Faculty Bibliography

STUDY DESIGN/METHODS:Clinical practice guideline development. OBJECTIVES/OBJECTIVE:Acute spinal cord injury (SCI) can result in devastating motor, sensory, and autonomic impairment; loss of independence; and reduced quality of life. Preclinical evidence suggests that early decompression of the spinal cord may help to limit secondary injury, reduce damage to the neural tissue, and improve functional outcomes. Emerging evidence indicates that "early" surgical decompression completed within 24 hours of injury also improves neurological recovery in patients with acute SCI. The objective of this clinical practice guideline (CPG) is to update the 2017 recommendations on the timing of surgical decompression and to evaluate the evidence with respect to ultra-early surgery (in particular, but not limited to, <12 hours after acute SCI). METHODS:A multidisciplinary, international, guideline development group (GDG) was formed that consisted of spine surgeons, neurologists, critical care specialists, emergency medicine doctors, physical medicine and rehabilitation professionals, as well as individuals living with SCI. A systematic review was conducted based on accepted methodological standards to evaluate the impact of early (within 24 hours of acute SCI) or ultra-early (in particular, but not limited to, within 12 hours of acute SCI) surgery on neurological recovery, functional outcomes, administrative outcomes, safety, and cost-effectiveness. The GRADE approach was used to rate the overall strength of evidence across studies for each primary outcome. Using the "evidence-to-recommendation" framework, recommendations were then developed that considered the balance of benefits and harms, financial impact, patient values, acceptability, and feasibility. The guideline was internally appraised using the Appraisal of Guidelines for Research and Evaluation (AGREE) II tool. RESULTS:The GDG recommended that early surgery (≤24 hours after injury) be offered as the preferred option for adult patients with acute SCI regardless of level. This recommendation was based on moderate evidence suggesting that patients were 2 times more likely to recover by ≥ 2 ASIA Impairment Score (AIS) grades at 6 months (RR: 2.76, 95% CI 1.60 to 4.98) and 12 months (RR: 1.95, 95% CI 1.26 to 3.18) if they were decompressed within 24 hours compared to after 24 hours. Furthermore, patients undergoing early surgery improved by an additional 4.50 (95% 1.70 to 7.29) points on the ASIA Motor Score compared to patients undergoing surgery after 24 hours post-injury. The GDG also agreed that a recommendation for ultra-early surgery could not be made on the basis of the current evidence because of the small sample sizes, variable definitions of what constituted ultra-early in the literature, and the inconsistency of the evidence. CONCLUSIONS:It is recommended that patients with an acute SCI, regardless of level, undergo surgery within 24 hours after injury when medically feasible. Future research is required to determine the differential effectiveness of early surgery in different subpopulations and the impact of ultra-early surgery on neurological recovery. Moreover, further work is required to define what constitutes effective spinal cord decompression and to individualize care. It is also recognized that a concerted international effort will be required to translate these recommendations into policy.

PURPOSE OF REVIEW/OBJECTIVE:This review provides medical practitioners with an overview of the present and emergent roles of telehealth and associated virtual reality (VR) applications in chronic pain (CP) management, particularly in the post-COVID-19 healthcare landscape. RECENT FINDINGS/RESULTS:Accumulated evidence points to the efficacy of now well-established telehealth modalities, such as videoconferencing, short messaging service (SMS), and mobile health (mHealth) applications in complementing remote CP care. More recently, and although still in early phases of clinical implementation, a wide range of VR-based interventions have demonstrated potential for improving the asynchronous remote management of CP. Additionally, VR-associated technologies at the leading edge of science and engineering, such as VR-assisted biofeedback, haptic technology, high-definition three-dimensional (HD3D) conferencing, VR-enabled interactions in a Metaverse, and the use of wearable monitoring devices, herald a new era for remote, synchronous patient-physician interactions. These advancements hold the potential to facilitate remote physical examinations, personalized remote care, and innovative interventions such as ultra-realistic biofeedback. Despite the promise of VR-associated technologies, several limitations remain, including the paucity of robust long-term effectiveness data, heterogeneity of reported pain-related outcomes, challenges with scalability and insurance coverage, and demographic-specific barriers to patient acceptability. Future research efforts should be directed toward mitigating these limitations to facilitate the integration of telehealth-associated VR into the conventional management of CP. Despite ongoing barriers to widespread adoption, recent evidence suggests that VR-based interventions hold an increasing potential to complement and enhance the remote delivery of CP care.

INTRODUCTION/BACKGROUND:Tau is a key pathology in chronic traumatic encephalopathy (CTE). Here, we report our findings in tau positron emission tomography (PET) measurements from the DIAGNOSE CTE Research Project. METHOD/METHODS:We compare flortaucipir PET measures from 104 former professional players (PRO), 58 former college football players (COL), and 56 same-age men without exposure to repetitive head impacts (RHI) or traumatic brain injury (unexposed [UE]); characterize their associations with RHI exposure; and compare players who did or did not meet diagnostic criteria for traumatic encephalopathy syndrome (TES). RESULTS:Significantly elevated flortaucipir uptake was observed in former football players (PRO+COL) in prespecified regions (p < 0.05). Association between regional flortaucipir uptake and estimated cumulative head impact exposure was only observed in the superior frontal region in former players over 60 years old. Flortaucipir PET was not able to differentiate TES groups. DISCUSSION/CONCLUSIONS:Additional studies are needed to further understand tau pathology in CTE and other individuals with a history of RHI.

The venom of cone snails has been proven to be a rich source of bioactive peptides that target a variety of ion channels and receptors. α-Conotoxins (αCtx) interact with nicotinic acetylcholine receptors (nAChRs) and are powerful tools for investigating the structure and function of the various nAChR subtypes. By studying how conotoxins interact with nAChRs, we can improve our understanding of these receptors, leading to new insights into neurological diseases associated with nAChRs. Here, we describe the discovery and characterization of a novel conotoxin from Conus ateralbus, αCtx-AtIA, which has an amino acid sequence homologous to the well-described αCtx-PeIA, but with a different selectivity profile towards nAChRs. We tested the synthetic αCtx-AtIA using the calcium imaging-based Constellation Pharmacology assay on mouse DRG neurons and found that αCtx-AtIA significantly inhibited ACh-induced calcium influx in the presence of an α7 positive allosteric modulator, PNU-120596 (PNU). However, αCtx-AtIA did not display any activity in the absence of PNU. These findings were further validated using two-electrode voltage clamp electrophysiology performed on oocytes overexpressing mouse α3β4, α6/α3β4 and α7 nAChRs subtypes. We observed that αCtx-AtIA displayed no or low potency in blocking α3β4 and α6/α3β4 receptors, respectively, but improved potency and selectivity to block α7 nAChRs when compared with αCtx-PeIA. Through the synthesis of two additional analogs of αCtx-AtIA and subsequent characterization using Constellation Pharmacology, we were able to identify residue Trp18 as a major contributor to the activity of the peptide.

BACKGROUND AND OBJECTIVES/OBJECTIVE:The choice of anesthesia type (general anesthesia [GA] vs nongeneral anesthesia [non-GA]) in middle meningeal artery embolization (MMAE) procedures for chronic subdural hematomas (cSDH) differs between institutions and left to care team discretion given lack of standard guidelines. We compare the outcomes of GA vs non-GA in MMAE. METHODS:Consecutive patients receiving MMAE for cSDH at 14 North American centers (2018-2023) were included. Clinical, cSDH characteristics, and technical/clinical outcomes were compared between the GA/non-GA groups. Using propensity score matching (PSM), patients were matched controlling for age, baseline modified Rankin Scale, concurrent/prior surgery, hematoma thickness/midline shift, and baseline antiplatelet/anticoagulation. The primary end points included surgical rescue and radiographic success rates (≥50% reduction in maximum hematoma thickness with minimum 2 weeks of imaging). Secondary end points included technical feasibility, procedural complications, and functional outcomes. RESULTS:Seven hundred seventy-eight patients (median age 73 years, 73.2% male patients) underwent 956 MMAE procedures, 667 (70.4%) were non-GA and 280 were GA (29.6%). After running 1:3 PSM algorithm, this resulted in 153 and 296 in the GA and non-GA groups, respectively. There were no baseline/procedural differences between the groups except radial access more significantly used in the non-GA group (P = .001). There was no difference between the groups in procedural technical feasibility, complications rate, length of stay, surgical rescue rates, or favorable functional outcome at the last follow-up. Subsequent 1:1 sensitivity PSM retained the same results. Bilateral MMAE procedures were more performed under non-GA group (75.8% vs 67.2%; P = .01); no differences were noted in clinical/radiographic outcomes between bilateral vs unilateral MMAE, except for longer procedure duration in the bilateral group (median 73 minutes [IQR 48.3-100] vs 54 minutes [39-75]; P < .0001). Another PSM analysis comparing GA vs non-GA in patients undergoing stand-alone MMAE retained similar associations. CONCLUSION/CONCLUSIONS:We found no significant differences in radiological improvement/clinical outcomes between GA and non-GA for MMAE.

OBJECTIVE:The aim of this study was to evaluate the diagnostic accuracy of common interview questions used to distinguish a diagnosis of epilepsy from seizure mimics including non-epileptic seizures (NES), migraine, and syncope. METHODS:200 outpatients were recruited with an established diagnosis of focal epilepsy (n = 50), NES (n = 50), migraine (n = 50), and syncope (n = 50). Patients completed an eight-item, yes-or-no online questionnaire about symptoms related to their events. Sensitivity and specificity were calculated. Using a weighted scoring for the questions alone with baseline characteristics, the overall questionnaire was tested for diagnostic accuracy. RESULTS:Of individual questions, the most sensitive one asked if events are sudden in onset (98 % sensitive for epilepsy (95 % CI: 89 %, 100 %)). The least sensitive question asked if events are stereotyped (46 % sensitive for epilepsy (95 % CI: 32 %, 60 %)). Overall, three of the eight questions showed an association with epilepsy as opposed to mimics. These included questions about "sudden onset" (OR 10.76, 95 % CI: (1.66, 449.21) p = 0.0047), "duration < 5 min" (OR 3.34, 95 % CI: (1.62, 6.89), p = 0.0008), and "duration not > 30 min" (OR 4.44, 95 % CI: (1.94, 11.05), p = <0.0001). When individual seizure mimics were compared to epilepsy, differences in responses were most notable between the epilepsy and migraine patients. Syncope and NES were most similar in responses to epilepsy. The overall weighted questionnaire incorporating patient age and sex produced an area under the ROC curve of 0.80 (95 % CI: 0.74, 0.87)). CONCLUSION/CONCLUSIONS:In this study, we examined the ability of common interview questions used by physicians to distinguish between epilepsy and prevalent epilepsy mimics, specifically NES, migraines, and syncope. Using a weighted scoring system for questions, and including age and sex, produced a sensitive and specific predictive model for the diagnosis of epilepsy. In contrast to many prior studies which evaluated either a large number of questions or used methods with difficult practical application, our study is unique in that we tested a small number of easy-to-understand "yes" or "no" questions that can be implemented in most clinical settings by non-specialists.

BACKGROUND:Middle meningeal artery (MMA) embolization is a promising intervention as a stand-alone or adjunct treatment to surgery in patients with chronic subdural hematomas. There are currently no large animal models for selective access and embolization of the MMA for preclinical evaluation of this endovascular modality. Our objective was to introduce a novel in vivo model of selective MMA embolization in swine. METHODS:Diagnostic cerebral angiography with selective microcatheter catheterization into the MMA was performed under general anesthesia in five swine. Anatomical variants in arterial meningeal supply were examined. In two animals, subsequent embolization of the MMA with a liquid embolic agent (Onyx-18) was performed, followed by brain tissue harvest and histological analysis. RESULTS:The MMA was consistently localized as a branch of the internal maxillary artery just distal to the origin of the ascending pharyngeal artery. Additional meningeal supply was observed from the external ophthalmic artery, although not present consistently. MMA embolization with Onyx was technically successful and feasible. Histological analysis showed Onyx material within the MMA lumen. CONCLUSIONS:Microcatheter access into the MMA in swine with liquid embolic agent delivery represents a reproducible model of MMA embolization. Anatomical variations in the distribution of arterial supply to the meninges exist. This model has a potential application for comparing therapeutic effects of various embolic agents in a preclinical setting that closely resembles the MMA embolization procedure in humans.

BACKGROUND:Elevated cardiac troponin (cTn) is detected in 10% to 30% of patients with acute ischemic stroke (AIS) and correlates with poor functional outcomes. Serial cTn measurements differentiate a dynamic cTn pattern (rise/fall >20%), specific for acute myocardial injury, from elevated but stable cTn levels (nondynamic), typically attributed to chronic cardiac/noncardiac conditions. We investigated if the direction of the cTn change (rising versus falling) affects mortality and outcome. METHODS AND RESULTS/RESULTS:<0.01). Twenty-two percent of patients with a rising pattern had an isolated dynamic cTn in the absence of any ECG or echocardiogram changes, compared with 53% with falling cTn. A rising pattern was associated with higher risk of 7-day mortality (adjusted odds ratio [OR]=32 [95% CI, 2.5-415.0] rising versus aOR=1.3 [95% CI, 0.1-38.0] falling versus nondynamic as reference) and unfavorable discharge disposition (aOR=2.5 [95% CI, 1.2-5.2] rising versus aOR=0.6 [95% CI, 0.2-1.5] versus falling). CONCLUSIONS:Rising cTn is independently associated with increased mortality and unfavorable discharge disposition in patients with AIS.

BACKGROUND:There are no effective medical therapies for patients with meningioma who progress beyond surgical and radiotherapeutic interventions. Somatostatin receptor Type 2 (SSTR2) represents a promising treatment target in meningiomas. In this multicenter, single-arm phase II clinical study (NCT03971461), the SSTR2-targeting radiopharmaceutical 177Lu-DOTATATE is evaluated for its feasibility, safety, and therapeutic efficacy in these patients. PATIENTS AND METHODS/METHODS:Adult patients with progressive intracranial meningiomas received 177Lu-DOTATATE at a dose of 7.4 GBq (200 mCi) every eight weeks for four cycles. 68Ga-DOTATATE PET-MRI was performed before and six months after begin of treatment. The primary endpoint was progression-free survival (PFS) at 6 months (PFS-6). Secondary endpoints were safety and tolerability, overall survival (OS) at 12 months (OS-12), median PFS, and median OS. RESULTS:Fourteen patients (F=11, M=3) with progressive meningiomas (WHO 1=3, 2=10, 3=1) were enrolled. Median age was 63.1 (range 49.7-78) years. All patients previously underwent tumor resection and at least one course of radiation. Treatment with 177Lu-DOTATATE was well tolerated. Seven patients (50%) achieved PFS-6. Best radiographic response by modified Macdonald criteria was stable disease (SD) in all seven patients. A >25% reduction in 68Ga-DOTATATE (PET) was observed in five meningiomas and two patients. In one lesion, this corresponded to >50% reduction in bidirectional tumor measurements (MRI). CONCLUSIONS:Treatment with 177Lu-DOTATATE was well tolerated. The predefined PFS-6 threshold was met in this interim analysis, thereby allowing this multicenter clinical trial to continue enrollment. 68Ga-DOTATATE PET may be a useful imaging biomarker to assess therapeutic outcome in patients with meningioma.