Faculty Bibliography

BACKGROUND:The Uniform Law Commission paused work of the Drafting Committee to Revise the Uniform Determination of Death Act (UDDA) in September 2023. METHODS:Thematic review was performed of comments submitted to the Uniform Law Commission by medical organizations (MO), organ procurement organizations (OPO), and advocacy organizations (AO) from 1/1/2023 to 7/31/2023. RESULTS:Of comments from 41 organizations (22 AO, 15 MO, 4 OPO), 34 (83%) supported UDDA revision (50% OPO, 33% MO recommended against revision). The most comments addressed modifications to "all functions of the entire brain, including the brainstem" (31; 95% AO, 75% OPO, 47% MO), followed by irreversible versus permanent (25; 77% AO, 50% OPO, 40% MO), accommodation of brain death/death by neurologic criteria (BD/DNC) objections (23; 100% OPO, 80% MO, 32% AO), consent for BD/DNC evaluation (18; 75% OPO, 47% MO, 36% AO), "accepted medical standards" (13; 36% AO, 33% MO, 0% OPO), notification before BD/DNC evaluation (14; 100% OPO, 53% MO, 9% AO), time to gather before discontinuation of organ support after BD/DNC determination (12; 60% MO, 25% OPO, 9% AO), and BD/DNC examiner credential requirements (2; 13% MO, 0% AO, 0% OPO). The predominant themes were that the revised UDDA should include the term "irreversible" and shouldn't (1) stipulate specific medical guidelines, (2) require notification before BD/DNC evaluation, or (3) require time to gather before discontinuation of organ support after BD/DNC determination. Views on other topics were mixed, but MO and OPO generally advocated for the revised UDDA to take a functional approach to BD/DNC, not require consent for BD/DNC evaluation, and not require opt-out accommodation of BD/DNC objections. Contrastingly, many AO and some MO with religious affiliations or a focus on advocacy favored the revised UDDA take an anatomic approach to BD/DNC or eliminate BD/DNC altogether, require consent for BD/DNC evaluation, and require opt-out accommodation of BD/DNC objections. CONCLUSIONS:Most commenting organizations support UDDA revision, but perspectives on the approach vary, so the Drafting Committee could not formulate revisions that would be agreeable to all stakeholders.

OBJECTIVE:To report a novel anatomical pattern of autoimmune encephalitis characterized by strictly unilateral cortical inflammation and a clinical picture overlapping with late-onset Rasmussen's encephalitis. METHODS:We retrospectively gathered data of patients identified at two tertiary referral academic centers who met inclusion criteria. RESULTS:We identified twelve cases (average age 65, +/- 19.8 years, 58% female). All patients had unilateral cortical inflammation manifesting with focal seizures, cognitive decline, hemicortical deficits, and unilateral MRI and/or EEG changes. Six cases were idiopathic, two paraneoplastic, two iatrogenic (in the setting of immune checkpoint inhibitors), and two post-COVID-19. Serologically, ten patients were seronegative, one had high titer anti-GAD65, and one had anti-NMDAR. Five patients met Rasmussen's encephalitis criteria, and six did not fully meet the criteria but had symptoms significantly overlapping with the condition. Most patients had significant improvement with immunotherapy. DISCUSSION/CONCLUSIONS:Unilateral cortical AE seems to be more prevalent in the elderly and more frequently idiopathic and seronegative. Patients with this anatomical variant of autoimmune encephalitis have overlapping features with late-onset Rasmussen's encephalitis but are more responsive to immunotherapy. In cases refractory to immunotherapy, interventions used in refractory Rasmussen's encephalitis may be considered, such as functional hemispherectomy.

PURPOSE OF REVIEW/OBJECTIVE:Multiple system atrophy (MSA) is a rapidly progressive synucleinopathy characterized by autonomic failure, parkinsonism, and cerebellar ataxia. Here, we provide an update on α-synuclein's role in MSA pathophysiology and review the new Movement Disorders Society (MDS) diagnostic criteria and the utility of α-synuclein-based biomarkers. We also highlight ongoing efforts toward clinical trial readiness and review potential disease-modifying therapies undergoing clinical trials. RECENT FINDINGS/RESULTS:A role of urinary tract infections in triggering α-synuclein aggregation and contribution of genes implicated in oligodendroglial development have been suggested in the MSA pathophysiology. The clinically probable MSA category of the new diagnostic criteria shows improved accuracy in early disease stages. Predictors of phenoconversion from pure autonomic failure to MSA are now better defined. Alpha-synuclein strains in CSF and serum, phosphorylated α-synuclein deposits in the skin, and brain α-synuclein pathology visualized using PET ligand [18F]ACI-12589 are emerging as valuable diagnostic tools. Clinical trials in MSA investigate drugs targeting α-synuclein aggregation or preventing α-synuclein expression, along with stem cell and gene therapies to halt disease progression. SUMMARY/CONCLUSIONS:New MSA diagnostic criteria and α-synuclein-based biomarkers may enhance diagnostic accuracy while promising therapies are in development to address disease progression.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Individuals with epilepsy have increased risk of suicidal ideation (SI) and behaviors when compared with the general population. This relationship has remained largely unexplored in adolescents. We investigated the prevalence of suicidality in adolescents with newly diagnosed focal epilepsy within 4 months of treatment initiation and over the following 36 months. METHODS:This was a post hoc analysis of the enrollment and follow-up data from the Human Epilepsy Project, an international, multi-institutional study that enrolled participants between 2012 and 2017. Participants enrolled were 11-17 years of age within 4 months of treatment initiation for focal epilepsy. We used data from the Columbia Suicide Severity Rating Scale (C-SSRS), administered at enrollment and over the 36-month follow-up period, along with data from medical records. RESULTS:A total of 66 adolescent participants were enrolled and completed the C-SSRS. At enrollment, 14 (21%) had any lifetime SI and 5 (8%) had any lifetime suicidal behaviors (SBs). Over the following 36 months, 6 adolescents reported new onset SI and 5 adolescents reported new onset SB. Thus, the lifetime prevalence of SI within this population increased from 21% to 30% (14-20 adolescents), and the lifetime prevalence of SB increased from 8% to 15% (5-10). DISCUSSION/CONCLUSIONS:The prevalence of suicidality in adolescents with newly diagnosed focal epilepsy reported in our study is consistent with previous findings of significant suicidality observed in epilepsy. We identify adolescents as an at-risk population at the time of epilepsy diagnosis and in the following years.

BACKGROUND:Mild traumatic brain injury is theorized to cause widespread functional changes to the brain. Resting-state fMRI may be able to measure functional connectivity changes after traumatic brain injury, but resting-state fMRI studies are heterogeneous, using numerous techniques to study ROIs across various resting-state networks. PURPOSE/OBJECTIVE:We systematically reviewed the literature to ascertain whether adult patients who have experienced mild traumatic brain injury show consistent functional connectivity changes on resting-state -fMRI, compared with healthy patients. DATA SOURCES/METHODS:We used 5 databases (PubMed, EMBASE, Cochrane Central, Scopus, Web of Science). STUDY SELECTION/METHODS:Five databases (PubMed, EMBASE, Cochrane Central, Scopus, and Web of Science) were searched for research published since 2010. Search strategies used keywords of "functional MR imaging" and "mild traumatic brain injury" as well as related terms. All results were screened at the abstract and title levels by 4 reviewers according to predefined inclusion and exclusion criteria. For full-text inclusion, each study was evaluated independently by 2 reviewers, with discordant screening settled by consensus. DATA ANALYSIS/METHODS:Data regarding article characteristics, cohort demographics, fMRI scan parameters, data analysis processing software, atlas used, data characteristics, and statistical analysis information were extracted. DATA SYNTHESIS/RESULTS:Across 66 studies, 80 areas were analyzed 239 times for at least 1 time point, most commonly using independent component analysis. The most analyzed areas and networks were the whole brain, the default mode network, and the salience network. Reported functional connectivity changes varied, though there may be a slight trend toward decreased whole-brain functional connectivity within 1 month of traumatic brain injury and there may be differences based on the time since injury. LIMITATIONS/CONCLUSIONS:Studies of military, sports-related traumatic brain injury, and pediatric patients were excluded. Due to the high number of relevant studies and data heterogeneity, we could not be as granular in the analysis as we would have liked. CONCLUSIONS:Reported functional connectivity changes varied, even within the same region and network, at least partially reflecting differences in technical parameters, preprocessing software, and analysis methods as well as probable differences in individual injury. There is a need for novel rs-fMRI techniques that better capture subject-specific functional connectivity changes.

BACKGROUND:Prior research has established a link between thalamic pathology and cognitive impairment (CI) in people with multiple sclerosis (pwMS). However, the translation of these findings to pwMS in everyday clinical settings has been insufficient. OBJECTIVE:To assess which global and/or thalamic imaging biomarkers can be used to identify pwMS at risk for CI and cognitive worsening (CW) in a real-world setting. METHODS:This was an international, multi-center (11 centers), longitudinal, retrospective, real-word study of people with relapsing-remitting MS (pwRRMS). Brain MRI exams acquired at baseline and follow-up were collected. Cognitive status was evaluated using the Symbol Digit Modalities Test (SDMT). Thalamic volume (TV) measurement was performed on T2-FLAIR, as well as on T1-WI, when available. Thalamic dysconnectivity, T2-lesion volume (T2-LV), and volumes of gray matter (GM), whole brain (WB) and lateral ventricles (LVV) were also assessed. RESULTS:332 pwMS were followed for an average of 2.8 years. At baseline, T2-LV, LVV, TV and thalamic dysconnectivity on T2-FLAIR (p < 0.016), and WB, GM and TV volumes on T1-WI (p < 0.039) were significantly worse in 90 (27.1 %) CI vs. 242 (62.9 %) non-CI pwRRMS. Greater SDMT decline over the follow-up was associated with lower baseline TV on T2-FLAIR (standardized β = 0.203, p = 0.002) and greater thalamic dysconnectivity (standardized β = -0.14, p = 0.028) in a linear regression model. CONCLUSIONS:PwRRMS with thalamic atrophy and worse thalamic dysconnectivity present more frequently with CI and experience greater CW over mid-term follow-up in a real-world setting.

PURPOSE/OBJECTIVE:DNA methylation profiling stratifies isocitrate dehydrogenase (IDH)-mutant astrocytomas into methylation low-grade and high-grade groups. We investigated the utility of the T2-FLAIR mismatch sign for predicting DNA methylation grade and cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) homozygous deletion, a molecular biomarker for grade 4 IDH-mutant astrocytomas, according to the 2021 World Health Organization (WHO) classification. EXPERIMENTAL DESIGN/METHODS:Preoperative MRI scans of IDH-mutant astrocytomas subclassified by DNA methylation profiling (n=71) were independently evaluated by two radiologists for the T2-FLAIR mismatch sign. The diagnostic utility of T2-FLAIR mismatch in predicting methylation grade, CDKN2A/B status, copy number variation, and survival was analyzed. RESULTS:The T2-FLAIR mismatch sign was present in 21 of 45 (46.7%) methylation low-grade and 1 of 26 (3.9%) methylation high-grade cases (p<0.001), resulting in 96.2% specificity, 95.5% positive predictive value, and 51.0% negative predictive value for predicting low methylation grade. The T2-FLAIR mismatch sign was also significantly associated with intact CDKN2A/B status (p=0.028) with 87.5% specificity, 86.4% positive predictive value, and 42.9% negative predictive value. Overall multivariable Cox analysis showed that retained CDKN2A/B status remained significant for PFS (p=0.01). Multivariable Cox analysis of the histologic grade 3 subset, which was nearly evenly divided by CDKN2A/B status, CNV, and methylation grade, showed trends toward significance for DNA methylation grade with OS (p=0.045) and CDKN2A/B status with PFS (p=0.052). CONCLUSIONS:The T2-FLAIR mismatch sign is highly specific for low methylation grade and intact CDKN2A/B in IDH-mutant astrocytomas.

FEZF2 encodes a transcription factor critical to neurodevelopment that regulates other neurodevelopment genes. Rare variants in FEZF2 have previously been suggested to play a role in autism, and cases of 3p14 microdeletions that include FEZF2 share a neurodevelopmental phenotype including mild dysmorphic features and intellectual disability. We identified seven heterozygous predicted deleterious variants in FEZF2 (three frameshifts, one recurrent missense in two independent cases, one nonsense, and one complete gene deletion) in unrelated individuals with neurodevelopmental disorders including developmental delay/intellectual disability, autism, and/or attention-deficit/hyperactivity. Variants were confirmed to be de novo in five of seven cases and paternally inherited from an affected father in one. Predicted deleterious variants in FEZF2 may affect the expression of genes that are involved in fate choice pathways in developing neurons, and thus contribute to the neurodevelopmental phenotype. Future studies are needed to clarify the mechanism by which FEZF2 leads to this neurodevelopmental disorder.