Faculty Bibliography

BACKGROUND/UNASSIGNED:In this short review/perspective, we asked what the frequencies would be for both postoperative spinal epidural hematomas (SpEH) and postoperative surgical site infections (SSI) in predominantly posterior lumbar procedures performed with or without the placement of wound drains? METHODS/UNASSIGNED:Many spine surgeons are trained to use wound drains to decrease the risk of postoperative SpEH, despite the potential increased risk of SSI. Alternatively, avoiding drains may increase the risk of SpEH but likely decrease the potential for SSI. RESULTS/UNASSIGNED:Performing predominantly posterior lumbar procedures with or without wound drains resulted in largely comparable frequencies of postoperative spinal epidural hematomas (SpEH; range of 0.10%-0.69%) and postoperative surgical site infections (SSI: range of 0.75%-7.3%). Notably, however, two studies documented that drains increased transfusion requirements, with one study showing a prolongation of the in-hospital length of stay. Critically, these series emphasized the importance of early/emergent diagnosis (i.e., with MR) and surgical treatment of SpEH to minimize residual neurological deficits. CONCLUSION/UNASSIGNED:Here, we showed that patients undergoing predominantly lumbar spine surgery performed with or without wound drains demonstrated comparable frequencies of postoperative SpEH and SSI. Nevertheless, spine surgeons must assess on a case-by-case basis whether, based on their education, training, and experience, placing a wound drain is appropriate for their particular patient.

Primary brain tumors are the most common solid tumor and cause of cancer-related deaths in children. Their clinical presentation depends on the age of the child and the location of tumor. Tumors in infancy often present with nonspecific symptoms, while focal neurological symptoms are more evident in older children. In this article, we review the most common acute neurological effects of pediatric primary brain tumors and their treatments.

BACKGROUND AND OBJECTIVES/UNASSIGNED:"Brain-writing" is a technique in which group members write down ideas individually, before a group discussion, to improve idea generation and individual engagement in group discussions. We assessed the feasibility of studying the impact of brain-writing on diagnostic quality and educational experience among neurology residents in a small case-based learning environment. METHODS/UNASSIGNED:We conducted a repeated-measures study, conducted over 6 sessions consisting of groups of 3 to 5 neurology residents from different years of training. During each session, 3 cases were treated as control, "brainstorming," cases, and 3 were intervention, "brain-writing," cases, in which the group wrote down possible diagnoses and tests before engaging in a group discussion. Tests and diagnoses from the brain-writing exercise and group discussion as well as a post case survey on participant experience were recorded through a Qualtrics survey, and video recordings were reviewed to determine speaking order and number of tests and diagnoses verbalized by each member. Feasibility was determined by recruitment and ability to complete the study procedures in a pragmatic fashion that incorporated resident education. The primary outcome was accuracy of diagnoses, and secondary outcomes included number of tests and diagnoses generated, percent of "can't miss diagnoses mentioned," speaking order and psychological reactions of group members. RESULTS/UNASSIGNED:= 0.07). Junior residents spoke later and verbalized significantly fewer diagnoses and tests than senior residents in both brainstorming and brain-writing groups. There was no statistically significant difference in psychological outcomes of junior and senior residents in each group. DISCUSSION/UNASSIGNED:It is feasible to examine the impact of a behavioral-based intervention among medical trainees in a small case-based learning environment. This study, limited by a small sample size, did not find that brain-writing improved decision quality.

Subjective cognitive decline (SCD) is associated with preclinical Alzheimer's disease (AD). Suboptimal sleep is also a risk factor for cognitive decline, but with unclear relationship to SCD. We conducted a retrospective cross-sectional study in a biracial research cohort of 148 cognitively normal older adults who underwent quantification of SCD (Cognitive Change Index; CCI), sleepiness (Epworth Sleepiness Scale; ESS), depression (Geriatric Depression Scale; GDS), and amyloid/tau PET. ESS score was associated with total, amnestic, and non-amnestic CCI scores, after adjustment for GDS, amyloid/tau burden, and race. This supports future longitudinal work on how sleepiness impacts SCD outcomes.

Spetzler-Martin Grade IV arteriovenous malformations (AVMs) are challenging due to high risks associated with both treatment and natural progression. This study compares the outcomes of microsurgical resection and stereotactic radiosurgery (SRS) in high-grade AVMs, analyzing obliteration rates, complications, and functional outcomes. A retrospective cohort of 96 patients treated with either microsurgical resection (33 patients) or SRS (63 patients) was analyzed. Propensity-score matching was employed to account for baseline variables such as AVM size (cm), preoperative embolization and rupture status. Primary endpoints included AVM obliteration, complication rates, and modified Rankin Scale (mRS) scores. After matching, 31 patients per group were analyzed. Microsurgical resection achieved significantly higher obliteration rates (87.1%) compared to SRS (32.3%, p < 0.001). In the matched SRS cohort (n = 31), the actuarial obliteration rates were 11% (95% CI: 0-22%) at 1 year, 17% (95% CI: 0-31%) at 3 years, and 43% (95% CI: 13-63%) at 5 years post-treatment. Complication rates were similar (32.3% resection, 38.7% SRS, p = 0.6). Functional outcomes in terms of improvement in modified Rankin Scale (mRS) scores were observed in 50.0% of microsurgery patients and 41.4% of SRS patients. However, the absolute number of patients improving was similar (13 vs. 12), and the microsurgery group had more cases of worsening mRS scores compared to the SRS group (4 vs. 2). The difference was not statistically significant (p = 0.4). Microsurgical resection offers superior obliteration rates for high-grade AVMs with comparable complication risks to SRS. SRS remains a valuable alternative for select patients, particularly those ineligible for resection. Future research should focus on optimizing multimodal treatment approaches. Clinical trial number Not applicable.

The value of preclinical diffusion MRI (dMRI) is substantial. While dMRI enables in vivo non-invasive characterization of tissue, ex vivo dMRI is increasingly being used to probe tissue microstructure and brain connectivity. Ex vivo dMRI has several experimental advantages including higher SNR and spatial resolution compared to in vivo studies, and enabling more advanced diffusion contrasts for improved microstructure and connectivity characterization. Another major advantage of ex vivo dMRI is the direct comparison with histological data, as a crucial methodological validation. However, there are a number of considerations that must be made when performing ex vivo experiments. The steps from tissue preparation, image acquisition and processing, and interpretation of results are complex, with many decisions that not only differ dramatically from in vivo imaging of small animals, but ultimately affect what questions can be answered using the data. This work represents "Part 2" of a three-part series of recommendations and considerations for preclinical dMRI. We describe best practices for dMRI of ex vivo tissue, with a focus on the value that ex vivo imaging adds to the field of dMRI and considerations in ex vivo image acquisition. We first give general considerations and foundational knowledge that must be considered when designing experiments. We briefly describe differences in specimens and models and discuss why some may be more or less appropriate for different studies. We then give guidelines for ex vivo protocols, including tissue fixation, sample preparation, and MR scanning. In each section, we attempt to provide guidelines and recommendations, but also highlight areas for which no guidelines exist (and why), and where future work should lie. An overarching goal herein is to enhance the rigor and reproducibility of ex vivo dMRI acquisitions and analyses, and thereby advance biomedical knowledge.

INTRODUCTION/UNASSIGNED:Seizures are common in autoimmune encephalitis (AE), but identifying patients at risk of chronic epilepsy in the post-acute phase remains challenging. This study aims to identify risk factors of treatment-resistant postencephalitic epilepsy. METHODS/UNASSIGNED:This retrospective cohort study included patients with AE who experienced new-onset seizures within one year of symptom onset from two tertiary care centers in New York. EEG findings were analyzed separately based on whether the EEG recording was obtained in the acute (<3 months from symptom onset) or subacute phase. A multivariate logistic regression model was used to identify independent predictors of postencephalitic epilepsy. RESULTS/UNASSIGNED:Eighty-nine patients were included (median age: 33 years). Neural antibodies were present in 73% of patients (NMDAR: 35, LGI1: 19, GAD65: 9, Hu: 1, AGNA-1: 1). Over a median follow-up of 4.9 years, 29.2% developed treatment-resistant postencephalitic epilepsy. Independent predictors of postencephalitic epilepsy included focal slowing on acute EEG (OR 0.15, CI 0.02-0.90), interictal epileptiform discharges (IEDs) or periodic discharges (PDs) on subacute EEG (OR 20.01, CI 1.94-206.44), and cell surface antibodies (OR 0.21, CI 0.05-0.89). Immunotherapy within three months of onset was associated with decreased epilepsy development in patients with neural antibodies (OR 4.16, CI 1.11-16.30). CONCLUSIONS/UNASSIGNED:Nearly one-third of patients with AE and acute seizures developed treatment-resistant postencephalitic epilepsy, with significant predictors including absence of focal slowing on acute EEG, presence of IEDs and PDs on subacute EEG, absence of cell surface antibodies, and absence of early immunotherapy treatment of patients with positive neural antibodies.

This study investigated the potential of combining multiple MR parameters to enhance the characterization of myelin in the mouse brain. We collected ex vivo multiparametric MR data at 7 T from control and Gli1^-/- mice; the latter exhibit enhanced myelination at Postnatal Day 10 (P10) in the corpus callosum and cortex. The MR data included relaxivity, magnetization transfer, and diffusion measurements, each targeting distinct myelin properties. This analysis was followed by and compared to myelin basic protein (MBP) staining of the same samples. Although a majority of the MR parameters included in this study showed significant differences in the corpus callosum between the control and Gli1^-/- mice, only T₂, T₁/T₂, and radial diffusivity (RD) demonstrated a significant correlation with MBP values. Based on data from the corpus callosum, partial least square regression suggested that combining T₂, T₁/T₂, and inhomogeneous magnetization transfer ratio could explain approximately 80% of the variance in the MBP values. Myelin predictions based on these three parameters yielded stronger correlations with the MBP values in the P10 mouse brain corpus callosum than any single MR parameter. In the motor cortex, combining T₂, T₁/T₂, and radial kurtosis could explain over 90% of the variance in the MBP values at P10. This study demonstrates the utility of multiparametric MRI in improving the detection of myelin changes in the mouse brain.

Space occupying cerebral edema is a feared complication after large ischemic stroke, occurring in up to 30% of patients with middle cerebral artery (MCA) occlusion and peaking 2-4 days after injury. Little is known about the factors and outcomes associated with peak edema timing, especially after 96 h. We aimed to characterize differences and compare discharge status between patients who experienced maximum midline shift (MLS) or decompressive hemicraniectomy (DHC) in the acute (< 48 h), average (48-96 h), and subacute (> 96 h) groups. We performed a two-center, retrospective study of patients with ≥ 1/2 MCA territory infarct and MLS. We constructed a multivariable model to test the association of subacute peak edema and favorable discharge status, adjusting for various confounders. Of 321 eligible patients, 32%, 36%, and 32% experienced acute, average, and subacute peak edema. Subacute peak edema was significantly associated with higher odds of favorable discharge than acute peak edema (aOR, 2.05; 95% CI, 1.03-4.11). Subacute peak edema after large MCA stroke is associated with better discharge status compared to acute peak edema courses. Understanding how the timing of cerebral edema affects risk of unfavorable discharge has important implications for treatment decisions and prognostication.

Collagen VI-related dystrophies (COL6-RDs) manifest with a spectrum of clinical phenotypes, ranging from Ullrich congenital muscular dystrophy (UCMD), presenting with prominent congenital symptoms and characterised by progressive muscle weakness, joint contractures and respiratory insufficiency, to Bethlem muscular dystrophy, with milder symptoms typically recognised later and at times resembling a limb girdle muscular dystrophy, and intermediate phenotypes falling between UCMD and Bethlem muscular dystrophy. Despite clinical and muscle pathology features highly suggestive of COL6-RD, some patients had remained without an identified causative variant in COL6A1, COL6A2 or COL6A3. With combined muscle RNA-sequencing and whole-genome sequencing we uncovered a recurrent, de novo deep intronic variant in intron 11 of COL6A1 (c.930+189C>T) that leads to a dominantly acting in-frame pseudoexon insertion. We subsequently identified and have characterised an international cohort of forty-four patients with this COL6A1 intron 11 causative variant, one of the most common recurrent causative variants in the collagen 6 genes. Patients manifest a consistently severe phenotype characterised by a paucity of early symptoms followed by an accelerated progression to a severe form of UCMD, except for one patient with somatic mosaicism for this COL6A1 intron 11 variant who manifests a milder phenotype consistent with Bethlem muscular dystrophy. Partial amelioration of the disease phenotype in this individual provides a strong rationale for the development of our pseudoexon skipping therapy to successfully suppress the pseudoexon insertion, resulting in normal COL6A1 transcripts. We have previously shown that splice-modulating antisense oligomers applied in vitro effectively decreased the abundance of the mutant pseudoexon-containing COL6A1 transcripts to levels comparable to the in vivo scenario of the somatic mosaicism shown here, indicating that this therapeutic approach carries significant translational promise for ameliorating the severe form of UCMD caused by this common recurrent COL6A1 variant.