Faculty Bibliography

PURPOSE/OBJECTIVE:To report a case of IgG4-related ophthalmic disease, which presented with papillitis and subretinal deposits. METHODS:Observational case report with multimodal imaging. RESULTS:A 52-year-old man with a history of persistent lymphadenopathy presented with decreased vision in his left eye. Funduscopic examination demonstrated cuticular drusen in both eyes and florid edema of the left optic nerve, along with scattered circumscribed grey-yellow subretinal deposits that were distinct from the cuticular drusen. Swept-source optical coherence tomography demonstrated a hyper-reflective subretinal material corresponding to the grey-yellow subretinal deposits on clinical examination along with diffuse outer retinal disruption. Fundus autofluorescence revealed scattered hypoautofluorescence corresponding to cuticular drusen and also larger patches of hypoautofluorescence corresponding to the grey-yellow subretinal deposits. Fluorescein angiography demonstrated hypofluorescence corresponding to the large subretinal deposits and leakage at the optic nerve. Lymph node biopsy demonstrated IgG4-positive plasma cells and elevated serum IgG4 levels leading to a diagnosis of IgG4-related ophthalmic disease. The patient was treated with oral prednisone with subsequent resolution of the optic nerve edema. CONCLUSION/CONCLUSIONS:We describe multimodal imaging of unique retinal and optic nerve findings associated with IgG4-related ophthalmic disease. Our report broadens the spectrum of ocular involvement associated with IgG4-related disease.

SARS-CoV-2 messenger RNA vaccination in healthy individuals generates immune protection against COVID-19. However, little is known about SARS-CoV-2 mRNA vaccine-induced responses in immunosuppressed patients. We investigated induction of antigen-specific antibody, B cell and T cell responses longitudinally in patients with multiple sclerosis (MS) on anti-CD20 antibody monotherapy (n = 20) compared with healthy controls (n = 10) after BNT162b2 or mRNA-1273 mRNA vaccination. Treatment with anti-CD20 monoclonal antibody (aCD20) significantly reduced spike-specific and receptor-binding domain (RBD)-specific antibody and memory B cell responses in most patients, an effect ameliorated with longer duration from last aCD20 treatment and extent of B cell reconstitution. By contrast, all patients with MS treated with aCD20 generated antigen-specific CD4 and CD8 T cell responses after vaccination. Treatment with aCD20 skewed responses, compromising circulating follicular helper T (T_FH) cell responses and augmenting CD8 T cell induction, while preserving type 1 helper T (T_H1) cell priming. Patients with MS treated with aCD20 lacking anti-RBD IgG had the most severe defect in circulating T_FH responses and more robust CD8 T cell responses. These data define the nature of the SARS-CoV-2 vaccine-induced immune landscape in aCD20-treated patients and provide insights into coordinated mRNA vaccine-induced immune responses in humans. Our findings have implications for clinical decision-making and public health policy for immunosuppressed patients including those treated with aCD20.

Background/Purpose: Sudden unexpected death in epilepsy (SUDEP) is a sudden death in epilepsy patients not explained by status epilepticus, trauma, or any another known cause. In Dravet syndrome (DS) the incidence of SUDEP is about 6- fold higher than in other forms of epilepsy. The objective of this study was to compare the incidence of SUDEP in FFA-treated DS patients with literature reports of SUDEP incidence in patients with DS receiving anticonvulsive treatment without FFA.
Method(s): For the study group without FFA, publications were identified in PubMed searching 'Dravet [title] AND (mortality OR death OR SUDEP).' The FFA-treated population comprised patients from 3 sources: international phase 3 clinical trials, US and European Early Access Programs (EAPs), and a long-term, open-label study spanning 32 years. The incidence of SUDEP was expressed as deaths per 1,000 person-years of observation.
Result(s): Nine studies describing the incidence of SUDEP in DS were identified. Cooper (Cooper MS, Epilepsy Res 2016;128:43-47) was considered the most rigorous, reporting a SUDEP rate of 9.32 per 1000 person-years (98% CI, 4.46- 19.45). 732 patients treated with fenfluramine provided 1185.3 person-years. The FFA-SUDEP rate was below the lower limit of 98% CI reported by Cooper, whereas the SUDEP rate before starting FFA was similar to the literature numbers.
Conclusion(s): Results show a lower incidence of SUDEP and all-cause mortality in the FFA-treated population compared to patients without FFA of the literature. Further research is warranted to clarify influencing factors on SUDEP to reduce its risks. The data were first presented at AES 2020 (Virtual 74th American Epilepsy Society Annual Meeting)

Since the onset of the COVID-19 pandemic, a substantial proportion of COVID-19 patients had documented thrombotic complications and ischemic stroke. Several mechanisms related to immune mediated thrombosis, the renin angiotensin system, and the effect of SARS-CoV-2 in cardiac and brain tissue may contribute to the pathogenesis of ischemic stroke in patients with COVID-19. Simultaneously, significant strains on global healthcare delivery, including ischemic stroke management, have made treatment of stroke in the setting of COVID-19 particularly challenging. In this review we summarize the current knowledge on epidemiology, clinical manifestation and pathophysiology of ischemic stroke in patients with COVID-19 to bridge the gap from bench to bedside and clinical practice during the most challenging global health crisis of the last decades.

Substantial progress has been made in understanding how tumors escape immune surveillance. However, few measures to counteract tumor immune evasion have been developed. Suppression of tumor antigen expression is a common adaptive mechanism that cancers use to evade detection and destruction by the immune system. Epigenetic modifications play a critical role in various aspects of immune invasion, including the regulation of tumor antigen expression. To identify epigenetic regulators of tumor antigen expression, we established a transplantable syngeneic tumor model of immune escape with silenced antigen expression and used this system as a platform for a CRISPR-Cas9 suppressor screen for genes encoding epigenetic modifiers. We found that disruption of the genes encoding either of the chromatin modifiers activating transcription factor 7-interacting protein (Atf7ip) or its interacting partner SET domain bifurcated histone lysine methyltransferase 1 (Setdb1) in tumor cells restored tumor antigen expression. This resulted in augmented tumor immunogenicity concomitant with elevated endogenous retroviral (ERV) antigens and mRNA intron retention. ERV disinhibition was associated with a robust type I interferon response and increased T-cell infiltration, leading to rejection of cells lacking intact Atf7ip or Setdb1. ATF7IP or SETDB1 expression inversely correlated with antigen processing and presentation pathways, interferon signaling, and T-cell infiltration and cytotoxicity in human cancers. Our results provide a rationale for targeting Atf7ip or Setdb1 in cancer immunotherapy.

BACKGROUND:Although falls are common, costly, and often preventable, emergency department (ED)-initiated fall screening and prevention efforts are rare. The Geriatric Emergency Medicine Applied Research Falls core (GEAR-Falls) was created to identify existing research gaps and to prioritize future fall research foci. METHODS:GEAR's 49 transdisciplinary stakeholders included patients, geriatricians, ED physicians, epidemiologists, health services researchers, and nursing scientists. We derived relevant clinical fall ED questions and summarized the applicable research evidence, adhering to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Scoping Reviews. The highest priority research foci were identified at the GEAR Consensus Conference. RESULTS:We identified two clinical questions for our review (1) fall prevention interventions (32 studies) and (2) risk stratification and falls care plan (19 studies). For (1) 21/32 (66%) of interventions were a falls risk screening assessment and 15/21 (71%) of these were combined with an exercise program or physical therapy. For (2) eleven fall screening tools were identified, but none were feasible and sufficiently accurate for ED patients. For both questions, the most frequently reported study outcome was recurrent falls, but various process and patient/clinician-centered outcomes were used. Outcome ascertainment relied on self-reported falls in 18/32 (56%) studies for (1) and 9/19 (47%) studies for (2). CONCLUSION/CONCLUSIONS:Harmonizing definitions, research methods and outcomes is needed for direct comparison of studies. The need to identify ED-appropriate fall risk assessment tools and role of Emergency Medical Services (EMS) personnel persists. Multifactorial interventions, especially involving exercise, are more efficacious in reducing recurrent falls, but more studies are needed to compare appropriate bundle combinations. GEAR prioritizes Five research priorities: (1) EMS role in improving fall-related outcomes, (2) identifying optimal ED fall assessment tools, (3) clarifying patient-prioritized fall interventions and outcomes, (4) standardizing uniform fall ascertainment and measured outcomes, and (5) exploring ideal intervention components.