Faculty Bibliography

BACKGROUND:Toxic metabolic encephalopathy (TME) has been reported in 7-31% of hospitalized patients with coronavirus disease 2019 (COVID-19); however, some reports include sedation-related delirium and few data exist on the etiology of TME. We aimed to identify the prevalence, etiologies, and mortality rates associated with TME in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-positive patients. METHODS:We conducted a retrospective, multicenter, observational cohort study among patients with reverse transcriptase-polymerase chain reaction-confirmed SARS-CoV-2 infection hospitalized at four New York City hospitals in the same health network between March 1, 2020, and May 20, 2020. TME was diagnosed in patients with altered mental status off sedation or after an adequate sedation washout. Patients with structural brain disease, seizures, or primary neurological diagnoses were excluded. The coprimary outcomes were the prevalence of TME stratified by etiology and in-hospital mortality (excluding comfort care only patients) assessed by using a multivariable time-dependent Cox proportional hazards models with adjustment for age, race, sex, intubation, intensive care unit requirement, Sequential Organ Failure Assessment scores, hospital location, and date of admission. RESULTS:Among 4491 patients with COVID-19, 559 (12%) were diagnosed with TME, of whom 435 of 559 (78%) developed encephalopathy immediately prior to hospital admission. The most common etiologies were septic encephalopathy (n = 247 of 559 [62%]), hypoxic-ischemic encephalopathy (HIE) (n = 331 of 559 [59%]), and uremia (n = 156 of 559 [28%]). Multiple etiologies were present in 435 (78%) patients. Compared with those without TME (n = 3932), patients with TME were older (76 vs. 62 years), had dementia (27% vs. 3%) or psychiatric history (20% vs. 10%), were more often intubated (37% vs. 20%), had a longer hospital length of stay (7.9 vs. 6.0 days), and were less often discharged home (25% vs. 66% [all P < 0.001]). Excluding comfort care patients (n = 267 of 4491 [6%]) and after adjustment for confounders, TME remained associated with increased risk of in-hospital death (n = 128 of 425 [30%] patients with TME died, compared with n = 600 of 3799 [16%] patients without TME; adjusted hazard ratio [aHR] 1.24, 95% confidence interval [CI] 1.02-1.52, P = 0.031), and TME due to hypoxemia conferred the highest risk (n = 97 of 233 [42%] patients with HIE died, compared with n = 631 of 3991 [16%] patients without HIE; aHR 1.56, 95% CI 1.21-2.00, P = 0.001). CONCLUSIONS:TME occurred in one in eight hospitalized patients with COVID-19, was typically multifactorial, and was most often due to hypoxemia, sepsis, and uremia. After we adjustment for confounding factors, TME was associated with a 24% increased risk of in-hospital mortality.

This cross-sectional study evaluated eight embedded performance validity tests (PVTs) previously derived from the Rey Auditory Verbal Learning Test (RAVLT), Wechsler Memory Scale-IV-Logical Memory (LM), and Brief Visuospatial Memory Test-Revised (BVMT-R) recognition trials among a single mixed clinical sample of 108 neuropsychiatric patients (83 valid/25 invalid) with (n = 54) and without (n = 29) mild neurocognitive disorder. Among the overall sample, all eight recognition PVTs significantly differentiated valid from invalid performance (areas under the curve [AUCs] = .64-.81) with 26% to 44% sensitivity (≥89% specificity) at optimal cut-scores depending on the specific PVT. After subdividing the sample by cognitive impairment status, all eight PVTs continued to reliably identify invalid performance (AUC = .68-.91) with markedly increased sensitivities of 56% to 80% (≥89% specificity) in the unimpaired group. In contrast, among those with mild neurocognitive disorder, RAVLT False Positives and LM became nonsignificant, whereas the other six PVTs remained significant (AUC = .64-.77), albeit with reduced sensitivities of 32% to 44% (≥89% specificity) at optimal cut-scores. Taken together, results cross-validated BVMT-R and most RAVLT recognition indices as effective embedded PVTs for identifying invalid neuropsychological test performance with diverse populations including examinees with and without suspected mild neurocognitive disorder, whereas LM had more limited utility as an embedded PVT, particularly when mild neurocognitive disorder was present.

Objectives/UNASSIGNED:We sought to evaluate the success of telemedicine during New York City's COVID-19 pandemic stay-at-home period, and understand the distribution of sleep complaints seen. We also compared positive airway pressure (PAP) therapy compliance for a random patient sample to determine whether the pandemic influenced PAP usage. Methods/UNASSIGNED:Encounters from the stay-at-home period were reviewed for patient characteristics and clinician impressions, and were compared to administrative data from the prior 2.5 months ("control" period). PAP compliance was compared between the periods for a randomly selected group of forty patients. Results/UNASSIGNED:The telemedicine show rate was 89.37%. Sleep apnea then insomnia were the predominant diagnoses. Insomnia complaints were higher during the stay-at-home period. PAP compliance and AHI were similar between the periods. Conclusions/UNASSIGNED:Sleep apnea and insomnia were common complaints; insomnia was significantly more common during the pandemic. PAP compliance was similar between the two periods for a randomly selected cohort.

BACKGROUND:Intracerebral hemorrhage (ICH) occurs in ~20%-30% of stroke patients undergoing endovascular therapy (EVT). However, there is conflicting evidence regarding the effect of asymptomatic ICH (aICH) on post-EVT outcomes. We sought to evaluate the effect of aICH on immediate and 90-day post-EVT neurological outcomes. METHODS:In this post-hoc analysis of the multicenter, prospective Blood Pressure after Endovascular Therapy (BEST) study we identified subjects with ICH following EVT. This population was divided into no ICH, aICH, and symptomatic ICH (sICH). Associations with 90-day modified Rankin Scale (mRS) dichotomized by functional independence (0-2 vs 3-6) and early neurological recovery (ENR) were determined using univariate/multivariate logistic regression models. RESULTS:Of 485 patients enrolled in BEST, 446 had 90-day follow-up data available. 92 (20.6%) developed aICH, and 18 (4%) developed sICH. Compared with those without ICH, aICH was not associated with worse 90-day outcome or lower ENR (OR 0.84 [0.53-1.35], P=0.55, aOR 0.84 [0.48-1.44], P=0.53 for 90-day mRS 0-2; OR 0.77 [0.48-1.23], P=0.34, aOR 0.72 [0.43-1.22] for ENR). aICH was not associated with 90-day outcome or ENR in patients with mTICI ≥2 b (OR 0.78 [0.48-1.26], P=0.33 for 90-day mRS 0-2; OR 0.89 [0.69-1.12], P=0.15 for ENR). A higher proportion of patients with aICH had mTICI ≥2 b than those without ICH (97%vs 87%, P=0.01). CONCLUSIONS:aICH was not associated with worse outcomes in patients with large-vessel stroke treated with EVT. aICH was more frequent in patients with successful recanalization. Further validation of our findings in large cohort studies of EVT-treated patients is warranted.

OBJECTIVE:The purpose of this study was to establish whether a past psychiatric history could play a role in the development of psychiatric treatment-emergent adverse events (PTEAEs) in patients randomized to perampanel (PER) or placebo. METHODS:The development of PTEAEs was compared between patients with/without a psychiatric history in a post hoc analysis from four randomized placebo-controlled trials (RPCTs) of PER (304/305/306/335) in patients with treatment-resistant focal epilepsy. RESULTS:Among the 2,187 patients enrolled in the RPCTs, 352 (16.1%) had a psychiatric history (PER n = 244; placebo n = 108), while 1835 patients (83.9%) did not (PER n = 1325; placebo n = 510). Compared to patients without a psychiatric history, those with a positive history reported more PTEAEs for both patients randomized to PER (11.8% vs. 29.9%, p < 0.01) or to placebo (9.2% vs. 19.4%, p < 0.01). The prevalence of PTEAEs was not higher among patients randomized to 2 mg and 4 mg/day doses than placebo in both those with and without psychiatric history. Rather, the higher prevalence rates were among subjects randomized to 8 mg (29.8%) and 12 mg (36.4%) PER doses in patients with a past psychiatric history. SIGNIFICANCE:A psychiatric history appears to increase the risk of PTEAEs in patients randomized to placebo and to PER at doses of 8 and 12 mg/day. It should be identified in all patients considered for treatment with PER, particularly when prescribed at doses above 4 mg/day.

Cavernous sinus dural arteriovenous fistulas (CS-DAVF) can have an indolent course, with insidious onset, but still showing a high likelihood of spontaneous resolution.1 Nevertheless, symptoms in a subset of patients evolve more rapidly, with malignant signs on imaging, warranting intervention.2 We report on a patient in his 40s presenting with redness and proptosis of the right eye, intermittent blurred vision and diplopia. Once ophthalmological examination revealed increased intraocular pressure and imaging showed cortical venous congestion, the decision was made to obliterate a CS-DAVF involving the posteromedial right cavernous sinus.Multiple arteries including branches of the ascending pharyngeal artery, occipital artery and bilateral meningohypophyseal trunks supplied the fistula. Once transarterial embolization was deemed unsafe and both inferior petrosal sinuses did not grant access to the right cavernous sinus, a direct puncture to the cavernous sinus was performed to successfully coil the involved compartments.3-5 The aid of DynaCT imaging and needle guidance software is emphasized (video 1).neurintsurg;neurintsurg-2020-017118v1/V1F1V1Video 1.

BACKGROUND:Patients with bipolar spectrum disorders (BSDs) exhibit an increased risk of Parkinson's disease (PD). OBJECTIVE:The aim is to investigate whether a previous diagnosis of BSDs influences the phenotype of PD. METHODS:Of 2660 PD patients followed for at least 6 years (6-27), 250 (BSD-PD) had BSDs, 6-20 years before PD diagnosis; 48%-43% had a PD or BSD family history, and 34 carried glucocerebrosidase (GBA) and Parkin (PRKN) mutations. The cohort was split into a subset of 213 BSD-PD patients, compared with 426 matched PD patients without BSDs, and a subset of 34 BSD-PD and 79 PD patients carrying GBA or PRKN mutations. Carriers of mutations absent in BSD-PD patients and of synuclein triplication were excluded. Structured clinical interviews and mood disorder questionnaires assessed BSDs. Linear mixed models evaluated the assessment scales over time. Thirteen BSD-PD patients underwent subthalamic nucleus deep brain stimulation (STN-DBS) and were compared with 27 matched STN-DBS-treated PD patients. RESULTS:Compared to PD patients, BSD-PD showed (1) higher frequency of family history of PD (odds ratio [OR] 3.31; 2.32-4.71) and BSDs (OR 6.20; 4.11-9.35) 5); (2) higher incidence of impulse control disorders (hazard ratio [HR] 5.95, 3.89-9.09); (3) higher frequency of functional disorders occurring before PD therapy (HR, 5.67, 3.95-8.15); (4) earlier occurrence of delusions or mild dementia (HR, 7.70, 5.55-10.69; HR, 1.43, 1.16-1.75); and (5) earlier mortality (1.48; 1.11-1.97). Genetic BSD-PD subjects exhibited clinical features indistinguishable from nongenetic BSD-PD subjects. STN-DBS-treated BSD-PD patients showed no improvements in quality of life compared to the control group. CONCLUSIONS:BSDs as a prodrome to PD unfavorably shape their course and are associated with detrimental neuropsychiatric features and treatment outcomes. © 2021 International Parkinson and Movement Disorder Society.

Background: We prepared an anti-p21Ras scFv which could specifically bind with mutant and wild-type p21Ras. However, it cannot penetrate the cell membrane, which prevents it from binding to p21Ras in the cytoplasm. Here, the RGD4C peptide was used to mediate the scFv penetration into tumor cells and produce antitumor effects.
Method(s): RGD4C-EGFP and RGD4C-p21Ras-scFv recombinant expression plasmids were constructed to express fusion proteins in E. coli, then the fusion proteins were purified with HisPur Ni-NTA. RGD4C-EGFP was used as reporter to test the factors affecting RGD4C penetration into tumor cell. The immunoreactivity of RGD4C-p21Ras-scFv toward p21Ras was identified by ELISA and western blotting. The ability of RGD4C-p21Ras-scFv to penetrate SW480 cells and colocalization with Ras protein was detected by immunocytochemistry and immunofluorescence. The antitumor activity of the RGD4C-p21Ras-scFv was assessed with the MTT, TUNEL, colony formation and cell migration assays. Chloroquine (CQ) was used an endosomal escape enhancing agent to enhance endosomal escape of RGD4C-scFv.
Result(s): RGD4C-p21Ras-scFv fusion protein were successfully expressed and purified. We found that the RGD4C fusion protein could penetrate into tumor cells, but the tumor cell entry of was time and concentration dependent. Endocytosis inhibitors and a low temperature inhibited RGD4C fusion protein endocytosis into cells. The change of the cell membrane potential did not affect penetrability. RGD4C-p21Ras-scFv could penetrate SW480 cells, effectively inhibit the growth, proliferation and migration of SW480 cells and promote this cells apoptosis. In addition, chloroquine (CQ) could increase endosomal escape and improve antitumor activity of RGD4C-scFv in SW480 cells.
Conclusion(s): The RGD4C peptide can mediate anti-p21Ras scFv entry into SW480 cells and produce an inhibitory effect, which indicates that RGD4C-p21Ras-scFv may be a potential therapeutic antibody for the treatment of ras-driven cancers.
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Background and Objectives/UNASSIGNED:syndrome by collecting data, including EEG, from a large cohort of affected patients. Methods/UNASSIGNED:Syndrome Foundation and the literature. Data on clinical, genetic, neuroimaging, and neurophysiologic features were obtained. Results/UNASSIGNED:without any clear genotype-phenotype associations. Discussion/UNASSIGNED:syndrome presents with a developmental and epileptic encephalopathy with characteristics recognizable from neonatal age, which should prompt genetic screening. Sixty percent have drug-resistant epilepsy with focal or generalized seizures. We collected more than 90 pathogenic variants without observing overt genotype-phenotype associations.

Oral cannabidiol (CBD) is approved by the Food and Drug Administration (FDA) to treat patients with Dravet and Lennox-Gastaut syndromes, and tuberous sclerosis complex. The therapeutic potential of oral CBD formulations is limited by extensive first-pass hepatic metabolism. Following oral administration, the inactive metabolite blood concentration is ∼40-fold higher than CBD. Inhalation bypasses the pharmacokinetic (PK) variability attributed to irregular gastrointestinal absorption and first-pass hepatic metabolism and may efficiently deliver CBD into systemic circulation. This phase 1 study compared the PK of a dry-powder inhaler (DPI) CBD formulation (10 mg; excipient containing 2.1 mg CBD) with an oral CBD solution (Epidiolex®, 50 mg) in healthy participants. Following a single dose of Epidiolex or DPI CBD (n=10 PK evaluable participants each), the maximum CBD concentration for the inhaled powder was 71-fold higher than that of Epidiolex while administering 24-fold less CBD. The mean time to reach maximum concentration was 3.8 minutes for the DPI CBD formulation compared with 122 minutes for Epidiolex. Both Epidiolex and DPI CBD were generally safe and well-tolerated. These data indicate that DPI CBD provided more rapid onset and increased bioavailability than oral CBD and support further investigations on the use of DPI CBD for acute indications.