The severity of epilepsy and related disorders justifies the indication of surgical treatment that is effective in 60-80% of cases (4, 6-7, 10, 17-18). Favorable results are correlated with complete resection of the dysplastic cortex. It should be noted the absence of morphological abnormalities observed intraoperatively
1. Objectives of the studyOur goal is to provide to the neurosurgeons qualitative and quantitative data in real time to accurately resect the dysplastic cortex without affecting the healthy tissue by using an innovative brain ultrasound imaging system (μDoppler) during neurosurgery.This approach aims to improve the information provided by conventional preoperative imaging and ultrasound probes currently available in the clinic, it should offer the neurosurgeon a new intraoperative tool to improve the accuracy of its gesture and functional outcome of the surgery.Our medical team at the CHSA has a recognized expertise in the management of patients undergoing DCF2 and has sufficient recruitment to evaluate the usefulness of this new tool. These patients should therefore be among the first beneficiaries of this technological advance, since the healing of their epilepsy depends heavily on the completeness of surgical excision. As a reminder, DCF2 is often located functional area, especially near the sensorimotor cortex. Therefore improving the distinction between functional/healthy cortex and epileptogenic dysplastic cortex offers new perspectives for patients whose seizures persist after incomplete resection.
2. Methodology of the studyIt is a single-center observational study on a reduced cohort because of the high specificity of the study and the assumed high value of the evaluated technique.We first describe the characteristics and advantages of ultrasound imaging in DCF2, its adaptation to the clinical use, technical measures during the surgery and their validation by establishing correlations with other parameters.
Figure 8: Schematic representation of the components of our ultrasound scanner dedicated to brain imaging.
In a second step, we have designed an ultrasound probe whose technical characteristics have been specifically selected for functional imaging. Indeed, the ultrasonic sensor is the heart of a medical ultrasound imaging system. Performance of the probe will indeed determine to a large extent the quality of the images provided by the system. For these experiments, we chose a probe geometry with a linear array (1D) formed by an array of 64 piezoelectric PZT elements. A schematic of the probe is shown in Figure 5. The inter-element width, which defines the spatial resolution, was reduced to only a 100 microns step. The center frequency of 15 MHz was chosen because it allows a good compromise between resolution and depth. This custom configuration enabled us to minimize the overall size of the probe (12 x 6 mm Figure 5A) and therefore its weight in order to facilitate its use on animals of small size (rodents) and during surgery in human. Acoustic performance is not the only requirements of the ultrasound probe that we want to use for this project in the clinic. Indeed, like all medical materials, the probe meets standards ensuring the safety of physician and patient. Several aspects will be taken into account during the qualification process and manufacturing as electrical safety, thermal cycling, the acoustic output, biocompatibility and resistance to sterilization. With the aim to further increase the precision of surgery, we want to increase the resolution of our technique. For this, we designate two new ultrasonic probes with technical characteristics very close to the initial probe but with a large number of elements and/or a different geometric organization while respecting specific size constraints. These probes will be needed to analyze the dysplastic focus in the case of DFC2 located deep inside the brain (greater than 3 cm from the dura). They will also allow a gain in resolution and field of view. Specialized French companies in the field will do manufacturing of these probes.Figure 5 : CAD 2D and 3D ultrasound probe dedicated to functional imaging data. A. Front view of the probe. B. Side view showing the fastening system of the probe C. View from above. D. 3D sensor format 2 View: 1. The values are in mm.The third part of our work was to design a set of new ultrasound sequences suitable for functional imaging. The critical point for the Doppler imaging is the repetition rate of the pulses (several kHz) to properly sample the Doppler signal. Conventional Doppler mode scan the medium line by line with focused beams but are too slow to acquire an entire image, which involves dividing the image into several sectors scanned sequentially. Added to this constraint is added the real-time imaging problem for commercial ultrasound and therefore classical Doppler systems use few shots for each line, typically 15. The speed estimation or blood volume from such a short Doppler signal is difficult, which explain why small vessels are not detectable with this method. With the high-speed imaging, a single plane wave is required to rebuild a complete picture. The imaging frame rate is no longer a limitation since speeds of the order of 20 kHz can be achieved. To increase significantly signal/noise ratio compared to conventional Doppler mode, we have developed an imaging sequence by combining several images taken of plane waves of different impacts and the number of which can be tailored to the characteristics of the lesion (size, depth). Meanwhile, as there is no loss of time to scan the image areas, the number of pulses “seen” by each pixel is increased to typically reach 200 pulses. The combination of improved signal to noise and a longer Doppler signal is called μDoppler mode, which increases the sensitivity, by a factor of from 30 to 100 compared to Doppler mode. This work on the ultrasonic waves was supplemented by an important development in the filtering of the image that is essential to extract information corresponding to the movement of red blood cells. We use a series of so-called intelligent filters that eliminate the noise associated with cardiac and respiratory movements while enhancing the signal.To propose a new comprehensive tool, we also worked on the software interface to control our imaging system and the development of dedicated plug-ins for doctors, researchers and physicians who use functional imaging. Indeed, it is necessary to have a precise control of the physiological parameters of the subject during the imaging experiments, including devices to monitor body temperature, respiration, heart beat (ECG), brain rhythms (EEG). We have developed a dedicated software called PILOT consists of a central application to control the system and modules dedicated capable of displaying real-time constants and record readings of all devices used in the imaging experiments. Figure 9 shows example of the interface during functional imaging in preclinical experiments .Figure 9 : Example of using the PILOT GUI. OBI credits.This easy to use interface allows real-time monitoring, data management and offers a dedicated module for the analysis of experiments including export data in most common formats. An external acquisition card that connects different devices via a BNC, USB or serial port ensures compatibility with external devices.Finally, we designed a set of ultrasound sequences that are completely new and suitable for clinical use in both infants and adults. These optimizations are described in Part B of this document.
B. Functional brain ultrasound imaging to improve surgery DFC2Brain ultrasound imaging has many advantages for neurosurgery. First, the spatiotemporal resolution of this technique exceeds MRI and PET. Moreover, ultrasound would be a very effective tool in addition to the neuronavigation already used for imaging in real time and with high accuracy the area to be resected. Our goal is to apply our new highly sensitive imaging sequence to DCF2 to increase the precision of surgery.For DCF2, brain ultrasound imaging will be used according to 2 modes:
- a μDoppler mode to study in detail the structure and microvasculature of the area containing dysplastic tissue
- a morphological mode to accurately assess the movement of tissues (brain shift) during resection and to guide the surgeon’s in complement of neuronavigation.
The μDoppler mode to better visualize the dysplastic tissueThe Doppler imaging is based on the detection of the movement of the red blood cells (25). The acquisition step consists in sending successive ultrasonic pulses in the medium and record the echoes produced after each pulse. In the presence of blood in the pixel, the intensity of the recorded signal fluctuates over time due to the movement of red blood cells with a characteristic frequency called Doppler frequency directly proportional to their speed. After a filtering step that eliminates unwanted movements from tissues, various information can be extracted from the signal of blood flow, called µDoppler signal, such as the speed or volume of the blood. μDoppler brain imaging that we will use in this project is based on a new way of doing Doppler imaging as shown in Figure 10. With this new method, we can perform very precise images of the cerebral microvasculature in only 200ms and with good spatial resolution (100 μm2 in the plane of the image) that can be further improved by increasing the frequency of ultrasound. Indeed, the penetration of ultrasound allow us to view the surface of the cortex but also the deeper regions (up to 5 cm from the dura) over a very wide field imaging that is compatible with the deep cortical localization of DCF2. μDoppler brain imaging should contribute to the improvement of current surgical techniques (neuronavigation, intraoperative stimulation) that often lack precision in highly functional areas such as the motor cortex, where DCF2 are often found.
Thus, all ultrasound images in patients will be made using the ultrasonic probe protected with a sterile sheath and applied directly on the brain surface after opening the dura. The μDoppler images of brain vasculature required no mechanical vibrations and therefore an effective fixation of the ultrasound probe to the skull. This attachment will be managed using a custom designed probe holder and will measure the precise application of the probe to the cortex before resection – and before sulcal dissection – without making any pressure on the surface, and thus without risk of cortical injury.
3. Detail of the clinical trialA) Measurement during the surgeryTo validate the sensitivity of our new μDoppler sequence applied to DCF2, we will realize for each patient a series of detailed images of the surgical area after opening the dura, before resection but also after resection – inside and around the lesion. These measures should help to define the characteristics of dysplastic tissue and to compare them with those of healthy tissue.The surgical protocol will not change, morphological ultrasound measurements and guidance being added to the usual operating time. After general anesthesia of the patient and fixation of its head, the usual environment is installed – operating microscope, neuronavigation, cortical stimulation device – and the intervention will include: skin incision, craniotomy adapted to the size and location dysplasia the opening of the dura mater, the sulcal and gyral identification using neuronavigation and its validation by the identification of these structures under the operating microscope. Before sulcal dissection, μDoppler and morphological ultrasound measurement will be carried out (estimated at 10-15 min scanning time), and then the dissection is resumed; once the dysplasia is identified macroscopically – abnormal color and consistency of the cortex, spatial correlation with the pointer neuronavigation – it is resected (usually in several fragments that are labeled for subsequent correlation) until the complete resection of dysplastic tissue. This resection is estimated at a macroscopic level and the spatial position of the border of the dysplastic tissue are explored using the neuronavigation pointer and supplemented by information provided by ultrasound imaging in morphological mode. At the end of resection, a new ultrasonic measurement will be conducted to check for any residual hyperechoic abnormal tissue and measure the brain-shift. When DCF2 is larger, occupying for example an entire gyrus, it is usually resected in a block with adjacent resection in safe area to be complete, thereby again providing healthy and pathological samples for histologic correlative study and echogenicity .In all cases, the morphological parameters measured by this new ultrasound technique (echogenicity and structure of the microvasculature) will be correlated with data from the preoperative imaging (morphological imaging ,T1- ,T2, FLAIR, diffusion, ASL (arterial spin labeling, areas of activations in fMRI brain metabolism by FDG-PET), neurophysiological (EEG surface electrical activity in SEEG if performed) and neuropathological cortical specimen taken during surgery and oriented to define precisely the location. Particular attention will be paid to correlations between morphological parameters collected intraoperatively and analysis of anomalies cytoarchitectural characteristics DCF2 in the operating room. A ratio of the volume of dysplastic vs non-dysplastic tissue will be established whenever the resection block is possible.
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SCHEDULE OF THE CLINICAL TRIALThe schedule will be organized as follows:
- Start of the clinical trial with the enrollment of the first patient.
- The number of operated patients is on average of 1 patient / month, the first part of the study will allow us to validate all parameters (choice of sequences) of the imaging system
- The table below summarizes information about the clinical trial:
|Inclusion period||24 months|
|Duration of patient participationincluding:||12 months|
|Duration of treatment||1 day|
|Medical monitoring||12 months|
|Total duration of the clinical trial||36 months|
RESEARCH TEAMThe members participating in this study will be:1 – Bertrand Devaux, neurosurgeon, CHSA, 30%2 – Francine CHASSOUX, neurologist, CHSA, 25%3 – Gabriel MONTALDO, physicist-researcher, CHSA, 50%4 – Alan URBAN, researcher, CPN – INSERM U894, 25%