Faculty Bibliography

OBJECTIVE:To characterize peri-ictal apnea and postictal asystole in generalized convulsive seizures (GCS) of intractable epilepsy. METHODS:This was a prospective, multicenter epilepsy monitoring study of autonomic and breathing biomarkers of sudden unexpected death in epilepsy (SUDEP) in patients ≥18 years old with intractable epilepsy and monitored GCS. Video-EEG, thoracoabdominal excursions, nasal airflow, capillary oxygen saturation, and ECG were analyzed. RESULTS:= 0.009). CONCLUSIONS:PCCA occurred in both focal and generalized epilepsies, suggesting a different pathophysiology from ICA, which occurred only in focal epilepsy. PCCA was seen in 2 near-SUDEP cases and 1 probable SUDEP case, suggesting that this phenomenon may serve as a clinical biomarker of SUDEP. Larger studies are needed to validate this observation. Rhythmic postictal muscle artifact is suggestive of post-GCS breathing effort rather than a specific biomarker of laryngospasm.

Importance:Within 2 decades of onset, 80% of untreated patients with relapsing-remitting multiple sclerosis (MS) convert to a phase of irreversible disability accrual termed secondary progressive MS. The association between disease-modifying treatments (DMTs), and this conversion has rarely been studied and never using a validated definition. Objective:To determine the association between the use, the type of, and the timing of DMTs with the risk of conversion to secondary progressive MS diagnosed with a validated definition. Design, Setting, and Participants:Cohort study with prospective data from 68 neurology centers in 21 countries examining patients with relapsing-remitting MS commencing DMTs (or clinical monitoring) between 1988-2012 with minimum 4 years' follow-up. Exposures:The use, type, and timing of the following DMTs: interferon beta, glatiramer acetate, fingolimod, natalizumab, or alemtuzumab. After propensity-score matching, 1555 patients were included (last follow-up, February 14, 2017). Main Outcome and Measure:Conversion to objectively defined secondary progressive MS. Results:Of the 1555 patients, 1123 were female (mean baseline age, 35 years [SD, 10]). Patients initially treated with glatiramer acetate or interferon beta had a lower hazard of conversion to secondary progressive MS than matched untreated patients (HR, 0.71; 95% CI, 0.61-0.81; P < .001; 5-year absolute risk, 12% [49 of 407] vs 27% [58 of 213]; median follow-up, 7.6 years [IQR, 5.8-9.6]), as did fingolimod (HR, 0.37; 95% CI, 0.22-0.62; P < .001; 5-year absolute risk, 7% [6 of 85] vs 32% [56 of 174]; median follow-up, 4.5 years [IQR, 4.3-5.1]); natalizumab (HR, 0.61; 95% CI, 0.43-0.86; P = .005; 5-year absolute risk, 19% [16 of 82] vs 38% [62 of 164]; median follow-up, 4.9 years [IQR, 4.4-5.8]); and alemtuzumab (HR, 0.52; 95% CI, 0.32-0.85; P = .009; 5-year absolute risk, 10% [4 of 44] vs 25% [23 of 92]; median follow-up, 7.4 years [IQR, 6.0-8.6]). Initial treatment with fingolimod, alemtuzumab, or natalizumab was associated with a lower risk of conversion than initial treatment with glatiramer acetate or interferon beta (HR, 0.66; 95% CI, 0.44-0.99; P = .046); 5-year absolute risk, 7% [16 of 235] vs 12% [46 of 380]; median follow-up, 5.8 years [IQR, 4.7-8.0]). The probability of conversion was lower when glatiramer acetate or interferon beta was started within 5 years of disease onset vs later (HR, 0.77; 95% CI, 0.61-0.98; P = .03; 5-year absolute risk, 3% [4 of 120] vs 6% [2 of 38]; median follow-up, 13.4 years [IQR, 11-18.1]). When glatiramer acetate or interferon beta were escalated to fingolimod, alemtuzumab, or natalizumab within 5 years vs later, the HR was 0.76 (95% CI, 0.66-0.88; P < .001; 5-year absolute risk, 8% [25 of 307] vs 14% [46 of 331], median follow-up, 5.3 years [IQR], 4.6-6.1). Conclusions and Relevance:Among patients with relapsing-remitting MS, initial treatment with fingolimod, alemtuzumab, or natalizumab was associated with a lower risk of conversion to secondary progressive MS vs initial treatment with glatiramer acetate or interferon beta. These findings, considered along with these therapies' risks, may help inform decisions about DMT selection.

OBJECTIVECerebral vasospasm causing delayed cerebral ischemia (DCI) is a source of significant morbidity after subarachnoid hemorrhage (SAH). Transcranial Doppler is used at most institutions to detect sonographic vasospasm but has poor positive predictive value for DCI. Automated assessment of the pupillary light reflex has been increasingly used as a reliable way of assessing pupillary reactivity, and the Neurological Pupil Index (NPi) has been shown to decrease hours prior to the clinical manifestation of ischemic injury or herniation syndromes. The aim of this study was to investigate the role of automated pupillometry in the setting of SAH, as a potential adjunct to TCD.METHODSOur analysis included patients that had been diagnosed with aneurysmal SAH and admitted to the neuro-intensive care unit of the University of Texas Southwestern Medical Center between November 2015 and June 2017. A dynamic infrared pupillometer was used for all pupillary measurements. An NPi value ranging from 3 to 5 was considered normal, and from 0 to 2.9 abnormal. Sonographic vasospasm was defined as middle cerebral artery velocities greater than 100 cm/sec with a Lindegaard ratio greater than 3 on either side on transcranial Doppler. Most patients had multiple NPi readings daily and we retained the lowest value for our analysis. We aimed to study the association between DCI and sonographic vasospasm, and DCI and NPi readings.RESULTSA total of 56 patients were included in the final analysis with 635 paired observations of daily TCD and NPi data. There was no statistically significant association between the NPi value and the presence of sonographic vasospasm. There was a significant association between DCI and sonographic vasospasm, χ2(1) = 6.4112, p = 0.0113, OR 1.6419 (95% CI 1.1163-2.4150), and between DCI and an abnormal decrease in NPi, χ2(1) = 38.4456, p < 0.001, OR 3.3930 (95% CI 2.2789-5.0517). Twelve patients experienced DCI, with 7 showing a decrease of their NPi to an abnormal range. This change occurred > 8 hours prior to the clinical decline 71.4% of the time. The NPi normalized in all patients after treatment of their vasospasm.CONCLUSIONSIsolated sonographic vasospasm does not seem to correlate with NPi changes, as the latter likely reflects an ischemic neurological injury. NPi changes are strongly associated with the advent of DCI and could be an early herald of clinical deterioration.

Patients with idiopathic generalised epilepsy (IGE) typically have normal conventional magnetic resonance imaging (MRI), hence diagnosis based on MRI is challenging. Anatomical abnormalities underlying brain dysfunctions in IGE are unclear and their relation to the pathomechanisms of epileptogenesis is poorly understood. In this study, we applied connectometry, an advanced quantitative neuroimaging technique for investigating localised changes in white-matter tissues in vivo. Analysing white matter structures of 32 subjects we incorporated our in vivo findings in a computational model of seizure dynamics to suggest a plausible mechanism of epileptogenesis. Patients with IGE have significant bilateral alterations in major white-matter fascicles. In the cingulum, fornix, and superior longitudinal fasciculus, tract integrity is compromised, whereas in specific parts of tracts between thalamus and the precentral gyrus, tract integrity is enhanced in patients. Combining these alterations in a logistic regression model, we computed the decision boundary that discriminated patients and controls. The computational model, informed with the findings on the tract abnormalities, specifically highlighted the importance of enhanced cortico-reticular connections along with impaired cortico-cortical connections in inducing pathological seizure-like dynamics. We emphasise taking directionality of brain connectivity into consideration towards understanding the pathological mechanisms; this is possible by combining neuroimaging and computational modelling. Our imaging evidence of structural alterations suggest the loss of cortico-cortical and enhancement of cortico-thalamic fibre integrity in IGE. We further suggest that impaired connectivity from cortical regions to the thalamic reticular nucleus offers a therapeutic target for selectively modifying the brain circuit for reversing the mechanisms leading to epileptogenesis.

Much concern exists over the role of blast-induced traumatic brain injury (TBI) in the chronic cognitive and mental health problems that develop in veterans and active duty military personnel. The brain vasculature is particularly sensitive to blast injury. The aim of this study was to characterize the evolving molecular and histologic alterations in the neurovascular unit induced by three repetitive low-energy blast exposures (3 × 74.5 kPa) in a rat model mimicking human mild TBI or subclinical blast exposure. High-resolution two-dimensional differential gel electrophoresis (2D-DIGE) and matrix-assisted laser desorption/ionization (MALDI) mass spectrometry of purified brain vascular fractions from blast-exposed animals 6 weeks post-exposure showed decreased levels of vascular-associated glial fibrillary acidic protein (GFAP) and several neuronal intermediate filament proteins (α-internexin and the low, middle, and high molecular weight neurofilament subunits). Loss of these proteins suggested that blast exposure disrupts gliovascular and neurovascular interactions. Electron microscopy confirmed blast-induced effects on perivascular astrocytes including swelling and degeneration of astrocytic endfeet in the brain cortical vasculature. Because the astrocyte is a major sensor of neuronal activity and regulator of cerebral blood flow, structural disruption of gliovascular integrity within the neurovascular unit should impair cerebral autoregulation. Disrupted neurovascular connections to pial and parenchymal blood vessels might also affect brain circulation. Blast exposures also induced structural and functional alterations in the arterial smooth muscle layer. Interestingly, by 8 months after blast exposure, GFAP and neuronal intermediate filament expression had recovered to control levels in isolated brain vascular fractions. However, despite this recovery, a widespread vascular pathology was still apparent at 10 months after blast exposure histologically and on micro-computed tomography scanning. Thus, low-level blast exposure disrupts gliovascular and neurovascular connections while inducing a chronic vascular pathology.

BACKGROUND:Electrical stimulation of the cortex using subdurally implanted electrodes can causally reveal structural connectivity by eliciting cortico-cortical evoked potentials (CCEPs). While many studies have demonstrated the potential value of CCEPs, the methods to evaluate them were often relatively subjective, did not consider potential artifacts, and did not lend themselves to systematic scientific investigations. NEW METHOD/UNASSIGNED:We developed an automated and quantitative method called SIGNI (Stimulation-Induced Gamma-based Network Identification) to evaluate cortical population-level responses to electrical stimulation that minimizes the impact of electrical artifacts. We applied SIGNI to electrocorticographic (ECoG) data from eight human subjects who were implanted with a total of 978 subdural electrodes. Across the eight subjects, we delivered 92 trains of approximately 200 discrete electrical stimuli each (amplitude 4-15 mA) to a total of 64 electrode pairs. RESULTS:We verified SIGNI's efficacy by demonstrating a relationship between the magnitude of evoked cortical activity and stimulation amplitude, as well as between the latency of evoked cortical activity and the distance from the stimulated locations. CONCLUSIONS:SIGNI reveals the timing and amplitude of cortical responses to electrical stimulation as well as the structural connectivity supporting these responses. With these properties, it enables exploration of new and important questions about the neurophysiology of cortical communication and may also be useful for pre-surgical planning.

PURPOSE/OBJECTIVE:Iniparib is a purported prodrug causing cell death through intracellular conversion to nitro radical ions. We assessed the efficacy and safety of iniparib with standard radiation therapy (RT) and temozolomide (TMZ) in patients with newly diagnosed glioblastoma (GBM). EXPERIMENTAL DESIGN/METHODS:Adults meeting eligibility criteria were enrolled in this prospective, single arm, open-label multi-institution phase II trial with median overall survival (mOS) compared to a historical control as the primary objective. A safety run-in component of RT+TMZ+iniparib (n=5) was followed by an efficacy study (n=76) with the recommended phase II doses of iniparib (8.0 mg/kg IV twice/week with RT + daily TMZ followed by 8.6 mg/kg IV twice/week with 5/28 day TMZ). RESULTS:The median age of the 81 evaluable participants was 58 years (63% male). Baseline KPS was ≥80% in 87% of participants. The mOS was 22 months (95%CI: 17-24) and the hazard rate was 0.44 (95%CI: 0.35-0.55) per-person year of follow-up. The 2 and 3 year survival rates were 38% and 25%, respectively. Treatment-related grade 3 adverse events (AE) occurred in 27% of patients; nine patients had AEs requiring drug discontinuation including: infusion-related reaction, rash, gastritis, increased liver enzymes, and thrombocytopenia. CONCLUSIONS:Iniparib is well tolerated with RT and TMZ in patients with newly diagnosed GBM at up to 17.2mg/kg weekly. The primary objective of improved mOS compared with historical a control was met, indicating potential antitumor activity of iniparib in this setting. Dosing optimization (frequency and sequence) is needed prior to additional efficacy studies.

PURPOSE/OBJECTIVE:T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive disease, affecting children and adults. Chemotherapy treatments show high response rates but have debilitating effects and carry risk of relapse. Previous work implicated NOTCH1 and other oncogenes. However, direct inhibition of these pathways affects healthy tissues and cancer alike. Our goal in this work has been to identify enzymes active in T-ALL whose activity could be targeted for therapeutic purposes. EXPERIMENTAL DESIGN/METHODS:To identify and characterize new NOTCH1 druggable partners in T-ALL, we coupled studies of the NOTCH1 interactome to expression analysis and a series of functional analyses in cell lines, patient samples and xenograft models. RESULTS:We demonstrate that ubiquitin-specific protease 7 (USP7) interacts with NOTCH1 and controls leukemia growth by stabilizing the levels of NOTCH1 and JMJD3 histone demethylase. USP7 is highly expressed in T-ALL and is transcriptionally regulated by NOTCH1. In turn, USP7 controls NOTCH1 levels through deubiquitination. USP7 binds oncogenic targets and controls gene expression through stabilization of NOTCH1 and JMJD3 and ultimately H3K27me3 changes. We also show that USP7 and NOTCH1 bind T-ALL superenhancers, and inhibition of USP7 leads to a decrease of the transcriptional levels of NOTCH1 targets and significantly blocks T-ALL cell growth in vitro and in vivo. CONCLUSIONS:These results provide a new model for USP7 deubiquitinase activity through recruitment to oncogenic chromatin loci and regulation of both oncogenic transcription factors and chromatin marks to promote leukemia. Our studies also show that targeting USP7 inhibition could be a therapeutic strategy in aggressive leukemia.