Faculty Bibliography

Andexanet-alpha is a specific reversal agent for direct factor Xa inhibitors (dFXaI). We aimed to project utilization rates and cost of andexanet for reversal of dFXaI-related major hemorrhage compared to 4-factor prothrombin complex concentrates (4F-PCC). A retrospective, multicenter review was conducted between 1/1/2014 and 7/15/2018 of patients who received 4F-PCC for reversal of dFXaI-related life-threatening hemorrhages. Total hospital reimbursements/patient were calculated based on national average MS-DRG payments adjusting for Medicare discounts. The projected cost for andexanet (based on dose and insurance) and % reimbursement/patient was compared to the actual cost of 4F-PCC. Hemostasis at 24 h (excellent/good vs. poor) and 30-day thrombotic complications were assessed. Of 126 patients who received 4F-PCC to reverse dFXaI, 46 (~ 10 per-year) met inclusion criteria. The median projected cost of andexanet was $22,120/patient, compared to $5670/patient for 4F-PCC (P < 0.001). The median hospital reimbursement was $11,492/hospitalization. The projected cost of andexanet alone would exceed the entire hospital reimbursement in 74% of patients by a median of $7604, while 4F-PCC cost exceeded the total hospital payments in 7% of patients in the same cohort (P < 0.001). Hemostasis was excellent/good in 72% of patients post-4F-PCC, compared to 82% in andexanet trials. Thromboembolic events occurred in 4% of patients following 4F-PCC versus 10% in andexanet trials. The projected cost of andexanet would exceed the national average hospital reimbursement/patient in nearly 75% of patients by over $7500/hospitalization. 4F-PCC was significantly less expensive, had lower rates of thrombosis, but also lower rates of good/excellent hemostasis compared to published data for andexanet.

OBJECTIVE:To determine the influence of self-reported Black African and Latin American identity on peripheral blood antibody-secreting cell (ASC) frequency in the context of relapsing-remitting MS. METHODS:In this cross-sectional study, we recruited 74 subjects with relapsing-remitting MS and 24 age-, and self-reported ethno-ancestral identity-matched healthy donors (HDs) to provide peripheral blood study samples. Subjects with MS were either off therapy at the time of study draw or on monthly natalizumab therapy infusions. Using flow cytometry, we assessed peripheral blood mononuclear cells for antibody-secreting B-cell subsets. RESULTS:subsets, were among those significantly increased. CONCLUSION:The enhanced peripheral blood plasmablast signature revealed among Black African or Latin American subjects with MS points to distinct underlying mechanisms associated with MS immunopathogenesis. This dysregulation may contribute to the disease disparity experienced by patient populations of Black African or Latin American ethno-ancestry.

There is increasing recognition in the neurological and psychiatric literature of patients with so-called isolated psychotic presentations (ie, with no, or minimal, neurological features) who have tested positive for neuronal autoantibodies (principally N-methyl-D-aspartate receptor antibodies) and who have responded to immunotherapies. Although these individuals are sometimes described as having atypical, mild, or attenuated forms of autoimmune encephalitis, some authors feel that that these cases are sufficiently different from typical autoimmune encephalitis to establish a new category of so-called autoimmune psychosis. We briefly review the background, discuss the existing evidence for a form of autoimmune psychosis, and propose a novel, conservative approach to the recognition of possible, probable, and definite autoimmune psychoses for use in psychiatric practice. We also outline the investigations required and the appropriate therapeutic approaches, both psychiatric and immunological, for probable and definite cases of autoimmune psychoses, and discuss the ethical issues posed by this challenging diagnostic category.

BACKGROUND AND PURPOSE/OBJECTIVE:The current left atrial appendage (LAA) classification system (cLAA-CS) categorizes it into 4 morphologies: chicken wing (CW), windsock, cactus, and cauliflower, though there is limited data on either reliability or associations between different morphologies and stroke risk. We aimed to develop a simplified LAA classification system and to determine its relationship to embolic stroke subtypes. METHODS:Consecutive patients with ischemic stroke from a prospective stroke registry who previously underwent a clinically-indicated chest CT were included. Stroke subtype was determined and LAA morphology was classified using the traditional system (in which CW = low risk) and a new system (LAA-H/L, in which low risk morphology (LAA-L) was defined as an acute angle bend or fold from the proximal/middle portion of the LAA and high risk morphology (LAA-H) was defined as all others). As a proof of concept study, we determined reliability for the two classification systems, and we assessed the associations between both classification systems with stroke subtypes in our cohort and previous studies. RESULTS:We identified 329 ischemic stroke patients with a qualifying chest CT (126 cardioembolic subtype, 116 embolic stroke of undetermined source (ESUS), and 87 non-cardioembolic subtypes). Intra- and inter-rater agreements improved using the LAA-H/L (0.95 and 0.85, respectively) vs. cLAA-CS (0.50 and 0.40). The LAA-H/L led to classifying 69 LAA morphologies that met criteria for CW as LAA-H. In fully adjusted models, LAA-H was associated with cardioembolic stroke (OR 5.4, 95%CI 2.1-13.7) and ESUS (OR 2.8 95% CI 1.2-6.4). Non-CW morphology was also associated with embolic stroke subtypes, but the effect size was much less pronounced. Studies using the cLAA-CS yielded mixed results for inter- and intra-rater agreements but most showed an association between a non-CW morphology and stroke with no difference among the three non-CW subtypes. CONCLUSION/CONCLUSIONS:The LAA-H/L classification system is simple, has excellent intra and inter-rater agreements, and may help risk identify patients with cardioembolic stroke subtypes. Larger studies are needed to validate these findings.

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Background/UNASSIGNED:Glioma is a family of primary brain malignancies with limited treatment options and in need of novel therapies. We previously demonstrated that the adhesion G protein-coupled receptor GPR133 (ADGRD1) is necessary for tumor growth in adult glioblastoma, the most advanced malignancy within the glioma family. However, the expression pattern of GPR133 in other types of adult glioma is unknown. Methods/UNASSIGNED:We used immunohistochemistry in tumor specimens and non-neoplastic cadaveric brain tissue to profile GPR133 expression in adult gliomas. Results/UNASSIGNED:We show that GPR133 expression increases as a function of WHO grade and peaks in glioblastoma, where all tumors ubiquitously express it. Importantly, GPR133 is expressed within the tumor bulk, as well as in the brain-infiltrating tumor margin. Furthermore, GPR133 is expressed in both isocitrate dehydrogenase (IDH) wild-type and mutant gliomas, albeit at higher levels in IDH wild-type tumors. Conclusion/UNASSIGNED:The fact that GPR133 is absent from non-neoplastic brain tissue but de novo expressed in glioma suggests that it may be exploited therapeutically.

BACKGROUND:Aquaporin-4 IgG (AQ4-IgG)-neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune inflammatory CNS disease that is predominantly characterized by severe relapses of optic neuritis and longitudinally extensive transverse myelitis (LETM). Women are disproportionately affected by AQ4-NMOSD, usually with disease onset occurring between the ages of 35-45. This has significant implications during pregnancy, as disease activity in NMOSD does not remit during gestation. The optimal treatment of NMOSD during pregnancy has not been established. METHODS:Case report. RESULTS:A 35-year old woman, 10 weeks pregnant, presented with bilateral optic neuritis and intractable hiccups. Workup revealed seropositive aquaporin-4 IgG. She was treated with pulse intravenous methylprednisolone and plasma exchange. Because of high risk for future relapse, Rituximab 1000 mg was given at weeks 15 and 17 of pregnancy. She had no further relapses during pregnancy. She delivered her daughter at 39 weeks without complication. CONCLUSION/CONCLUSIONS:This case demonstrated a favorable outcome in administering rituximab for NMOSD with disease onset during pregnancy. This description of therapy for disease onset during pregnancy is novel, and adds to the few existing case reports of administering rituximab during pregnancy.

Background/UNASSIGNED:Spinal neurofibromas (SNFs) in neurofibromatosis type 1 (NF1) can cause progressive spinal cord compression and neurological dysfunction. The MEK inhibitor selumetinib shrinks the majority of plexiform neurofibromas (PNs) in patients with NF1. We assessed the effect of selumetinib on SNF. Methods/UNASSIGNED:/dose twice daily (max 50 mg b.i.d.; 1 cycle = 28 days). We qualitatively assessed the effect of selumetinib on SNF-related spinal canal distortion, cerebrospinal fluid distribution, and spinal cord deformity on MRI. Results/UNASSIGNED:Twenty-four patients (18 male), median age 16.9 years (range, 6.2-60.3), had SNF, 22 of which were associated with the same nerves as the target PN assessed on the clinical trial. Twenty patients had spinal cord deformity. Twenty-three patients completed at least 12 treatment cycles to date. Eighteen patients showed subtle to a marked improvement in SNF burden, 5 remained stable, and no worsening was observed during treatment. Conclusions/UNASSIGNED:This is the first study describing the effect of selumetinib on SNF. Of 24 patients, 18 exhibited some improvement of SNF burden on imaging. These findings suggest that selumetinib may prevent the worsening of cord compression, potentially reducing the need for surgical interventions in select patients or benefitting patients who do not have a surgical option. Prospective evaluation of the clinical benefit of selumetinib for SNF is warranted.

Background and Purpose/UNASSIGNED:Many studies supporting the association between specific surgical procedure categories and postoperative stroke (POS) do not account for differences in patient-level characteristics between and within surgical categories. The risk of POS after high-risk procedure categories remains unknown after adjusting for such differences in patient-level characteristics. Methods/UNASSIGNED:Using inpatients in the American College of Surgeons National Surgical Quality Initiative Program database, we conducted a retrospective cohort study between January 1, 2000, and December 31, 2010. Our primary outcome was POS within 30 days of surgery. We characterized the relationship between surgical- and individual patient-level factors and POS by using multivariable, multilevel logistic regression that accounted for clustering of patient-level factors with surgical categories. Results/UNASSIGNED:We identified 729 886 patients, 2703 (0.3%) of whom developed POS. Dependent functional status (odds ratio [OR]: 4.11, 95% confidence interval [95% CI]: 3.60-4.69), history of stroke (OR: 2.35, 95%CI: 2.06-2.69) or transient ischemic attack (OR: 2.49 95%CI: 2.19-2.83), active smoking (OR: 1.20, 95%CI: 1.08-1.32), hypertension (OR: 2.11, 95%CI: 2.19-2.82), chronic obstructive pulmonary disease (OR: 1.39 95%CI: 1.21-1.59), and acute renal failure (OR: 2.35, 95%CI: 1.85-2.99) were significantly associated with POS. After adjusting for clustering, patients who underwent cardiac (OR: 11.25, 95%CI: 8.52-14.87), vascular (OR: 4.75, 95%CI: 3.88-5.82), neurological (OR: 4.60, 95%CI: 3.48-6.08), and general surgery (OR: 1.40, 95%CI: 1.15-1.70) had significantly greater odds of POS compared to patients undergoing other types of surgical procedures. Conclusions/UNASSIGNED:Vascular, cardiac, and neurological surgery remained strongly associated with POS in an analysis accounting for the association between patient-level factors and surgical categories.

AIMS:Exposure to recurrent hypoglycemia (RH) is common in diabetic patients receiving glucose-lowering therapies and is implicated in causing cognitive impairments. Despite the significant effect of RH on hippocampal function, the underlying mechanisms are currently unknown. Our goal was to determine the effect of RH exposure on hippocampal metabolism in treated streptozotocin-diabetic rats. METHODS:Hyperglycemia was corrected by insulin pellet implantation. Insulin-treated diabetic (ITD) rats were exposed to mild/moderate RH once a day for 5 consecutive days. RESULTS:The effect of RH on hippocampal metabolism revealed 65 significantly altered metabolites in the RH group compared with controls. Several significant differences in metabolite levels belonging to major pathways (eg, Krebs cycle, gluconeogenesis, and amino acid metabolism) were discovered in RH-exposed ITD rats when compared to a control group. Key glycolytic enzymes including hexokinase, phosphofructokinase, and pyruvate kinase were affected by RH exposure. CONCLUSION:Our results demonstrate that the exposure to RH leads to metabolomics alterations in the hippocampus of insulin-treated streptozotocin-diabetic rats. Understanding how RH affects hippocampal metabolism may help attenuate the adverse effects of RH on hippocampal functions.