Faculty Bibliography

Objective: To compare humoral and T-cell responses to COVID- 19 vaccines in 400 MS patients who were on Ocrelizumab ('OCR') v. other disease-modifying therapies ('non-OCR') at the time of vaccination. Introduction: Peripheral B-cell depletion with anti-CD20 therapies attenuates humoral responses to vaccines. Whether immune responses to COVID-19 vaccines differ between B-cell depleted and non-B cell depleted MS patients is not known.
Method(s): Consecutive MS patients from NYU MS Care Center were invited to participate if they completed COVID-19 vaccination >=6 weeks previously. Immune testing included anti-spike RBD antibody (Elecsys Anti-SARS-CoV-2) (Roche Diagnostics); multiplex bead-based immunoassays of antibody-responses to SARS-COV-2 spike proteins; T-cell responses to SARS-CoV-2 Spike protein using IFNgamma enzyme-linked immune-absorbent spot (Invitrogen) and TruCulture (Myriad RBM) assays; high dimensional immunophenotyping; and live virus immunofluorescencebased microneutralization assay.
Result(s): As of 7/15/2021, 105 MS subjects were enrolled (mean age: 40.5 years; 76% female; 41% non-white; 38% on OCR; 12% with prior COVID-19 infection). 95% were fully vaccinated with mRNA vaccines (Pfizer/Moderna); 5% - with adenovirus-based vaccine (Johnson&Johnson). Median time from sample collection to last vaccine was 79 days. Positive Elecsys Anti-SARS-CoV-2 Ab titers post-vaccine were detected in 11/37 (30%) in OCR (mean level: 702 U/mL among seropositives) and 54/54 (100%) patients in non-OCR (mean level: 2310 U/mL; p<0.0001). Positive response by multiplex assay (threshold of 'positive' defined as 2 SD below the mean for the non-OCR) were detected in 10/27 (37%) OCR and 29/31 (94%) non-OCR (p<0.00001). T-cell activation based on induced IFNgamma secretion (TruCulture) was detected in 20/25 (80%) OCR and 16/19 (84%) non-OCR patients (p=0.71).
Conclusion(s): Preliminary results suggest robust T-cell immune response to SARS-CoV2 vaccines in approximately 80% of both OCR and non-OCR MS patients. Antibody responses were markedly attenuated in OCR compared to non-OCR group. Updated results will be presented

BACKGROUND:To enhance knowledge about religious objections to brain death/death by neurologic criteria (BD/DNC), we surveyed hospital chaplains about their experience with and beliefs about BD/DNC. METHODS:We distributed an online survey to five chaplaincy organizations between February and July 2019. RESULTS:There were 512 respondents from all regions of the USA; they were predominantly Christian (450 of 497; 91%), board certified (413 of 490; 84%), and employed by community hospitals (309 of 511; 61%). Half (274 of 508; 56%) of the respondents had been involved in a case in which a family objected to BD/DNC on the basis of their religious beliefs. In 20% of cases involving a religious objection, the patient was Buddhist, Hindu, Jewish, or Muslim. Most respondents believed that a person who is declared brain dead in accordance with the American Academy of Neurology standard is dead (427 of 510; 84%). A minority of respondents believed that a family should be able to choose whether an assessment for determination of BD/DNC is performed (81 of 512; 16%) or whether organ support is discontinued after BD/DNC (154 of 510; 30%). These beliefs were all significantly related to lack of awareness that BD/DNC is the medical and legal equivalent of cardiopulmonary death throughout the USA and that organ support is routinely discontinued after BD/DNC, outside of organ donation. CONCLUSIONS:Hospital chaplains, who work at the intersection between religion and medicine, commonly encounter religious objections to BD/DNC. To prepare them for these situations, they should receive additional education about BD/DNC and management of religious objections to BD/DNC.

BACKGROUND:Infusion therapy refers to the intravenous administration of medicines and fluids for the treatment of status migrainosus, severe persistent headaches, or chronic headache. Headache practices and centers offer this treatment for patients as an alternative to the emergency department (ED) setting. However, little information is available in the literature on understanding the operations of an infusion center. OBJECTIVE:We sought to survey the Inpatient Headache & Emergency Medicine specialty section and the Academic Program Directors listserv of the American Headache Society (AHS) to better understand current practices. METHODS:A survey was advertised and distributed to the listservs of both the Inpatient Headache & Emergency Medicine specialty section and the Academic Program Directors, which combined included both academic and private practices. In addition, the survey was available on laptops at related events at an annual AHS meeting in Scottsdale. RESULTS:Of the 127 members of the combined group of both listservs, 50 responded with an overall survey response rate of 39%. Ten out of fifty were from programs with more than one responder completing the survey, leaving 40 unique headache programs. Academic programs made up the majority of programs (85%, 34/40). The total of 40 participating programs is comparable with the 47 academic headache programs listed on the American Migraine Foundation website at the time of the survey. Of the academic programs surveyed, most were hospital based (n = 23) compared with a satellite location (n = 11). Of all programs surveyed, 68% (27/40) offered infusion therapy. Of those that did not have an infusion practice (n = 13), the most common reason cited was insufficient staffing (n = 8). Key highlights of the survey included the following: The majority of programs offering infusions obtain prior authorization before scheduling (70%, 19/27) and offer patient availability 5 days/week (78%, 21/27) typically only during business hours (81%, 22/27). Programs reported that they typically give three to four medications during each infusion session (72%, 18/25). Treatment paradigms varied between programs. Programs surveyed were concentrated in the Northeast and Midwest regions of the United States. CONCLUSION/CONCLUSIONS:The limited number of headache infusion centers overall may contribute to the limited ability of headache infusion centers to prevent ED migraine visits. Headache patients can have unpredictable headache onset, and most of the infusion practices surveyed appeared to adapt to this by offering infusions most days during a work week. However, this need for multiple days per week may also explain the most common reason for not having an infusion practice, which is insufficient staffing. Various treatment paradigms are implemented by different practitioners, and future studies will have to focus on investigation of best practice.

Background: Ocrelizumab (OCR), a humanized, anti-CD20 antibody therapy for multiple sclerosis (MS), is given at 6-month intervals. Some patients on OCR report worsening of MS-related symptoms in the weeks leading up to their infusion ('wearing-off' phenomena), but there are no published reports quantifying symptom variation in relation to the timing of OCR infusions.
Objective(s): We will measure symptom burden using SymptoMScreen, NeuroQol and WPAI:MS at 3 points in each infusion cycle over 2 infusion cycles and also obtain Ocrelizumab concentration (PK), neurofilament light chain (NfL), B-cell subsets, and routine clinical labs prior to each infusion.
Aim(s): To quantitate change in symptom burden throughout the infusion cycle in OCR-treated MS patients and to determine which clinical and paraclinical variables correlate with symptom worsening.
Method(s): Prospective, observational, two-center study enrolled patients with relapsing and progressive forms of MS that are initiating OCR or who have been on OCR for >= 1 year (ClinicalTrials. gov Identifier: NCT04855617). All patients receive MS care at NYU MS Care Center (NYU) in New York, NY, or the Elliot Lewis MS Center for MS (ELC) in Wellesley, MA. Patients aged 18-80 and with EDSS scores between 0-7 are eligible for enrollment.
Result(s): 110 participants were enrolled and are actively followed in the study (55 from NYU/55 from ELC). At baseline visit, the mean age was 46.0+/-12.7 years; 64.6% were female; 31.8% were non-White; 20.0% were Hispanic/ Latino; disease duration was 12.6+/-9.6 years; OCR treatment duration was 2.8+/-1.0 years; mean EDSS was 3.3+/-2.1 (EDSS<4, n=69 (62.7%), EDSS>=4, n=41 (37.3%)). Breakdown by disease subtypes was: relapsing-remitting, n=68 (61.8%), secondary progressive, n=24 (21.8%), primary progressive, n=18 (16.4%). Among 58 patients who completed at least 2 questionnaires to date, the symptom burden, as assessed with the SymptoMScreen, was unchanged from week 4 post-infusion to week 12 post-infusion (p-values ranged from 0.2-0.9 for each of the 11 individual domains by Wilcoxon nonparametric test).
Conclusion(s): SymBOLS, designed to assess for the wearing-off effect in OCR-treated patients, has successfully enrolled 110 patients across two US sites. Preliminary data suggest there are no changes to symptom burden during the first half of the infusion cycle. Additional data regarding changes during the second half of the cycle as well as NeuroQoL and work productivity (WPAI) data will be presented

BACKGROUND:Intracranial artery dissection is a rare and generally under-recognized cause of ischaemic stroke or subarachnoid haemorrhage. OBJECTIVES/OBJECTIVE:The aim of this study was to analyse the efficacy of cone-beam computed tomography angiography (CBCT-A) to detect arterial ultrastructural alterations in intracranial artery dissection. METHOD/METHODS:This is an observational and retrospective case series. RESULTS:Between January 2018 and November 2020, four patients were admitted with an acute ischaemic stroke due to intracranial dissection studied with CBCT-A. In all cases, the CBCT-A documented vascular ultrastructural alterations related with the intracranial dissection. CONCLUSIONS:CBCT-A is an intraprocedural diagnostic technique that is useful for the diagnosis of intracranial dissections.

BACKGROUND:Only recently has the first disease-modifying therapy been approved for children with multiple sclerosis (MS) and practice patterns including substantial off-label use have evolved. Understanding attitudes towards treatment of paediatric MS and whether this has changed due to the ongoing COVID-19 pandemic is vital to guide future therapeutic trials and for developing guidelines that reflect practice. METHODS:We performed an online survey within the International Paediatric Multiple Sclerosis Study Group between July and September 2020. The survey was sent to 130 members from 25 countries and consisted of five sections: demographic data, treatment, disease modifying therapies and COVID-19, outcome and three patient cases. RESULTS:The survey was completed by 66 members (51%), both paediatric neurologists and adult neurologists. Fingolimod and β-interferons were the most frequently used disease-modifying therapies, especially among paediatric neurologists. Almost a third (31%) of respondents had altered their prescribing practice due to COVID-19, in particular at the beginning of the pandemic. CONCLUSIONS:The survey results indicate a tendency of moving from the traditional escalation therapy starting with injectables towards an early start with newer, highly effective disease modifying therapies. The COVID-19 pandemic only slightly affected prescribing patterns and treatment choices in paediatric MS.

Prion diseases or prionoses are a group of rapidly progressing and invariably fatal neurodegenerative diseases. The pathogenesis of prionoses is associated with self-replication and connectomal spread of PrP^Sc, a disease specific conformer of the prion protein. Microglia undergo activation early in the course of prion pathogenesis and exert opposing roles in PrP^Sc mediated neurodegeneration. While clearance of PrP^Sc and apoptotic neurons have disease-limiting effect, microglia-driven neuroinflammation bears deleterious consequences to neuronal networks. Apolipoprotein (apo) E is a lipid transporting protein with pleiotropic functions, which include controlling of the phagocytic and inflammatory characteristics of activated microglia in neurodegenerative diseases. Despite the significance of microglia in prion pathogenesis, the role of apoE in prionoses has not been established. We showed here that infection of wild type mice with 22L mouse adapted scrapie strain is associated with significant increase in the total brain apoE protein and mRNA levels and also with a conspicuous cell-type shift in the apoE expression. There is reduced expression of apoE in activated astrocytes and marked upregulation of apoE expression by activated microglia. We also showed apoE ablation exaggerates PrP^Sc mediated neurodegeneration. Apoe^-/- mice have shorter disease incubation period, increased load of spongiform lesion, pronounced neuronal loss, and exaggerated astro and microgliosis. Astrocytes of Apoe^-/- mice display salient upregulation of transcriptomic markers defining A1 neurotoxic astrocytes while microglia show upregulation of transcriptomic markers characteristic for microglial neurodegenerative phenotype. There is impaired clearance of PrP^Sc and dying neurons by microglia in Apoe^-/- mice along with increased level of proinflammatory cytokines. Our work indicates that apoE absence renders clearance of PrP^Sc and dying neurons by microglia inefficient, while the excess of neuronal debris promotes microglial neurodegenerative phenotype aggravating the vicious cycle of neuronal death and neuroinflammation.

Patients often recognize unmet needs that can improve patient-provider experiences in disease treatment management. These needs are rarely captured and may be hard to quantify in difficult-to-treat disease states such as drug-resistant epilepsy (DRE). To further understand challenges living with and managing DRE, a team of medical anthropologists conducted ethnographic field assessments with patients to qualitatively understand their experience with DRE across the United States. In addition, healthcare provider assessments were conducted in community clinics and Comprehensive Epilepsy Centers to further uncover patient-provider treatment gaps. We identified four distinct stages of the treatment and management journey defined by patients' perceived control over their epilepsy: Gripped in the Panic Zone, Diligently Tracking to Plan, Riding a Rollercoaster in the Dark, and Reframing Priorities to Redefine Treatment Success. We found that patients sought resources to streamline communication with their care team, enhanced education on treatment options beyond medications, and long-term resources to protect against a decline in control over managing their epilepsy once drug-resistant. Likewise, treatment management optimization strategies are provided to improve current DRE standard of care with respect to identified patient-provider gaps. These include the use of digital disease management tools, standardizing neuropsychiatrists into patients' initial care team, and introducing surgical and non-pharmacological treatment options upon epilepsy and DRE diagnoses, respectively. This ethnographic study uncovers numerous patient-provider gaps, thereby presenting a conceptual framework to advance DRE treatment. Further Incentivization from professional societies and healthcare systems to support standardization of the treatment optimization strategies provided herein into clinical practice is needed.

The spatiotemporal structure of functional magnetic resonance imaging (fMRI) signals has provided a valuable window into the network underpinnings of human brain function and dysfunction. Although some cross-regional temporal correlation patterns (functional connectivity; FC) exhibit a high degree of stability across individuals and species, there is growing acknowledgment that measures of FC can exhibit marked changes over a range of temporal scales. Further, FC can co-vary with experimental task demands and ongoing neural processes linked to arousal, consciousness and perception, cognitive and affective state, and brain-body interactions. The increased recognition that such interrelated neural processes modulate FC measurements has raised both challenges and new opportunities in using FC to investigate brain function. Here, we review recent advances in the quantification of neural effects that shape fMRI FC and discuss the broad implications of these findings in the design and analysis of fMRI studies. We also discuss how a more complete understanding of the neural factors that shape FC measurements can resolve apparent inconsistencies in the literature and lead to more interpretable conclusions from fMRI studies.