Three neuromodulation therapies have been appropriately tested and approved in refractory focal epilepsies: vagus nerve stimulation (VNS), deep brain stimulation of the anterior nucleus of the ...thalamus (ANT-DBS), and closed-loop responsive neurostimulation of the epileptogenic zone or zones. These therapies are primarily palliative. Only a few individuals have achieved complete freedom from seizures for more than 12 months with these therapies, whereas more than half have benefited from long-term reduction in seizure frequency of more than 50%. Implantation-related adverse events primarily include infection and pain at the implant site. Intracranial haemorrhage is a frequent adverse event for ANT-DBS and responsive neurostimulation. Other stimulation-specific side-effects are observed with VNS and ANT-DBS. Biomarkers to predict response to neuromodulation therapies are not available, and high-level evidence to aid decision making about when and for whom these therapies should be preferred over other antiepileptic treatments is scant. Future studies are thus needed to address these shortfalls in knowledge, approve other forms of neuromodulation, and develop personalised closed-loop therapies with embedded machine learning. Until then, neuromodulation could be considered for individuals with intractable seizures, ideally after the possibility of curative surgical treatment has been carefully assessed and ruled out or judged less appropriate.
Summary
We convened an international group of experts to standardize definitions of New‐Onset Refractory Status Epilepticus (NORSE), Febrile Infection‐Related Epilepsy Syndrome (FIRES), and related ...conditions. This was done to enable improved communication for investigators, physicians, families, patients, and other caregivers. Consensus definitions were achieved via email messages, phone calls, an in‐person consensus conference, and collaborative manuscript preparation. Panel members were from 8 countries and included adult and pediatric experts in epilepsy, electroencephalography (EEG), and neurocritical care. The proposed consensus definitions are as follows: NORSE is a clinical presentation, not a specific diagnosis, in a patient without active epilepsy or other preexisting relevant neurological disorder, with new onset of refractory status epilepticus without a clear acute or active structural, toxic or metabolic cause. FIRES is a subcategory of NORSE, applicable for all ages, that requires a prior febrile infection starting between 2 weeks and 24 hours prior to onset of refractory status epilepticus, with or without fever at onset of status epilepticus. Proposed consensus definitions are also provided for Infantile Hemiconvulsion‐Hemiplegia and Epilepsy syndrome (IHHE) and for prolonged, refractory and super‐refractory status epilepticus. This document has been endorsed by the Critical Care EEG Monitoring Research Consortium. We hope these consensus definitions will promote improved communication, permit multicenter research, and ultimately improve understanding and treatment of these conditions.
Summary
We report the proceedings of the First International new‐onset refractory status epilepticus (NORSE) and febrile infection‐related epilepsy syndrome (FIRES) Symposium. To promote awareness of ...this condition and foster research efforts, we conveyed the First International new‐onset refractory status epilepticus (NORSE) and febrile infection‐related epilepsy syndrome (FIRES) Symposium. The conference was supported by The NORSE Institute (http://www.norseinstitute.org). This article summarizes the discussions that were held during the Symposium and presents our strategy to unravel the cause of these disorders and to improve patient care. The standardized definitions for these disorders that have been developed, are required to improve communication and facilitate the development of multicenter registries and biobanks. A distinction between childhood‐ and adult‐onset forms of the syndrome is not supported by strong scientific evidence and it is argued that both should be studied together. Although the pathophysiology remains elusive, nascent evidence suggests a role for a postinfectious cytokine‐mediated mechanism, which should be further investigated. It also appears important to develop tools for their early recognition and prompt treatment. Recent evidence suggests that specific electroencephalography (EEG) features might be helpful. The optimal treatment options remain to be determined; immune therapies are usually disappointing, but the ketogenic diet has proved effective in uncontrolled trials. NORSE and FIRES represent a very delicate clinical situation with specific communication issues between physicians and with patients and families. Standardized consensus definitions and a multidisciplinary multicenter strategy will help research efforts and improve clinical care for patients with NORSE and FIRES.
Psychiatric and behavioral side effects (PBSEs) are common, undesirable effects associated with antiepileptic drug (AED) use. The objective of the study was to compare the PBSE profiles of older and ...newer AEDs in a large specialty practice-based sample of patients diagnosed with epilepsy.
As part of the Columbia and Yale AED Database Project, we reviewed patient records including demographics, medical history, AED use, and side effects for 4085 adult patients (age: 18 years) newly started on an AED regimen. Psychiatric and behavioral side effects were determined by patient or physician report in the medical record, which included depressive mood, psychosis, anxiety, suicidal thoughts, irritability, aggression, and tantrum. Significant non-AED predictors of PBSE rate were first determined from 83 variables using logistic regression. Predictors were then controlled for in the comparison analysis of the rate of PBSEs and intolerable PBSEs (PBSEs that led to dosage reduction or discontinuation) between 18 AEDs.
Psychiatric and behavioral side effects occurred in 17.2% of patients and led to intolerability in 13.8% of patients. History of psychiatric condition(s), secondary generalized seizures, absence seizures, and intractable epilepsy were associated with increased incidence of PBSE. Levetiracetam (LEV) had the greatest PBSE rate (22.1%). This was statistically significant when compared with the aggregate of the other AEDs (P<0.001, OR=6.87). Levetiracetam was also significantly (P<0.001) associated with higher intolerability rate (17.7%), dose decreased rate (9.4%), and complete cessation rate (8.3%), when compared with the aggregate of the other AEDs. Zonisamide (ZNS) was also significantly associated with a higher rate of PBSE (9.7%) and IPBSE (7.9%, all P<0.001). On the other hand, carbamazepine (CBZ), clobazam (CLB), gabapentin (GBP), lamotrigine (LTG), oxcarbazepine (OXC), phenytoin (PHT), and valproate (VPA) were significantly associated with a decreased PBSE rates (P<0.001). Carbamazepine, GBP, LTG, PHT, and VPA were also associated with lower IPBSE rates when compared individually with the aggregate of other AEDs. All other AEDs were found to have intermediate rates that were not either increased or decreased compared with other AEDs. When each AED was compared to LTG, only CBZ had a significantly lower PBSE rate. The main limitations of this study were that the study design was retrospective and not blinded, and the AEDs were not randomly assigned to patients.
Psychiatric and behavioral side effects occur more frequently in patients taking LEV and ZNS than any other AED and led to higher rates of intolerability. Lower PBSE rates were seen in patients taking CBZ, CLB, GBP, LTG, OXC, PHT, and VPA. Our findings may help facilitate the AED selection process.
•Rates of psychiatric and behavioral side effect (PBSE) are compared between AEDs.•History of psychiatric condition and seizures failing to improve with ≥2 AEDs are associated with PBSEs.•History of absence and secondarily generalized seizures are associated with PBSEs.•Levetiracetam and zonisamide are associated with higher PBSEs.•Lower PBSE rates are seen in carbamazepine compared with that in lamotrigine.
The aim of the study was to provide an overview of the prevalence, risk factors, burden, and current and emerging pharmacologic treatments for seizure clusters in patients with epilepsy.
Close to ...half of patients with active epilepsy experience seizure clusters, and the clinical, social, and financial burdens of seizure clusters are high. However, there is no widely accepted definition of seizure clusters; their prevalence is underappreciated, contingencies for addressing them (seizure action plans) are often lacking, and their effects are not well-studied. These issues have resulted in an insufficient number of investigations and approved medications for this condition. Novel formulations are in late-stage development to meet this unmet need.
•Up to 46% of patients treated for epilepsy experience seizure clusters.•Only about half of patients experiencing seizure clusters have seizure action plans.•Fewer than half of patients who experience seizure clusters receive rescue treatment.•Published guidelines for use of rescue therapies and management of seizure clusters are urgently needed.•Also needed are better rescue treatment options in this setting.
Objective
The objective of this study was to investigate inflammation using cerebrospinal fluid (CSF) and serum cytokines/chemokines in patients with new‐onset refractory status epilepticus (NORSE) ...to better understand the pathophysiology of NORSE and its consequences.
Methods
Patients with NORSE (n = 61, including n = 51 cryptogenic), including its subtype with prior fever known as febrile infection‐related epilepsy syndrome (FIRES), were compared with patients with other refractory status epilepticus (RSE; n = 37), and control patients without SE (n = 52). We measured 12 cytokines/chemokines in serum or CSF samples using multiplexed fluorescent bead‐based immunoassay detection. Cytokine levels were compared between patients with and without SE, and between the 51 patients with cryptogenic NORSE (cNORSE) and the 47 patients with a known‐etiology RSE (NORSE n = 10, other RSE n = 37), and correlated with outcomes.
Results
A significant increase of IL‐6, TNF‐α, CXCL8/IL‐8, CCL2, MIP‐1α, and IL‐12p70 pro‐inflammatory cytokines/chemokines was observed in patients with SE compared with patients without SE, in serum and CSF. Serum innate immunity pro‐inflammatory cytokines/chemokines (CXCL8, CCL2, and MIP‐1α) were significantly higher in patients with cNORSE compared to non‐cryptogenic RSE. Patients with NORSE with elevated innate immunity serum and CSF cytokine/chemokine levels had worse outcomes at discharge and at several months after the SE ended.
Interpretation
We identified significant differences in innate immunity serum and CSF cytokine/chemokine profiles between patients with cNORSE and non‐cryptogenic RSE. The elevation of innate immunity pro‐inflammatory cytokines in patients with NORSE correlated with worse short‐ and long‐term outcomes. These findings highlight the involvement of innate immunity‐related inflammation, including peripherally, and possibly of neutrophil‐related immunity in cNORSE pathogenesis and suggest the importance of utilizing specific anti‐inflammatory interventions. ANN NEUROL 2023;94:75–90
Purpose
To determine the temporal evolution, clinical correlates, and prognostic significance of electroencephalographic (EEG) patterns in post-cardiac arrest comatose patients treated with ...hypothermia.
Methods
Prospective cohort study of consecutive post-anoxic patients receiving hypothermia and continuous EEG monitoring between May 2011 and June 2014 (
n
= 100). In addition to clinical variables, 5-min EEG clips at 6, 12, 24, 48, and 72 h after return of spontaneous circulation (ROSC) were reviewed. EEG background was classified according to the American Clinical Neurophysiological Society critical care EEG terminology. Clinical outcome at discharge was dichotomized as good Glasgow outcome scale (GOS) 4–5, low to moderate disability vs. poor (GOS 1–3, severe disability to death).
Results
Non-ventricular fibrillation/tachycardia arrest, longer time to ROSC, absence of brainstem reflexes, extensor or no motor response, lower pH, higher lactate, hypotension requiring >2 vasopressors, and absence of reactivity on EEG were all associated with poor outcome (all
p
values ≤0.01). Suppression-burst at any time indicated a poor prognosis, with a 0 % false positive rate (FPR) 95 % confidence interval (CI) 0–10 %. All patients (54/54) with suppression-burst or a low voltage (<20 µV) EEG at 24 h had a poor outcome, with an FPR of 0 % 95 % CI 0–8 %. Normal background voltage ≥20 µV without epileptiform discharges at any time interval carried a positive predictive value >70 % for good outcome.
Conclusions
Suppression-burst or a low voltage at 24 h after ROSC was not compatible with good outcome in this series. Normal background voltage without epileptiform discharges predicted a good outcome.
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