New-onset refractory status epilepticus and febrile infection-related epilepsy syndrome.

PURPOSE OF REVIEW: The concept and understanding of new-onset refractory status epilepticus (NORSE), and its subtype with prior fever known as febrile infection-related epilepsy syndrome (FIRES) have evolved in the recent past. This review aims to summarize the recent developments in the pathophysiology, diagnosis and management of these challenging conditions. RECENT FINDINGS: NORSE and FIRES can have many different causes. Although the list of possible causes is still growing, they mostly fall in the categories of autoimmune encephalitis and genetic disorders. However, despite extensive investigations, most cases of NORSE and FIRES remain cryptogenic. Recent studies have pointed towards the key role of autoinflammation as a unifying pathophysiological mechanism in these cases. These findings also support the use of immunomodulatory treatment in this setting. Consensus recommendations on the management of NORSE and FIRES have recently been published. SUMMARY: NORSE and FIRES remain challenging conditions to diagnose and treat. Recent findings from clinical and basic research and new recommendations, reviewed in this article, contribute to an emerging framework for management and future research.

On-Scalp Optically Pumped Magnetometers versus Cryogenic Magnetoencephalography for Diagnostic Evaluation of Epilepsy in School-aged Children.

Background Magnetoencephalography (MEG) is an established method used to detect and localize focal interictal epileptiform discharges (IEDs). Current MEG systems house hundreds of cryogenic sensors in a rigid, one-size-fits-all helmet, which results in several limitations, particularly in children. Purpose To determine if on-scalp MEG based on optically pumped magnetometers (OPMs) alleviates the main limitations of cryogenic MEG. Materials and Methods In this prospective single-center study conducted in a tertiary university teaching hospital, participants underwent cryogenic (102 magnetometers, 204 planar gradiometers) and on-scalp (32 OPMs) MEG. The two modalities for the detection and localization of IEDs were compared. The t test was used to compare IED amplitude and signal-to-noise ratio (SNR). Distributed source modeling was performed on OPM-based and cryogenic MEG data. Results Five children (median age, 9.4 years [range, 5-11 years]; four girls) with self-limited idiopathic (n = 3) or refractory (n = 2) focal epilepsy were included. IEDs were identified in all five children with comparable sensor topographies for both MEG devices. IED amplitudes were 2.3 (7.2 of 3.1) to 4.6 (3.2 of 0.7) times higher (P < .001) with on-scalp MEG, and the SNR was 27% (16.7 of 13.2) to 60% (12.8 of 8.0) higher (P value range: .001-.009) with on-scalp MEG in all but one participant (P = .93), whose head movements created pronounced motion artifacts. The neural source of averaged IEDs was located at approximately 5 mm (n = 3) or higher (8.3 mm, n = 1; 15.6 mm, n = 1) between on-scalp and cryogenic MEG. Conclusion Despite the limited number of sensors and scalp coverage, on-scalp magnetoencephalography (MEG) based on optically pumped magnetometers helped detect interictal epileptiform discharges in school-aged children with epilepsy with a higher amplitude, higher signal-to-noise ratio, and similar localization value compared with conventional cryogenic MEG. Online supplemental material is available for this article. © RSNA, 2022 See also the editorial by Widjaja in this issue.

Hippocampal sclerosis and epilepsy surgery in neurofibromatosis type 1: case report of a 3-year-old child explored by SEEG and review of the literature.

PURPOSE: Epilepsy associated with neurofibromatosis type 1 (NF1) is infrequent and usually controlled with anti-epileptic drugs. However, in some drug-resistant patients a presurgical evaluation should be considered. Hippocampal sclerosis (HS) is one of the rare causes of epilepsy in neurofibromatosis type 1, which can lead to surgery. METHODS: We present a three-year-old child with refractory epilepsy associated with several structural brain abnormalities but normal hippocampi on brain MRI and a heterozygous variant in the NF1 gene (c.2542G > A). A complete presurgical evaluation was performed including stereo-electroencephalography (SEEG). RESULTS: Usual seizures were recorded, and the seizure onset zone was delineated in the anterior hippocampus. Pathological examination performed after a tailored mesio-temporal resection confirmed hippocampal sclerosis, and the child achieved seizure freedom with 2 years of follow-up. CONCLUSION: This rare pediatric case illustrates that NF1 may be associated with early-onset refractory epilepsy secondary to MRI-negative HS, supporting the major role of SEEG in the presurgical evaluation of patients with extended cortical malformations.

Clinical presentation of new onset refractory status epilepticus in children (the pSERG cohort).

OBJECTIVE: We aimed to characterize the clinical profile and outcomes of new onset refractory status epilepticus (NORSE) in children, and investigated the relationship between fever onset and status epilepticus (SE). METHODS: Patients with refractory SE (RSE) between June 1, 2011 and October 1, 2016 were prospectively enrolled in the pSERG (Pediatric Status Epilepticus Research Group) cohort. Cases meeting the definition of NORSE were classified as "NORSE of known etiology" or "NORSE of unknown etiology." Subgroup analysis of NORSE of unknown etiology was completed based on the presence and time of fever occurrence relative to RSE onset: fever at onset (≤24 h), previous fever (2 weeks-24 h), and without fever. RESULTS: Of 279 patients with RSE, 46 patients met the criteria for NORSE. The median age was 2.4 years, and 25 (54%) were female. Forty (87%) patients had NORSE of unknown etiology. Nineteen (48%) presented with fever at SE onset, 16 (40%) had a previous fever, and five (12%) had no fever. The patients with preceding fever had more prolonged SE and worse outcomes, and 25% recovered baseline neurological function. The patients with fever at onset were younger and had shorter SE episodes, and 89% recovered baseline function. SIGNIFICANCE: Among pediatric patients with RSE, 16% met diagnostic criteria for NORSE, including the subcategory of febrile infection-related epilepsy syndrome (FIRES). Pediatric NORSE cases may also overlap with refractory febrile SE (FSE). FIRES occurs more frequently in older children, the course is usually prolonged, and outcomes are worse, as compared to refractory FSE. Fever occurring more than 24 h before the onset of seizures differentiates a subgroup of NORSE patients with distinctive clinical characteristics and worse outcomes.

Long-term outcomes of status epilepticus: A critical assessment.

We reviewed 37 studies reporting long-term outcomes after a status epilepticus (SE) episode in pediatric and adult populations. Study design, length of follow-up, outcome measures, domains investigated (mortality, SE recurrence, subsequent epilepsy, cognitive outcome, functional outcome, or quality of life), and predictors of long-term outcomes are summarized. Despite heterogeneity in the design of prior studies, overall risk of poor long-term outcome after SE is high in both children and adults. Etiology is the main determinant of outcome, and the effect of age or SE duration is often difficult to distinguish from the underlying cause. The effect of the treatment on long-term outcome after SE is still unknown.

New-onset refractory status epilepticus (NORSE) and febrile infection-related epilepsy syndrome (FIRES): State of the art and perspectives.

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.

A First Case of Acute Flaccid Myelitis Related to Enterovirus D68 in Belgium: Case Report.

Introduction: We describe the first case of acute flaccid myelitis (AFM) related to enterovirus D68 (EV-D68) infection in Belgium. The clinical and radiological presentation of AFM associated with EV-D68 although well described currently remains a challenging diagnosis. Through this interesting clinical case, we aimed to review the differential diagnosis of acute flaccid palsy in a child and discuss the specific point of interest related to AFM. Case Presentation: We present the case of a 4-year-old girl with a torticollis associated with an acute palsy of the right upper limb. The magnetic resonance imaging revealed an increased T2 signal intensity of the entire central gray matter of the cervical cord with involvement of the posterior brainstem. A polymerase chain reaction (PCR) conducted on a nasopharyngeal swab was found positive for EV-D68. The definition of AFM proposed by the Center for Disease Control and Prevention (CDC) is an acute-onset flaccid weakness of one or more limbs in the absence of a clear alternative diagnosis and the radiological evidence of gray matter involvement on an MRI picture, and our case fits these two criteria. A prompt and detailed workup is required to distinguish this emergent disease from other forms of acute flaccid palsy. The functional prognosis of AFM is poor, and there are no evidence-based treatment guidelines so far. Conclusion: AFM is an emerging pathology that requires the attention of pediatricians to quickly rule out differential diagnoses and adequately manage the patient. Further research is needed to optimize treatments, improve outcomes, and provide scientifically based guidelines.

Tri-axial rubidium and helium optically pumped magnetometers for on-scalp magnetoencephalography recording of interictal epileptiform discharges: a case study.

Cryogenic magnetoencephalography (MEG) enhances the presurgical assessment of refractory focal epilepsy (RFE). Optically pumped magnetometers (OPMs) are cryogen-free sensors that enable on-scalp MEG recordings. Here, we investigate the application of tri-axial OPMs [87Rb (Rb-OPM) and 4He gas (He-OPM)] for the detection of interictal epileptiform discharges (IEDs). IEDs were recorded simultaneously with 4 tri-axial Rb- and 4 tri-axial He-OPMs in a child with RFE. IEDs were identified visually, isolated from magnetic background noise using independent component analysis (ICA) and were studied following their optimal magnetic field orientation thanks to virtual sensors. Most IEDs (>1,000) were detectable by both He- and Rb-OPM recordings. IEDs were isolated by ICA and the resulting magnetic field oriented mostly tangential to the scalp in Rb-OPMs and radial in He-OPMs. Likely due to differences in sensor locations, the IED amplitude was higher with Rb-OPMs. This case study shows comparable ability of Rb-OPMs and He-OPMs to detect IEDs and the substantial benefits of triaxial OPMs to detect IEDs from different sensor locations. Tri-axial OPMs allow to maximize spatial brain sampling for IEDs detection with a limited number of sensors.

Focal polymicrogyria in children: Contribution of invasive explorations and epileptogenicity mapping in the surgical decision.

OBJECTIVE: Report of the contribution of invasive EEG (iEEG) and epileptogenicity mappings (EM) in a pediatric cohort of patients with epilepsy associated with focal polymicrogyria (PMG) and candidates for resective surgery. METHOD: Retrospective pediatric case series of patients presenting focal PMG-related refractory epilepsy undergoing an invasive exploration (iEEG) at Fondation Rothschild Hospital. We reviewed clinical data, structural MRI, and visual analysis of iEEG recordings. Moreover, time-frequency analysis of SEEG signals with a neuroimaging approach (epileptogenicity maps) was used to support visual analysis. RESULTS: Between 2012 and 2019, eight patients were selected. Five patients were explored with stereoelectroencephalography (SEEG) only, one patient with subdural exploration (SDE) only and two patients first underwent SEEG and then SDE. The mean age at seizure onset was 40.3 months (range 3-120), and the mean age for the iEEG 10.8 years (range 7-15). The epileptogenic zone (EZ) appeared concordant to the PMG lesion in only one case, was larger in three cases, smaller in two cases and different in one case. Four cases were selected for tailored resective surgery and one for total callosotomy. Two patients remained seizure-free at their last follow-up (mean 32.6 months, range 7-98). Epileptogenicity mapping (EM) refined the qualitative analysis, showing in four patients an EZ larger than visually defined. CONCLUSION: This study is the first pediatric study to analyze the value of iEEG and EM as well as operability in focal PMG-related refractory epilepsy. The results illustrate the complexity of this pathology with variable concordance between the EZ and the lesion and mixed response to surgery.

New onset refractory status epilepticus (NORSE).

PURPOSE: To summarize the clinical features, suggested work-up, treatment and prognosis of new-onset refractory status epilepticus (NORSE), a condition recently defined as the occurrence of refractory status epilepticus (RSE) in a patient without active epilepsy, and without a clear acute or active structural, toxic or metabolic cause; and of the related syndrome of febrile infection-related epilepsy syndrome (FIRES), also recently defined as a subgroup of NORSE preceded by a febrile illness between 2 weeks and 24 h prior to the onset of RSE. METHOD: Narrative review of the medical literature about NORSE and FIRES. RESULTS: NORSE and FIRES mainly affect school-age children and young adults. A prodromal phase with flu-like symptoms precedes the SE onset in two third of NORSE cases, and by definition in all FIRES. Status epilepticus usually starts with repeated focal seizures with secondary bilateralization. Most cases evolve to super RSE (SRSE) and have unfavorable outcome, with short-term mortality of 12-27%, long-term disability and epilepsy. No specific imaging or laboratory abnormalities have been identified so far that allows an early diagnosis and half of adult cases remain of unknown etiology. A standardized diagnostic algorithm is provided and. Autoimmune encephalitis is the most frequent identified cause. In the absence of specific diagnosis, immunotherapy could be tried in addition to antiepileptic treatment. CONCLUSIONS: This review presents the rare but devastating syndrome of NORSE, including the subcategory of FIRES. Early recognition with complete work-up is primordial to identify the underlying cause and promptly start appropriate treatment.

SCN1B-linked early infantile developmental and epileptic encephalopathy.

OBJECTIVE: Patients with Early Infantile Epileptic Encephalopathy (EIEE) 52 have inherited, homozygous variants in the gene SCN1B, encoding the voltage-gated sodium channel (VGSC) ß1 and ß1B non-pore-forming subunits. METHODS: Here, we describe the detailed electroclinical features of a biallelic SCN1B patient with a previously unreported variant, p.Arg85Cys. RESULTS: The female proband showed hypotonia from birth, multifocal myoclonus at 2.5 months, then focal seizures and myoclonic status epilepticus (SE) at 3 months, triggered by fever. Auditory brainstem response (ABR) showed bilateral hearing loss. Epilepsy was refractory and the patient had virtually no development. Administration of fenfluramine resulted in a significant reduction in seizure frequency and resolution of SE episodes that persisted after a 2-year follow-up. The patient phenotype is more compatible with early infantile developmental and epileptic encephalopathy (DEE) than with typical Dravet syndrome (DS), as previously diagnosed for other patients with homozygous SCN1B variants. Biochemical and electrophysiological analyses of the SCN1B variant expressed in heterologous cells showed cell surface expression of the mutant ß1 subunit, similar to wild-type (WT), but with loss of normal ß1-mediated modification of human Nav 1.1-generated sodium current, suggesting that SCN1B-p.Arg85Cys is a loss-of-function (LOF) variant. INTERPRETATION: Importantly, a review of the literature in light of our results suggests that the term, early infantile developmental and epileptic encephalopathy, is more appropriate than either EIEE or DS to describe biallelic SCN1B patients.

Autoimmune paraneoplastic syndromes associated to lung cancer: A systematic review of the literature: Part 3: Neurological paraneoplastic syndromes, involving the central nervous system.

The development of new immune treatment in oncology and particularly for lung cancer may induce new complications, particularly activation or reactivation of auto-immune diseases. In this context, a systematic review on the auto-immune paraneoplastic syndromes that can complicate lung cancer appears useful. This article is the third of a series of five and deals mainly with neurological paraneoplastic syndromes involving the central nervous system.

Autoimmune paraneoplastic syndromes associated to lung cancer: A systematic review of the literature Part 4: Neurological paraneoplastic syndromes, involving the peripheral nervous system and the neuromuscular junction and muscles.

The development of new immune treatment in oncology and particularly for lung cancer may induce new complications, particularly activation or reactivation of auto-immune diseases. In this context, a systematic review on the auto-immune paraneoplastic syndromes that can complicate lung cancer appears useful. This article is the fourth of a series of five and deals mainly with neurological paraneoplastic syndromes involving the peripheral nervous system and the neuromuscular junction and muscles.

Acquired epileptic opercular syndrome related to a heterozygous deleterious substitution in GRIN2A.

Epileptic encephalopathies with continuous spike-and-waves during sleep (CSWS) are characterized by cognitive or language impairment, and are occasionally associated with pathogenic variants of the GRIN2A gene. In these disorders, speech dysfunction could be either related to cerebral dysfunction caused by the GRIN2A deleterious variant or intense interictal epileptic activity. Here, we present a patient with apraxia of speech, clearly linked to severity of epilepsy, carrying a GRIN2A variant. A 6-year-old boy developed acute regression of expressive language following epileptic seizures, leading to complete mutism, at which time EEG revealed CSWS. MEG showed bilateral superior parietal and opercular independent CSWS onsets and PET with fluorodeoxyglucose demonstrated significant increase in relative glucose metabolism in bilateral superior parietal regions. Corticosteroids induced a regression of CSWS together with impressive improvement in speech abilities. This case supports the hypothesis of a triggering role for epileptic discharges in speech deterioration observed in children carrying a deleterious variant of GRIN2A. When classic antiepileptic drugs fail to control epileptic activity, corticosteroids should be considered. Multimodal functional neuroimaging suggests a role for opercular and superior parietal areas in acquired epileptic opercular syndrome. [Published with video sequences on www.epilepticdisorders.com].

Autoimmune paraneoplastic syndromes associated to lung cancer: A systematic review of the literature: Part 5: Neurological auto-antibodies, discussion, flow chart, conclusions.

The development of new immune treatment in oncology and particularly for lung cancer may induce new complications, particularly activation or reactivation of auto-immune diseases. In this context, a systematic review on the auto-immune paraneoplastic syndromes that can complicate lung cancer appears useful. This article is the last of a series of five and deals mainly with onconeural antibodies involved in neurological paraneoplastic syndromes and provides the final discussion.

Chronic brain hypoperfusion due to multi-vessel extracranial atherosclerotic disease: a potentially reversible cause of cognitive impairment.

A 62-year-old patient presented with persistent cognitive deficits 3 months after a right temporal ischemic stroke due to ipsilateral carotid occlusion. Work-up disclosed hemodynamically significant contralateral carotid artery stenosis and left subclavian steal phenomenon. Brain SPECT imaging revealed bihemispheric chronic brain hypoperfusion that substantially improved on repeat imaging when the subclavian steal was temporarily diminished by inflating a cuff around the left arm. Carotid endarterectomy of the asymptomatic carotid stenosis substantially ameliorated bihemispheric brain perfusion and reversed cognitive impairment. This case highlights that multi-vessel, extracranial atherosclerotic disease may cause chronic diffuse brain hypoperfusion that can be associated with cognitive impairment.