High Frequency Oscillation in Pediatric Epilepsy Surgery
Phase: NA
Conditions: Pediatric Epilepsy, Epilepsy Surgery, High Frequency Oscillation
Sponsor: University of California, Los Angeles

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PROTOCOL TITLE: 
 
High Frequency Oscillation in Pediatric Epilepsy Surgery 
 
Protocol Version Date: 26 Oct 2017 
 
NCT03790280 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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PROTOCOL TITLE: 
 
High Frequency Oscillation in Pediatric Epilepsy Surgery 
 
Protocol Version Date: 26 Oct 2017 
 
NCT03790280 
 
Principal Investigator: 
Joyce Y. Wu, MD 
 
UCLA Mattel Children’s Hospital  
David Geffen School of Medicine at UCLA 
Division of Pediatric Neurology 
10833 Le Conte Avenue 22-474 MDCC 
Los Angeles, California, USA 
Phone: 310-206-4037 
Fax: 310-206-4316 
 
 
Co-Investigators: 
Shaun Hussain, MD, MS 
Raman Sankar, MD, PhD 
Aria Fallah, MD, MS 
Hiroki Nariai, MD 
 
Study Coordinators: 
Angela Martinez 
Ruby Escalante 
Natalie Solis 
Alyssa Holt 
 
Funding: 
None 
 
 
 
 
 

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Introduction: 
Intra-operative electrocorticography (ECoG), based on interictal spike and spike 
patterns, is performed to optimize delineation of the epileptogenic tissue in the operating 
room during epilepsy surgery. Similarly, extra-operative electrocorticography is often 
recorded over days to weeks with intracranial grids and depth electrodes, when the 
epileptogenic zone is not clearly localized with non-invasive studies and/or with intra-
operative ECoG. Surgical resection following extra-operative ECoG is then "tailored' by 
the seizure onset zone as the gold standard. High frequency oscillations have been 
identified as a more precise biomarker for epileptogenic tissue. The aim of the study is 
to determine prospectively if ECoG- tailored surgery combining HFOs and standard 
clinical resection with ECoG, compared to standard clinical resection with ECoG alone, 
is feasible and will lead to an equal or better seizure outcome; the comparison to HFO + 
ECoG, versus ECoG alone, could be either in the form of interictal spikes on intra-
operative ECoG or seizure onset zone on extra-operative ECoG.  
 
Background and Rationale: 
Epilepsy occurs in 0.5-0.7% of the population, of which 25% are children. About 30% of 
subjects with focal epilepsy do not respond well to medication, and half of them are 
eligible for epilepsy surgery. In recent years, the importance of early epilepsy surgery 
has been stressed, as successful surgery may lead to seizure- and medication-freedom 
and improved social and cognitive development, especially in children. The current rate 
of seizure freedom following epilepsy surgery is around 65%. During surgery, in most 
medical centers, either intra-operative ECoG is recorded to identify the irritative zone, 
defined by the spatial distribution of interictal spikes, or extra-operative ECoG is 
recorded to identify the seizure onset zone. The presence of epileptiform brain 
activity/spikes, or the seizure onset zone, identified by clinical neurophysiologists, is 
used to guide the neurosurgeon with respect to the boundaries of brain tissue that is 
necessary for resection to achieve seizure freedom. Spikes are considered biomarkers 
of the presence of epilepsy, and seizure onset zone indicates where the seizures may 
be generated. Neither spikes nor seizure onset zones accurately identify the location 
and the extent of the epileptogenic zone, defined as the cortical tissue whose complete 
removal is necessary to achieve post-operative seizure freedom.  
 
High frequency oscillations (HFOs, 80-500 Hz) on ECoG have recently been identified 
as a new biomarker for epileptogenic tissue. Retrospective observational research, as 
well as more recent prospective observational studies, show that HFO presence 
strongly relates to, and may predict more accurately, the epileptogenic zone, and that 
the resection of brain tissue containing HFO may be superior than resection of brain 
tissue containing spikes and seizure onset zone in rendering patients seizure-free. The 
area showing HFOs usually overlaps with, but may be smaller than, the area with spikes 

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and seizure onset, and HFOs do not tend to propagate to distant sites as spikes and 
seizures do.  
 
Standard Clinical Practice 
During surgery, current clinical practice is to measure epileptic activity that we call 
epileptic spikes (on intra-operative ECoG) or seizure onset zone (extra-operative ECoG) 
with EEG recordings. Current clinical standard of practice in either intra-operative ECoG 
or extra-operative ECoG is recorded to identify epileptic zone and seizure onset zone. 
The presence of epileptiform brain activity/spikes, or the seizure onset zone, identified 
by clinical neurophysiologists, is used to guide the neurosurgeon with respect to the 
boundaries of brain tissue that is necessary for resection to achieve seizure freedom. 
The particular part of the brain that has either of these abnormalities, is removed. We 
have used this method for over 40 years. 
New Research HFO Method 
Recently, it has been discovered that we can also measure other epileptic activity, High 
Frequency Oscillations or HFOs, by recording EEGs at a higher frequency rate. These 
HFOs on the EEG recordings appear to point out the epileptic brain tissue better than 
epileptic spikes or seizure onset zone.  
 
 In this study we will compare the two groups of patients to see what works best: 
standard clinical practice only, or standard clinical practice along with HFOs. The results 
of this study may change the way we operate on epilepsy surgery patients in the future.  
 
Hypothesis: We hypothesize that the strategy of incorporating HFO data to a standard 
ECoG-guided resection in pediatric epilepsy surgery will result in improved 
postoperative seizure outcome than the traditional approach.  
 
Objective: 
The primary objective is to determine if HFO data in addition to ECoG data  
(experimental group, arm 1), compared to standard ECoG data alone (current standard 
control group, arm 2), will lead to improved post-surgical seizure outcome 1 year after 
surgery.   
 
Secondary objectives include the comparison of incidence of neurologic deficits, 
neuropsychological outcomes (when available with clinical testing), and quality of life 
outcomes.  
 
Study Design and Procedures: 
A single-blinded randomized control trial including subjects with refractory focal epilepsy 
who undergo surgery with intra- or extra-operative electrocorticography. Surgery is 

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tailored by HFOs and standard ECoG interpretation (spikes on intra-operative ECoG or 
seizure onset on extra-operative ECoG) (arm 1), or tailored by standard ECoG alone 
(arm 2).  
 
Randomization 
Informed consent will be obtained 1 to 7 days to up to 3 months prior to the day of 
surgery. Prior to surgery, the subject will be randomized into the cohort arm in a 1:1 
ratio. 
 
 
Blinding 
Blinding of the clinical neurophysiologists and neurosurgeons for treatment allocation is 
not feasible because of the character of the intervention. Therefore, this is a single-
blinded trial as subjects will be blinded to the cohort arm to minimize bias of the follow-
up results. The treating neurologist, if other than the clinical neurophysiologists in this 
study, will remain blinded.  
 
Number of Subjects: 
30 
 
Inclusion Criteria: 
 Age 0-21 
 Refractory focal epilepsy 
 Planned resective epilepsy neurosurgery with ECoG, with the goal of tailoring the 
resection 
 
Exclusion Criteria: 
 Subjects undergoing non-resective neurosurgery 
Recruitment of Subjects: 
Subjects with refractory epilepsy undergoing epilepsy surgery with ECoG to guide the 
extent of the resection.  
 
Length of Study Visits and detail: 
 
This research study will not require any additional time in the hospital after surgery.  
However, will be following the subject for epilepsy outcome up to 12 months after 
surgery. 
 
Chart review of clinical records such as neurological, MRI, EEG and other clinically 
relevant information pertaining to the outcome of surgery will be collected. 
 

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Subjects or their caregivers will be asked to fill out questionnaires about seizure 
frequency, medication and day to day function in various life areas at each visit with the 
neurosurgeon/neurologist. 
 
Schedule of events below: 
PRE-
SURGERY 
SURGERY 
POST-SURGERY 
Visit 1 
/Baseline 
 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
0 day-3 months 
prior to surgery 
 
1-7 days 
after 
surgery 
3 months 
6 months 
9 months 
12 months 
 
Pre-Surgery  
 Consent 
 Neurosurgeon visit  
 Baseline Questionnaire 
 
Post-Surgery (at every visit) 
 Neurosurgery/Neurology Visit 
 Follow-up Questionnaires 
 
Questionnaires will take about 30 minutes to complete.  We may send the 
questionnaires home a week prior to a return visit to alleviate time at the doctor’s office. 
 
Questionnaires  
NIH Pediatric Stroke Scale 
Child Behavior Check List 
Quality of Life in Epilepsy (Adults) 
Quality of Life in Childhood Epilepsy   
 
Procedure Detail: 
Intra-operative ECoG, which could be pre-resection, post-resection, or both, during 
brain surgery would be determined based on clinical decisions. Similarly, extra-
operative ECoG would also be determined based on clinical decisions, and would be 
pre-resection.  
 
For those subjects randomized to the standard clinical care with ECoG only (control 
arm), ECoG would be recorded but not assessed for HFO until after the clinical decision 
has been made with respect to site and margin of the resection. Only cortical areas 
deemed abnormal by standard clinical ECoG would be resected.  
 

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For those subjects randomized to the HFO + standard clinical care with ECoG 
combined (experimental arm), ECoG would be recorded AND assessed for HFO rapidly 
in the operating room (within 10 minutes) to minimize patient risk and while the 
neurosurgeon begins the initial resection. Should HFO persist after resection, further 
resection to ensure complete removal of HFO and standard clinical ECoG abnormalities 
may be possible. Cortical areas generating HFO and/or abnormal by standard clinical 
ECoG would be resected, with the exception of HFO-only presence in eloquent cortex, 
which would be spared. Eloquent cortex is defined as sensorimotor cortex, primary 
language cortex (Wernicke's and Broca's areas), and primary visual cortex.   
 
Benefits of Study: 
HFO analysis could determine/predict a better surgical outcome. 
 
Potential Risks: 
 
In epilepsy surgery there are always risks.  
1. The patient may not become seizure free.  
2. The patient may lose or may damage an area that is close to important function such 
as motor or speech functions.  
3. The patient may develop a surgical complication such as infection, hydrocephalus or 
stroke. 
 
In Standard Surgery plus HFO Method Risk: Additional risk may be unexpected 
neurologic deficit.  
 
There will be every effort made to minimize loss of major brain function, such as 
language, motor skills, sensation, and vision, to what may be already anticipated from 
the standard clinical care approach. Should any of these 4 major brain function areas be 
found to have HFOs only, and not on standard ECoG analysis, these important areas of 
brain function will not be resected. 
The likelihood of longer anesthesia time is very low since HFO analysis will begin before or 
concurrently with standard method. Therefore we do not expect any additional time under 
anesthesia for either method. 
There is no additional risk of recording HFOs at higher frequencies. Higher frequency simply 
allows us to capture brain signals at higher frequency rate.  
Randomization: There is no risk or benefit from randomization given that standard of 
care ECoG will be completed during surgery.  
 

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Questionnaires: There are no risks to these questionnaires other than the 
inconvenience of the time involved in answering the questions. 
 
Potential risks include loss of confidentiality. To protect you from this risk, all electronic 
study data will be kept in a password-protected, encrypted database. Other study 
related materials that include personal health information will be kept in a secure area 
accessible only by study personnel.  
 
Where will data be stored? 
Data will be stored in an encrypted database which is password protected. Only study 
personnel will have access to the data. EEGs data done at UCLA, for data analysis will 
be de-identified. This information will be stored in a secure area accessible to 
authorized personnel only and data will be kept for future studies and or publication.