Faculty Bibliography

Excess mortality due to epilepsy is greatest among young adults. However, the relative proportions of sudden unexpected death in epilepsy (SUDEP) and other epilepsy-related causes of death are not well defined. We prospectively adjudicated cause of death in all 18- to 45-year-olds with a history of seizure/epilepsy who underwent medicolegal investigation in San Diego County between 2014 and 2017. We identified 108 decedents with definite or probable epilepsy; 62% died from an epilepsy-related cause. SUDEP accounted for 42.6% (N = 46) of deaths, which were usually unwitnessed deaths, at home in bed. Other frequent causes of death were drug overdose (N = 23), suicide (N = 8), trauma (N = 8), and drowning (N = 6). SUDEP autopsies were similar to those of decedents from other causes. Most deaths in young adults with epilepsy that undergo medico-legal investigation are epilepsy-related, and SUDEP is the leading cause. Improved seizure control can potentially save many lives.

BACKGROUND:Endovascular therapy (EVT) for stroke improves outcomes but is time sensitive. OBJECTIVE:To compare times to treatment and outcomes between patients taken to the closest primary stroke center (PSC) with those triaged in the field to a more distant comprehensive stroke center (CSC). METHODS:During the study, a portion of our region allowed field triage of patients who met severity criteria to a more distant CSC than the closest PSC. The remaining patients were transported to the closest PSC. We compared times to treatment and clinical outcomes between those two groups. Additionally, we performed a matched-pairs analysis of patients from both groups on stroke severity and distance to CSC. RESULTS:Over 2 years, 232 patients met inclusion criteria and were closest from the field to a PSC; 144 were taken to the closest PSC and 88 to the more distant CSC. The median additional transport time to the CSC was 7 min. Times from scene departure to alteplase and arterial puncture were faster in the direct group (50 vs 62 min; 93 vs 152 min; p<0.001 for both). Among patients who were independent before the stroke, the OR for less disability in the direct group was 1.47 (95% CI 1.13 to 1.93, p=0.003), and 2.06 (95% CI 1.10 to 3.89, p=0.01) for the matched pairs. CONCLUSIONS:In a densely populated setting, for patients with stroke who are EVT candidates and closest to a PSC from the field, triage to a slightly more distant CSC is associated with faster time to EVT, no delay to alteplase, and less disability at 90 days.

OBJECTIVE:To determine if the concentration and saturation of natalizumab (NTZ) administration at extended interval dosing (EID; every 5-8 weeks) over 18 months is able to be maintained in the range considered adequate to sustain the clinical efficacy of NTZ. METHODS:-integrin receptor saturations were analyzed via cytometry, in blood samples obtained at trough timepoints. RESULTS:Trough serum concentration was above the "therapeutic" concentration of 2.0 μg/mL in 72% of EID patients. Trough saturation was above the "therapeutic" 50% threshold in 79% of EID-treated patients. Our model predicted that at least 9 NTZ infusions/year are required to maintain adequate trough saturation and concentration levels. Higher body mass index (BMI) was a predictor of suboptimal trough saturation on EID NTZ. CONCLUSIONS:Trough α4-integrin receptor saturation >50% correlated with high clinical efficacy of NTZ in previous studies. A continual treatment with EID maintains receptor saturation and concentration that are in the "therapeutic range" for most patients. This finding provides biological plausibility for the clinical efficacy of NTZ EID. Patients with higher BMI may require closer clinical and MRI follow-up.

OBJECTIVE:To describe seizure outcomes in patients with medically refractory epilepsy who had evidence of bilateral mesial temporal lobe (MTL) seizure onsets and underwent MTL resection based on chronic ambulatory intracranial EEG (ICEEG) data from a direct brain-responsive neurostimulator (RNS) system. METHODS:We retrospectively identified all patients at 17 epilepsy centers with MTL epilepsy who were treated with the RNS System using bilateral MTL leads, and in whom an MTL resection was subsequently performed. Presumed lateralization based on routine presurgical approaches was compared to lateralization determined by RNS System chronic ambulatory ICEEG recordings. The primary outcome was frequency of disabling seizures at last 3-month follow-up after MTL resection compared to seizure frequency 3 months before MTL resection. RESULTS:We identified 157 patients treated with the RNS System with bilateral MTL leads due to presumed bitemporal epilepsy. Twenty-five patients (16%) subsequently had an MTL resection informed by chronic ambulatory ICEEG (mean = 42 months ICEEG); follow-up was available for 24 patients. After MTL resection, the median reduction in disabling seizures at last follow-up was 100% (mean: 94%; range: 50%-100%). Nine patients (38%) had exclusively unilateral electrographic seizures recorded by chronic ambulatory ICEEG and all were seizure-free at last follow-up after MTL resection; eight of nine continued RNS System treatment. Fifteen patients (62%) had bilateral MTL electrographic seizures, had an MTL resection on the more active side, continued RNS System treatment, and achieved a median clinical seizure reduction of 100% (mean: 90%; range: 50%-100%) at last follow-up, with eight of fifteen seizure-free. For those with more than 1 year of follow-up (N = 21), 15 patients (71%) were seizure-free during the most recent year, including all eight patients with unilateral onsets and 7 of 13 patients (54%) with bilateral onsets. SIGNIFICANCE/CONCLUSIONS:Chronic ambulatory ICEEG data provide information about lateralization of MTL seizures and can identify additional patients who may benefit from MTL resection.

Background and Purpose- The first of the 2 NINDS (National Institute of Neurological Disorders and Stroke) Study trials did not show a significant increase in early neurological improvement, defined as National Institutes of Health Stroke Scale (NIHSS) improvement by ≥4, with alteplase treatment. We hypothesized that early neurological improvement defined as a percentage change in NIHSS (percent change NIHSS) at 24 hours is superior to other definitions in predicting 3-month functional outcomes and using this definition there would be treatment benefit of alteplase over placebo at 24 hours. Methods- We analyzed the NINDS rt-PA Stroke Study (Parts 1 and 2) trial data. Percent change NIHSS was defined as ([admission NIHSS score-24-hour NIHSS score]×100/admission NIHSS score] and delta NIHSS as (admission NIHSS score-24-hour NIHSS score). We compared early neurological improvement using these definitions between alteplase versus placebo patients. We also used receiver operating characteristic curve to determine the predictive association of early neurological improvement with excellent 3-month functional outcomes (Barthel Index score of 95-100 and modified Rankin Scale score of 0-1), good 3-month functional outcome (modified Rankin Scale score of 0-2), and 3-month infarct volume. Results- There was a significantly greater improvement in the 24-hour median percent change NIHSS among patients treated with alteplase compared with the placebo group (28% versus 15%; P=0.045) but not median delta NIHSS (3 versus 2; P=0.471). Receiver operating characteristic curve comparison showed that percent change NIHSS (ROC_percent) was better than delta NIHSS (ROC_delta) and admission NIHSS (ROC_admission) with regards to excellent 3-month Barthel Index (ROC_percent, 0.83; ROC_delta, 0.76; ROC_admission, 0.75), excellent 3-month modified Rankin Scale (ROC_percent, 0.83; ROC_delta, 0.74; ROC_admission, 0.78), and good 3-month modified Rankin Scale (ROC_percent, 0.83; ROC_delta, 0.76; ROC_admission, 0.78). Conclusions- In the NINDS rt-PA trial, alteplase was associated with a significant percent change improvement in NIHSS at 24 hours. Percent change in NIHSS may be a better surrogate marker of thrombolytic activity and 3-month outcomes.

Memory consolidation is hypothesized to involve the distribution and restructuring of memory representations across hippocampal and cortical regions. Theories suggest that, through extended hippocampal-cortical interactions, cortical ensembles come to represent more integrated, or overlapping, memory traces that prioritize commonalities across related memories. Sleep processes, particularly fast sleep spindles, are thought to support consolidation, but evidence for this relationship has been mostly limited to memory retention benefits. Whether fast spindles provide a mechanism for neural changes hypothesized to support consolidation, including the strengthening of hippocampal-cortical networks and integration across memory representations, remains unclear, as does the specificity of regions involved. Using functional connectivity analyses of human fMRI data (both sexes), we show that fast spindle density during overnight sleep is related to enhanced hippocampal-cortical functional connectivity the next day, when re-studying information learned before sleep. Spindle density modulated connectivity in distinct hippocampal-cortical networks depending on the category of the consolidated stimuli. Specifically, spindle density correlated with functional connectivity between anterior hippocampus and ventromedial prefrontal cortex (vmPFC) for object-word pairs, and posterior hippocampus and posteromedial cortex (PMC) for scene-word pairs. Using multivariate pattern analyses, we also show fast spindle density during post-learning sleep is associated with greater pattern similarity, or representational overlap, across individual object-word memories in vmPFC the next day. Further, the relationship between fast spindle density and representational overlap in vmPFC was mediated by the degree of anterior hippocampal-vmPFC functional connectivity. Together, these results suggest fast spindles support the network distribution of memory traces, potentially restructuring memory representations in vmPFC.SIGNIFICANCE STATEMENTHow new experiences are transformed into long-term memories remains a fundamental question for neuroscience research. Theories suggest that memories are stabilized as they are reorganized in the brain, a process thought to be supported by sleep oscillations, particularly sleep spindles. Although sleep spindles have been associated with benefits in memory retention, it is not well understood how spindles modify neural memory traces. This study found that spindles during overnight sleep correlate with changes in neural memory traces, including enhanced functional connectivity in distinct hippocampal-cortical networks and increased pattern similarity amongst memories in the cortex. The results provide critical evidence that spindles during overnight sleep may act as a physiological mechanism for the restructuring of neural memory traces.

OBJECTIVE:To investigate clinical characteristics and treatment patterns in persistent post-traumatic headache attributed to mild traumatic brain injury. METHODS:A total of 100 individuals with persistent post-traumatic headache attributed to mild traumatic brain injury were enrolled between July 2018 and June 2019. Deep phenotyping was performed using a semi-structured interview while allodynia was assessed using the 12-item Allodynia Symptom Checklist. RESULTS:In 100 subjects with persistent post-traumatic headache, the mean headache frequency was 25.4 ± 7.1 days per month. The most common headache phenotype was chronic migraine-like headache (n = 61) followed by combined episodic migraine-like and tension-type-like headache (n = 29) while nine subjects reported "pure" chronic tension-type-like headache. The most frequent trigger factors were stress, lack of sleep, and bright lights. A history of preventive medication use was reported by 63 subjects, of which 79% reported failure of at least one preventive drug, while 19% reported failure of at least four preventive drugs. Cutaneous allodynia was absent in 54% of the subjects, mild in 23%, moderate in 17%, and severe in 6%. CONCLUSIONS:The headache profile of individuals with persistent post-traumatic headache most often resembled a chronic migraine-like phenotype or a combined episodic migraine-like and tension-type-like headache phenotype. Migraine-specific preventive medications were largely reported to be ineffective. Therefore, there is a pressing need for pathophysiological insights and disease-specific therapies.

INTRODUCTION/BACKGROUND:Deep brain stimulation (DBS) targeting the subthalamic nucleus (STN) has been shown to reliably improve several symptoms of Parkinson's disease (PD) in appropriately selected patients. Various factors may preclude patients from undergoing DBS and for them, non-invasive lesion-based therapies such as focused ultrasound and Gamma Knife (GK) radiosurgery may present a safer alternative. MATERIALS AND METHODS/METHODS:Based on preliminary positive reports of STN GK for PD, we conducted a prospective, open-label, single-center, pilot study in PD patients deemed potential candidates for unilateral DBS based on their disease characteristics, but contraindicated due to age >74, an irreversible bleeding diathesis, or significant comorbid medical disease. Stereotactic MRI-guided GK radiosurgery was performed using a single 110- or 120-Gy dose targeting the STN contralateral to the more symptomatic extremity. Clinical follow-up and imaging assessed the safety and efficacy of the procedure over a 12-month period. RESULTS:Four PD patients with medication-refractory tremors and disabling dyskinesias underwent unilateral STN GK radiosurgery. Contraindications to DBS included high-risk comorbid cardiovas-cular disease in 3 patients and an irreversible bleeding diathesis in 1. There were no immediate post-procedural adverse events. One patient who underwent left STN GK radiosurgery developed right hemiparesis and dysarthria 7 months post-procedure followed by hospitalization at 9 months for bacterial endocarditis and liver failure from which he died. The remaining 3 patients were free of adverse events up to 12 months post-procedure and experienced a reduction in contralateral rigidity, bradykinesia, and tremor. Upon extended follow-up, 2 patients developed subacute worsening of gait. One died at 16 months due to complications of a fall whereas the other saw no change in gait up to 42 months post-procedure. All 3 patients with adverse events demonstrated a hyper-response in the targeted area on follow-up neuroimaging. DISCUSSION/CONCLUSION/CONCLUSIONS:Despite the potential for clinical improvement, our results suggest that unilateral STN GK radiosurgery should be approached cautiously in medically frail PD patients who may be at higher risk of GK hyper-response and neurologic complications.

INTRODUCTION/BACKGROUND:Horner's syndrome has been reported after carotid artery endarterectomy (CEA) and carotid artery stenting (CS). This study evaluates pupillary changes after these procedures using automated pupillometry. METHODS:Retrospective analysis from a prospective database of pupillometry readings. Cases (14 patients with CEA/CS) were matched to controls (14 patients without CEA/CS). t test models were constructed to examine pupillary light reflex measures for CEA, CS, and controls. RESULTS:The 28 subjects had a mean age of 70 years, 50% were male, and 96% were Caucasian. There was no significant difference in the mean pupil size, constriction velocity (CV), dilation velocity (DV) between the procedural side compared to the contralateral side. However, the mean DV in the left eye after a left sided procedure among CS patients (.67) was lower than mean DV in left eye among controls (.88; P < .0001) and patients undergoing CEA (1.03; P < .0001). DISCUSSION/CONCLUSIONS:CS may result in disruption of the carotid artery plexus and decreased sympathetic response thereby reducing DV in the ipsilateral pupil. In addition, decreased CV can also been seen. CONCLUSION/CONCLUSIONS:The findings confirm and extend those of previous authors suggesting that pupillary changes may be seen after CS and automated handheld pupillometry may aid in the detection of Horner Syndrome.