The difference between Engel Ⅰ and Engel Ⅱ in epileptogenicity biomarkers after stereotactic thermocoagulation

doi:10.21203/rs.3.rs-4817636/v1

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The difference between Engel Ⅰ and Engel Ⅱ in epileptogenicity biomarkers after stereotactic thermocoagulation

https://doi.org/10.21203/rs.3.rs-4817636/v1

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Objective

Stereoscopic electroencephalography(SEEG) is an important invasive assessment method in epilepsy surgery. After electrode implantation, radiofrequency thermocoagulation(RF-TC) guided by Stereoscopic electroencephalography(SEEG) is performed on the discharge initiation and rapid propagation areas by monitoring intracranial electroencephalography.High-frequency oscillations (HFOs) and spikes, are quantifiable epileptogenic biomarkers before and after RF-TC.In this study, we sought to evaluate, using SEEG signals recorded before and after thermocoagulation, whether a difference between Engel Ⅰ and Engel Ⅱ patient.

Methods 3 minutes

segments of SEEG signals were analyzed in 22 patients before and after thermocoagulation.We used Anywave software to quantify the rate of spikes, rate of HFOs(80-512Hz), rate of HFOs(80-250Hz) and rate of HFOs(250-512Hz).We analyzed the differences both at an individual level(paired t-text and pencentage) and at a group level(Fisher exact test).

Results After

RF-TC guided by SEEG,12 patients showed Engel Ⅰ,10 patients showed Engel Ⅱ.In EZ, an intra individual decrease in HFOs was significantly more frequent in Engel grade Ⅰ patients than in Engel grade Ⅱ patients (80-513Hz:p = .038; 80-250Hz:p = .026;250-513Hz:p = .038).In thermocoagulated zones was an intraindividual decrease of HFOs (250-512Hz) significantly more frequent in Engel grade Ⅰ patients than in Engel grade Ⅱ patients (p = .038) .

Conclusion

Quantified changes in the rate of spikesand rate of HFOs can be observed after RF-TC guided by SEEG.There may be difference between Engel Ⅰ and Engel Ⅱ in HFOs and no difference in spikes after stereotactic thermocoagulation.

Epileptogenicity biomarkers

RF-TC guided by SEEG

Engel grading

Currently, there are over 60 million epilepsy patients worldwide, of which one-third are drug-resistant epilepsy(DRE). Stereoscopic electroencephalography(SEEG) is an important invasive assessment method in epilepsy surgery. After electrode implantation, radiofrequency thermocoagulation(RF-TC) therapy is performed on the discharge initiation and rapid propagation areas by monitoring intracranial electroencephalography.[1, 8, 12]

Multiple studies have shown that RF-TC guided by SEEG has good clinical efficacy and safety, but the improvement rate of epilepsy symptoms in patients after SEEG guided RF-TC reported by various research centers varies greatly.[2, 7, 10] Possible reasons may be related to the evaluation of the epileptic area and the selection of targets. Therefore, there is an increasing amount of research on electrophysiological markers that induce epilepsy.

High frequency oscillations and spikes in intracranial electrode electroencephalography have long been considered important electrophysiological features of epileptic zone(EZ).Studies have shown that quantified changes in the rate of spikes, rate of HFOs, and cross-rate can be observed after thermocoagulation, and the reduction of these markers correlates with a favorable clinical outcome after RF-TC and with successful resective surgery.[6] This may suggest that interictal biomarker modifications after RF-TC can be clinically used to predict the effectiveness of the thermocoagulation procedure and the outcome of resective surgery.

However, there has been no research on the differences in electrophysiological markers among refractory epilepsy patients with better grading(Engel gradeⅠand Ⅱ) after thermocoagulation.The aim of the present study was to perform a quantitative and reproducible assessment of the effects of RF-TC on the electrophysiological markers of epileptogenicity (spikes, HFOs,)and to study the difference of biomarker between EngelⅠand EngelⅡin the EZ, thermocoagulated zones and irritative zones.

Patient

We extracted from the database of the Epileptology Unit of Huanhu Hospital of Tianjin all the patients in the period January 2019 to December 2022 according to the following inclusion criteria: having undergone SEEG-guided RF-TC for DRE patients and the availability of at least 24 hours of SEEG recording just before and after the end of an RF-TC session sampled at 1024 Hz or more.

The institutional review board approved this study (No. 2021-059), and written patient consent was obtained both for the implantation of the electrodes for SEEG and for the subsequent RF-TC procedures.

All patients underwent a comprehensive evaluation that included seizure data analysis, semiology, long-term scalp video electroencephalography structural imaging studies [computed tomography (CT), 3-dimensional (3D) T1-weighted magnetic resonance imaging (MRI), T2-weighted MRI, fluid-attenuated inversion recovery MRI, susceptibility-weighted imaging, and 18 fluoro- 2-deoxyglucose positron emission tomography], and neuropsychological testing.⁸Both scalp electroencephalogram and stereotactic electroencephalogram were independently analyzed by two experienced electrophysiologists.

Hypothesis of epileptic foci and electrode implantation plan are based on the location of the patient's epileptic network.The preoperative planning was completed using the Sinoplan system (SINOVATION, China). All patients underwent magnetic resonance angiography (MRA) and magnetic resonance venography (MRV), data of which were combined and used for electrode planning.[14] At the end of the SEEG exploration, SEEG guided RF-TC was performed and the intracerebral activity was recorded before, during, and at the end of the procedure.A epilepsy surgeon followed up on epilepsy frequency and complications in patients at least 3 months after RF-TC and Evaluating patient prognosis using Engel grading.

SEEG recording and thermocoagulation procedures

We have successively used Leksell stereotactic headframe (ELKTA, Sweden) and SINO ROBOTICS (Beijing, China)for electrode implantation.We use Talairach's stereotactic implantation method of multi contact electrodes from SINO ROBOTICS (Beijing, China) in the brain.Standard electrodes have 6 or 16 contacts. Each contact is 2 mm in length and 0.8 mm in diameter. The intercontact space is 1.5 mm.The position of the electrode is determined based on the hypothesis of the epileptogenic zone from the first stage evaluation.After surgery, computed tomography (CT) and/or MRI scans of head were performed to verify the presence of complications such as intracranial hemorrhage and the accuracy of electrode position. We used Software of Huake Precision for CT/MRI image registration to check the anatomical position of electrode trajectory.We use the computer electrical monitoring software(Nihon Kohden system from Japanese) to record SEEG at least three habitual seizures in patients (1–3 weeks).The contacts used for RF-TC were selected for each patient according to the 4 criteria[6]: (1) contacts sampling structures that belong to the EZ, as defined by visual analysis complemented by quantitative SEEG signal analysis using the Epileptogenicity Index; (2) contacts sampling structures that belong to the early propagation zone; (3) contacts located within or at the MRI-visible borders of the lesion suspected to be epileptogenic; and/or (4) induction of habitual ictal clinical phenomena by electrical stimulation of those contacts. If the contact point of thermalcoagulation is adjacent to the functional area or closely related to blood vessels, thermalcoagulation will not be performed.The parameters of the RF-TC device (Model No. R2000B-M1, BNS, Beijing, China) were set as follows: 7.5 W power applied in two sessions of 30 seconds each, with a 30-second pause between the sessions.

Analysis of SEEG signal

SEEG signal was recorded on a Nihon Kohden system with a 1024 Hz sampling rate and a 16-bit resolution.The system included a hardware high-pass filter (cut off 0.16 Hz), and an antialiasing low-pass filter (cut-off 340Hz).To avoid potential confounding factors and for comparison purposes, we decided to analyze the same time before the beginning of the RF-TC session and after the RF-TC had been performed.All patients were awake during these periods of time.At last,3 minutes-long SEEG segments were manually chosen before and after the RF-TC.Signal analysis was computed using Anywave software[5],via which SEEG traces were pre-processed with a notch filter at 50 Hz and a low-pass filter at 512Hz and high-pass filter at 0.16 Hz.A specific bipolar montage was created for each patient removing channels with too many artifacts via a visual evaluation of the traces.Spikes and HFOs (80–512 Hz) were automatically quantified in Anywave using Delphos (Detector of Electrophysiological Oscillations and Spikes). We calculated the rates (number of events/minute) before and after RF-TC of the following markers: spikes, HFOs,then,two surgeons and one electrophysiologist jointly determine the contacts of interest.First,the irritative zone is defined as the channels presenting, all along SEEG recordings, interictal activity.Second,the EZ is defined the channels involved at seizure onset by analyzing quantitative SEEG signal using EI(Epileptogenicity Index) and visual analysis.Finally,the thermocoagulated zone is composed of the thermocoagulated channels.[6, 15]

Analyzed of three categories

We calculated the rates (number of events/minute) before and after RF-TC of the following markers: spikes, HFOs(80-513Hz), HFOs(80-250Hz)and HFOs(250-513Hz).Rates were first calculated from all channels and secondarily divided into three categories of interest(EZ、irritative zone and thermocoagulated zone) as identified by an epileptologist during SEEG evaluation。In our patients, these zones could be overlapped each other.

Statistics

The rates of all electrodes in each region were calculated and using statistical analyzed using SPSS 25 software. The changes in rates before and after RF-TC were analyzed using paired t-test and chi square test.

42 patients who underwent SEEG-RF-TC were followed up in our center. The results are shown in Table 1.Among them,there were 28 males and 14 females,Age of onset of epilepsy 20.6 ± 1.9 years old,duration of epileptic seizures 6.5(0.8,11.3)years;Seizure frequency:10 cases occur daily,11 cases occur weekly,20 cases occur monthly,and 1 cases occur every six months.Types of antiepileptic drugs are taken:2.0(1.0,3.0);Side of electrode implantation:10 cases on the right side,9 cases on the left side,13 cases on both sides (left hemisphere dominance),8 cases on both sides (right hemisphere dominance) and 2 cases on both sides;Number of electrodes implants are 7.7 ± 0.4.There were no electrode breakage,infection,cerebrospinal fluid leakage,1 case of intracerebral hematoma with a volume of approximately 3ml,which did not affect SEEG monitoring.The hematoma was absorbed upon discharge and did not cause any adverse effects on the patient.We captures habitual epileptic seizure ≥ 3 times for each patient.4 cases underwent surgical treatment within one week after RF-TC,3 cases underwent surgical treatment within three months,4 cases underwent surgical treatment within six months,and 5 cases underwent surgical treatment within one year.The remaining patients did not undergo surgical treatment before the follow-up time.Follow up time:32(13.5, 43.3) months,including 12 cases of Engel grade I and 10 cases of grade Ⅱ.

Table 1

Population's clinical features and characteristics regarding the RF-TC guided by SEEG procedures, and the Engel grading to RF-TC, N = 42.
Variable	n	Range	Median (%)
Age of onset of epilepsy(years old)	42	4–50	20.6 ± 1.9
sex
male	28
female	14
duration of epileptic seizures(years)	42	0.1–39	6.5(0.8, 11.3)
Seizure frequency
daily	10
weekly	11
monthly	20
every six months	1
Febrile seizures during childhood	1
Familiar history of epilepsy	0
History of perinatal complications	1
History of cranial trauma	2
History of cerebral hemorrhage	2
History of CNS infection	1
Delay in development	0
AEDs tried before RF-TC		1–4	2
Etiology of epilepsy
MCD	4
Polymicrogyria	1
FCD	3
NDT	3
HS	12
CT	2
CVD	2
Unspecified histology	6
Normal MRI	9
Lateralization of epilepsy
Right-sided	18
Left-sided	22
Bilateral	2
Lateralization of electrode implantation
Right-sided	10
Left-sided	9
Bilateral with left hemispheric predominance	13
Bilateral with right hemispheric predominance	8
Bilateral-sided	2
Number of electrodes implants		5–12	7.7 ± 0.4
Total contacts	2562	85–163	116 ± 8
Contacts in EZ	330	8–24	15.0 ± 1.7
Contacts in irritative zone	456	9–33	21 ± 2
Contacts thermocoagulated	330	9–24	15.1 ± 1.6
Follow up time(month)	42	3–51	32(13.5, 43.3)
Engel grade I	12
Engel grade Ⅱ	10
Abbreviations: AED, antiepileptic drug; CNS, central nervous system; CVD,
cerebrovascular disease;CT, cranial trauma; EZ, epileptogenic zone; FCD, focal cortical dysplasia; HS, hippocampal sclerosis; MCD, malformations of cortical development; MRI, magnetic resonance imaging; NDT, neurodevelopmental tumors; RF-TC, radiofrequency thermocoagulation.

At an individual level of 22 patient, in the EZ, 6 patients (27%) showed a significant intraindividual reduction of spikes, 10 patients (45%) of HFOs (80-513Hz),8 patients (36%) of HFOs (80-250Hz),and 9 patients (41%) of HFOs (250-513Hz).In the irritative zone, 9 patients (41%) showed a significant intraindividual reduction of spikes, 10 patients (45%) of HFOs (80-513Hz),10 patients (45%) of HFOs (80-250Hz),and 9 patients (41%) of HFOs (250-513Hz). In the thermocoagulated zone, 6 patients (27%) showed a significant intraindividual reduction of spikes, 11 patients (50%) of HFOs (80-513Hz),10 patients (45%) of HFOs (80-250Hz),and 10 patients (45%) of HFOs (250-513Hz).

Results of statistic analysis with regard to the Engel grade after RF-TC are shown in Table 2.In EZ, an intra individual decrease in HFOs (80-513Hz)was significantly more frequent in Engel grade Ⅰ patients than in Engel grade Ⅱ patients (

Table 2

Statistic analysis according to the presence of Engel grading after RF-TC guided by SEEG for 22 patients who showed significant intraindividual reduction of the different markers in the three areas.
Analyzed zone	Spike reduction	HFOs(80-513Hz)reduction	HFOs(80-250Hz)reduction	HFOs(250-513Hz)reduction
Epileptogenic zone
Engel grade I	2	8	7	7
Engel grade Ⅱ	4	2	1	2
Fisher exact test	p = .229	p = .038^a	p = .026^a	p = .038^a
Irritative zone
Engel grade I	3	7	7	7
Engel grade Ⅱ	6	3	3	2
Fisher exact test	p = .110	p = .185	p = .185	p = .082
Thermocoagulated zone
Engel grade I	2	8	7	7
Engel grade Ⅱ	4	3	3	2
Fisher exact test	p = .229	p = .099	p = .185	p = .038^a
Note:Values are given as n (%). Also reported are the p-values resulting from Fisher exact tests performed
between Engel Ⅰ and Engel Ⅱ patients for each marker in each area.Abbreviation: HFO, high-frequency oscillation.
a Statistically significant p-values.a:Statistically significant p-values.

8[66.7%] vs 2[20.0%], p = .038) ,similarly for HFOs (80-250Hz)

(7[58.3%] vs 1 [10.0%], p = .026) and HFOs (250-512Hz)

( 8[66.7%] vs 2[20.0%], p = .038), whereas this difference was not significant for spike (4 [33.3%] vs 2 [20.0%].Within the thermocoagulated and irritative zones, we found a greater proportion of improved patients with an intraindividual reduction of the spike and HFOs, but this did not reach significance.Only in thermocoagulated zones was an intraindividual decrease of HFOs (250-512Hz) significantly more frequent in Engel grade Ⅰ patients than in Engel grade Ⅱpatients ( 8[66.7%] vs 2[20.0%], p = .038) .

The treatment of drug refractory epilepsy (DRE) is achieved by accurately locating the epileptic zone (EZ) through anatomical electrical clinical and stereotactic electroencephalography (SEEG), and then performing radiofrequency thermocoagulation (RF-TC) or surgical resection of the epileptic lesion to cure the epilepsy.[3]

However, the therapeutic effects after this procedure are uncertain,[2, 4, 7, 9, 11, 13] and the predictive factors of success remain poorly known, especially the potential electrophysiological predictors.The reduction of HFOs and spikes after RF-TC was reported,[6] which corresponded to good clinical outcomes after the surgery, but detailed Engel grading was not studied. This study aims to evaluate the effect of RF-TC on several epileptic interictal biomarkers measured from SEEG records in patients with good Engel grading.

Regarding spikes, we found a significant intraindividual reduction of spike rate in 41% of patients within the irritative zone, and in 27% of patients within the thermocoagulated zone and EZ. This is basically consistent with the results reported in previous articles.[6]It reported a certain correlation between spikes decline and clinical prognosis, but in patients with better prognosis, no comparison was made. Our research results show no statistical difference between Engel grade I patients and Engel grade II patients. This may be related to the small number of cases and the varying severity of epilepsy in preoperative patients.

With regard to HFOs, we observed a statistically significant reduction of their rate after RF-TC in the thermocoagulated zone and EZ.These results are in line with the previous work considering the role of HFOs as

markers of epileptogenicity.but,we only showed a significantly greater reduction of HFOs(includeing 80-250Hz,250-512Hz,80-512Hz) in the EZ in patients with Engel gradeⅠpatients after RF-TC in comparison with Engel gradeⅡ patients.In the thermocoagulated zone and irritative zones,we showed no significantly reduction of HFOs in patients with Engel gradeⅠpatients after RF-TC in comparison with Engel gradeⅡpatients,exception of HFOs(250-512Hz).It can be seen that there may be a certain correlation between HFOs and Engel grading in EZ.HFO representing biomarkers of epileptogenicity would run down following ablation or inactivation of the epileptogenic zone, as observed in other case.

This dynamics of spike and HFOs rates was in good correlation with significantly improved seizure control suggesting that in this case, the disease activity was well mirrored by different interictal epileptogenicity markers.We think there may be a good correlation between the Engel grading and ictal epileptogenicity markers especially HFOs in the EZ.Further research is needed to determine our opinion.

In this respect, our study underlines the changes of different interictal biomarkers, including HFO and spike analysis, to get the full information of the EZ, thermocoagulated and irritative zones.The pathophysiological role of HFOs and spike generated by various etiology of epilepsyneeds to be clarified.The high rates of HFOs and spikes in EZ could be due to other factors, not strictly reflecting epileptogenicity.Further research is needed.More evidence and study are necessary to determine the exact place of SEEG-guided RF-TC in the surgical management and prognosis of drug-resistant epilepsies.

Author contribution JY designed the study and wrote main sections of the paper. LW designed the study and performed the data collection. CD and GL conducted a literature search.WJ and SY are the heads of the department, designed the study, and supervised the trial. DC wrote sections of the paper and performed the statistical analysis. All authors critically revised the manuscript and approved its final version.

Funding National Key R&D Program of China （2021YFF1200700）

Ethics approval All procedures performed in this study were in accordance with the ethical standards of the 1964 Helsinki Declaration. This article does not contain any studies with animals performed by any of the authors.

Consent to participate This study was approved by Tianjin Huanhu Hospital ethical board(No. 2021-059). All participants of the study at hand gave their informed consent for participation in the study.

Consent for publication Written informed consent was obtained from all patients (Tianjin Huanhu Hospital ethical board,No. 2021-059).

Conflict of interest The authors declare no competing interests.

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No competing interests reported.

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The difference between Engel Ⅰ and Engel Ⅱ in epileptogenicity biomarkers after stereotactic thermocoagulation

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