Faculty Bibliography

Chronic progressive external ophthalmoplegia (CPEO), a genetic syndrome characterized by slowly progressive paresis of extraocular muscles, is often due to single large-scale deletions of the mitochondrial genome (mtDNA). Owing to heteroplasmy, mtDNA variants are often not uniformly expressed across tissues. This genetic variability affects clinical presentation and diagnostic testing. We report a case of a 34-year-old woman who presented with symptoms suspicious for a genetic myopathy: chronic asymmetric ptosis, slowly progressive asymmetric weakness, and external ophthalmoplegia. After initial nondiagnostic peripheral genetic testing, whole-exome and mitochondrial genome sequencing of muscle revealed a single large-scale mtDNA deletion, consistent with a diagnosis of mtDNA deletion-associated CPEO. Of interest, electrophysiologic studies showed myotonia in select muscles, a rarely reported finding. We discuss the clinical presentation and diagnostic approach in suspected CPEO, with an emphasis on common pitfalls in genetic testing for mitochondrial myopathies and the need for appropriate tissue and genetic testing modality selection.

After stroke, upper extremity (UE) motor recovery may be mediated in part by transcallosal projections between hemispheres. The interhemispheric competition model posits that transcallosal inhibition (TI) from the contralesional hemisphere is abnormally strengthened following stroke and interferes with motor recovery. This model has recently been questioned. In this longitudinal study, we aimed to definitively confirm or refute a maladaptive role of contralesional TI in subacute motor recovery. We assessed 30 mild-to-moderately impaired subjects over the six months following ischemic stroke. We tracked contralesional TI and motor functions in the proximal and distal segments of the paretic UE. We used transcranial magnetic stimulation to examine the ipsilateral silent period (iSP) in an arm and hand muscle. We used quantitative and clinical testing to examine deficits in muscle strength, motor control, and individuation; UE segmental impairment; and UE activity limitation. We assessed the relationships of contralesional TI to motor functions in the subacute period. Despite recovery of most motor functions in the proximal and distal UE, contralesional TI was largely static and unrelated to recovery of any motor function. There were inconsistent associations between stronger TI, less hand impairment, and less activity limitation in the subacute period overall. We found no compelling evidence to suggest a maladaptive role of contralesional TI in UE motor recovery in mild-to-moderately impaired stroke subjects. The scattered associations between stronger TI and better levels of paretic UE function suggest a potential supportive role rather than a limiting one. These findings challenge the validity of the interhemispheric competition model in the subacute recovery period, and prompt reconsideration of neuromodulatory strategies that subacutely target contralesional TI.

BACKGROUND AND PURPOSE/OBJECTIVE:Cerebrovascular reactivity (CVR) is a widely studied biomarker of cerebral hemodynamics, commonly used in risk stratification and treatment planning in patients with steno-occlusive disease (SOD). Conventional use relies on normalization of estimates to contralateral hemisphere reference values, which is unsuitable for bilateral or indeterminate distributions of disease. We report upon a custom data-driven approach leveraging random forest classifiers (RFc) to identify candidate voxels for normalization in order to facilitate interrogation outside conditions of known unilateral SOD MATERIALS AND METHODS: We retrospectively analyzed 16 patients with unilateral SOD who underwent acetazolamide-augmented BOLD-MRI and DSC perfusion. Three RFc models were trained using leave-one-out cross-validation (LOOCV) to identify candidate voxels brain-wide whose CVR were within 10% of the normal hemispheric median: i. all voxels; ii. gray matter only; and iii. white matter only. Model input features included time-to-maximum (Tmax), mean transit time (MTT), cerebral blood flow (CBF), and cerebral blood volume (CBV) from contemporaneous DSC. The median model-predicted reference CVR (CVRref) was compared to ground-truth medians in LOOCV, and its impact on threshold-based volumetric classification of CVR reduction assessed. RESULTS:RFc models effectively predicted ground-truth CVR voxels, achieving median absolute percent differences of 12.8% (IQR: 5.0%-18.9%) using all voxels, 11.3% (IQR: 9.3%-16.1%) for gray matter, and 9.8% (IQR: 4.4%-16.9%) for white matter. Volumetric estimates of CVR reduction across thresholds for the models revealed excellent agreement between ground-truth and model estimates without statistically significant differences (p>0.01), excepting lowest white matter CVR thresholds. Model use in a small pilot deployment of bilateral SOD cases demonstrated the potential utility, enabling voxel-wise CVR assessment without reliance on contralateral reference. CONCLUSIONS:We present a novel data-driven approach for normalizing CVR maps in patients with bilateral or indeterminate SOD. Using an RFc, our method provides an individualized, brain-wide reference CVR, expanding the utility of CVR estimates beyond the typical constraints of unilateral disease, and with potential application to other, similarly constrained scenarios such as for SPECT or PET hemodynamic studies. ABBREVIATIONS/BACKGROUND:CVR = cerebrovascular reactivity; RFc = random forest classifier; SOD = steno-occlusive disease.

OBJECTIVE:People with focal epilepsy experience one or more seizures prior to diagnosis. The Human Epilepsy Project (HEP) was a prospective study enrolling people with newly diagnosed focal epilepsy. It collected information including cognitive testing at the time of enrollment. This was completed utilizing a computerized test battery called the Cogstate Brief Battery (CBB). A prior analysis found that enrollment CBB test scores were below that of age matched controls and that performance on testing was not independently associated with the longer-term development of treatment resistance over the course of the HEP study. The present study assesses the impact of pretreatment seizures on cognition at time of diagnosis, considering time-to-treatment initiation in relation to seizure onset, pre-treatment seizure frequency, and pretreatment seizure classification. METHODS:Participants with newly diagnosed focal epilepsy and no other major medical comorbidities or intellectual disability (estimated IQ > 70) were enrolled between June 29, 2012, and September 1, 2019. A subset of the 448 enrolled participants (N = 183) were over 18 years old, had complete HEP enrollment data that included pre-treatment seizure histories, and complete enrollment CBB testing for analysis in this study. Performance on enrollment CBB testing was modeled using multiple linear regression with pre-treatment seizure characteristics including seizure type and duration between seizure onset and treatment initiation, controlling for other key baseline participant characteristics. RESULTS:There were no independent associations between cognitive measures on the CBB at the time of enrollment and pre-treatment seizures after correcting for potentially confounding variables. Z-scores for the attention composite on CBB (an average of Identification and Detection tests) were not associated with a global pre-treatment seizure score that quantified time with seizures (days) and seizure count by seizure type (motor, non-motor, bilateral tonic clonic) (p = 0.29). Similarly, z-scores for the memory composite (an average of the One Card Learning test and One Back tests) were not associated with the pre-treatment seizure score (p = 0.1). No additional independent associations were found to be significant between z-scores for attention or memory composites and other potential explanatory variables. SIGNIFICANCE/CONCLUSIONS:This study highlights an important finding for people who develop focal epilepsy and otherwise are in good health: pre-treatment time-limited seizures do not have an independent impact on cognition early on, as measured by a brief validated cognitive screening test. This suggests that that cognition at the time of epilepsy diagnosis may be more strongly related to underlying etiology, chronic disease, and comorbidities.

BACKGROUND AND OBJECTIVES/OBJECTIVE:While reductions in optical coherence tomography (OCT) pRNFL and ganglion cell-inner plexiform layer thicknesses have been shown to be associated with brain atrophy in adult-onset MS (AOMS) cohorts, the relationship between OCT and brain MRI measures is less established in pediatric-onset MS (POMS). Our aim was to examine the associations of OCT measures with volumetric MRI in a cohort of patients with POMS to determine whether OCT measures reflect CNS neurodegeneration in this patient population, as is seen in AOMS cohorts. METHODS:This was a cross-sectional study with retrospective ascertainment of patients with POMS evaluated at a single center with expertise in POMS and neuro-ophthalmology. As part of routine clinical care, patients with POMS are evaluated by a POMS expert and undergo volumetric brain MRI, including whole-brain (WB), subregional, and gray matter (GM) volume analyses. Patients with POMS are routinely referred to neuro-ophthalmology for evaluation that includes high-contrast visual acuity, color vision testing, and OCT. Generalized estimating equation (GEE) models, accounting for within-patient, intereye correlations (both eyes of each patient were included), MS disease duration, and disease-modifying therapy efficacy, were used to determine the relationship between visual pathway structure and function and volumetric MRI measures. RESULTS:= 0.015, respectively). DISCUSSION/CONCLUSIONS:Our results demonstrate that changes in visual pathway structures are associated with reductions in overall brain volume and GM volumes, as well as greater lesion and black hole burden. Collectively, our results emphasize the importance of visual assessment in POMS and suggest that OCT reflects overall CNS neurodegeneration in this cohort.

BACKGROUND:There is paucity of data on long-term functional and cognitive outcomes after COVID-19 compared to COVID-negative controls. METHODS:We conducted an observational cohort study of patients ≥ 1 year after COVID-19 compared to contemporaneous COVID-19 negative controls (SARS-CoV-2 nucleocapsid IgG negative with no history of COVID-19). Functional (modified Rankin Scale [mRS], Barthel Index), cognitive (telephone MoCA [t-MoCA]), and patient-reported neuropsychiatric symptoms were compared between groups using multivariable logistic regression analysis. In a subgroup of COVID-19 patients who were followed longitudinally, trajectories of recovery were assessed using the paired samples Sign test. RESULTS:Of 145 participants, N = 115 COVID-19 patients (median age 62, 51 % female, 33 % hospitalized for COVID-19, median 2.9 years from index infection), and N = 30 non-COVID-19 controls (median age 75, 70 % female) were enrolled. Neuropsychiatric symptoms were reported in 76 % of COVID-19 patients versus 7 % of controls (aOR 15.0, 95 %CI 3.09-72.47, P < 0.001). Abnormal mRS> 0 occurred in 42 % of COVID-19 patients compared to 11 % of controls (P = 0.002). However, this difference was not significant after adjusting for age, sex, COVID-19 hospitalization and history of mood disorder (aOR 2.10, 95 %CI 0.52-8.51). Rates of abnormal t-MoCA≤ 18 (40 % of COVID-19 versus 41 % of controls, P = 1.00) and Barthel scores< 100 (19 % of COVID-19 versus 14 % in controls, P = 0.785) were similar. Among N = 26 COVID-19 patients with repeated measures, mRS significantly improved between 6-months to 3-years post-COVID (+1.3 points, p = 0.004), while no changes were observed in t-MoCA or Barthel. CONCLUSIONS:Three years after COVID-19, neuropsychiatric symptoms were significantly more frequent compared to controls, however no differences in functional or cognitive status were detected.

Sound structures such as phonemes and words have highly variable durations. Therefore, there is a fundamental difference between integrating across absolute time (for example, 100 ms) versus sound structure (for example, phonemes). Auditory and cognitive models have traditionally cast neural integration in terms of time and structure, respectively, but the extent to which cortical computations reflect time or structure remains unknown. Here, to answer this question, we rescaled the duration of all speech structures using time stretching and compression and measured integration windows in the human auditory cortex using a new experimental and computational method applied to spatiotemporally precise intracranial recordings. We observed slightly longer integration windows for stretched speech, but this lengthening was very small (~5%) relative to the change in structure durations, even in non-primary regions strongly implicated in speech-specific processing. These findings demonstrate that time-yoked computations dominate throughout the human auditory cortex, placing important constraints on neurocomputational models of structure processing.

OBJECTIVE:Antiseizure medications (ASMs) are the first-line treatment for epilepsy, yet they are ineffective in controlling seizures in about 40% of patients with unpredictable individual response to treatment. This study aimed to develop and validate artificial intelligence (AI) models using clinical and brain magnetic resonance imaging (MRI) data to predict responses to the first two ASMs in people with epilepsy. METHODS:People with recently diagnosed epilepsy treated with ASM monotherapy at the Alfred Hospital, Melbourne, Australia formed the development cohort. We developed AI models employing various combinations of clinical features, prescribed ASMs, and brain multimodal MRI images/features to predict the probability of seizure freedom at 12 months while taking the first or second ASM monotherapy. Five-fold cross-internal validation was performed. External validation was conducted on a validation cohort comprising participants of the Human Epilepsy Project. RESULTS:The development cohort included 154 individuals (36% female, 85% focal epilepsy), of whom 29% had received both the first and second ASM monotherapy. The validation cohort included 301 individuals (61% female, all focal epilepsy), of whom 33% had received both the first and second ASM monotherapy. A fusion deep learning (DL) model comprising an 18-layer 3D videoResNet (for multi-sequence MRI data), a transformer encoder (ASM regimens), and a dual linear neural network (for clinical characteristics) outperformed other models. It achieved an internal cross validation F1 score of 0.75 ± 0.05 (average ± 95% confidence interval), higher than other machine learning (ML) models and DL models with less complex architecture or integration of fewer imaging sequences. This DL model significantly outperformed the best ML model on validation cohort (p < 0.001). SIGNIFICANCE/CONCLUSIONS:AI-based models incorporating brain MRI, clinical, and medication data can efficiently predict seizure freedom in recently diagnosed epilepsy. They may enhance treatment selection in epilepsy and offer a foundation for clinical decision support systems. Further validation in larger cohorts is warranted.

PURPOSE/OBJECTIVE:Establish the minimally clinically important difference (MCID) for the Orthostatic Hypotension Questionnaire (OHQ). BACKGROUND:Neurogenic orthostatic hypotension (nOH) causes disabling symptoms that impair daily function and quality of life. The OHQ is a validated patient-reported outcome with a symptom assessment (OHSA) and daily activity scale (OHDAS), widely used in clinical trials, despite the MCID being unestablished. METHODS:We analyzed data from two phase 3, randomized placebo-controlled trials (SEQUOIA and REDWOOD), evaluating ampreloxetine for symptomatic nOH in patients with Parkinson disease, multiple system atrophy, and pure autonomic failure. Using anchor-based and distribution-based methods, we calculated the MCID for the total OHQ score, OHSA and OHDAS composite subscales, and for the single dizziness/lightheadedness question (OHSA1). RESULTS:The analysis included 184 subjects from SEQUOIA and 128 from REDWOOD. The total OHQ MCID for improvement was a reduction of 0.9-1.2 points and for worsening was an increase of 0.7-1.1 points. The MCID for the OHSA composite ranged from a reduction of 0.9-1.3 points for improvement and an increase of 0.7-1.1 points for worsening. For the single-item OHSA1, the MCID was a reduction of 2.0-3.0 points for improvement and an increase of 1.0 point for worsening. Owing to poor correlation with the symptom-based anchors, a reliable MCID for the OHDAS component was not established. CONCLUSIONS:These MCID thresholds for the OHQ, OHSA and OHSA item 1 alone, enhance the interpretability of scores and support their use in evaluating clinical benefit.