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In response to the evolving treatment landscape for new‐onset refractory status epilepticus (NORSE) and the publication of consensus recommendations in 2022, we conducted a comparative analysis of NORSE management over time. Seventy‐seven patients were enrolled by 32 centers, from July 2016 to August 2023, in the NORSE/FIRES biorepository at Yale. Immunotherapy was administered to 88% of patients after a median of 3 days, with 52% receiving second‐line immunotherapy after a median of 12 days (anakinra 29%, rituximab 25%, and tocilizumab 19%). There was an increase in the use of second‐line immunotherapies (odds ratio [OR] = 1.4, 95% CI = 1.1–1.8) and ketogenic diet (OR = 1.8, 95% CI = 1.3–2.6) over time. Specifically, patients from 2022 to 2023 more frequently received second‐line immunotherapy (69% vs 40%; OR = 3.3; 95% CI = 1.3–8.9)—particularly anakinra (50% vs 13%; OR = 6.5; 95% CI = 2.3–21.0), and the ketogenic diet (OR = 6.8; 95% CI = 2.5–20.1)—than those before 2022. Among the 27 patients who received anakinra and/or tocilizumab, earlier administration after status epilepticus onset correlated with a shorter duration of status epilepticus (ρ =.519, p =.005). Our findings indicate an evolution in NORSE management, emphasizing the increasing use of second‐line immunotherapies and the ketogenic diet. Future research will clarify the impact of these treatments and their timing on patient outcomes. [ABSTRACT FROM AUTHOR]

Febrile infection‐related epilepsy syndrome (FIRES) is a subset of new onset refractory status epilepticus (NORSE) that involves a febrile infection prior to the onset of the refractory status epilepticus. It is unclear whether FIRES and non‐FIRES NORSE are distinct conditions. Here, we compare 34 patients with FIRES to 30 patients with non‐FIRES NORSE for demographics, clinical features, neuroimaging, and outcomes. Because patients with FIRES were younger than patients with non‐FIRES NORSE (median = 28 vs. 48 years old, p =.048) and more likely cryptogenic (odds ratio = 6.89), we next ran a regression analysis using age or etiology as a covariate. Respiratory and gastrointestinal prodromes occurred more frequently in FIRES patients, but no difference was found for non‐infection‐related prodromes. Status epilepticus subtype, cerebrospinal fluid (CSF) and magnetic resonance imaging findings, and outcomes were similar. However, FIRES cases were more frequently cryptogenic; had higher CSF interleukin 6, CSF macrophage inflammatory protein‐1 alpha (MIP‐1a), and serum chemokine ligand 2 (CCL2) levels; and received more antiseizure medications and immunotherapy. After controlling for age or etiology, no differences were observed in presenting symptoms and signs or inflammatory biomarkers, suggesting that FIRES and non‐FIRES NORSE are very similar conditions. [ABSTRACT FROM AUTHOR]

Introduction: For drug resistant epilepsy patients who are either not candidates for resective surgery or have already failed resective surgery, neuromodulation is a promising option. Neuromodulatory approaches include responsive neurostimulation (RNS), deep brain stimulation (DBS), and vagal nerve stimulation (VNS). Thalamocortical circuits are involved in both generalized and focal onset seizures. This paper explores the use of RNS in the centromedian nucleus of the thalamus (CMN) and in the anterior thalamic nucleus (ANT) of patients with drug resistant epilepsy. Methods: This is a retrospective multicenter study from seven different epilepsy centers in the United States. Patients that had unilateral or bilateral thalamic RNS leads implanted in the CMN or ANT for at least 6 months were included. Primary objectives were to describe the implant location and determine changes in the frequency of disabling seizures at 6 months, 1 year, 2 years, and > 2 years. Secondary objectives included documenting seizure free periods, anti-seizure medication regimen changes, stimulation side effects, and serious adverse events. In addition, the global clinical impression scale was completed. Results: Twelve patients had at least one lead placed in the CMN, and 13 had at least one lead placed in the ANT. The median baseline seizure frequency was 15 per month. Overall, the median seizure reduction was 33% at 6 months, 55% at 1 year, 65% at 2 years, and 74% at >2 years. Seizure free intervals of at least 3 months occurred in nine patients. Most patients (60%, 15/25) did not have a change in anti-seizure medications post RNS placement. Two serious adverse events were recorded, one related to RNS implantation. Lastly, overall functioning seemed to improve with 88% showing improvement on the global clinical impression scale. Discussion: Meaningful seizure reduction was observed in patients who suffer from drug resistant epilepsy with unilateral or bilateral RNS in either the ANT or CMN of the thalamus. Most patients remained on their pre-operative anti-seizure medication regimen. The device was well tolerated with few side effects. There were rare serious adverse events. Most patients showed an improvement in global clinical impression scores. [ABSTRACT FROM AUTHOR]

Introduction: For drug resistant epilepsy patients who are either not candidates for resective surgery or have already failed resective surgery, neuromodulation is a promising option. Neuromodulatory approaches include responsive neurostimulation (RNS), deep brain stimulation (DBS), and vagal nerve stimulation (VNS). Thalamocortical circuits are involved in both generalized and focal onset seizures. This paper explores the use of RNS in the centromedian nucleus of the thalamus (CMN) and in the anterior thalamic nucleus (ANT) of patients with drug resistant epilepsy. Methods: This is a retrospective multicenter study from seven different epilepsy centers in the United States. Patients that had unilateral or bilateral thalamic RNS leads implanted in the CMN or ANT for at least 6 months were included. Primary objectives were to describe the implant location and determine changes in the frequency of disabling seizures at 6 months, 1 year, 2 years, and > 2 years. Secondary objectives included documenting seizure free periods, anti-seizure medication regimen changes, stimulation side effects, and serious adverse events. In addition, the global clinical impression scale was completed. Results: Twelve patients had at least one lead placed in the CMN, and 13 had at least one lead placed in the ANT. The median baseline seizure frequency was 15 per month. Overall, the median seizure reduction was 33% at 6 months, 55% at 1 year, 65% at 2 years, and 74% at >2 years. Seizure free intervals of at least 3 months occurred in nine patients. Most patients (60%, 15/25) did not have a change in anti-seizure medications post RNS placement. Two serious adverse events were recorded, one related to RNS implantation. Lastly, overall functioning seemed to improve with 88% showing improvement on the global clinical impression scale. Discussion: Meaningful seizure reduction was observed in patients who suffer from drug resistant epilepsy with unilateral or bilateral RNS in either the ANT or CMN of the thalamus. Most patients remained on their pre-operative anti-seizure medication regimen. The device was well tolerated with few side effects. There were rare serious adverse events. Most patients showed an improvement in global clinical impression scores. [ABSTRACT FROM AUTHOR]

The authors' purpose in this study was to compare the perception of fatigue severity as measured by different fatigue questionnaires. The authors evaluated 3 groups of patients in a cross-sectional study: chronic fatigue syndrome (CFS, n = 20), non-CFS fatigue (n = 20), and familial Mediterranean fever (FMF, n = 25). In addition, the authors tracked 7 patients with CFS longitudinally for severity of fatigue. The severity of fatigue-related symptoms was assessed with 2 questionnaires: the unidimensional Chalder's Fatigue Severity Scale (CH) and the composite Fatigue Impact Scale (FI) which has 3 subscales--cognitive, physical, and social--and a total score. In the cross-sectional study, correlations between CH and FI cognitive scores were r = .78 (p < .0001), CH versus FI physical scores r = .603 (p < .0001), CH versus FI social scores r = .66 (p < .0001), and CH versus FI total scores r = .74 (p < .0001). In the longitudinal survey of CFS patients, the authors compared 30 questionnaires revealing correlations of CH versus FI cognitive scores r = .64 (p = .0004), CH versus FI physical r = .68 (p = .0001), CH versus FI social r = .87 (p < .0001), and CH versus FI total r = .90 (p < .0001). Fatigue severity as assessed by the unidimensional CH scale and the composite FI scale is comparable. The simple CH scale may be adequate for the assessment of the feeling of fatigue, in general, and for monitoring the severity of fatigue in CFS, in particular. Index Terms: chronic fatigue syndrome, fatigue, fatigue questionnaire, Population-based studies confirm that fatigue is one of the most common somatic symptoms. Twenty to 30% of the population complains of chronic fatigue. (1) Fatigue refers to a sense of [...]

Objective: The electroencephalographic (EEG) terms "brief potentially ictal rhythmic discharges" (BIRDs) and "paroxysmal fast activity" (PFA) are considered distinct entities; however, their definitions overlap, and they may have similar clinical significance. We investigated their clinical significance and their association with seizures and the seizure onset zone (SOZ). Methods: We retrospectively identified an adult cohort (July 2015 to March 2018) whose long‐term (>12 h) EEGs in any setting reported BIRDs (>4 Hz, lasting.5–10 s) and/or PFA. Different frequency cutoffs for PFA (>13 Hz or ≥8 Hz) were tested to compare their clinical significance. Patient demographics, clinical history, and EEG features were recorded. Results: We identified 94 patients with BIRDs/PFA out of 3520 patients (3%); 36 were critically ill (12 with epilepsy), and 58 were noncritically ill (all with epilepsy). The frequency of BIRDs/PFA was largely dependent on EEG background: it tended to be slower (theta) in the absence of a posterior dominant rhythm or in the presence of continuous focal slowing in the same region (p =.01). Sixty‐two of 94 patients (66%; 32/36 [89%] critically ill, 30/58 [52%] noncritically ill) had electrographic seizures during the recording. The scalp EEG SOZ colocalized with BIRDs/PFA in all cases. BIRDs with faster frequency (also qualifying as PFA by definition) had similar seizure risk to that of slower BIRDs (62%–71%), regardless of frequency cutoff used to define PFA. In addition, 30 of 30 (100%) patients with evolving BIRDs/PFA (which lasted a median of 6 s, range = 2–9.5 s) had electrographic seizures (>10 s), compared to 32 of 64 (50%) with nonevolving BIRDs (median = 1 s, range =.5–3.5 s; p <.01). Significance: A high proportion of patients with BIRDs/PFA had seizures on EEG, regardless of their frequency (i.e., whether they also qualified as PFA), and their location colocalized with scalp SOZ in all cases. BIRDs appear to be a scalp EEG biomarker of uncontrolled seizure activity and a reliable localizing sign of the SOZ. [ABSTRACT FROM AUTHOR]

The RNS System is not approved in patients under 18, although a critical need for novel treatment modalities in this vulnerable population persist. We present two pediatric patients with drug‐resistant epilepsy secondary to Lennox‐Gastaut Syndrome (LGS) and autism spectrum disorder (ASD) treated with the RNS System. Both patients have experienced 75–99% clinical seizure reductions in >1 year of follow‐up. We illustrate that children with diffuse onset, multifocal epilepsy, including frontal and thalamic circuits thought to exist in the generation of LGS seizures, can be treated with responsive neurostimulation safely and effectively, targeting thalamic networks, and avoiding palliative disconnections and resections. [ABSTRACT FROM AUTHOR]

Objective: Surgical resection of seizure‐producing brain tissue is a gold standard treatment for drug‐resistant focal epilepsy. However, several patient‐specific factors can preclude resective surgery, including a spatially extensive ("regional") seizure‐onset zone (SOZ). For such patients, responsive neurostimulation (RNS) represents a potential treatment, but its efficacy has not been investigated in this population. Methods: We performed a multicenter retrospective cohort study of patients (N = 30) with drug‐resistant focal epilepsy and a regional neocortical SOZ delineated by intracranial monitoring who were treated with the RNS System for at least 6 months. RNS System leads were placed at least 1‐cm apart over the SOZ, and most patients were treated with a lead‐to‐lead stimulation pathway. Five patients underwent partial resection of the SOZ concurrent with RNS System implantation. We assessed change in seizure frequency relative to preimplant baseline and evaluated correlation between clinical outcome and stimulation parameters. Results: Median follow‐up duration was 21.5 months (range 6‐52). Median reduction in clinical seizure frequency was 75.5% (interquartile range [IQR] 40%‐93.9%). There was no significant difference in outcome between patients treated with and without concurrent partial resection. Most patients were treated with low charge densities (1‐2.5 µC/cm2), but charge density, interlead distance, and duration of treatment were not significantly correlated with outcome. Significance: RNS is a feasible and effective treatment in patients with drug‐resistant regional neocortical seizures. Prospective studies in larger cohorts are necessary to determine optimal lead configuration and stimulation parameters, although our results suggest that lead‐to‐lead stimulation and low charge density may be effective in some patients. [ABSTRACT FROM AUTHOR]

Purpose: MRI-negative epilepsy patients could benefit from advanced imaging techniques such as high-resolution diffusion magnetic resonance imaging (dMRI). Our aim was to perform hippocampal subfield-specific tractography and quantify connectivity of the subfields in MRI-negative patients. Abnormal connectivity of the hippocampal subfields may help inform seizure focus hypothesis and provide information to guide surgical intervention.Methods: Hippocampal structural imaging and dMRI was acquired in 25 drug resistant MRI-negative patients and 25 healthy volunteers. The hippocampi of each subject was segmented on high-resolution structural images and dMRI-based probabilistic tractography was performed in each subfield. The degrees of connectivity and fiber densities of the hippocampal subfields were quantified and compared between epilepsy patients and healthy volunteers.Results: We were able to perform subfield-specific hippocampal tractography in each subject that participated in this study. These methods identified some hippocampal subfields that are abnormally connected in MRI-negative patients. In particular patients suspected of left temporal seizure focus exhibited increased connectivity of certain ipsilateral subfields, especially the subiculum, presubiculum, and parasubiculum, and reduced connectivity of some contralateral subfields, such as CA1 and subiculum.Conclusions: Our data suggest that the hippocampal subfields are connected in distinct ways in different types of epilepsy. These results may provide important information that could help inform seizure focus hypothesis and in the surgical treatment of MRI-negative patients. These observations suggest that high-resolution dMRI-based tractography of the hippocampal subfields can detect subtle abnormalities in otherwise normal-appearing MRI-negative patients. [ABSTRACT FROM AUTHOR]

Palinacousis is an auditory illusion rarely reported in cases of temporal lobe dysfunction. Detailed observations where made by Jacobs et al. in 1973. Since that time, only a few other cases have been described in the literature. After reviewing the literature and comparing our clinical experience, we believe that palinacousis can occur as an aura, a simple partial seizure, a complex partial seizure, and/or a postictal event. Within one academic year, we observed two patients who experienced palinacousis. Palinacousis maybe more common than recognized in patients with receptive aphasias or diffuse cerebral dysfunction, whose language deficits preclude adequate description. It is important to differentiate palinacousis from auditory hallucinations seen in psychotic and psychiatric patients. Identification of palinacousis as an aura, simple partial seizure, complex partial seizure, and/or postictal phenomenon can help localize potential lesions and improve patient care. [ABSTRACT FROM AUTHOR]

Identifying genetic risk factors for highly heterogeneous disorders like epilepsy remains challenging. Here, we present the largest whole-exome sequencing study of epilepsy to date, with >54,000 human exomes, comprising 20,979 deeply phenotyped patients from multiple genetic ancestry groups with diverse epilepsy subtypes and 33,444 controls, to investigate rare variants that confer disease risk. These analyses implicate seven individual genes, three gene sets, and four copy number variants at exome-wide significance. Genes encoding ion channels show strong association with multiple epilepsy subtypes, including epileptic encephalopathies, generalized and focal epilepsies, while most other gene discoveries are subtype-specific, highlighting distinct genetic contributions to different epilepsies. Combining results from rare single nucleotide/short indel-, copy number-, and common variants, we offer an expanded view of the genetic architecture of epilepsy, with growing evidence of convergence among different genetic risk loci on the same genes. Top candidate genes are enriched for roles in synaptic transmission and neuronal excitability, particularly postnatally and in the neocortex. We also identify shared rare variant risk between epilepsy and other neurodevelopmental disorders. Our data can be accessed via an interactive browser, hopefully facilitating diagnostic efforts and accelerating the development of follow-up studies., Competing Interests: Competing Interests B.M.N is a member of the scientific advisory board at Deep Genomics and Neumora. No other authors have competing interests to declare

Purpose: Individuals with autism spectrum disorder (ASD) have comorbid epilepsy at much higher rates than the general population, and about 30% will be refractory to medication. Patients with drug-resistant epilepsy (DRE) should be referred for surgical evaluation, yet many with ASD and DRE are not resective surgical candidates. The aim of this study was to examine the response of this population to the responsive neurostimulator (RNS) System., Methods: This multicenter study evaluated patients with ASD and DRE who underwent RNS System placement. Patients were included if they had the RNS System placed for 1 year or more. Seizure reduction and behavioral outcomes were reported. Descriptive statistics were used for analysis., Results: Nineteen patients with ASD and DRE had the RNS System placed at 5 centers. Patients were between the ages of 11 and 29 (median 20) years. Fourteen patients were male, whereas five were female. The device was implanted from 1 to 5 years. Sixty-three percent of all patients experienced a >50% seizure reduction, with 21% of those patients being classified as super responders (seizure reduction >90%). For the super responders, two of the four patients had the device implanted for >2 years. The response rate was 70% for those in whom the device was implanted for >2 years. Improvements in behaviors as measured by the Clinical Global Impression Scale-Improvement scale were noted in 79%. No complications from the surgery were reported., Conclusions: Based on the authors' experience in this small cohort of patients, the RNS System seems to be a promising surgical option in people with ASD-DRE., Competing Interests: S. Ghatan is an unpaid consultant to Neuropace. F. Panov is a consultant for Zimmer Biomet and Neuropace. The remaining authors have no funding or conflicts of interest to disclose., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Clinical Neurophysiology Society.)

Introduction: Brief potentially ictal rhythmic discharges (B(I)RDs) have been described in neonates and critically ill adults, and their association with seizures has been demonstrated. Their significance in noncritically ill adults remains unclear. We aimed to investigate their prevalence, electrographic characteristics, and clinical significance., Methods: We identified adult patients with B(I)RDs who received long-term EEG recordings either in the epilepsy monitoring unit or in the ambulatory setting. Patients with acute findings on imaging or status epilepticus were excluded. B(I)RDs were defined as very brief (<10 seconds) runs of focal or generalized sharply contoured rhythmic activity greater than 4 Hz, with or without evolution, that were not consistent with any known normal or benign pattern. The clinical history, EEG, and imaging results were retrieved. Each patient with B(I)RDs was matched by age and etiology to a control group with epileptiform discharges but without B(I)RDs in a 1:2 ratio., Results: We identified B(I)RDs in 15 patients of 1,230 EEGs (1.2%). The pattern typically consisted of 0.5 to 4 second runs of sharply contoured alpha activity without evolution. All patients with B(I)RDs had epilepsy, and, when compared with controls with epilepsy but without BIRDs, were more likely to be medically refractory (10 of 15 [67%] vs. 5 of 30 [17%]; P < 0.01). All seizure onsets colocalized to the B(I)RDs, and most were morphologically similar., Conclusions: In noncritically ill patients, B(I)RDs are associated with refractory epilepsy and their location is correlated with the seizure onset area.

Objective: To evaluate disease-specific cardiovascular reactivity patterns in patients with fibromyalgia (FM) using a recently described method called fractal and recurrence analysis score (FRAS)., Methods: The study group included 30 women with FM, average age 46.7 years (SD 7.03). An age matched group of 30 women with other rheumatic disorders or having a dysautonomic background [chronic fatigue syndrome (CFS), non-CFS fatigue, neurally mediated syncope, and psoriatic arthritis (PsA)] served as controls. Subjects were evaluated with a head-up tilt test with beat-to-beat recording of the heart rate (HR) and pulse transit time. A 10-minute supine phase was followed by 600 cardiac cycles recorded on tilt. Data were processed by recurrence plot and fractal analysis. Variables acting as independent predictors of the cardiovascular reactivity were identified in FM patients versus controls., Results: No statistically significant differences were found between the groups by univariate analysis comparing 92 variables of cardiovascular reactivity in FM patients compared to controls., Conclusion: Study of cardiovascular reactivity utilizing a head-up tilt test and processing the data using the FRAS method did not reveal a specific FM-associated abnormality. Our data confirm studies that utilized other methodologies and reached similar conclusions. Patients with FM represent a heterogenous group with respect to their pattern of cardiovascular reactivity.