Dual Treatment of Refractory Focal Epilepsy and Obsessive-Compulsive Disorder With Intracranial Responsive Neurostimulation.

Purpose of the Review: Intracranial neurostimulation is a well-established treatment of neurologic conditions such as drug-resistant epilepsy (DRE) and movement disorders, and there is emerging evidence for using deep brain stimulation to treat obsessive-compulsive disorder (OCD) and depression. Nearly all published reports of intracranial neurostimulation have focused on implanting a single device to treat a single condition. The purpose of this review was to educate neurology clinicians on the background literature informing dual treatment of 2 comorbid neuropsychiatric conditions epilepsy and OCD, discuss ethical and logistical challenges to dual neuropsychiatric treatment with a single device, and demonstrate the promise and pitfalls of this approach through discussion of the first-in-human closed-looped responsive neurostimulator (RNS) implanted to treat both DRE (on-label) and OCD (off-label). Recent Findings: We report the first implantation of an intracranial closed-loop neurostimulation device (the RNS system) with the primary goal of treating DRE and a secondary exploratory goal of managing treatment-refractory OCD. The RNS system detects electrophysiologic activity and delivers electrical stimulation through 1 or 2 electrodes implanted into a patient's seizure-onset zones (SOZs). In this case report, we describe a patient with treatment-refractory epilepsy and OCD where the first lead was implanted in the right superior temporal gyrus to target the most active SOZ based on stereotactic EEG (sEEG) recordings and semiology. The second lead was implanted to target the right anterior peri-insular region (a secondary SOZ on sEEG) with the distal-most contacts in the right nucleus accumbens, a putative target for OCD neurostimulation treatment. The RNS system was programmed to detect and record the unique electrophysiologic signature of both the patient's seizures and compulsions and then deliver tailored electrical pulses to disrupt the pathologic circuitry. Summary: Dual treatment of refractory focal epilepsy and OCD with an intracranial closed-loop neurostimulation device is feasible, safe, and potentially effective. However, there are logistical challenges and ethical considerations to this novel approach to treatment, which require complex care coordination by a large multidisciplinary team.

Responsive neurostimulation as a therapy for epilepsy following new-onset refractory status epilepticus: Case series and review of the literature.

OBJECTIVE: To report clinical outcomes of patients who presented with new-onset refractory status epilepticus (NORSE), developed drug-resistant epilepsy (DRE), and were treated with responsive neurostimulation (RNS). METHODS: We performed a retrospective review of patients implanted with RNS at our institution and identified three who originally presented with NORSE. Through chart review, we retrieved objective and subjective information related to their presentation, workup, and outcomes including patient-reported seizure frequency. We reviewed electrocorticography (ECoG) data to estimate seizure burden at 3, 6, 12, and 24 months following RNS implantation. We performed a review of literature concerning neurostimulation in NORSE. RESULTS: Use of RNS to treat DRE following NORSE was associated with reduced seizure burden and informed care by differentiating epileptic from non-epileptic events. CONCLUSIONS: Our single-center experience of three cases suggests that RNS is a safe and potentially effective treatment for DRE following NORSE. SIGNIFICANCE: This article reports outcomes of the largest case series of NORSE patients treated with RNS. Since patients with NORSE are at high risk of adverse neuropsychiatric and cognitive sequelae beyond seizures, a unique strength of RNS over other surgical options is the ability to distinguish ictal or peri-ictal from non-epileptic events.

In-Person and Telehealth Provider Access and Glycemic Control for People With Diabetes During the COVID-19 Pandemic.

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.

Electrocorticography Analysis in Patients With Dual Neurostimulators Supports Desynchronization as a Mechanism of Action for Acute Vagal Nerve Stimulator Stimulation.

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 <0.05. 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.

Telemedicine and health access inequalities during the COVID-19 pandemic.

Background: 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. Methods: 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. Results: 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. Conclusion: 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.

Concurrent brain-responsive and vagus nerve stimulation for treatment of drug-resistant focal epilepsy.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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%). SIGNIFICANCE: 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.

Limited-Montage EEG as a Tool for the Detection of Nonconvulsive Seizures.

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.

Recognizing encephalopathy in immune checkpoint inhibitor therapy: A single-center experience.

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.

Ambulatory care for epilepsy via telemedicine during the COVID-19 pandemic.

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 ±â€¯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.

Vagus nerve stimulation with tachycardia detection provides additional seizure reduction compared to traditional vagus nerve stimulation.

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.

Two Pools of Vesicles Associated with Synaptic Ribbons Are Molecularly Prepared for Release.

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 Ca2+-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.

Histamine elevates free intracellular calcium in mouse retinal dopaminergic cells via H1-receptors.

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Synaptotagmin-2 controls regulated exocytosis but not other secretory responses of mast cells.

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.