Reconsidering non‐convulsive status epilepticus diagnosis: 2.5 Hz or etiology‐driven frequency cutoffs?

We would like to extend our congratulations to Gijs and colleagues on their recent publication in Epilepsia, titled “Focal Hypermetabolism in suspected non-convulsive status epilepticus.”1 The group investigated 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) as a biomarker in suspected non-convulsive status epilepticus (NCSE). They applied the Salzburg EEG criteria2 and the American Clinical Neurophysiology Society (ACNS) terminology for electroencephalography (EEG) diagnosis of NCSE. One of the key conclusions of this study was the observation that the frequency of epileptiform discharges may not necessarily correlate with the metabolic burden of NCSE. Specifically, the degree of hypermetabolism observed through PET in patients with NCSE varied significantly across different discharge frequencies, without following a distinct or predictable pattern. This finding represents a significant contribution to our understanding of the pathophysiology of NCSE and raises important questions regarding the relationship between EEG features and increased metabolic demand in this condition. However, it is important to acknowledge that the study had some notable limitations: (i) the number of patients (n = 24) included in the study was relatively small, (ii) The patient sample is represented by an elderly population with a median age of 62 years, and, finally, (iii) most patients had symptomatic etiologies—either acute or remote (20/24, 83%) — showing frequencies of lateralized periodic discharges (LPDs- 17/24, 71%) at or below 2 Hz (15/17, 88%). EEG features other than LPDs were underrepresented, but were equally important in diagnosing NCSE. In this context, hypermetabolism is a compensatory mechanism, which may have an influence on EEG features, including the frequency of discharges. Figure 1 shows a patient with lower frequencies of LPDs showing hyperperfusion on arterial spin labeling (cohort from Salzburg). It is well established that the Salzburg criteria,3 including the 2.5 Hz cutoff, were validated in populations with a high prevalence of epilepsy, in which higher frequencies of epileptiform discharges are more commonly observed. A paradigmatic example is typical absence status epilepticus, typically of patients with a diagnosis of idiopathic generalized epilepsy and well characterized by a discharge frequency at around 3 Hz or more and not associated with long-term consequences—either in animal models4 or in humans.5 This suggests that higher frequencies may, in fact, reflect more effective compensatory metabolic mechanisms in patients with epilepsy. Given the well-recognized heterogeneity of status epilepticus (SE) etiologies,6, 7 and in light of these findings, we believe it might be time to consider re-defining NCSE criteria based on underlying etiology, with adjusted frequency thresholds accordingly, rather than a uniform approach to all kind of etiologies. To support such an approach, further neuroimaging studies are needed—ideally focusing on peri-ictal imaging features,8, 9 with larger patient cohorts and different etiologies that allow for subgroup analyses, as these may provide insights into different relevant pathophysiological mechanisms. Different etiologies of SE may relate to certain frequencies of epileptiform discharges and help refine EEG criteria tailored to specific causes of SE. The magnetic resonance image of a patient (Figure 1) is part of a prospective project supported by the Austrian Science Fund (FWF, Project Number KLI 969-B), with ethics approval granted by the Ethics Committee of the Region of Salzburg (approval number 415-E/2422) and written informed consent obtained from the patient. Eugen Trinka reports personal fees from EVER Pharma, Marinus, Arvelle, Angelini, Argenx, Alexion, Medtronic, BIAL – Portela & Cª, S.A, NewBridge, GL Pharma, GlaxoSmithKline, Boehringer Ingelheim, LivaNova, Eisai, UCB, Biogen, Sanofi, Jazz Pharmaceuticals, STOKE Therapeutics, and Actavis. He is co-director of the European Consortium on Epilepsy Trials (ECET). His institution received grants from Biogen, UCB Pharma, Eisai, Red Bull, Merck, Bayer, the European Union, FWF Osterreichischer Fond zur Wissenschaftsforderung, Bundesministerium für Wissenschaft und Forschung, and Jubiläumsfond der Österreichischen Nationalbank—none related to the presented work. Giorgi Kuchukhidze received a research grant from Austrian Research Fund (FWF), Project Number KLI 969; and travel grants and honoraria from UCB, Jazz Pharmaceuticals, and Novartis. Pilar Bosque-Varela received travel grants and honoraria from UCB. Lukas Machegger has no conflicts of interest to disclose. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. Open Access funding provided by Paracelsus Medizinische Privatuniversitat/KEMÖ. The data that support the findings of this study are available from the corresponding author upon reasonable request.