Surveying neurologist perspectives and knowledge of epilepsy surgery to identify barriers to surgery referral.

OBJECTIVE: Epilepsy surgery is an effective means of treating medically refractory epilepsy (MRE), but it remains underused. We aimed to analyze the perspectives and knowledge of referring neurologists in the New York metropolitan area, who serve a large epilepsy population. METHODS: We adapted a previous Canadian survey by Roberts et al. (2015), adding questions regarding demographic descriptors, insurance coverage, training and practice details, and perceived social barriers for patients. We surveyed neurologists directly affiliated with Montefiore Medical Center and those referring to Montefiore's Comprehensive Epilepsy Center. Participants had 10 weeks to fill out an online Qualtrics survey with weekly reminders. RESULTS: Of 117 neurologists contacted, 51 eligible neurologists completed the survey (63.8% Montefiore, 35.0% referring group). A high proportion of the results were from epilepsy-trained individuals (41.2%) and neurologists who graduated residency ≤19 years ago (80.4%). 80.4% of respondents felt that epilepsy surgery is safe, but only 56.9% would refer a patient for surgical workup after two failed trials of anti-seizure medications. Epileptologists and providers with a larger volume of epilepsy patients and electroencephalogram readings had better knowledge of the epilepsy surgery workup guidelines. When asked to rank social barriers to patients receiving surgery, participants were most concerned about lack of social support, financial insecurity, and a patient's dual role as a caregiver. SIGNIFICANCE: Our study suggests continued reluctance of neurologists regarding epilepsy surgery, and deficiencies in the knowledge and adherence to the recommended guidelines. In the context of prior studies, these results showed improved understanding of the definition of MRE (80.4%) and an increased likelihood to refer eligible patients as early as possible (78.4%) in line with current consensus recommendations. The finding that epilepsy-trained and more epilepsy/electroencephalogram-facing neurologists showed better understanding of the guidelines suggests that increased education efforts should be targeted at non-epileptologists. PLAIN LANGUAGE SUMMARY: Our study asked New York City doctors about their approach to epilepsy surgery. Many do not consider it as early as they could in treatment plans. The doctors with extra epilepsy training were better at knowing when to consider surgery.

Readability and content gaps in online epilepsy surgery materials as potential health literacy and shared-decision-making barriers.

OBJECTIVE: Epilepsy surgery is an effective albeit underused treatment for refractory epilepsy, and online materials are vital to patient understanding of the complex process. Our goal is to analyze the readability and content inclusion of online patient health education materials designed for epilepsy surgery. METHODS: A private browser setting was used on Google and Bing to identify the top 100 search results for the terms "epilepsy+surgery". Scientific papers, insurance pages, pay-wall access sites, and non-text content were excluded. The website text was reformatted to exclude graphics, contact information, links, and headers. Readability metrics were calculated using an online tool. Text content was analyzed for inclusion of important concepts (pre-surgical evaluation, complications, risks of continued seizures, types of surgery, complimentary diagrams/audiovisual material). Comparison of readability and content inclusion was performed as a function of organization types (epilepsy center, community health organization, pediatric-specific) and location (region, country). RESULTS: Browser search yielded 82 distinct websites with information regarding epilepsy surgery, with 98.7% of websites exceeding the recommended 6th-grade reading level for health information. Epilepsy centers had significantly worse readability (Flesch-Kincaid Grade Level (FKGL) P < 0.01 and Flesch Reading Ease (FRE) P < 0.05). Content analysis showed that only 37% of websites discuss surgical side effects and only 23% mention the risks of continued seizures. Epilepsy centers were less likely to report information on surgical side effects (P < 0.001). UK-based websites had better readability (FKGL P < 0.01 and FRE P < 0.01) and were more likely to discuss side effects (P = 0.01) compared to US-based websites. SIGNIFICANCE: The majority of online health content is overly complex and relatively incomplete in multiple key areas important to health literacy and understanding of surgical candidacy. Our findings suggest academic organizations, including level 4 epilepsy centers, need to simplify and broaden online education resources. More comprehensive, publicly accessible, and readable information may lead to better-shared decision-making.

Suppression of Experimental Autoimmune Encephalomyelitis by ILT3.Fc.

Multiple sclerosis (MS) is a chronic autoimmune disease of the CNS that is characterized by demyelination, axonal loss, gliosis, and inflammation. The murine model of MS is the experimental autoimmune encephalopathy (EAE) induced by immunization of mice with myelin oligodendrocyte glycoprotein (MOG)35-55 Ig-like transcript 3 (ILT3) is an inhibitory cell surface receptor expressed by tolerogenic human dendritic cells. In this study, we show that the recombinant human ILT3.Fc protein binds to murine immune cells and inhibits the release of proinflammatory cytokines that cause the neuroinflammatory process that result in paralysis. Administration of ILT3.Fc prevents the rapid evolution of the disease in C57BL/6 mice and is associated with a profound reduction of proliferation of MOG35-55-specific Th1 and Th17 cells. Inhibition of IFN-γ and IL-17A in mice treated with ILT3.Fc is associated with delayed time of onset of the disease and its evolution to a peak clinical score. Neuropathological analysis shows a reduction in inflammatory infiltrates and demyelinated areas in the brains and spinal cords of treated mice. These results indicate that inhibition of Th1 and Th17 development provides effective suppression of EAE and suggests the feasibility of a clinical approach based on the use of ILT3.Fc for treatment of MS. Furthermore, our results open the way to further studies on the effect of the human ILT3.Fc protein in murine experimental models of autoimmunity and cancer.

Molecular and Cellular Characterization of Human CD8 T Suppressor Cells.

Bidirectional interactions between dendritic cells and Ag-experienced T cells initiate either a tolerogenic or immunogenic pathway. The outcome of these interactions is of crucial importance in malignancy, transplantation, and autoimmune diseases. Blockade of costimulation results in the induction of T helper cell anergy and subsequent differentiation of antigen-specific CD8+ T suppressor/regulatory cells (Ts). Ts, primed in the presence of inhibitory signals, exert their inhibitory function in an antigen-specific manner, a feature with tremendous clinical potential. In transplantation or autoimmunity, antigen-specific Ts can enforce tolerance to auto- or allo-antigens, while otherwise leaving the immune response to pathogens uninhibited. Alternatively, blockade of inhibitory receptors results in the generation of cytolytic CD8+ T cells, which is vital toward defense against tumors and viral diseases. Because CD8+ T cells are MHC Class I restricted, they are able to recognize HLA-bound antigenic peptides presented not only by APC but also on parenchymal cells, thus eliciting or suppressing auto- or allo-immune reactions.

ILT3.Fc inhibits the production of exosomes containing inflammatory microRNA in supernatants of alloactivated T cells.

Immune activation needs to be tightly regulated to control immune-mediated tissue damage. Inhibitory pathways serve to terminate an immune response and resolve inflammation. Persistent exposure to antigens can drive development of adaptive regulatory cells. Similarly exposure of activated T cells to the recombinant ILT3-Fc molecule during priming triggers the differentiation of CD8 T suppressor cells and the induction of CD4 T helper anergy. Ts express high levels of immunoregulatory signature genes together with low levels of microRNA which control their function. Analysis of microRNA contained by exosomes from cultures in which T cells were alloactivated in the presence or absence of ILT3.Fc, demonstrated that this agent inhibits the release of inflammatory microRNA. The source of such inflammatory microRNA was found to reside in alloactivated CD4 T cells, since exosomes from MLC primed CD4 T cells were shown to diminish the suppressive activity of ILT3-Fc-induced CD8(+) Ts at high effector to suppressor T cell ratios. This indicates that inflammatory exosomes can swing the balance between effector and regulatory T cells in favor of immunity. These data suggest that isolation and characterization of micro-RNA containing exosomes in patients' circulation may be of use for treatment, prevention and monitoring of immune activation.

Allospecific CD8 T suppressor cells induced by multiple MLC stimulation or priming in the presence of ILT3.Fc have similar gene expression profiles.

Alloantigen specific CD8 T suppressor cells can be generated in vitro either by multiple stimulations of CD3 T cells with allogeneic APC or by single stimulation in primary MLC containing recombinant ILT3.Fc protein. The aim of the present study was to determine whether multiple MLC stimulation induced in CD8(+) CD28(-) T suppressor cells molecular changes that are similar to those observed in CD8 T suppressor cells from primary MLC containing ILT3.Fc protein. Our study demonstrates that the characteristic signatures of CD8 T suppressor cells, generated by either of these methods are the same consisting of up-regulation of the BCL6 transcriptional repressor and down-regulation of inflammatory microRNAs, miR-21, miR-30b, miR-146a, and miR-155 expression. In conclusion microRNAs which are increased under inflammatory conditions in activated CD4 and CD8 T cells with helper or cytotoxic function show low levels of expression in CD8 T cells which have acquired antigen-specific suppressor activity.