New-onset refractory status epilepticus (NORSE).

New-onset refractory status epilepticus and its subcategory febrile infection-related epilepsy syndrome are rare devastating clinical presentations in those without pre-existing relevant history, often in schoolchildren or young adults, without a clear cause on initial investigations. A cause is later identified in up to half of adults, but in many fewer children. Patients often require protracted intensive care and are at significant risk of dying. Functional disability is common and subsequent chronic epilepsy is the norm, but some people do have good outcomes, even after prolonged status epilepticus. Patients need prompt investigations and treatment. Anaesthetic and antiseizure medications are supplemented by other treatment modalities, including the ketogenic diet. Despite limited evidence, it is appropriate to try to modify the presumed underlying pathogenesis with immune modulation early, with a more recent focus on using interleukin inhibitors. Optimising management will require concerted multicentre international efforts.

Lentiviral expression of GAD67 and CCK promoter-driven opsins to target interneurons in vitro and in vivo.

BACKGROUND: The ability to manipulate the activity of interneurons with optogenetic tools offers the possibility of interfering with diseases caused by altered neuronal inhibition and synchrony, including epilepsy and schizophrenia. To develop vectors for therapeutic approaches, targeting optogenetic constructs to interneurons is therefore a key requirement. We investigated whether the interneuron-specific promoters glutamic acid decarboxylase (GAD)67 and cholecystokinin (CCK) allowed targeted lentiviral delivery of opsins to interneurons as a whole, or specifically CCK+ interneurons. METHODS: We generated lentiviral (LV) plasmids encoding channelrhodopsin (ChR2) and halorhodopsin (NpHR) tagged with fluorophores and driven by GAD67 or CCK promoters. Adeno-associated virus (AAV) and LV vectors carrying opsins driven by pyramidal cell promoters were used as controls. We transduced neuronal cultures and rodent brain in vivo, immunostained specimens 6-8 weeks after in vivo injection and 7-14 days after in vitro transduction, and evaluated volume and specificity of expression by confocal microscopy. RESULTS: In vitro, 90% (19/21) of LV-CCK-NpHR2.0-EYFP expressing neurons were CCK+. In vivo, LV-GAD67-ChR2-mCherry was expressed in 2.6% (5/193), LV-GAD67-NpHR2.0-EYFP in approximately 15% (43/279) and LV-CCK-NpHR2.0-EYFP in 47% (9/19) of hippocampal GABA+ interneurons. GAD67 vectors expressed in larger volumes than CCK-driven constructs. AAV vector controls achieved the largest expression volumes. CONCLUSIONS: LV-CCK-NpHR2.0-EYFP may be useful for targeting CCK+ interneurons in culture. GAD67/CCK-driven lentiviral constructs are expressed in vivo, although expression is not specific for interneurons. Overall, expression levels are low compared to opsins driven by pyramidal cell promoters. A better understanding of GAD67 and CCK promoter structure or alternative techniques is required to reliably target opsins to interneurons using viral vectors.

WONOEP appraisal: optogenetic tools to suppress seizures and explore the mechanisms of epileptogenesis.

Optogenetics is a novel technology that combines optics and genetics by optical control of microbial opsins, targeted to living cell membranes. The versatility and the electrophysiologic characteristics of the light-sensitive ion-channels channelrhodopsin-2 (ChR2), halorhodopsin (NpHR), and the light-sensitive proton pump archaerhodopsin-3 (Arch) make these optogenetic tools potent candidates in controlling neuronal firing in models of epilepsy and in providing insights into the physiology and pathology of neuronal network organization and synchronization. Opsins allow selective activation of excitatory neurons and inhibitory interneurons, or subclasses of interneurons, to study their activity patterns in distinct brain-states in vivo and to dissect their role in generation of synchrony and seizures. The influence of gliotransmission on epileptic network function is another topic of great interest that can be further explored by using light-activated Gq protein-coupled opsins for selective activation of astrocytes. The ever-growing optogenetic toolbox can also be combined with emerging techniques that have greatly expanded our ability to record specific subtypes of cortical and hippocampal neurons in awake behaving animals such as juxtacellular recording and two-photon guided whole-cell recording, to identify the specific subtypes of neurons that are altered in epileptic networks. Finally, optogenetic tools allow rapid and reversible suppression of epileptic electroencephalography (EEG) activity upon photoactivation. This review outlines the most recent advances achieved with optogenetic techniques in the field of epilepsy by summarizing the presentations contributed to the 13th ILAE WONOEP meeting held in the Laurentian Mountains, Quebec, in June 2013.

Perspective: Vagal nerve stimulation in the treatment of new-onset refractory status epilepticus.

Introduction: Resistance to drug therapy is a major hurdle in new-onset refractory status epilepticus (NORSE) treatment and there is urgent need to develop new treatment approaches. Non-drug approaches such as neuromodulation offer significant benefits and should be investigated as new adjunct treatment modalities. An important unanswered question is whether desynchronizing networks by vagal nerve stimulation (VNS) may improve seizure control in NORSE patients. Main text: We present a summary of published NORSE cases treated with VNS and our own data, discuss possible mechanisms of action, review VNS implantation timing, stimulation setting titration protocols and outcomes. Further, we propose avenues for future research. Discussion: We advocate for consideration of VNS for NORSE both in early and late stages of the presentation and hypothesize a possible additional benefit from implantation in the acute phase of the disease. This should be pursued in the context of a clinical trial, harmonizing inclusion criteria, accuracy of documentation and treatment protocols. A study planned within our UK-wide NORSE-UK network will answer the question if VNS may confer benefits in aborting unremitting status epilepticus, modulate ictogenesis and reduce long-term chronic seizure burden.

Safe and effective implantation and use of vagal nerve stimulation in new-onset refractory status epilepticus in early pregnancy: a case report.

Introduction: The management of new-onset refractory status epilepticus (NORSE) in pregnancy may be complicated by anti-seizure medication (ASM) polytherapy-associated teratogenicity. We aim to demonstrate the safety and efficacy of vagal nerve stimulation (VNS) in a pregnant patient presenting with NORSE. Case description: A 30-year old female, at 5-weeks' gestation presented with drug-refractory myoclonic status epilepticus, responsive only to high levels of anesthetic agents. The severity of seizures did not allow extubation, and the patient remained ventilated and sedated. VNS was implanted 26 days after seizure onset. The immediate post-operative output was 0.25 mA, which was rapidly titrated up to 0.5 mA the next morning, and to 0.75 mA that afternoon. This was further increased to 1.0 mA on 3rd day post-operation, and to 1.25 mA 7 days post-op. Myoclonic jerks diminished significantly 7 days post-op, allowing extubation. Twenty days after VNS implantation, no myoclonic jerks were observed. There was also a notable neurological improvement including increased alertness and mobility, and ability to obey commands. Drug overdose was subsequently found to be the most likely etiology of her NORSE. An early pregnancy assessment 17 days after VNS implantation showed a normally sited pregnancy, normal fetal heart activity and crown-rump length. The patient remained seizure free, gained functional independence and delivered a premature but otherwise healthy baby at 33 weeks' gestation. Conclusion: NORSE is challenging to manage, further compounded in pregnancy due to the teratogenicity of ASMs and ASM polytherapy. This is the first case-study to report the safe implantation and use of VNS during the first trimester of pregnancy for the management of NORSE.

Non-convulsive status epilepticus: COVID-19 or clozapine induced?

We present a case of non-convulsive status epilepticus in a 57-year-old woman with a schizoaffective disorder, without an antecedent seizure history, with two possible aetiologies including SARS-CoV-2 infection and clozapine uptitration. We discuss the presentation, investigations, differential diagnosis and management. In particular, we focus on the electroencephalogram (EEG) findings seen in this case and the electroclinical response to antiepileptic medication. We review the literature and discuss the relevance of this case to the SARS-CoV-2 global pandemic. We emphasise the importance of considering possible neurological manifestations of SARS-CoV-2 infection and highlight seizure disorder as one of the possible presentations. In addition, we discuss the possible effects of clozapine on the electroclinical presentation by way of possible seizure induction as well as discuss the possible EEG changes and we highlight that this needs to be kept in mind especially during rapid titration.

Clinical reasoning: rapidly progressive quadriparesis in a forgetful patient.

A 50-year-old right-handed retired family business manager developed progressive left-sided weakness over 5 days after a mechanical fall. She remembered catching her foot on the carpet and falling down a flight of stairs, followed by severe neck pain over C4-C5 and inability to get up for nearly an hour. Over the subsequent month her symptoms progressed and she presented to hospital with an asymmetric spastic paraparesis, loss of pinprick sensation in her arms and legs, loss of vibration sense to both hips, and double incontinence.