GRAYMATTERS

LETTERS

Clarification of previously publishedperspective

To the Editors:I would like to correct any ambiguity surrounding a con-

tribution to a perspective published in Epilepsia.1 In thisperspective, in addition to including previously unpub-lished data (Fig. 2), I included as panels in Figures 1, 3,and 4, unpublished alternative versions of images derivedfrom the same source images that had been used to gener-ate panels of previously published figures. Specifically,the left panels of Figure 1 are the separated green and redchannels, shown now in grayscale, of the color imagesshown as Figure 6 panels C1–C4 in Wenzel et al.2 Fig-ures 3 and 4 are color versions, with additional Kv2.1labeling now included, of selected panels from the blackand white, single-label images presented as Figure 1 inMenegola et al.3 The intent of using the alternate versionsof these figures was to both review the findings from thosepreviously published studies and to provide furtherinsights by showing them in a manner distinct from thepublished figures. I apologize for any confusion regardingthe novelty of the data.

DISCLOSURE

I have no conflicts of interest to disclose. I confirm that I have read theJournal’s position on issues involved in ethical publication and affirm thatthis report is consistent with those guidelines.

James S. Trimmer1,2

jtrimmer@ucdavis.edu1Department of Neurobiology, Physiology and Behavior,University of California Davis, Davis, California, U.S.A.;

and2Department of Physiology and Membrane Biology,

University of California Davis School of Medicine, Davis,California, U.S.A.,

REFERENCES

1. Menegola M, Clark E, Trimmer JS. The importance ofimmunohistochemical analyses in evaluating the phenotype of Kvchannel knockout mice. Epilepsia 2012;53(Suppl. 1):142–149.

2. Wenzel HJ, Vacher H, Clark E, et al. Structural consequences ofKcna1 gene deletion and transfer in the mouse hippocampus.Epilepsia 2007;48:2023–2046.

3. Menegola M, Trimmer JS. Unanticipated region- and cell-specificdownregulation of individual KChIP auxiliary subunit isotypes inKv4.2 knock-out mouse brain. J Neurosci 2006;26:12137–12142.

The NeuroPace trial: Missing knowledgeand insights

To the Editors:The recently published manuscript “Two-year seizure

reduction in adultswithmedically intractable partial onset epi-lepsy treated with responsive neurostimulation: Final resultsof the RNS System Pivotal trial,”1 is a landmark in the annalsof epilepsy therapeutics. NeuroPace and the team of epileptol-ogists involved in this trial are deserving of recognition.

Assessment of the efficacy of antiseizure therapies hasof necessity relied on seizure diaries, which are grosslyinaccurate. This limitation has been unavoidable in drugtrials, but it is problematic to justify the use of diaries in theNeuroPace study,1 given that the responsive focal corticalstimulation (RNS System) is endowed with means forautomated detection that should allow for reasonably accu-rate computation of seizure frequency. Other variablessuch as intensity, duration, and extent of spread withoutwhich meaningful assessment of efficacy (or of adverseeffects) is not possible, were not reported.

Contingent or responsive electrical stimulation does notappear to decrease total (clinical and subclinical) seizurefrequency, only to prevent, if efficacious, the evolution ofsubclinical into clinical or of partial simple into complexor secondarily generalized seizures.2 Using clinical seizurefrequency derived from diaries as the sole efficacy metric,leads, in the case of electrotherapies, to an incompleteand possibly distorted assessment of its effects on the epi-leptic brain.3 Application of principal component analysisand linear regression models3 to data from a trial of high-frequency electrical stimulation (HFES) triggered by theautomated detection of seizure onset2 revealed multifari-ous effects on intensity, duration, extent of spread, andtime between seizures.3 For example, HFES may decreaseseizure intensity but also the time to the next seizure, or itmay increase the intensity of the treated seizure butincrease the time to next seizure.3 A reduction in clinicalseizure frequency may be observed at the expense ofincreases in subclinical seizures with the net effect beingeither no change or an increase in total seizure burden. TheRNS trial is silent on these relevant issues.1

Delivery of electrical currents to epileptogenic tissue maytrigger seizures in regions remote from the site of deliv-ery,2,3 and may, over time, exert pro-epileptogenic actions(e.g., “kindling”), especially if they elicit afterdischarges.

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Did RNS cause paradoxical effects on seizure intensity orduration? Delivery of electrical current in response to false-positive detections is unavoidable. Did RNS elicit afterdis-charges in these instances?

Regarding the statistical analysis,1 a host of germanedetails about the application of generalized estimatingequations (GEEs) to the data were omitted, depriving thereader of information required to gauge its correctness andvalidity. To wit, the degree of dispersion of the data wasnot disclosed, a potential critical omission, because thisfactor, if present, must be accounted for in the finalanalysis.

Epileptic seizures are subject to multiple sources ofvariation (i.e., circadian, sleep–wake cycle, hormonal, drugserum concentrations),2,3 and as a consequence, appropriatestatistical tools are required for their objective characteriza-tion, which GEE lacks.

The main effect of responsive electrical stimulation,provided it does not trigger seizures, is on seizure inten-sity, duration, and extent of spread, not on total fre-quency.2,3 Thus, valid assessment and optimization ofany antiseizure therapy require quantitative analyses thatinclude subclinical—not just clinical—seizures, as wellas statistical methods that take into account the effects oftiming of stimulation in relation to seizure onset as wellpresence or absence of immediate and prolonged (“carry-over”) stimulation effects and their “valence” (positiveor negative), and time elapsed since delivery of the lasttreatment.2,3

Substantive advances in the electrotherapy of seizuresare unlikely to materialize unless objective and reproduc-ible quantification of relevant variables is performed andincorporated into suitable statistical models. The Neuro-Pace trial1 provides an exceptional opportunity to learnmore about how to better treat pharmacoresistant seizures.

DISCLOSURE

I have no conflicts of interest to disclose. I confirm that I have read theJournal’s position on issues involved in ethical publication and affirm thatthis report is consistent with those guidelines.

Ivan Osorioiosorio@kumc.edu

University of Kansas Medical Center, Kansas City,Kansas, U.S.A.

REFERENCES

1. Heck CN, King-Stephens D, Massey AD, et al. Two-year seizurereduction in adults with medically intractable partial onset epilepsytreated with responsive neurostimulation: final results of the RNSSystem Pivotal trial. Epilepsia 2014;55:432–441.

2. Osorio I, Frei MG, Sunderam S, et al. Automated seizure abatementin humans using electrical stimulation. Ann Neurol 2005;57:258–268.

3. Osorio I, Manly B, Sunderam S. Toward a quantitative multivariateanalysis of the efficacy of antiseizure therapies. Epilepsy Behav2010;18:335–343.

In response: The RNS Systemmulticenterrandomized double-blinded controlled trial

of responsive cortical stimulation foradjunctive treatment of intractable partialepilepsy: Knowledge and insights gained

To the Editors:We thank Dr. Osorio for the opportunity to highlight the

objectives of the RNS System Pivotal trial, to describe theelectrocorticographic (ECoG) data obtained by the RNSSystem, and to provide additional information on theprimary effectiveness analysis method.

Dr. Osorio correctly identifies the limitations of assess-ing the severity of epilepsy with seizure diaries and pro-poses that efficacy of the RNS System should have beenassessed with quantitative ECoG measures of subclinicalas well as clinical seizures. We would like to clarify thatthis was not possible.

The RNS System is not designed to function as a preciseseizure counter. The neurostimulator is programmed bythe physician to detect and respond to specific ECoG pat-terns. In some cases these will be electrographic seizures,but in most cases these are interictal discharges. Therefore,detected events cannot be used to provide a reliable seizurecount.

In addition, although the RNS Neurostimulator continu-ously senses the ECoG, it stores a limited quantity ofrecordings. Therefore, stored ECoG events provide a sam-ple of the total number of events.

Finally, the RNS System senses and provides responsivefocal stimulation to one or two seizure foci via two quadri-polar leads (each containing four electrodes). Determiningthe duration and extent of seizure spread requires greaterspatial coverage than is possible with the RNS System.

The intent of the Pivotal trial was to demonstrate safetyand effectiveness of the RNS System and to provide infor-mation necessary for U.S. Food and Drug Administration(FDA) approval for a specific indication for use. The trialdesign was agreed upon with the FDA and, as in all epi-lepsy trials leading to FDA approval, efficacy was evalu-ated with seizure diaries.

Based on his ownwork, Dr. Osorio asserts that responsiveelectrical stimulation does not decrease the total frequencyof clinical and subclinical seizures. The RNS System Pivotaltrial demonstrated that responsive stimulation significantlyreduced the frequency of clinical seizures compared to shamstimulation. The effect of responsive stimulation improvesover time and is associated with significant improvementsin quality of life. The effect on features of the ECoG isarguably less relevant. As we learned in our neurology train-ing, we treat the patient, not the electroencephalogram(EEG).

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GRAYMATTERS