Use of a Tonometer to Identify Epileptogenic Lesions During Pediatric Epilepsy Surgery
Use of a Tonometer to Identify Epileptogenic Lesions During Pediatric Epilepsy Surgery
Refractory epilepsy, meaning epilepsy that no longer responds to medication, is a common
 neurosurgical indication in children. In such cases, surgery is the treatment of choice.
 Complete resection of affected brain tissue is associated with highest probability of seizure
 freedom. However, epileptogenic brain tissue is visually identical to normal brain tissue,
 complicating complete resection. Modern investigative methods are of limited use.

 An important subjective assessment during surgery is that affected brain tissue feels
 stiffer, however there is presently no way to determine this without committing to resecting
 the affected area. It is hypothesized that intra-operative use of a tonometer (Diaton) will
 identify abnormal brain tissue stiffness in affected brain relative to normal brain. This
 will help identify stiffer brain regions without having to resect them.

 The objective is to determine if intra-operative use of a tonometer to measure brain tissue
 stiffness will offer additional precision in identifying epileptogenic lesions.

 In participants with refractory epilepsy, various locations on the cerebral cortex will be
 identified using standard pre-operative investigations like magnetic resonance imagin (MRI)
 and positron emission tomography (PET). These are areas of presumed normal and abnormal brain
 where the tonometer will be used during surgery to measure brain tissue stiffness. Brain
 tissue stiffness measurements will then be compared with results of routine pre-operative and
 intra-operative tests. Such comparisons will help determine if and to what extent
 intra-operative brain tissue stiffness measurements correlate with other tests and help
 identify epileptogenic brain tissue.

 24 participants have already undergone intra-operative brain tonometry. Results in these
 participants are encouraging: abnormally high brain tissue stiffness measurements have
 consistently been identified and significantly associated with abnormal brain tissue.

 If the tonometer adequately identifies epileptogenic brain tissue through brain tissue
 stiffness measurements, it is possible that resection of identified tissue could lead to
 better post-operative outcomes, lowering seizure recurrences and neurological deficits.
Rationale: Refractory epilepsy, meaning epilepsy that no longer responds to medication, is a
 common neurosurgical indication in children. Focal cortical dysplasia (FCD) is the most
 common cause. Tuberous sclerosis complex (TSC) is a rare genetic disease causing epilepsy in
 over 90% of affected patients. This epilepsy can also become refractory to medication. In
 such cases of FCD or TSC, surgery is the treatment of choice. Complete resection of brain
 tissue affected by FCD or TSC is associated with highest probability of seizure freedom.
 However, epileptogenic brain tissue is visually identical to normal brain tissue,
 complicating complete resection. Modern investigative methods such as magnetic resonance
 imaging (MRI), electro-encephalography (EEG) and positron emission tomography (PET), are of
 limited use. Failure to achieve complete resection may lead to seizure recurrence, which is
 costly and requires additional surgeries, increasing risks of morbidity and mortality
 compared to achieving remission.

 Changes in tissue stiffness due to an underlying pathology are common in medicine, especially
 in neurological disorders. An important subjective assessment during epilepsy surgery,
 particularly in FCD cases, is that affected brain tissue feels stiffer. However, there is
 currently no way to determine stiffness without committing to resecting the affected area.

 Hypothesis: Epileptogenic brain tissue stiffness, as measured intra-operatively using a
 digital tonometer (Diaton), will likely be increased relative to normal brain tissue. This
 could allow identification of regions of higher stiffness without having to commit to
 resection.

 The tonometer is a widely-used and FDA-approved tool to measure intraocular pressure. It is a
 simple and reliable tool to measure brain tissue stiffness without obstructing the operative
 field. It requires only minimal contact in brain tissue.

 This study is multicentric and includes University of California, Los Angeles (UCLA) Mattel
 Children's Hospital in Los Angeles and Sainte-Justine University Hospital in Montreal.
 Results from 24 participants in a preliminary study from UCLA Mattel Children's Hospital were
 encouraging, prompting expansion of the study to include both sites.

 Objectives:

 Primary objective: To determine if intra-operative use of a tonometer to measure brain tissue
 stiffness will offer additional precision in identifying affected epileptogenic brain tissue,
 notably in FCD. This could also allow identification of resection margins.

 Secondary objective: Eventually, to investigate is epilepsy surgery guided by brain tissue
 stiffness measurements can lead to better post-operative outcomes, especially regarding
 seizure recurrences and neurological deficits.

 Methods: Participants with refractory epilepsy and considered candidates for surgery
 following a multidisciplinary meeting and consultation with a neurosurgeon, will undergo
 standard pre-operative investigations such as MRI, EEG and PET, to identify regions of
 presumed normal and abnormal brain. Precise locations in both presumed normal and abnormal
 brain will be identified for intra-operative brain stiffness measurements using the
 tonometer. Measurements will be taken on all lobes exposed during surgery.

 During surgery, a craniotomy will be performed and the dura mater will be folded to maximize
 brain exposition. Once the brain is exposed, a sterilized tonometer will be used to obtain
 brain tissue stiffness measurements at all predetermined locations of the cortex. Precise
 stereotactic coordinates for each measurement will be recorded in a neuronavigation software
 to facilitate comparisons with results of other tests. Brain tissue stiffness measurements
 will then be compared to results of aforementioned pre-operative tests, as well as results of
 routine intra-operative tests, namely electro-corticography (ECoG) and histopathological
 analysis of resected brain tissue (if brain tissue is ultimately resected).

 With this method, it will be possible to determine if and to what extent intra-operative use
 of the tonometer can identify epileptogenic brain tissue.

 There are no known risks to the patient associated with intra-operative use of the tonometer.
 Data collection adds approximately 10 minutes to surgery, which typically lasts around 7
 hours (420 minutes). Therefore, time in surgery and general anesthesia is only lengthened by
 2%.

 Importantly, no surgical decision concerning resection of brain tissue is currently based on
 brain tissue stiffness measurements obtained with the tonometer.

 Recruiting: Participants suffering from refractory epilepsy and deemed candidates for
 surgical treatment during a multidisciplinary meeting will consult with a neurosurgeon.
 During this consultation, if surgery is adequate and participant is eligible, the present
 study will be explained and discussed with the participant and his/her parent(s) or legal
 tutor(s). They will receive the informed consent form. Their questions will be answered. Time
 will be given to think about their participation to this study. If they consent, consent will
 be obtained through signing the informed consent form. If they refuse to participate, medical
 and surgical treatment will resume as planned.

 File review: Medical files of patients prospectively recruited will be reviewed with the
 participant's consent. Data relevant to the study includes: sex, ethnicity, age at onset of
 epilepsy, age at surgery, number of antiepileptic medications, etiology, video-EEG results,
 MRI results, PET results, digital pictures of the brain during surgery, individual brain
 stiffness measurements taken with the tonometer along with co-recorded neuronavigation images
 and coordinates.

 Tests: Before surgery, each participant will undergo routine pre-operative work-up including
 video-EEG, MRI and PET. During surgery, ECoG will be performed. If brain tissue is resected,
 in will be analyzed by pathologist to establish a histopathological diagnosis. These are
 routine investigations in epilepsy surgery. They are not modified by the results of
 tonometry. The only additional test is intra-operative brain tissue stiffness measurements
 using the tonometer. As discussed previously, this is not associated with any risks to the
 participant.

 It is predicted that 150 participants will be enrolled across both sites for this study.
 Anonymized data for each patient will be shared between both sites.

 Importantly, there are no possible controls for such a study. Post-mortem brain tissue
 undergoes irreversible biomechanical changes and no healthy patient undergoes comparable
 neurosurgical procedures. To overcome this issue, an experimental model involving intra- and
 inter-participant comparisons is used.

 Data analysis: Once data will be collected, statistical analysis will be performed.
 Continuous data will be reported using means and standard-deviations. Dichotomic data will be
 reported using frequencies and percentages. Mean and standard-deviations of brain tissue
 stiffness measurements will be compared for each covariable category using a t-test or ANOVA.
 Findings will be reported with a beta coefficient, 95 percent confidence intervals and
 p-values. P-values under 0.05 will be considered statistically significant. Further
 statistical analyses will be determined during the study.

 Timeframe: This study is predicted to last 36 months. Recruiting and treatment of
 participants, along with data collection will be performed initially. Following this, data
 will be analyzed and results discussed. Article(s) related to this study will be written
 afterwards.
Inclusion Criteria:

 -  Participants with epilepsy who candidates for surgical treatment as established by a
 multidisciplinary committee specialized in epilepsy.

 -  Participants undergoing resective surgery for epilepsy of dysplastic (examples: focal
 cortical dysplasia, tuberous sclerosis, hemimegalencephaly, polymicrogyria) or
 non-dysplastic etiology (examples: developmental tumors, gliosis, stroke, Rasmussen
 encephalitis, Sturge-Weber syndrome).

 Exclusion Criteria:

 -  Lesion of interest located in a difficult to access region, such as paralimbic
 structures, insula, depth-of-sulci or inter-hemispheric.