Comparative analysis of patients with new onset refractory status epilepticus preceded by fever (febrile infection-related epilepsy syndrome) versus without prior fever: An interim analysis.

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.

Elevated phase amplitude coupling as a depression biomarker in epilepsy.

Depression is prevalent in epilepsy patients and their intracranial brain activity recordings can be used to determine the types of brain activity that are associated with comorbid depression. We performed case-control comparison of spectral power and phase amplitude coupling (PAC) in 34 invasively monitored drug resistant epilepsy patients' brain recordings. The values of spectral power and PAC for one-minute segments out of every hour in a patient's study were correlated with pre-operative assessment of depressive symptoms by Beck Depression Inventory-II (BDI). We identified an elevated PAC signal (theta-alpha-beta phase (5-25 Hz)/gamma frequency (80-100 Hz) band) that is present in high BDI scores but not low BDI scores adult epilepsy patients in brain regions implicated in primary depression, including anterior cingulate cortex, amygdala and orbitofrontal cortex. Our results showed the application of PAC as a network-specific, electrophysiologic biomarker candidate for comorbid depression and its potential as treatment target for neuromodulation.

Responsive Neurostimulation for People With Drug-Resistant Epilepsy and Autism Spectrum Disorder.

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.

A multicenter retrospective study of patients treated in the thalamus with responsive neurostimulation.

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.

The Sensitivity of Scalp EEG at Detecting Seizures-A Simultaneous Scalp and Stereo EEG Study.

PURPOSE: Compare the detection rate of seizures on scalp EEG with simultaneous intracranial stereo EEG (SEEG) recordings. METHODS: Twenty-seven drug-resistant epilepsy patients undergoing SEEG with simultaneous scalp EEG as part of their surgical work-up were included. A total of 172 seizures were captured. RESULTS: Of the 172 seizures detected on SEEG, 100 demonstrated scalp ictal patterns. Focal aware and subclinical seizures were less likely to be seen on scalp, with 33% of each observed when compared with focal impaired aware (97%) and focal to bilateral tonic-clonic seizures (100%) (P < 0.001). Of the 72 seizures without ictal scalp correlate, 32 demonstrated an abnormality during the SEEG seizure that was identical to an interictal abnormality. Seizures from patients with MRI lesions were statistically less likely to be seen on scalp than seizures from nonlesional patients (P = 0.0162). Stereo EEG seizures not seen on scalp were shorter in duration (49 seconds) compared with SEEG seizures seen on scalp (108.6 seconds) (P < 0.001). CONCLUSIONS: Scalp EEG is not a sensitive tool for the detection of focal aware and subclinical seizures but is highly sensitive for the detection of focal impaired aware and focal to bilateral tonic-clonic seizures. Longer duration of seizure and seizures from patients without MRI lesions were more likely to be apparent on scalp. Abnormalities seen interictally may at times represent an underlying seizure. The cognitive, affective, and behavioral long-term effects of ongoing difficult-to-detect seizures are not known.

Ictal head roll: a seizure semiology from the anterior prefrontal lobe.

Longstanding epilepsy can lead to modulation of cortical networks over time and unexpected seizure onset zones. Frontal lobe seizures, in particular, can have diverse semiologies and evolution patterns. We present a male patient with drug-resistant epilepsy secondary to severe traumatic brain injury who underwent bilateral stereo electroencephalography (SEEG) for surgical planning. SEEG localized an ictal circular head roll to the right anterior prefrontal region. This was followed by spread to the left orbitofrontal region and later the left amygdala and hippocampus, at which point a different semiology with behavioral arrest, lip smacking and oral automatisms began. This case, in which an ictal circular head roll was localized to the anterior prefrontal region, demonstrates the complexity of broad seizure networks that develop over time, leading to remote seizure spread.

Utility of 7 tesla MRI brain in 16 "MRI Negative" epilepsy patients and their surgical outcomes.

The objective is to quantitatively assess surgical outcomes in epilepsy patients who underwent scanning at 7T MRI whose lesions were undetectable at conventional field strengths (1.5T/3T). 16 patients who underwent an initial 1.5T/3T scan that was marked as non-lesional by a neuroradiologist and were candidates for epilepsy surgery were scanned at 7T. The 7T findings were evaluated by an expert neuroradiologist blinded to the suspected seizure onset zone (sSOZ). The relation of the neuroradiologist's findings compared with the sSOZ was classified as non-definite (no 7T lesion or lesion of no epileptogenic significance, or lesion of epileptogenic potential which localizes to the patient's sSOZ but is not the definitive cause), or definite (7T lesion of epileptogenic potential that highly localizes to the sSOZ and is confirmed through surgical intervention).. Each patient underwent neurosurgical intervention and postoperative Engel outcomes were obtained through retrospective chart review by an epileptologist. Of the 16 patients, 7 had imaging findings of definite epileptogenic potential at 7T while 9 had non-definite imaging findings. 15 out of 16 patients had Engel I, II, or III outcomes indicating worthwhile improvement. Patients with definite lesion status achieved Engel I surgical outcomes at higher rates (57.1%) than patients with non-definite lesion status (33.3%). Patients with normal clinical diagnostic scans at lower field strengths who have definite radiological findings on 7T corresponding to the sSOZ may experience worthwhile improvement from surgical intervention.

Brief potentially ictal rhythmic discharges and paroxysmal fast activity as scalp electroencephalographic biomarkers of seizure activity and seizure onset zone.

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.

Psychiatric comorbidities, sexual health and neurodevelopmental outcomes of offspring in men with epilepsy.

BACKGROUND: There is a paucity of data in the literature specific to men with epilepsy on anti-seizure medication (ASM). The current study investigated the time to conception as well as the gestational and the neurodevelopmental outcomes of offspring of men with epilepsy on ASM compared to controls. Additionally, the prevalence of psychiatric comorbidities, and measures of sexual performance in males with and without epilepsy were analyzed. METHODS: A total of 450 male patients with and without epilepsy at one hospital were provided questionnaires to determine demographic characteristics, epilepsy history, type of ASM at the time of conception, comorbidities and sexual health. Time to conception, fertility methods and offspring birth and developmental history born to males with and without epilepsy was recorded. Survey data was evaluated using Student's t-test for continuous variables and Fisher's exact test for categorical variables. Odds ratio (OR) were calculated to determine associations between the measured data. RESULTS: After matching for age, we analyzed a total of 110 males with epilepsy and 110 without epilepsy. In the epilepsy group there was a higher rate of psychiatric comorbidities such as major depressive disorder, general anxiety disorder, bipolar disorder, and suicidal ideation when compared to the control group (N = 110; OR 3.39; 95% IC: 1.87-6.13, p < 0.001). Males with epilepsy also had a higher frequency of low erection scores when compared to males without epilepsy (N = 70 with epilepsy, N = 76 without epilepsy; OR 3.67; 95% IC: 1.44-9.39, p = 0.005). Of the 110 men with a diagnosis of epilepsy, 17 conceived children while using ASMs (38 total children). A total of 18.42% of children born to fathers on ASMs experienced developmental delays compared to 2.63% of controls, however this result was not statistically significant (p = 0.056). In addition, we did not find that offspring had significantly different birth weights or gestational ages in men on ASM compared to controls (p > 0.05). CONCLUSIONS: The present study suggests that men with epilepsy have an increased incidence of psychiatric comorbidities, and altered sexual performance, specifically erectile dysfunction, when compared with men without epilepsy. There was no statistically significant difference in the rates of developmental disorders and birth characteristics among those men with epilepsy on ASM at the time of conception and controls.

Centromedian thalamic responsive neurostimulation for Lennox-Gastaut epilepsy and autism.

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.

Responsive neurostimulation for regional neocortical epilepsy.

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.

Quantitative Signal Characteristics of Electrocorticography and Stereoelectroencephalography: The Effect of Contact Depth.

PURPOSE: Patients undergoing epilepsy surgery often require invasive EEG, but few studies have examined the signal characteristics of contacts on the surface of the brain (electrocorticography, ECOG) versus depth contacts, used in stereoelectroencephalography (SEEG). As SEEG and ECOG have significant differences in complication rates, it is important to determine whether both modalities produce similar signals for analysis, to ultimately guide management of medically intractable epilepsy. METHODS: Twenty-seven patients who underwent SEEG (19), ECOG (6), or both (2) were analyzed for quantitative measures of activity including spectral power and phase-amplitude coupling during approximately 1 hour of wakefulness. The position of the contacts was calculated by coregistering the postoperative computed tomography with a reconstructed preoperative MRI. Using two types of referencing schemes-local versus common average reference-the brain regions where any quantitative measure differed systematically with contact depth were established. RESULTS: Using even the most permissive statistical criterion, few quantitative measures were significantly correlated with contact depth in either ECOG or SEEG contacts. The factors that predicted changes in spectral power and phase-amplitude coupling with contact depth were failing to baseline correct spectral power measures, use of a local rather than common average reference, using baseline correction for phase-amplitude coupling measures, and proximity of other grey matter structures near the region where the contact was located. CONCLUSIONS: The signals recorded by ECOG and SEEG have very similar spectral power and phase-amplitude coupling, suggesting that both modalities are comparable from an electrodiagnostic standpoint in delineation of the epileptogenic network.

Subfield-specific tractography of the hippocampus in epilepsy patients at 7 Tesla.

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.

Theta band network supporting human episodic memory is not activated in the seizure onset zone.

Episodic memory, everyday memory for events, is frequently impaired in patients with epilepsy. We tested patients undergoing intracranial electroencephalography (intracranial EEG) monitoring for the treatment of medically-refractory epilepsy on a well-characterized paradigm that requires episodic memory. We report that an anatomically diffuse network characterized by theta-band (4-7 Hz) coherence is activated at the time of target selection in a task that requires episodic memory. This distinct network of oscillatory activity is absent when episodic memory is not required. Further, the theta band synchronous network was absent in electrodes within the patient's seizure onset zone (SOZ). Our data provide novel empirical evidence for a set of brain areas that supports episodic memory in humans, and it provides a pathophysiologic mechanism for the memory deficits observed in patients with epilepsy.

Language mapping using electrocorticography versus stereoelectroencephalography: A case series.

Direct electrical stimulation (DES) is sometimes used in epilepsy surgery to identify areas that may result in language deficits if resected. Extraoperative language mapping is usually performed using electrocorticography (ECOG) - grids and strip electrodes; however, given the better safety profile of stereoelectroencephalogaphy (SEEG), it would be desirable to determine if mapping using SEEG is also effective. We report a case series of fifteen patients that underwent language mapping with either ECOG (5), SEEG (9), or both (1). Six patients in the SEEG group underwent resection or ablation with only mapping via SEEG. No patients in the SEEG group that underwent resective or ablative surgery experienced persistent language deficits. These results suggest that language mapping with SEEG may be considered as a clinically useful alternative to language mapping with ECOG.

Palinacousis, Palinacousis: Seven New Cases.

PURPOSE: Palinacousis is an auditory illusion of sound persisting or repeating after the cessation of an auditory stimulation. Up until now, approximately 32 cases have been reported. The purpose of this study is to describe an additional seven cases of palinacousis and review our understanding of audition and palinacousis. METHODS: Patients seen in the epilepsy clinic or admitted to the Epilepsy Monitoring Unit (EMU) at The Mount Sinai Hospital who experienced palinacousis were included. In all these patients, an EEG and MRI were performed at some point during their clinical course. RESULTS: In one case, palinacousis occurred with stimulation of the superior temporal gyrus during brain mapping after a spoken word as well as after the thought of a word. Two people experienced palinacousis during a seizure captured on video EEG. The remaining four cases had palinacousis in the peri- or post-ictal period. CONCLUSIONS: We propose that palinacousis may be coming from the superior temporal gyrus secondary to seizure activity, either onset or spread, or dysfunction of the area in a postictal state. The existence of palinacousis in these pathologic states can help us to understand how we process auditory information.

Brief Potentially Ictal Rhythmic Discharges [B(I)RDs] in Noncritically Ill Adults.

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.

Palinacousis.

Palinacousis is derived from the Greek words palin, which means again or anew, and acousis, meaning hearing. It was first described by Jacobs et al. (1971), who defined the phenomenon as "an auditory illusion of perseveration or persistence of sound impressions for seconds, minutes, or hours after the cessation of auditory stimulation." The auditory perseveration does not occur spontaneously but is triggered by something in the environment. A limited number of cases have been described in the literature. This chapter describes the anatomic abnormalities that may cause this phenomenon, the clinical characteristics that define palinacousis, differential diagnosis and potential etiologies.