Faculty Bibliography

INTRODUCTION/BACKGROUND:Hematoma expansion (HE) in patients with intracerebral hemorrhage (ICH) is a key predictor of poor prognosis and potentially amenable to treatment. This study aimed to build a classification model to predict HE in patients with ICH using deep learning algorithms without using advanced radiological features. METHODS:Data from the ATACH-2 trial (Antihypertensive Treatment of Acute Cerebral Hemorrhage) was utilized. Variables included in the models were chosen as per literature consensus on salient variables associated with HE. HE was defined as increase in either >33% or 6 mL in hematoma volume in the first 24 h. Multiple machine learning algorithms were employed using iterative feature selection and outcome balancing methods. 70% of patients were used for training and 30% for internal validation. We compared the ML models to a logistic regression model and calculated AUC, accuracy, sensitivity and specificity for the internal validation models respective models. RESULTS:[5.03-18.17] and 25.2% had HE. The best performing model across all feature selection groups and sampling cohorts was using an artificial neural network (ANN) for HE in the testing cohort with AUC 0.702 [95% CI, 0.631-0.774] with 8 hidden layer nodes The traditional logistic regression yielded AUC 0.658 [95% CI, 0.641-0.675]. All other models performed with less accuracy and lower AUC. Initial hematoma volume, time to initial CT head, and initial SBP emerged as most relevant variables across all best performing models. CONCLUSION/CONCLUSIONS:We developed multiple ML algorithms to predict HE with the ANN classifying the best without advanced radiographic features, although the AUC was only modestly better than other models. A larger, more heterogenous dataset is needed to further build and better generalize the models.

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.

OBJECTIVES/OBJECTIVE:Carotid interventions are indicated for both patients with symptomatic and a subset of patients with severe asymptomatic carotid artery stenosis (CAS). Symptomatic CAS accounts for up to 12%-25% of overall carotid interventions, but predictors of symptomatic presentation remain poorly defined. The aim of this study was to identify factors associated with symptomatic CAS in our patient population. METHODS:Between January 2015 and February 2022, an institutional retrospective cohort study of prospectively collected data on patients undergoing interventions for CAS was performed. Procedures included carotid endarterectomy (CEA), transcarotid artery revascularization (TCAR), and transfemoral carotid artery stenting (TF-CAS). Demographic data, comorbidities, procedural details, and anatomic features from various imaging modalities were collected. Comparisons were made between symptomatic (symptoms within the prior 6 months) and asymptomatic patients. RESULTS:< .001), and symptomatic patients with ulcerated plaques more frequently had less than 50% compared to moderate/severe CAS. Nine patients who presented with symptoms had mild CAS and underwent intervention. CONCLUSIONS:Symptomatic CAS was associated with a history of remote prior symptoms and lack of anti-platelet therapy at time of presentation. Furthermore, symptomatic patients not on anti-platelet agents were more likely to have a greater area of parenchymal involvement when presenting with stroke and symptomatic patients with ulcerated plaques were more likely to have mild CAS, suggesting the role of plaque instability in symptomatic presentation. These findings underscore the importance of appropriate medical management and adherence in all patients with CAS and perhaps a role for more frequent surveillance in those with potentially unstable plaque morphology.

INTRODUCTION/BACKGROUND:This study aims to validate the Seizure-Related Impact Assessment Scale (SERIAS). This novel patient-reported outcome measure (PROM) compares the 'trade-off' between seizures and treatment-related adverse effects, and measures epilepsy disability qualitatively and quantitively. It fills an important gap in PROMs for epilepsy clinical trials and practice. METHODS AND ANALYSIS/METHODS:Adults with epileptologist-confirmed epilepsy from two Australian Epilepsy Centres are being recruited. People with functional seizures, or who are unable to self-complete English-language validated instruments are excluded. Participants providing informed consent are invited to complete questionnaires at baseline, 3 and 6 months later. SERIAS includes five questions that ask about the number of days per month that seizures or treatment-related adverse effects partially or fully impact work/home/school and family/social/non-work activities, as well as a visual analogue scale regarding epilepsy-related disability. SERIAS is completed alongside seven internationally validated instruments measuring treatment-related adverse effects, mood disorders and quality of life. Target recruitment is n=100, ensuring>50 people complete all questionnaires at all timepoints. Comprehensive psychometric analysis will be performed. Convergent validity will be investigated using bivariate correlations with relevant measures. Reliability will be investigated using Cronbach's alpha, McDonald's omega and test-retest correlation coefficients. SERIAS will be a novel PROM for epilepsy clinical trials and practice. ETHICS AND DISSEMINATION/BACKGROUND:Multisite ethics approval was granted by the Alfred Health Ethics Committee (HREC 17/23). Results of this study will be disseminated through publication in peer-reviewed journals and presentations at scientific conferences. TRIAL REGISTRATION NUMBER/BACKGROUND:ACTRN12623000599673.

BACKGROUND AND PURPOSE/OBJECTIVE:Because the corpus callosum connects the left and right hemispheres and a variety of WM bundles across the brain in complex ways, damage to the neighboring WM microstructure may specifically disrupt interhemispheric communication through the corpus callosum following mild traumatic brain injury. Here we use a mediation framework to investigate how callosal interhemispheric communication is affected by WM microstructure in mild traumatic brain injury. MATERIALS AND METHODS/METHODS:Multishell diffusion MR imaging was performed on 23 patients with mild traumatic brain injury within 1 month of injury and 17 healthy controls, deriving 11 diffusion metrics, including DTI, diffusional kurtosis imaging, and compartment-specific standard model parameters. Interhemispheric processing speed was assessed using the interhemispheric speed of processing task (IHSPT) by measuring the latency between word presentation to the 2 hemivisual fields and oral word articulation. Mediation analysis was performed to assess the indirect effect of neighboring WM microstructures on the relationship between the corpus callosum and IHSPT performance. In addition, we conducted a univariate correlation analysis to investigate the direct association between callosal microstructures and IHSPT performance as well as a multivariate regression analysis to jointly evaluate both callosal and neighboring WM microstructures in association with IHSPT scores for each group. RESULTS:Several significant mediators in the relationships between callosal microstructure and IHSPT performance were found in healthy controls. However, patients with mild traumatic brain injury appeared to lose such normal associations when microstructural changes occurred compared with healthy controls. CONCLUSIONS:This study investigates the effects of neighboring WM microstructure on callosal interhemispheric communication in healthy controls and patients with mild traumatic brain injury, highlighting that neighboring noncallosal WM microstructures are involved in callosal interhemispheric communication and information transfer. Further longitudinal studies may provide insight into the temporal dynamics of interhemispheric recovery following mild traumatic brain injury.

Music provides a reward that can enhance learning and motivation in humans. While music is often combined with exercise to improve performance and upregulate mood, the relationship between music-induced reward and motor output is poorly understood. Here, we study music reward and motor output at the same time by capitalizing on music playing. Specifically, we investigate the effects of music improvisation and live accompaniment on motor, autonomic, and affective responses. Thirty adults performed a drumming task while (i) improvising or maintaining the beat and (ii) with live or recorded accompaniment. Motor response was characterized by acceleration of hand movements (accelerometry), wrist flexor and extensor muscle activation (electromyography), and the drum strike count (i.e., the number of drum strikes played). Autonomic arousal was measured by tonic response of electrodermal activity (EDA) and heart rate (HR). Affective responses were measured by a 12-item Likert scale. The combination of improvisation and live accompaniment, as compared to all other conditions, significantly increased acceleration of hand movements and muscle activation, as well as participant reports of reward during music playing. Improvisation, regardless of type of accompaniment, increased the drum strike count and autonomic arousal (including tonic EDA responses and several measures of HR), as well as participant reports of challenge. Importantly, increased motor response was associated with increased reward ratings during music improvisation, but not while participants were maintaining the beat. The increased motor responses achieved with improvisation and live accompaniment have important implications for enhancing dose of movement during exercise and physical rehabilitation.

The late-onset GM2 gangliosidoses, comprising late-onset Tay-Sachs and Sandhoff diseases, are rare, slowly progressive, neurogenetic disorders primarily characterized by neurogenic weakness, ataxia, and dysarthria. The aim of this longitudinal study was to characterize the natural history of late-onset GM2 gangliosidoses using a number of clinical outcome assessments to measure different aspects of disease burden and progression over time, including neurological, functional, and quality of life, to inform the design of future clinical interventional trials. Patients attending the United States National Tay-Sachs & Allied Diseases Family Conference between 2015 and 2019 underwent annual clinical outcome assessments. Currently, there are no clinical outcome assessments validated to assess late-onset GM2 gangliosidoses; therefore, instruments used or designed for diseases with similar features, or to address various aspects of the clinical presentations, were used. Clinical outcome assessments included the Friedreich's Ataxia Rating Scale, the 9-Hole Peg Test, and the Assessment of Intelligibility of Dysarthric Speech. Twenty-three patients participated in at least one meeting visit (late-onset Tay-Sachs, n = 19; late-onset Sandhoff, n = 4). Patients had high disease burden at baseline, and scores for the different clinical outcome assessments were generally lower than would be expected for the general population. Longitudinal analyses showed slow, but statistically significant, neurological progression as evidenced by worsening scores on the 9-Hole Peg Test (2.68%/year, 95% CI: 0.13-5.29; p = 0.04) and the Friedreich's Ataxia Rating Scale neurological examination (1.31 points/year, 95% CI: 0.26-2.35; p = 0.02). Time since diagnosis to study entry correlated with worsening scores on the 9-Hole Peg Test (r = 0.728; p < 0.001), Friedreich's Ataxia Rating Scale neurological examination (r = 0.727; p < 0.001), and Assessment of Intelligibility of Dysarthric Speech intelligibility (r = -0.654; p = 0.001). In summary, patients with late-onset GM2 gangliosidoses had high disease burden and slow disease progression. Several clinical outcome assessments suitable for clinical trials showed only small changes and standardized effect sizes (change/standard deviation of change) over 4 years. These longitudinal natural history study results illustrate the challenge of identifying responsive endpoints for clinical trials in rare, slowly progressive, neurogenerative disorders where arguably the treatment goal is to halt or decrease the rate of decline rather than improve clinical status. Furthermore, powering such a study would require a large sample size and/or a long study duration, neither of which is an attractive option for an ultra-rare disease with no available treatment. These findings support the development of potentially more sensitive late-onset GM2 gangliosidoses-specific rating instruments and/or surrogate endpoints for use in future clinical trials.

IMPORTANCE/UNASSIGNED:Neurological manifestations during acute SARS-CoV-2-related multisystem inflammatory syndrome in children (MIS-C) are common in hospitalized patients younger than 18 years and may increase risk of new neurocognitive or functional morbidity. OBJECTIVE/UNASSIGNED:To assess the association of severe neurological manifestations during a SARS-CoV-2-related hospital admission with new neurocognitive or functional morbidities at discharge. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:This prospective cohort study from 46 centers in 10 countries included patients younger than 18 years who were hospitalized for acute SARS-CoV-2 or MIS-C between January 2, 2020, and July 31, 2021. EXPOSURE/UNASSIGNED:Severe neurological manifestations, which included acute encephalopathy, seizures or status epilepticus, meningitis or encephalitis, sympathetic storming or dysautonomia, cardiac arrest, coma, delirium, and stroke. MAIN OUTCOMES AND MEASURES/UNASSIGNED:The primary outcome was new neurocognitive (based on the Pediatric Cerebral Performance Category scale) and/or functional (based on the Functional Status Scale) morbidity at hospital discharge. Multivariable logistic regression analyses were performed to examine the association of severe neurological manifestations with new morbidity in each SARS-CoV-2-related condition. RESULTS/UNASSIGNED:Overall, 3568 patients younger than 18 years (median age, 8 years [IQR, 1-14 years]; 54.3% male) were included in this study. Most (2980 [83.5%]) had acute SARS-CoV-2; the remainder (588 [16.5%]) had MIS-C. Among the patients with acute SARS-CoV-2, 536 (18.0%) had a severe neurological manifestation during hospitalization, as did 146 patients with MIS-C (24.8%). Among survivors with acute SARS-CoV-2, those with severe neurological manifestations were more likely to have new neurocognitive or functional morbidity at hospital discharge compared with those without severe neurological manifestations (27.7% [n = 142] vs 14.6% [n = 356]; P < .001). For survivors with MIS-C, 28.0% (n = 39) with severe neurological manifestations had new neurocognitive and/or functional morbidity at hospital discharge compared with 15.5% (n = 68) of those without severe neurological manifestations (P = .002). When adjusting for risk factors in those with severe neurological manifestations, both patients with acute SARS-CoV-2 (odds ratio, 1.85 [95% CI, 1.27-2.70]; P = .001) and those with MIS-C (odds ratio, 2.18 [95% CI, 1.22-3.89]; P = .009) had higher odds of having new neurocognitive and/or functional morbidity at hospital discharge. CONCLUSIONS AND RELEVANCE/UNASSIGNED:The results of this study suggest that children and adolescents with acute SARS-CoV-2 or MIS-C and severe neurological manifestations may be at high risk for long-term impairment and may benefit from screening and early intervention to assist recovery.