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During the COVID-19 pandemic, health systems rapidly introduced in-home telehealth to maintain access to care. Evidence is evolving regarding telehealth's impact on health disparities. Our objective was to evaluate associations between socioeconomic factors and rurality with access to ambulatory care and telehealth use during the COVID-19 pandemic.We conducted a retrospective study at an academic medical centre in midwestern United States. We included established and new patients who received care during a one-year COVID-19 period vs pre-COVID-19 baseline cohorts. The primary outcome was the occurrence of in-person or telehealth visits during the pandemic. Multivariable analyses identified factors associated with having a health care provider visit during the COVID-19 vs pre-COVID-19 period, as well as having at least one telehealth visit during the COVID-19 period.All patient visit types were lower during the COVID-19 vs the pre-COVID-19 period. During the COVID-19 period, 125 855 of 255 742 established patients and 53 973 new patients had at least one health care provider visit, with 41.1% of established and 23.5% of new patients having at least one telehealth visit. Controlling for demographic and clinical characteristics, established patients had 30% lower odds of having any health care provider visit during COVID-19 vs pre-COVID-19 (adjusted odds ratio (aOR) = 0.71, 95% confidence interval (CI) = 0.698-0.71) period. Factors associated with lower odds of having a telehealth visit during COVID-19 period for established patients included older age, self-pay or other insurance vs commercial insurance, Black or Asian vs White race and non-English preferred languages. Female patients, patients with Medicare or Medicaid coverage, and those living in lower income zip codes were more likely to have a telehealth visit. Living in a zip code with higher average internet access was associated with telehealth use but living in a rural zip code was not. Factors affecting telehealth visit during the COVID-19 period for new patients were similar, although new patients living in more rural areas had a higher odds of telehealth use.Healthcare inequities existed during the COVID-19 pandemic, despite the availability of in-home telehealth. Patient-level solutions targeted at improving digital literacy, interpretive services, as well as increasing access to stable high-speed internet are needed to promote equitable health care access.

Background In this pilot study, we examined the characteristics of patients with and without central nervous system (CNS) malignancies who developed immune checkpoint inhibitor (ICI)‐induced encephalopathy. Methods We identified adult patients treated with ICIs between 1 January 2013 and 9 May 2018 at our tertiary care center who developed encephalopathy within 30 days of the last dose of ICI without other explained causes. Demographic and clinical features were compared between patients with primary and metastatic malignant CNS tumors and those without. Results Of the 480 patients treated with ICIs, 14 (2.9%) developed encephalopathy induced by nivolumab (8), pembrolizumab (4), and combined ipilimumab‐nivolumab (2). Median age was 64.5 years. Patients with CNS malignancies tolerated more treatment cycles and developed encephalopathy later than patients without CNS lesions (20 and 32 days, respectively, p = 0.04) following ICI initiation. Four of seven patients with CNS tumors developed new contrast‐enhancing lesions on brain imaging despite having no changes on imaging for a median of 61 (30–545) days. Electroencephalogram (EEG) revealed features of generalized dysfunction in patients in both cohorts. Two patients without and three with CNS malignancies were treated with steroids. Two thirds of patients without and 29% of those with CNS malignancies expired during ICI therapy or shortly thereafter. Conclusions Lack of the uniform evaluation limits the definitive conclusion of the cause of encephalopathy in some patients but reflects the standard of care at the time of their assessment. ICI‐associated neurotoxicity presenting with encephalopathy is an ominous complication of ICI therapy, especially if left untreated. Prompt recognition and involvement of multidisciplinary care, including neurologists, would facilitate timely administration of recommended therapies., Patients receiving treatment with immune checkpoint inhibitors, a novel class of anticancer medications, can develop confusion, decreased responsiveness, headaches, and seizures that, if left untreated, can be fatal. We assessed the frequency of these neurological side effects in patients with and without tumors of the brain and compared their management at our institution. We found that the evaluation of patients in both groups was often incomplete. We also determined that the majority of patients were not treated according to the recommended guidelines and most of these patients were deceased shortly following their admission to the hospital. We concluded that the complications of immune checkpoint inhibitor therapy are not readily recognized by practitioners. We summarized the existing recommendations for the evaluation and treatment of these patients and proposed that neurologists be included in multidisciplinary efforts to treat these patients.

Background: Ambulatory care underwent rapid changes at the onset of the COVID-19 pandemic. Care for people with diabetes shifted from an almost exclusively in-person model to a hybrid model consisting of in-person visits, telehealth visits, phone calls, and asynchronous messaging. Methods: We analyzed data for all patients with diabetes and established with a provider at a large academic medical center to identify in-person and telehealth ambulatory provider visits over two periods of time (a “pre-COVID” and “COVID” period). Results: While the number of people with diabetes and any ambulatory provider visit decreased during the COVID period, telehealth saw massive growth. Per Hemoglobin A1c, glycemic control remained stable from the pre-COVID to COVID time periods. Conclusions: Findings support continued use of telehealth, and we anticipate hybrid models of care will be utilized for people with diabetes beyond the pandemic.

Clinical trials of a brain-responsive neurostimulator, RNS® System (RNS), excluded patients with a vagus nerve stimulator, VNS® System (VNS). The goal of this study was to evaluate seizure outcomes and safety of concurrent RNS and VNS stimulation in adults with drug-resistant focal-onset seizures.A retrospective multicenter chart review was performed on all patients with an active VNS and RNS who were treated for a minimum of 6 months with both systems concurrently. Frequency of disabling seizures at baseline before RNS, at 1 year after RNS placement, and at last follow-up were used to calculate the change in seizure frequency after treatment. Data on adverse events and complications related to each device were collected.Sixty-four patients from 10 epilepsy centers met inclusion criteria. All but one patient received RNS after VNS. The median follow-up time after RNS implantation was 28 months. Analysis of the entire population of patients with active VNS and RNS systems revealed a median reduction in seizure frequency at 1 year post-RNS placement of 43% with a responder rate of 49%, and at last follow-up a 64% median reduction with a 67% responder rate. No negative interactions were reported from the concurrent use of VNS and RNS. Stimulation-related side-effects were reported more frequently in association with VNS (30%) than with RNS (2%).Our findings suggest that concurrent treatment with VNS and RNS is safe and that the addition of RNS to VNS can further reduce seizure frequency.

Purpose Both vagal nerve stimulation (VNS) and responsive neurostimulation (RNS System) are treatment options for medically refractory focal epilepsy. The mechanism of action of both devices remains poorly understood. Limited prior evidence suggests that acute VNS stimulation may reduce epileptiform activity and cause EEG desynchronization on electrocorticography (ECoG). Our study aims to isolate effects of VNS on ECoG as recorded by RNS System in patients who have both devices, by comparing ECoG samples with and without acute VNS stimulation. Methods Ten 60-second ECoGs each from 22 individuals at 3 epilepsy centers were obtained-5 ECoGs with VNS "off" and 5 ECoGs with VNS "on." Electrocorticograps containing seizures or loss of telemetry connection artifact were excluded from analysis (total of 169 ECoGs were included). Electrocorticographs were analyzed for differences in spectral content by generating average spectrograms for "on" and "off" states and using a linear mixed-effects model to isolate effects of VNS stimulation. Results Acute VNS stimulation reduced average power in the theta band by 4.9%, beta band by 3.8%, and alpha band by 2.5%. The reduction in theta power reached statistical significance with a P value of Conclusions Our results provide evidence that acute VNS stimulation results in desynchronization of specific frequency bands (salient decrease in theta and beta bands, smaller decrease in alpha band) in ECoGs recorded by the RNS device in patients with dual (VNS and RNS) neurostimulators. This finding offers support for desynchronization as a theorized mechanism of action of VNS. Further research may lead to future improved neurostimulator efficacy by informing optimal stimulation programming parameters.

BackgroundOne-third of epilepsy patients become refractory to anti-epileptic medications. In these patients neurostimulation devices are considered as potential treatment options. The FDA has approved vagal nerve stimulation (VNS) and responsive neurostimulation (RNS system) for the treatment of focal epilepsy. There is limited data on interaction between the two devices and their mechanism of action is actively being researched. Limited prior evidence suggests that acute VNS stimulation may reduce epileptiform activity and cause EEG desynchronization. Our study aims to isolate the effects of VNS on electrocorticography (ECoG) as recorded by the RNS system.MethodsECoG from 20 patients were obtained. For each patient, five pairs of ‘on’ recordings of 60-second VNS stimulation on ECoGs were compared to ‘off’ baseline 60s recordings. ECoGs were analyzed for differences in spectral content.ResultsPreliminary results show that acute VNS stimulation is associated with significant decrease in power (i.e. desynchronization) in the theta, beta, and (50–70 Hz) gamma bands.ConclusionThis study demonstrates desynchronization as a mechanism of action of VNS, as recorded by the RNS system. As more patients receive dual neurostimulators, it will be crucial to understand isolated effects of each device to optimize programming and improve therapeutic efficacy.navya.joseph@unmc.edu

Objective To assess feasibility, patient satisfaction, and financial advantages of telemedicine for epilepsy ambulatory care during the current COVID-19 pandemic. Methods The demographic and clinical characteristics of all consecutive patients evaluated via telemedicine at a level 4 epilepsy center between March 20 and April 20, 2020 were obtained retrospectively from electronic medical records. A telephone survey to assess patient satisfaction and preferences was conducted within one month following the initial visit. Results Among 223 telehealth patients, 85.7% used both synchronous audio and video technology. During the visits, 39% of patients had their anticonvulsants adjusted while 18.8% and 11.2% were referred to laboratory/diagnostic testing and specialty consults, respectively. In a post-visit survey, the highest degree of satisfaction with care was expressed by 76.9% of patients. The degree of satisfaction tended to increase the further a patient lived from the clinic (p = 0.05). Beyond the pandemic, 89% of patients reported a preference for continuing telemedicine if their epilepsy symptoms remained stable, while only 44.4% chose telemedicine should their symptoms worsen. Inclement weather and lack of transportation were factors favoring continued use of telemedicine. An estimated cost saving to patient attributed to telemedicine was $30.20 ± 3.8 per visit. Significance Our findings suggest that epilepsy care via telemedicine provided high satisfaction and economic benefit, without compromising patients’ quality of care, thereby supporting the use of virtual care during current and future epidemiological fallouts. Beyond the current pandemic, patients with stable seizure symptoms may prefer to use telemedicine for their epilepsy care.

Purpose Prefabricated arrays with a limited number of electrodes offer an opportunity to hasten the diagnosis of seizures; however, their accuracy to detect seizures is unknown. We examined the utility of two limited-montage EEG setups for the detection of nonconvulsive seizures. Methods Thirty previously interpreted EEG segments with nonconvulsive seizures from 30 patients and 60 segments with background slowing or normal EEG from 60 patients were rendered in a bipolar "double banana" montage, a double distance "neonatal" montage, and a circumferential "hatband" montage. Experts reviewed 60 to 180 seconds long segments to determine whether seizures were present and if the EEG data provided were sufficient to make a decision on escalation of clinical care by ordering an additional EEG or prescribing anticonvulsants. The periodic patterns on the ictal-interictal continuum were specifically excluded for this analysis to keep the focus on definite electrographic seizures. Results The sensitivities for seizure of the neonatal and hatband montages were 0.96 and 0.84, respectively, when compared with full montage EEG, whereas the specificities were 0.94 and 0.98, respectively. Appropriate escalation of care was suggested for 96% and 92% of occurrences of seizure patterns in neonatal and hatband montages, respectively. When compared with clinical EEG, the sensitivities of the neonatal and hatband montages for seizure diagnosis were 0.85 and 0.69, respectively. Conclusions Nonconvulsive seizures were detected with high accuracy using the limited electrode array configuration in the neonatal and hatband montages. The sensitivity of the neonatal montage EEG in detecting seizures was superior to that of a hatband montage. These findings suggest that in some patients with nonconvulsive seizures, limited-montage EEG may allow to differentiate ictal and slow patterns.

Neurons that form ribbon-style synapses are specialized for continuous exocytosis. To this end, their synaptic terminals contain numerous synaptic vesicles, some of which are ribbon associated, that have difference susceptibilities for undergoing Ca 2+ -dependent exocytosis. In this study, we probed the relationship between previously defined vesicle populations and determined their fusion competency with respect to SNARE complex formation. We found that both the rapidly releasing vesicle pool and the releasable vesicle pool of the retinal bipolar cell are situated at the ribbon-style active zones, where they functionally interact. A peptide inhibitor of SNARE complex formation failed to block exocytosis from either pool, suggesting that these two vesicle pools have formed the SNARE complexes necessary for fusion. By contrast, a third, slower component of exocytosis was blocked by the peptide, as was the functional replenishment of vesicle pools, indicating that few vesicles outside of the ribbon-style active zones were initially fusion competent. In cone photoreceptors, similar to bipolar cells, fusion of the initial ribbon-associated synaptic vesicle cohort was not blocked by the SNARE complex-inhibiting peptide, whereas a later phase of exocytosis, attributable to the recruitment and subsequent fusion of vesicles newly arrived at the synaptic ribbons, was blocked. Together, our results support a model in which stimulus-evoked exocytosis in retinal ribbon synapses is SNARE-dependent; where vesicles higher up on the synaptic ribbon replenish the rapidly releasing vesicle pool; and at any given time, there are sufficient SNARE complexes to support the fusion of the entire ribbon-associated cohort of vesicles. An important implication of these results is that ribbon-associated vesicles can form intervesicular SNARE complexes, providing mechanistic insight into compound fusion at ribbon-style synapses.

Purpose This study investigates the clinical and cost effectiveness of switching from traditional vagus nerve stimulation (VNS) to responsive VNS (rVNS), which has an additional ictal tachycardia detection and stimulation (AutoStim) mode. Methods Retrospective chart review was used to collect data from patients with medically refractory epilepsy who underwent generator replacements. Patients with confounding factors such as medication changes were excluded. Vagus nerve stimulation parameters, seizure frequency, and healthcare costs were collected for the 1-year period following generator replacement with the rVNS device. Results Documented seizure frequency was available for twenty-five patients. After implant with rVNS, 28% of patients had an additional ≥ 50% seizure reduction. There was a significant decrease in the average monthly seizure count (p = 0.039). In patients who were not already free of disabling seizures (n = 17), 41.2% had ≥ 50% additional seizure reduction. There was no difference in healthcare costs during the 1-year follow-up after the rVNS implant compared with one year prior. Conclusions Ictal tachycardia detection and stimulation provided a significant clinical benefit in patients who were not free of disabling seizures with treatment from traditional VNS. There was no additional increase in healthcare costs during the first year after device replacement.

Background: Recent trials have failed to show benefit of intra-arterial therapy (IAT) in acute ischemic stroke (AIS) patients. Patients with posterior circulation occlusions, however, were vastly underrepresented (only 4 patients in IMS3, MR-RESCUE and SYNTHESIS combined). IAT is often pursued, due to the inherent poor outcome associated with brainstem infarction. We sought to evaluate potential benefit with IAT in this population. Methods: A US multicenter retrospective cohort of 106 patients with AIS and LAO in the vertebrobasilar distribution presenting 01/05-3/14 within 12 hours from stroke onset was examined. Patients were divided into two groups (IAT vs No IAT). Logistic regression with good and poor (discharge mRS 0-2 and 4-6) outcome was performed. Univariate and multivariate analyses evaluated independent predictors of good outcome after IAT. Results: Patients in the IAT group (n=57) had more severe strokes (NIHSS 24 vs 12) than the medical management group (n=49); otherwise the two groups were comparable (Table 1). IAT was not associated with improved odds of good outcome (OR 0.76, 95%CI 0.27-2.14, p=0.60), even after adjusting for admission NIHSS, recanalization, and time to IAT start (OR 1.35, 95%CI 0.39-4.68, p=0.63). The subgroup with basilar occlusions also did not benefit from IAT. Stroke severity predicted treatment with IAT; each additional point in NIHSS was associated with 5% increased chances of IAT (P 0.07). There were more deaths in the IAT group (Figure 1); 73% of these, however, were associated with care withdrawal decisions. Conclusion: While vascular neurologists intervene more often on severe posterior circulation strokes, our results suggest poor outcome was not averted, even after adjusting for stroke severity. While our results are affected by the inherited limitations of a retrospective cohort and selection bias of a non- randomized design, it addressed an underrepresented stroke population. RCTs are needed to validate these results.

Background: Collateral flow and early ischemic changes on CT are pivotal determinants of outcome in patients with large artery occlusion (LAO). Evolution of stroke occurs during inter-facility transfer. We sought to evaluate the association between collaterals and stroke evolution measured by ASPECTS decay and the relationship of these imaging findings with patient outcomes. Methods: In a cross-sectional multicenter study, we evaluated 313 transferred patients with AIS and LAO (MCA or ICA) from 01/08-04/14. The collateral score (CS) (Figure 1) and ASPECTS were measured. Good collaterals were defined as scores 2-3 (poor; scores 0-1). ASPECTS decay was defined as dichotomized deterioration in ASPECTS from good (8-10) to bad (0-7) during transfer. ASPECTS was also analyzed as an ordinal variable. Logistic regression and mediation analyses were performed to evaluate the association between the collaterals, ASPECTS and patients good and poor (mRS 0-2 and 4-6, respectively) outcomes. Results: Table 1 depicts baseline characteristics. Patients with poor CS had greater odds of ASPECTS decay during transfer (OR 13.4, 95%CI 7.5-24, p Conclusion: Our cohort shows that stroke evolution is determined by transfer time and collateral flow, which are pivotal determinants of clinical outcome in patients with AIS and LAO.

Background: Intra-arterial therapy (IAT) is an approach to promote recanalization in acute ischemic stroke (AIS) patients. While IAT continues to go through further evaluation in multiple phase III trials using new devices and focusing on time improvement, patients with LAO continue to be treated with IAT. Multiple clinical, radiographic and time factors go into vascular neurologists’ decisions whether to pursue IAT or not. We aimed to evaluate factors affecting determination of IAT for stroke amongst patients transferred to tertiary centers. Methods: A US multicenter retrospective cohort analysis was conducted on 313 consecutive transferred patients who met vessel criteria from 01/08-4/14. Collateral were measured by the collateral score (CS). ASPECTS decay was defined as a change from good (8-10) to poor (0-7) scores between center CT scans. IAT patients were compared with no IAT patients with regard to factors predictive of IAT. Results: Table 1 shows baseline characteristics of the two groups. Age was not a predictor of IAT. NIHSS was associated with IAT, but was not a predictor of IAT. For each escalating point on CS, the odds of IAT increased more than 4 times (OR 4.27, 95% CI 2.86-7.87, p Conclusions: Infarction evolution measured by ASPECTS decay, collaterals status and time from stroke ictus are all major determinants of the vascular neurologist decision whether to proceed with IAT. Our findings further support the time-sensitivity of the process for transferring candidates for IAT.

A 52-year-old man was found wandering at night. He was oriented to name only with no other neurologic signs. Laboratory work, CSF analysis, and brain MRI were unremarkable. EEG (figure) showed profuse generalized spike wave activity. His symptoms and EEG normalized with levetiracetam. On recovery, the patient denied previous seizures but admitted to a benzodiazepine habit.

Ribbon synapses of the vertebrate retina are specialized synapses that release neurotransmitter by synaptic vesicle exocytosis in a manner that is proportional to the level of depolarization of the cell. This release property is different from conventional neurons, in which the release of neurotransmitter occurs as a short-lived burst triggered by an action potential. Synaptic vesicle exocytosis is a calcium regulated process that is dependent on a set of interacting synaptic proteins that form the so-called SNARE (soluble N-ethylmaleimide sensitive factor attachment protein receptor) complex. Syntaxin 3B has been identified as a specialized SNARE molecule in ribbon synapses of the rodent retina. However, the best physiologically-characterized neuron that forms ribbon-style synapses is the rod-dominant or Mb1 bipolar cell of the goldfish retina. We report here the molecular characterization of syntaxin 3B from the goldfish retina. Using a combination of reverse transcription (RT) polymerase chain reaction (PCR) and immunostaining with a specific antibody, we show that syntaxin 3B is highly enriched in the plasma membrane of bipolar cell synaptic terminals of the goldfish retina. Using membrane capacitance measurements we demonstrate that a peptide derived from goldfish syntaxin 3B inhibits synaptic vesicle exocytosis. These experiments demonstrate that syntaxin 3B is an important factor for synaptic vesicle exocytosis in ribbon synapses of the vertebrate retina.

Mast cell degranulation is a highly regulated, calcium-dependent process, which is important for the acute release of inflammatory mediators during the course of many pathological conditions. We previously found that Synaptotagmin-2, a calcium sensor in neuronal exocytosis, was expressed in a mast cell line. We postulated that this protein may be involved in the control of mast cell-regulated exocytosis, and we generated Synaptotagmin-2 knock-out mice to test our hypothesis. Mast cells from this mutant animal conferred an abnormally decreased passive cutaneous anaphylaxis reaction on mast cell-deficient mice that correlated with a specific defect in mast cell-regulated exocytosis, leaving constitutive exocytosis and nonexocytic mast cell effector responses intact. This defect was not secondary to abnormalities in the development, maturation, migration, morphology, synthesis, and storage of inflammatory mediators, or intracellular calcium transients of the mast cells. Unlike neurons, the lack of Synaptotagmin-2 in mast cells was not associated with increased spontaneous exocytosis.

Objectives – Comparative evaluation of cardiac dysautonomia in spinocerebellar ataxias (SCA) and idiopathic sporadic ataxias (IA) not fulfilling the criteria of multiple system atrophy. Material and methods – Cardiac autonomic functions were evaluated in 14 SCA (SCA1 = 6, SCA2 = 5 and SCA3 = 3) and 10 IA patients, comparable for age, age at onset, duration and severity of illness. The results were categorized as early, definitive, or severe autonomic involvement (EI, DI and SI respectively) based on the degree of abnormalities on tests of parasympathetic and sympathetic pathways. Results – Cardiac autonomic dysfunction was present in all (EI = 25.0%, DI = 41.7% and SI = 33.3%), parasympathetic dysfunction being an early feature. SI was most often present in SCA3 (100%), followed by those with SCA1 (66.7%), and SCA2 (20%) and none in IA. Conclusions – Cardiac dysautonomia was common in both SCA and IA, although the severity was greater in SCA. Among SCAs, the severity was greatest in SCA3, followed by SCA2 and least in SCA1.

Previously, retinopetal axons containing histamine and dopaminergic neurons expressing histamine H(1)-receptor had been localized in mouse retinas using anatomic techniques. The goal of these experiments was to demonstrate that these receptors are functional.Dopaminergic cells were acutely isolated from retinas of transgenic mice expressing red fluorescent protein under control of the tyrosine hydroxylase promoter and loaded with the calcium indicator Fura-2.Under control conditions, there were spontaneous oscillations in the levels of free intracellular calcium in dopaminergic cells. These oscillations were abolished in nominally calcium-free extracellular medium and in 1 μM tetrodotoxin, findings suggesting that the oscillations were mediated by calcium entry across the plasma membrane in response to sodium-dependent action potentials. Histamine increased the mean free intracellular calcium in the dopaminergic cells by increasing the frequency and/or amplitude of the calcium oscillations. The effects of histamine were dose-dependent and reached maximum at 5 μM. With this dose, there was a 65% increase in the mean free intracellular calcium concentration. The histamine H(1)-receptor antagonist, pyrilamine, blocked the effects of 5 μM histamine when applied at 50 μM. The selective histamine H(1)-receptor agonists, 2-(3-trifluoromethylphenyl) histamine and methylhistaprodifen significantly increased mean free intracellular calcium when applied at 5 μM.Histamine released from retinopetal axons in the mouse retina can elevate intracellular calcium levels in the perikarya of dopaminergic cells via the activation of histamine H(1)-receptors.