Clinical Neurophysiology 126 (2015) 221–222

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Editorial

Small worlds See Article, pages 257–267

Finally, we need to decide whether to operate, and where. Clinical history is helpful, and imaging often crucial, in deciding both of these, but we use electroencephalography (EEG) to help with the fine points. It is frustrating, however, that, despite all of the improvements in our abilities to make decisions before surgery, many patients have seizures after surgery, whether sooner or later. How can we do better? Ictal seizure activity can come from everywhere, or somewhere, or several somewheres. We used to think that if the ‘‘seizure focus’’ was found and removed, this would predict good seizure control, but have found it hard to determine just where the focus is located. Is it the site(s) where epileptiform activity occurs at seizure onset, or that plus regions with interictal epileptiform activity, or that plus regions with early spread of epileptiform activity, or regions with hypometabolism, or some subset of these, or are there other factors that we need to consider when localizing potentially epileptogenic regions? A paper in this issue of Clinical Neurophysiology (JiménezJiménez et al., 2015), reviews experience with a group of patients varying in presumed sites of seizure onset and in EEG seizure onset patterns. Does the presence or absence, or the removal, of a lesion matter? Other than with mesial temporal sclerosis, it did not seem to. For instance, with frontal lobe seizures and focal cortical dysplasia, three patients had Engel class I outcomes, three Engel class 4, and two were in the middle. The key finding in this paper is that focal fast activity at seizure onset showed the greatest correlation with post-operative seizure control. This fast activity showed a mean frequency of 25.5 Hz, whereas fast activity preceded by a focal spike, with a mean frequency of 16.5 Hz, did not correlate with seizure control. Slower (alpha, delta range) rhythmic patterns also did not predict good outcome, but this could have been because of the small numbers of patients. Still, is there a sweet spot for good outcomes, with a mean somewhere in the 25 Hz range? Or is it the preceding focal spike that correlated with poorer outcome? As might be expected, diffuse electrodecremental events (DEE) also correlated with poor outcome. It is possible that electrodecremental activity only appears so because of the recording characteristics of the EEG machines we usually have used, and would turn out to be higher frequency activity with newer machines. The EEGs were recorded with a low pass filter of 70, so these faster activities would have been missed. Does fast activity (25.5 Hz) help predict good, but still faster activity, poor outcome? That is not suggested by this paper, and in any case seems unlikely given the recent findings regarding high frequency oscillations (HFO), which show that

post-surgical outcome can be good if the regions producing HFO are removed (Jacobs et al., 2008). What about the ‘‘diffuse’’ in DEE? On the one hand, it is focal HFO that have been found to predict good post-surgical outcome if removed. So maybe it is focal vs diffuse that matters. On the other hand, Jiménez-Jiménez et al. found that single discharges at seizure onset (called PED by them) did not predict poor outcome, even though they were the first EEG sign of the seizure. Moreover, when fast activity also occurred it did not matter whether PEDs were focal or widespread; in both circumstances, 6 of 7 cases had Engel class I outcomes. Why did the one (DEE) matter, but not the other (PED)? One possibility, suggested by Jiménez-Jiménez et al., is that a PED is followed by inhibition, with this followed by a rebound increase in excitation, which results in a seizure. This seems possible, but they also note that interictal epileptiform activity also is likely to be associated with inhibition. As the name implies, interictal discharges are not seizures. The difference may depend on whether and where epileptogenic links occur, in other words on whether there is an epileptogenic network, and on how extensive and strong the network linkage is. There are data indicating that epileptic networks can be widespread (Fahoum et al., 2012; Holtkamp et al., 2012). The more extensive the links, perhaps the more widespread the HFO or DEE. The stronger and more integrated the links, perhaps the more likely a seizure, regardless of how connected neurons are in more restricted areas of the brain (Netoff et al., 2004; Ponten et al., 2007). Links may be dormant for a time, unfortunately including the times when a patient comes for seizure monitoring. When this occurs, we may mis-localize the extent of the potentially epileptogenic region. Links may later reawaken, or increase in synaptic strength (Netoff et al., 2004), and with this wakening or strengthening, seizures may resume. However, at least some network theory and data suggest that high-frequencies synchronize activity in restricted areas of the brain, whereas low-frequencies synchronize activity more widely, and that overall cortical network topologies remain relatively stable (Kramer et al., 2011). If this is true, by what mechanism does the fast activity that underlies at least some DEE become more widespread, transforming from localized and interictal to widespread and epileptogenic? Does this mean that the apparently focal activities that epileptologists see on both scalp and intracranial recordings are epiphenomena, or perhaps tips of epileptogenic icebergs? Interictal epileptiform discharges and interictal positron emission tomography (PET) do not pinpoint but at least help point to the region of seizure onset (Bautista, 2013; Goncharova et al.,

http://dx.doi.org/10.1016/j.clinph.2014.06.004 1388-2457/Ó 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

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Editorial / Clinical Neurophysiology 126 (2015) 221–222

2013). Perhaps in the future we will use a combination of raw EEG analysis, findings on imaging, and network theory to help determine not only where seizures start now, but also when, where, and how they might start in the future. Conflict of interest statement None. References Bautista RE. On the nature of interictal epileptiform discharges. Clin Neurophysiol 2013;124:2073–4. Fahoum F, Lopes R, Pittau F, Dubeau F, Gotman J. Widespread epileptic networks in focal epilepsies: EEG-fMRI study. Epilepsia 2012;53:1618–27. Goncharova II, Spencer SS, Duckrow RB, Hirsch LJ, Spencer DD, Zaveri HP. Intracranially recorded interictal spikes: relation to seizure onset area and effect of medication and time of day. Clin Neurophysiol 2013;124:2119–28. Holtkamp M, Sharan A, Sperling MR. Intracranial EEG in predicting surgical outcome in frontal lobe epilepsy. Epilepsia 2012;53:1739–45. Jacobs J, LeVan P, Chander R, Hall J, Dubeau F, Gotman J. Interictal high-frequency oscillations (80–500 Hz) are an indicator of seizure onset areas independent of spikes in the human epileptic brain. Epilepsia 2008;49:1893–907.

Jiménez-Jiménez D, Nekkare R, Flores L, Chatzidimou K, Bodi I, Honavar M, et al. Prognostic value of intracranial seizure onset patterns for surgical outcome of the treatment of epilepsy. Clin Neurophysiol 2015;126:257–67. Kramer MA, Eden UT, Lepage KQ, Kolaczyk ED, Bianchi MT, Cash SS. Emergence of persistent networks in long-term intracranial EEG recordings. J Neurosci 2011;31:15757–67. Netoff TI, Clewley R, Arno S, Keck T, White JA. Epilepsy in small-world networks. J Neurosci 2004;24:8075–83. Ponten SC, Bartolomei F, Stam CJ. Small-world networks and epilepsy: graph theoretical analysis of intracerebrally recorded mesial temporal lobe seizures. Clin Neurophysiol 2007;118:918–27.



Ronald P. Lesser Johns Hopkins Medical Institutions, Baltimore, MD 21287-7247, USA ⇑ Tel.: +1 4109551270; fax: +1 4109550751. E-mail address: [email protected] Available online 23 June 2014

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