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A New Method for Delineation of Epileptic Brian Tissue During Epilepsy Surgery (The HFO Study)

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ClinicalTrials.gov Identifier: NCT02207673
Recruitment Status : Unknown
Verified May 2016 by G.J.M. Zijlmans, UMC Utrecht.
Recruitment status was:  Recruiting
First Posted : August 4, 2014
Last Update Posted : May 12, 2016
Sponsor:
Collaborator:
Rudolf Magnus Institute – University of Utrecht
Information provided by (Responsible Party):
G.J.M. Zijlmans, UMC Utrecht

Brief Summary:

Epilepsy occurs in 0.5-0.7% of the population, of which 25% are children. 30% Of patients 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 seizure and medication freedom and improved social and cognitive development, especially in children. The current success rate of epilepsy surgery is around 65%; During surgery intracranial electrocorticography (acute ECoG, aECoG) is recorded in some medical centers. The presence of epileptiform brian activity, spikes, identified by clinical neurophysiologists, is used to guide the neurosurgeon in the extent of the brain tissue that needs to be resected. Spikes are considered markers of the presence of epilepsy. High Frequency Oscillations (HFOs, >80-500Hz) in the ECoG have recently been identified as a new biomarker for epileptogenic tissue. Retrospective research shows that their local presence strongly relates to the seizure onset, and removal of tissue with HFOs could predict a better surgical outcome. The area showing HFOs usually overlaps with, but is smaller than the area with spikes, and HFOs do not tend to propagate to distant sites as spikes do. The identification of HFOs is more objective than of spikes and automatic detection software exists.

A pilot study is performed to test the hypothesis : The intra-operative use of HFOs to delineate the epileptogenic cortex does not yield significantly worse outcome in seizure freedom than the current method based on spikes.

Study design is a single blinded multi-center randomized controlled trial. In two Dutch centers, the VU medical center ( Amsterdam) and University Medical Center Utrecht.

The study population (sample size 78) consists of patients of all ages with refractory epilepsy undergoing epilepsy surgery with aECoG to guide the extent of the resection.

Eligible patients are randomised, after informed consent, into group 1 (HFOs) in whom a resection guided by HFOs in the aECoG (new), or into group 2 (spikes) in whom a resection is guided by epileptiform spikes in the aECoG (current standard). Ictiform spike patterns will always be resected.

Main study endpoint is outcome after epilepsy surgery after 1 year of follow-up dichotomized in total seizure freedom (Engel Ia&b) vs. seizure recurrence (Engel Ic-IV).


Condition or disease Intervention/treatment Phase
Refractory Localization-related Epilepsy Procedure: Tailoring of the resection based on biomarker in aEcoG during epilepsy surgery Not Applicable

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 78 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Participant)
Primary Purpose: Treatment
Official Title: Intra-operative Detection and Localisation of High Frequency Oscillations in the ECoG to Guide Epilepsy Surgery
Study Start Date : November 2014
Estimated Primary Completion Date : April 2018


Arm Intervention/treatment
Active Comparator: Spikes as biomarker
In arm " spikes" the resection of epileptogenic tissue is guided by epileptiform spikes in the aECoG (current standard). (Independent of the randomisation ictiform spike patterns will always be resected.)
Procedure: Tailoring of the resection based on biomarker in aEcoG during epilepsy surgery
Experimental: HFOs as biomarker
In arm "HFOs" resection of epileptogenic tissue is guided by HFOs in the aECoG (new). (Independent of the randomisation ictiform spike patterns will always be resected.)
Procedure: Tailoring of the resection based on biomarker in aEcoG during epilepsy surgery



Primary Outcome Measures :
  1. Post-surgical outcome [ Time Frame: 12 months after surgery ]

    To simplify analysis outcome scores will be dichotomized in two categories, total seizure freedom (Engel Ia+Ib) versus seizure recurrence (Engel Ic-IV).To enable interim analysis of the outcome in terms of seizures, we will determine preliminary post-surgical outcomes at 6-8 weeks and 6 months. A final outcome will be determined after 12 months. This will require the patients to fill in an additional short questionnaire on their seizure frequency at pre-surgical baseline (after singing informed consent), at 6-8 weeks, 6 and 12 months post- operatively (by telephone/email).

    So called 'running down' seizures, seizures that occur in the first 2 weeks after surgery are not considered as seizure recurrence.



Secondary Outcome Measures :
  1. Volume of resected tissue [ Time Frame: 3 months after surgery a post-resection MRI is made ]
    With HFOs being a more specific and sensitive biomarker for epileptogenic tissue than spikes, potentially the resection size could become smaller or larger. Therefore, the volume of resected tissue (in cm3) is investigated as a secondary parameter. The amount of resected tissue is determined by voxel-based volumetrics of the pre- and post-surgical MRI using Curryscan7 Neuroimaging Suite (Compumedics Neuroscan, Hamburg, GER).

  2. Neurological deficits [ Time Frame: baseline + post operative before discharge, 6-8 weeks, 6 and 12 months ]
    Neurological changes (e.g visual field defects, hemiparesis, word finding difficulties) can be divided into pre-existing, aggravated /improved, or new deficits, and can be anticipated or unexpected. The neurological changes and severity will be assessed by the doctor in charge/neurologist before surgery and prior to discharge out of hospital. In case of deficits they will be classified/quantified using the National Institutes of Health Stroke Scale (NIHSS) . This will be repeated by the doctor in charge/neurologist/neurosurgeon after 6 months and 12 months in case of initial neurological changes/deficits. The patient's total NIHSS scores is calculated by summation of all scores (NIHSS score range 0-42). A difference of 1 point on the NIHSS scale between 2 tests is considered clinical relevant in our population of epilepsy patients.

  3. Cognitive functioning [ Time Frame: pre- vs. post surgery (6 or 12 months) ]
    Comparison of test results of pre- and post-operative (6 or 12 months) neurophysiological 695 investigation (NPO). This routine neurophysiological investigation includes testing of IQ (verbal and performal), working memory and processing speed. All tests conform to the age of the patient, but report on the same domains. Per domain individual patients' results will be dichotomized into negative/no/positive change compared to pre-surgical performance. This enables comparison of all patients, independent from age, at group level.

  4. Health related Quality of life (HRQOL) [ Time Frame: pre- vs. post-operative (6 or 12 months) ]
    Health related quality of life (HRQOL; QUOLI89 for adults and an age adapted comparable list for children) will be determined pre-and post-operatively (6 or 12 months) during routine neurophysiological investigation (NPO). Interim assessment of HRQol will be enabled by a visual analogue scale (VAS) on overall self-perceived health (including their epilepsy) included in the baseline and follow-up questionnaire. This VAS scale is also part of the HRQoL tests.

  5. Procedure duration [ Time Frame: intraoperative ]
    Post-hoc analysis of duration of surgery (minutes) and aECoG recording time (minutes).

  6. Complications related to study procedures [ Time Frame: during 12 months of post-opertive follow-up ]
    Complications related to study procedures Accounts are kept of the number of (post-)operative complications, such as bleeding, infection, unexpected or aggravated neurological deficits. These events will also be reported as (Serious) Adverse Events ((S)AEs). Monitoring and interim analysis by the DMC will be based on these numbers , as well as end-point determination.



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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Patients of all ages with:

  • Refractory Focal Epilepsy; at least ≥2 experienced seizures in the past 24 months, in spite of 2 or more different anti-epileptic drugs tried.
  • Planned neurosurgery with aECoG, with the goal of tailoring the resection.
  • Command of Dutch language of the patient/parents/legal representatives and capability of completing the questionnaires (by email or phone).

Exclusion Criteria:

  • Patients who underwent chronic ECoG monitoring preceding epilepsy surgery (grids). This is a biased population, since the results of the extensive pre-surgical work-up as well as the results of the cECoG monitoring period are included in the final decision making regarding the resection, and a precise seizure onset zone as well as spike and HFO area are known.
  • Patients with an occipital focus undergoing aECoG. Currently, it is not possible to discriminate between pathological or physiological occipital HFOs, and thus unsafe to perform HFO guided resections in patients with a presumed occipital focus.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02207673


Contacts
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Contact: Maryse A. van 't Klooster, MSc. +3188-7557959 m.a.vanhetklooster-2@umcutrecht.nl
Contact: Maeike Zijlmans, MD, PhD +3188-7557959 g.j.m.zijlmans@umcutrecht.nl

Locations
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Netherlands
VU University medical center Not yet recruiting
Amsterdam, Netherlands, 1081 HV
Contact: M. A. van 't Klooster, MSc    088-7557959    m.a.vanhetklooster-2@umcutrecht.nl   
Principal Investigator: S. Idema, MD, PhD         
University Medical Center Utrecht Recruiting
Utrecht, Netherlands, 3584 CG
Contact: Maryse van 't Klooster, MSc.         
Sponsors and Collaborators
UMC Utrecht
Rudolf Magnus Institute – University of Utrecht
Investigators
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Principal Investigator: Maeike Zijlmans, MD, PhD University Medical Center Utrecht, the Netherlands
Study Director: Maryse van 't Klooster, MSc. University Medical Center Utrecht, the Netherlands

Additional Information:
Publications of Results:
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Responsible Party: G.J.M. Zijlmans, MD, PhD, UMC Utrecht
ClinicalTrials.gov Identifier: NCT02207673     History of Changes
Other Study ID Numbers: NL44527.041.13
13-389 ( Other Identifier: Ethical review board UMC Utrecht )
2012-4 ( Other Grant/Funding Number: Dutch Epilepsy Foundation )
First Posted: August 4, 2014    Key Record Dates
Last Update Posted: May 12, 2016
Last Verified: May 2016
Keywords provided by G.J.M. Zijlmans, UMC Utrecht:
epilepsy surgery
biomarker
high frequency oscillations (HFOs)
acute electrocorticography (aECoG)
Additional relevant MeSH terms:
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Epilepsy
Epilepsies, Partial
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases