.5 days). Provider recommendation of genetic testing at the diagnostic visit and greater number of follow-up visits were associated with CMA completion. On multivariate regression, CMA completion was inversely associated with age (odds ratio [OR] = 0.8 for each year older, 95% confidence interval [CI] 0.7, 0.9; P = 0.001) and directly associated with intellectual disability or global developmental delay (OR = 2.2, 95% CI 1.3, 3.8; P = 0.004), first-degree relative with ASD (OR = 2.5, 95% CI 1.0, 6.0; P = 0.044), and public insurance (OR = 1.7, 95% CI 1.0, 2.9; P = 0.037). Parental concern and cost/insurance coverage were the most frequently documented barriers. CONCLUSIONS:Workflows to support early genetic testing recommendation and ordering soon after diagnosis may increase utilization, incorporating both family and provider perspectives. Genetic counseling highlighting the utility of genetic testing across the life span, phenotypic variability of genetic disorders, and possibility of de novo variants in ASD may also improve utilization.

BACKGROUND:The relationship between perceived social support and continuous positive airway pressure remains understudied among individuals with obstructive sleep apnea. The aim of this prospective cohort study was to determine if baseline perceived social support and subtypes predict regular continuous positive airway pressure use after 1month of therapy. METHODS:Adults with obstructive sleep apnea initiating continuous positive airway pressure therapy were recruited from sleep clinics in New York City. Demographics, medical history, and comorbidities were obtained from patient interview and review of medical records. Objective continuous positive airway pressure adherence data was collected at the first clinical follow-up. RESULTS:Seventy-five participants (32% female; non-Hispanic Black 41%; mean age of 56 ± 14years) provided data. In adjusted analyses, poorer levels of overall social support, and subtypes including informational/emotional support, and positive social interactions were associated with lower continuous positive airway pressure use at 1month. Relative to patients reporting higher levels of support, participants endorsing lower levels of overall social support, positive social interaction and emotional/informational support had 1.6 hours (95% CI: 0.5,2.7, hours; p = .007), 1.3 hours (95% CI: 0.2,2.4; p = .026), and 1.2 hours (95% CI: 0.05,2.4; p = .041) lower mean daily continuous positive airway pressure use at 1month, respectively. CONCLUSION/CONCLUSIONS:Focusing on social support overall and positive social interaction particularly, could be an effective approach to improve continuous positive airway pressure adherence in patients at risk of suboptimal adherence.

OBJECTIVE:To examine the usefulness of carotid web (CW), carotid bifurcation and their combined angioarchitectural measurements in assessing stroke risk. METHODS:Anatomic data on the internal carotid artery (ICA), common carotid artery (CCA), and the CW were gathered as part of a retrospective study from symptomatic (stroke) and asymptomatic (nonstroke) patients with CW. We built a model of stroke risk using principal-component analysis, Firth regression trained with 5-fold cross-validation, and heuristic binary cutoffs based on the Minimal Description Length principle. RESULTS:The study included 22 patients, with a mean age of 55.9 ± 12.8 years; 72.9% were female. Eleven patients experienced an ischemic stroke. The first 2 principal components distinguished between patients with stroke and patients without stroke. The model showed that ICA-pouch tip angle (P = 0.036), CCA-pouch tip angle (P = 0.036), ICA web-pouch angle (P = 0.036), and CCA web-pouch angle (P = 0.036) are the most important features associated with stroke risk. Conversely, CCA and ICA anatomy (diameter and angle) were not found to be risk factors. CONCLUSIONS:This pilot study shows that using data from computed tomography angiography, carotid bifurcation, and CW angioarchitecture may be used to assess stroke risk, allowing physicians to tailor care for each patient according to risk stratification.

UNLABELLED:The superior hypophyseal arteries (SHAs) are well known in anatomical and surgical literature, with a well-established role in supply of the anterior hypophysis and superjacent optic apparatus. However, due to small size and overlap with other vessels, in vivo imaging by any modality has been essentially non-existent. Advances in high resolution cone beam CT angiography (CBCTA) now enables this deficiency to be addressed. This paper presents, to the best of our knowledge, the first comprehensive in vivo imaging evaluation of the SHAs. METHODS:Twenty-five CBCTA studies of common or internal carotid arteries were obtained for a variety of clinical reasons. Dedicated secondary reconstructions of the siphon were performed, recording the presence, number, and supply territory of SHAs. A spectrum approach, emphasizing balance with adjacent territories (inferior hypophyseal, ophthalmic, posterior and communicating region arteries) was investigated. RESULTS:The SHAs were present in all cases. Supply of the anterior pituitary was nearly universal (96%) and almost half (44%) originated from the 'cave' region, in excellent agreement with surgical literature. Optic apparatus supply was more difficult to adjudicate, but appeared present in most cases. The relationship with superior hypophyseal aneurysms was consistent. Patency following flow diverter placement was typical, despite a presumably rich collateral network. Embryologic implications with respect to the ophthalmic artery and infraoptic course of the anterior cerebral artery are intriguing. CONCLUSIONS:SHAs are consistently seen with CBCTA, allowing for correlation with existing anatomical and surgical literature, laying the groundwork for future in vivo investigation.

PURPOSE OF REVIEW/OBJECTIVE:We evaluate evidence-based treatments for posttraumatic headache (PTH), a secondary headache disorder resulting from traumatic brain injury (TBI), comprising nearly 4% of all symptomatic headache disorders. Utilizing recent publications, we aim to inform clinicians of current treatment methods. RECENT FINDINGS/RESULTS:There is limited research on PTH treatment. A randomized controlled trial (RCT) of metoclopramide with diphenhydramine for acute PTH found that the treatment group (N = 81) experienced more significant pain improvement than placebo by 1.4 points. For persistent PTH, an open-label study of erenumab (N = 89) found that 28% of participants reported ≥ 50% reduction in moderate-to-severe headache days, but an RCT of fremanezumab showed a non-significant reduction in moderate-to-severe headache days. A randomized crossover study of 40 patients with persistent PTH found that onabotulinum toxin-A decreased cumulative number of headaches/week by 43.3% in the treatment group and increased by 35.1% among placebos. In a study of military veterans with severe posttraumatic stress disorder and persistent/delayed onset PTH (N = 193), patients who received Cognitive Behavioral Therapy reported significant improvements in headache-related disability compared to usual care (aggregate mean HIT-6, -3.4). A transcranial magnetic stimulation (N = 24) study found that 58% of participants with mild TBI-related headache experienced a 50% reduction in headache frequency. New studies indicate promise in improving clinically important outcomes of PTH. However, more research is necessary to determine the optimal treatment and whether combining pharmacologic and nonpharmacologic treatment versus a single modality is more effective.