EP4676305A1

EP4676305A1 - System for long-term intracranial stereoelectroencephalgraphy

Info

Publication number: EP4676305A1
Application number: EP24700692.7A
Authority: EP
Inventors: Vasileios KOKKINOS
Original assignee: Individual
Current assignee: Individual
Priority date: 2023-03-03
Filing date: 2024-01-08
Publication date: 2026-01-14
Also published as: WO2024183960A1; AU2024233572A1; GR1010577B; CN120882363A

Abstract

A system for long-term intracranial stereo-electroencephalography (stereo-EEG), for determining a patient's epileptogenic zone, comprising an implantable long-term stereo-EEG device connected to intracranial depth stereo-EEG electrodes surgically implantable within the brain parenchyma. The implantable device is designed to perform regular background EEG recordings, and priority seizure recordings, in real time and transmit them in an asynchronous manner. With the asynchronous transmission mode, the device is protected from overheating and battery consumption is reduced, making the process of long-term stereo-EEG safe and feasible. The implantable long-term stereo-EEG device may also include a temperature monitoring module, which protects the device from overheating due to data processing or transmission load and any manufacturing failures. The present device may include an external stereo-EEG data storage device, which enables long-term intracranial stereo-EEG without imposing particular limitations in the patient's daily life.

Description

SYSTEM FOR LONG-TERM INTRACRANIAL STEREO¬

ELECTROENCEPHALGRAPHY

DESCRIPTION

TECHNICAL FIELD

The present invention concerns a system that supports the realization of a long-term intracranial stereo-electroencephalographic investigation in the context of treating epilepsy and other brain disorders that include seizures and need chronic intracranial electroencephalographic monitoring.

PRIOR ART

Epilepsy is a devastating brain disorder that affects nearly 50 million people worldwide. Epilepsy is the 4th most common neurological disorder and is manifested by seizures. Epilepsy is defined as a "sudden, excessive, and rapid discharge" of neuronal populations in the brain, detected by the electroencephalogram (EEG). Seizures have significant and often devastating consequences for patients' quality of life, excluding them from common activities (such as driving, swimming, etc.), affecting their personal life and family planning, as well as stigmatizing them socially and professionally. In addition, poorly controlled seizures can cause harmful conditions of varying severity, ranging from prolonged seizures leading to the condition known as status epilepticus to seizures followed by severe cardiorespiratory arrest, either during or after their end, which are responsible for "sudden, unexpected death in epilepsy - SUDEP".

Today, two main therapeutic avenues are widely available: antiepileptic drugs and epilepsy surgery. Treatment of epilepsy with antiepileptic drugs achieves freedom from seizures in 70% of patients. Nevertheless, the side effects of antiepileptic drugs can have significant consequences on patients' quality of life, resulting in the failure of therapeutic goals in 40% of patients. Epilepsy surgery is an established treatment option for drugresistant patients. The main goal of epilepsy surgery is to completely resect (or completely disconnect) areas of the brain responsible for the primary organization of epileptic activity that gives rise to seizures. This procedure often includes an invasive diagnostic phase, in which sharp deep electrodes are implanted into the brain parenchyma in order to locate the area of the brain responsible for producing seizures, the epileptogenic zone. This surgical technique is performed stereotactically (i.e. based on precise coordinates) and is called stereoelectroencephalography (stereo-EEG). During this phase, and with the deep stereo-EEG electrodes implanted within the brain parenchyma, the patient remains and his EEG is recorded in the specially configured Epilepsy Monitoring Unit (EMU) within the hospital unit.

The usual stay of patients in the EMU is on average 7-10 days internationally, and rarely exceeds 3 weeks. This duration is generally accepted by the scientific community of epilepsy surgery and is only a snapshot in the context of a chronic disorder such as epilepsy. In several cases this snapshot of the patient's intracranial electroencephalographic signals and seizures is representative, and therefore the therapeutic phase following said diagnostic phase is successful. Nevertheless, in a significant percentage of cases the relatively short stay in the EMU cannot capture the overall dynamics of the seizure disorder. One of the reasons is that a significant percentage of patients suffer from a multifocal form of epilepsy, where more than one area of the brain causes seizures. In these cases, the short period of stay and recording of seizures within the respective hospital may not be sufficient to reveal all the cerebral epileptic foci, which results in multifocal patients continuing to suffer from epileptic seizures after the therapeutic phase. Another reason is that another percentage of patients suffer from catastrophic forms of seizures (such as sudden and intense generalized tonic- clonic seizures), which have as a direct consequence injuries, transfer to the Emergency Department and possibly the Intensive Care Unit, but appear at a low frequency throughout the year (for example once or twice a year). For this group of patients, not only does their intracranial stereo-EEG recording have a high chance of being unsuccessful, but often the epileptologists who tend to them advise them not to undergo these pre-operative procedures due to the high risk of diagnostic failure.

The time limitations in the stay of patients in the EMU within hospitals result in insufficient pre-operative diagnostic investigations, which in turn leads to sub-optimal treatment or to complete impossibility of surgical treatment in the absence of the necessary intracranial stereo-EEG information. In order to fill this gap in the treatment of drug-resistant epilepsy that needs pre-operative investigation, it is advantageous to design a system that allows the intracranial stereo-EEG procedure to be performed for long periods of time and with the patient simultaneously going about his life ambulatory and without special restrictions outside hospital units or other healthcare institutions.

SUMMARY OF THE INVENTION

According to the present invention, there is provided a system for long-term intracranial stereo-electroencephalography (stereo-EEG) according to claim 1.

According to an embodiment of the present invention, a system for long-term intracranial stereo-EEG is provided for carrying out the diagnostic minimally invasive stereo-EEG investigation outside the hospital units, where it takes place to date, with the patient at the same time going about his life ambulatory and without special restrictions in his daily life. Said system comprises a long-term stereo-EEG device (4), implanted preferably in the subclavicular region of the chest, which is connected (3) to depth stereo-EEG electrodes (2) implanted within the brain parenchyma to determine the area of the brain that generates seizures. The long-term stereo-EEG device (4) makes regular (background) and priority (seizure) recordings, both of short duration (typically 5 minutes each), in real time, and transmits them asynchronously over multiple intervals (typically 25 minutes). Notably, the majority of the diagnostic information in seizure recordings resides in the first 30-60 seconds, including both seizure onset and seizure propagation information, thereby rendering a 5-minute recording diagnostically adequate. Thus the device is protected from overheating and over-consumption of the battery in relation to the case where the recording and transmission of the data was continuous and uninterrupted, making the process of long-term stereo-EEG safe and feasible. The long-term stereo-EEG device (4) may also include a temperature monitoring subunit (11), which protects the device from overheating due to data processing load, data transmission load and any manufacturing failures.

In a preferred embodiment, the system for long-term intracranial stereo-EEG also includes an external stereo-EEG data storage device (17), which can be carried by the patients in a backpack (16), and from which the stereo-EEG data can be read and retrieved from an external computing unit of the supervising physician or the EMU of the healthcare institution performing the stereo-EEG investigation. In another preferred embodiment, the system for long-term intracranial stereo-EEG may include an external wireless battery charging device (26), which refreshes the battery power of the implantable long-term stereo-EEG device (4) at regular intervals, thereby significantly reducing the need for patients to undergo repeated surgical procedures to replace the battery. Finally, the system for long-term intracranial stereo-EEG may include an external parameterization device (33), with which any authorized operator can view and enter information related to the operating parameters of the long-term stereo-EEG device (4).

Further features and advantages of the present invention, as well as the structure and operation of various embodiments of the present invention, are described in detail below with reference to the accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

The present invention will now be described with reference to certain embodiments thereof illustrated in the accompanying drawings. It should be noted that the attached drawings illustrate preferred embodiments of the invention, therefore they should not be considered as limiting the scope of the invention. It is also understood that the illustrations may include optional features which are not necessary in any embodiment.

Figure 1 illustrates the surgical technique of stereo-EEG, where depth electrodes (2) are implanted into the brain parenchyma (1), either in an orthogonal (left) or in an oblique manner (right).

Figure 2 schematically illustrates how the long-term stereo-EEG device (4) is implanted in the subclavicular region of the chest, with the connection cables (3) passing subcutaneously from the cranial implantation site to the device, in two stereo-EEG coverage scenarios: unilateral hemispheric coverage of stereo-EEG electrode implantation (A in front view and B in profile), and bilateral hemispheric coverage (C).

Figure 3 schematically illustrates an integration of the implantable long-term stereo-EEG device (4) with its constituent subunits. Figure 4 schematically illustrates the interconnections of the temperature monitoring subunit (11) with the chassis temperature sensors (14) and the subunit temperature sensors (15) of the implantable long-term stereo-EEG device (4).

Figure 5 schematically illustrates a protocol for temporary storage and asynchronous transmission of intracranial stereo-EEG data from the corresponding subunit (9) of the implantable long-term stereo-EEG device (4), where in a 25- minute period, 5 minutes of regular/scheduled continuous uninterrupted background stereo-EEG recording are progressively transmitted asynchronously.

Figure 6 schematically illustrates a protocol for temporary storage and asynchronous transmission of intracranial stereo-EEG data from the corresponding subunit (9) of the implantable long-term stereo-EEG device (4), in the event of an epileptic seizure.

Figure 7 schematically illustrates a protocol for temporary storage and asynchronous transmission of the intracranial stereo-EEG data from the corresponding subunit (9) of the implantable long-term stereo-EEG device (4), in the event of the occurrence of two epileptic seizures in a short period of time between them.

Figure 8 schematically illustrates a protocol for temporary storage and asynchronous transmission of intracranial stereo-EEG data from the corresponding subunit (9) of the implantable long-term stereo-EEG device (4), in the event of three epileptic seizures occurring within a short period of time between them.

Figure 9 schematically illustrates a protocol for temporary storage and asynchronous transmission of the intracranial stereo-EEG data from the corresponding subunit (9) of the implantable long-term stereo-EEG device (4), in the event of a temperature increase above the permissible limits in one of the corresponding sensors (14, 15).

Figure 10 schematically illustrates an embodiment of the implantable long-term stereo-EEG device (4) and the external data storage device (17), arranged such as to allow the patient to go about his life ambulatory and without particular restrictions. Figure 11 schematically illustrates an embodiment of the external data storage device (17) with its constituent subunits.

Figure 12 schematically illustrates an embodiment of the external wireless battery charging device (26).

Figure 13 schematically illustrates an embodiment of the external wireless battery charging device (26) with its constituent subunits.

Figure 14 schematically illustrates an embodiment of the external parameterization device (33).

Figure 15 schematically illustrates an embodiment of the external parameterization device (33) with its constituent subunits.

DETAILED DESCRIPTION OF THE INVENTION

The invention is described below, with reference to detailed illustrative embodiments. It will be apparent that a system according to the invention can be embodied in a wide variety of forms. Accordingly, the specific structural and functional details disclosed herein are representative and do not limit the scope of the invention.

Terms not specifically defined herein should be given the meaning that would be given to them by one skilled in the art in light of the present disclosure and the general context.

The present invention takes into account the already well-established fact that the surgical treatment is a widely accepted and effective approach for the optimal control of seizures that do not respond adequately to the variety of available pharmaceutical antiepileptic treatments. It is also well documented that the level of effectiveness of the surgical approach strongly depends on the data provided during the pre-operative investigation to determine the epileptogenic zone, i.e. the area of the brain responsible for generating seizures. One of the main and popular methods of obtaining data to determine the epileptogenic zone is a minimally invasive surgical procedure involving the stereotactic implantation of electrodes deep within the brain, called stereo-electroencephalography (stereo-EEG). Figure 1 shows an example of stereo-EEG depth electrode implantation of prior art (2) within the brain parenchyma (1), with two of the most popular implantation modes of orthogonal (left) and oblique orientation (right). This method allows for the direct recording of data from the epileptic brain and the optimal determination of the epileptogenic zone, since it is the only technique that provides the possibility of recording data from brain structures located deep in relation to the surface of the hemispheres. This method also, due to its minimally invasive nature, minimizes the risk of complications and infections, and makes the process of patients' stay in the EMU more tolerable. For the same reason, it is the methodology of choice for investigating the epileptogenic zone in pediatric populations.

The present invention also takes into account the already well established fact that, despite the stereo-EEG’s reaching the deepest structures of the brain, as well as its unique ability to perform bilateral coverage of the cerebral hemispheres with depth electrodes, epilepsy remains a complex and multifaceted disorder for which a definitive therapeutic approach eludes the scientific and medical community. Therefore, although in several cases the stereo-EEG procedure is successful in determining the epileptogenic zone, and therefore the therapeutic phase following said diagnostic phase is successful, in a significant percentage of cases this diagnostic procedure becomes unsuccessful, thus depriving this group of patients of the opportunity for surgical treatment. One of the main reasons for the failure of the stereo-EEG diagnostic process is the relatively short stay of the patients in the EMU, as many times this period of time cannot capture the overall dynamics of the seizure disorder. The usual stay of patients in the EMU is on average 7-10 days internationally, and rarely exceeds 3 weeks. It is generally agreed by the epilepsy surgery scientific community that this duration is only a snapshot in the context of a chronic disorder such as epilepsy. In several patient cases, this snapshot of the patient's intracranial electroencephalographic signals and seizures is representative, and therefore the surgical treatment phase following said diagnostic phase is successful. Nevertheless, in a significant percentage of patients with epilepsy, the relatively short stay in the EMU cannot capture the overall dynamics of the seizure disorder. One of the reasons is attributed to the well-documented fact that a significant percentage of patients suffer from a multifocal form of epilepsy, where more than one area of the brain has the potential to independently generate seizures. In these cases, the short period of stay in the EMU may not be enough to reveal all the epileptic foci of the brain. In this time-limited setting, the diagnostic stereo-EEG procedure can become misleading, showing a single brain focus as responsible for the seizures. This results in the curative surgical phase focusing on one of the epileptic foci, and post-operatively patients continue to suffer from seizures generated by the remaining undetected foci. Another reason concerns another category of patients, who suffer from catastrophic forms of seizures (such as sudden and intense generalized tonic-clonic seizures), which have as a direct consequence injuries, transfer to the Emergency Unit and possibly to the Intensive Care Unit, but occur with a low frequency throughout the year (for example once or twice a year). For this group of patients, not only does the pre-operative diagnostic stereo-EEG recording have a high chance of being unsuccessful, but often the epileptologists tending to these patients advise them not to undergo these pre-operative procedures because of the high risk of diagnostic failure. In other words, the limited time frames in which diagnostic interventional stereo-EEG procedures are performed may exclude patients from the opportunity of surgical treatment and/or lead to suboptimal surgical management with subsequent poor postoperative control of the patients’ seizures.

The present invention is based on the original idea that the above-mentioned time limitations of the stereo-EEG procedure within healthcare institutions can be relieved by designing a system that enables the intracranial stereo-EEG procedure to be performed for long periods of time, for example for intervals longer than the current clinical practice of 7-14 consecutive days, and with the patient at the same time carrying out his life ambulatory and without special restrictions outside hospital units or other healthcare institutions. Figure 2 shows an embodiment of the long-term intracranial stereo-EEG system of the present invention. Based on current neurosurgical techniques, implantation can be performed in several ways. The one proposed here as the most suitable is the subcutaneous implantation of the long-term stereo-EEG device (4), in the subclavicular area in the upper part of the chest, however implantation in other sites, such as the skull, is also possible. In a unilateral hemispheric coverage implantation (Figure 2, A and B) of the depth electrodes (2), the connecting cables (3) between the depth electrodes (2) and the long-term stereo-EEG device (4) are passing subcutaneously from the cranial site of implantation to the subclavicular region of the chest. In a bilateral hemispheric coverage implantation (Figure 2, C) of the depth electrodes (2), the connecting cables (3) between the contralateral depth electrodes (2) and the long-term stereo-EEG device (4) pass subcutaneously from the cranial implantation site along the coronal direction to the hemisphere ipsilateral to the long-term stereo-EEG device (4) accompanied by the ipsilateral connecting wires (3) to the subclavicular region of the chest.

According to this embodiment, the implantable stereo-EEG electrodes (2) are interconnected via the corresponding connection cables (3) with the interface subunit (5). Through said interface subunit, the implantable long-term stereo-EEG device (4) can be interfaced with at least one stereo-EEG depth electrode (2). Preferably, the implantable long-term stereo-EEG device (4) is interconnected with two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen or sixteen depth stereo-EEG electrodes (2), more preferably with six to twelve depth stereo-EEG electrodes. Each depth electrode may comprise of (at least) four, or six, or eight, or ten, or twelve, or fourteen, or sixteen, or eighteen, or twenty recording contacts. This proposed configuration allows the stereo-EEG procedure to be performed with said long-term stereo-EEG device (4) in such a way that the implantation coverage is equivalent to the way it is currently performed in the EMUs.

The implantable long-term stereo-EEG device (4) of the present invention is designed to record in real time two types of stereo-EEG data: 1. regular recordings of background stereo-EEG, and 2. priority recordings of seizure stereo-EEG data triggered after seizure detection. As used throughout the description and claims, the word “priority” in the term “priority epileptic seizure recordings” refers both to the order of recording and the order of transmission of signals. Both background and ictal stereo-EEG data are indispensable and complementary for the diagnostic purposes of the stereo-EEG investigation, as they provide independent biomarkers of epileptogenicity. In turn, said device can transmit the recorded data to an external device or storage medium in an asynchronous way in a multiple time interval. The term "asynchronous" (or "discontinuous") data transmission refers to digital data transmission where packets of information are not transmitted continuously and uninterrupted from start to finish, but with pauses where data transmission is temporarily interrupted before restarting. An advantage of asynchronous data transmission is that it is free from strict timing constraints, which makes the design of the circuits that implement it more flexible. A second advantage is that pauses, discontinuities in transmission allow the temperature of the subunit serving asynchronous transmission to decrease, since synchronous/continuous data transmission is an energy- intensive operation that would significantly increase the temperature in said subunit.

Each recording may be performed for a period of 1, 2, 5, or 10 minutes. The recording is then transmitted over a period that is at least two times, three times, four times, five times or six times longer in duration than that of the recording. As an example, the regular recordings are performed for a period of five minutes per every 30 minutes. The priority recordings are performed for a period of five minutes every time a seizure is detected. The regular and the priority recordings are independently transmitted asynchronously in the 10-, 15-, 20- or 25-minute period immediately following the recording, resulting in a total maximum interval for both recording and transmission of 30 minutes.

Preferably, real-time stereo-EEG data acquisition and asynchronous transmission thereof is performed by a wireless asynchronous stereo-EEG data transmission subunit (9) of the implantable long-term stereo-EEG device (4) (Figure 3). As an example of the asynchronous transmission, after the completion of a 5 -minute regular (background) recording, the wireless asynchronous stereo-EEG data transmission subunit (9) organizes and performs the stereo-EEG data transmission over a 25 minute interval, instead of transmitting all stereo-EEG data immediately after the recording’s completion in 1-5 minutes which would be the case in synchronous modes of data transmission. This is achieved by breaking down the recording in shorter intervals (e.g. 60 seconds) and transmitting them in 5 interrupted blocks, each over a 5-minute interval. During the transmission intervals, the wireless asynchronous stereo-EEG data transmission subunit (9) simultaneously monitors for flags from the seizure detection subunit (8), in which case the transmission of background data is temporarily suspended and the transmission of seizure stereo-EEG data is prioritized (Figures 5-8), as well as from the temperature monitoring subunit (11), in which case the transmission halts temporarily until the temperature returns to safety levels (Figure 9). The procedure is unsupervised by the patients, thus freeing them from any obligation to engage with said long-term intracranial stereo-EEG system during the ambulatory conduct of their daily life.

According to one embodiment, the implantable long-term stereo-EEG device (4) may include a seizure detection subunit (8) which reads real-time stereo-EEG data in order to identify seizure patterns in the recorded stereo-EEG signals (Figure 3). The seizure detection subunit (8) probes the stereo-EEG from all electrode contacts (2) simultaneously and identifies changes in the stereo-EEG background. For instance, the seizure detection subunit (8) identifies changes in the stereo-EEG signal with the following characteristics: 1. The signals involve paroxysmal elements (low-voltage fast activity, paroxysmal fast activity, spikes, polyspikes, spike-wave complexes, polyspike-wave complexes, sharp waves, etc); 2. The paroxysmal elements manifest the features of rhythmicity and evolution over time. 3. The signals may manifest features of propagation from one or few contacts to many or all contacts. A feature-extraction algorithm or computational intelligence, adapted to identify these features in the stereo-EEG signal, can be implemented within the seizure detection subunit (8). The feature-extraction algorithm or computational intelligence defines the seizure onset at the point in time where in one or more stereo-EEG channels the stereo-EEG background interictal features are lost and aggressive rhythmic ictal features appear on stereo-EEG. The person skilled in the art knows how to choose and apply a suitable algorithm or computational intelligence to identify these features in the stereo-EEG signal. Upon seizure detection, the seizure detection subunit (8) provides a flag signal to the stereo-EEG data recording subunit (7) that kick-starts the recording of a priority (seizure) set of data, preferably including 30 (or 60) seconds before the onset identification and 4:30 (or 4) minutes after the onset identification. The stereo-EEG data recording subunit (7) incorporates a data first-in first- out (FIFO) buffer that keeps real-time data for at least 60 seconds and discards them if no seizure is detected. The priority seizure data is then transmitted wirelessly to an external device or storage medium.

The recording and storage of the stereo-EEG data can be performed by the stereo-EEG data recording subunit (7) of the implantable long-term stereo-EEG device (4). Preferably said subunit includes data memory architecture capable of writing (implementing a “First- In-First-Out” (FIFO) mode of operation) and reading data, with at least two distinct memory buffers (Bl and B2, Figures 5-9). The stereo-EEG data recording subunit (7) stores the two types of stereo-EEG data: 1. the regular background stereo-EEG recordings (for instance, recording of 5 minutes of background stereo-EEG every 30 minutes), and 2. the priority stereo-EEG data recordings, when a seizure is detected by the seizure detection subunit (8). The stereo-EEG data recording subunit (7) relays continuously realtime stereo-EEG data to the seizure detection subunit (8) in order for the latter to recognize seizure patterns in the stereo-EEG signal. When a seizure is detected, the seizure detection subunit (8) relays a flag signal to the stereo-EEG data recording subunit (7), and the latter begins the recording of the 5-minute priority seizure stereo-EEG data block.

The device (4) may include a stereo-EEG data digitization subunit (6) adapted to digitize the analog data recorded by the intracranial stereo-EEG depth electrodes (2) (Figure 3). According to a preferred embodiment, the stereo-EEG data digitization subunit (6) comprises an initial stage of analog intracranial stereo-EEG signal amplification and then a stage of converting the amplified analog stereo-EEG data to digital, in order to generate digitized stereo-EEG data. In a further embodiment, the intracranial stereo-EEG data digitized by the intracranial data digitization subunit (6) are stored temporarily and in real time in the stereo-EEG data recording subunit (7). If the stereo-EEG data recording subunit (7) receives a seizure detection flag signal from the seizure detection subunit (8), the digitized temporary stereo-EEG data will begin forming the priority recording block within the predetermined data duration specifications. If no seizure detection flag signal is received, every 5 minutes per half an hour, the digitized temporary stereo-EEG data will begin forming the regular recording block within the predetermined data duration specifications.

The implantable long-term stereo-EEG device (4) may further include a wireless system parameter exchange subunit (13), which is intended to store and update parameters related to the orderly, smooth and intended operation of the system. The wireless system parameter exchange unit is exclusively coupled with an external parameterization device (33), for the purpose of allowing an authorized user to update system parameters on the implantable long-term stereo-EEG device (4).

As one skilled in the relevant art would find apparent from the above description, the arrangement illustrated in Figure 3 is only one example of the present invention. Many other configurations or modifications are possible, as discussed in the present disclosure and as could be made by one skilled in the art without departing from the scope of the invention as defined by the claims.

In another preferred embodiment, the implantable long-term stereo-EEG device (4) further comprises a temperature monitoring subunit (11) which is connected to one or more temperature sensors (14). Said subunit is designed to stop the transmission of said data if the temperature exceeds the predetermined safety limits. Figure 4 schematically shows such an embodiment, where a group of temperature sensors (14) are placed on the chassis of the long-term stereo-EEG device in order to record the temperature in the inner shell of the implanted device, and another group of temperature sensors (15) placed in contact with the subunits of the long-term stereo-EEG device in order to record the temperature individually in each subunit. The measurements of the set of sensors are sent to the temperature monitoring subunit (11), which in turn informs the central control unit (12) (Figure 3). In the event that a rise in temperature above safety limits is detected at one or more temperature detectors (14, 15), the central control unit (12) stops transmitting regular background data until the temperature returns within safety limits. After the temperature levels have returned within safety limits, and as long as no increase in another temperature sensor(s) has been detected beyond safety limits in the meantime, the cycle of recording and transmitting new regular background stereo-EEG data continues. Objectives and advantages of said temperature monitoring are the safety of the patient and the protection of the patient from overheating of the device due to: 1. Data processing overload, mainly from the seizure detection subunit (8) and the central control unit (12), 2. Overload of data to be transmitted by the wireless asynchronous stereo-EEG data transmission subunit (9), and 3. Due to any manufacturing failure during the manufacturing process of electronics and packaging materials of the long-term stereo-EEG device (4). The main advantage of this integration is the fact that temperature monitoring of the implantable long-term stereo- EEG device (4) allows the adjustment of the pause/discontinuity time intervals of the wireless data transmission to an external device or storage medium, which is the most energy-intensive process when dealing with continuous stereo-EEG data.

In a preferred embodiment, the implantable long-term stereo-EEG device (4) includes a wireless asynchronous stereo-EEG data transmission subunit (9). The wireless asynchronous stereo-EEG data transmission subunit (9) receives stereo-EEG data, preferably from the stereo-EEG data recording subunit (7), and transmits it to an external device or storage medium in an asynchronous manner. Figure 5 shows an example of asynchronous transmission of regular 5-minute background stereo-EEG data. Regular background data is recorded during the first 5 -minutes in the primary memory buffer Bl of the stereo-EEG data recording subunit (7), and then transmitted progressively over a 25-minute period via the wireless asynchronous stereo-EEG data transmission subunit (9) (the wireless asynchronous transmission process is symbolized by the lightning bolt icon within a circle).

In a preferred embodiment, the wireless asynchronous stereo-EEG data transmission subunit (9) is designed to process the stereo-EEG data prior to its transmission, in such a way that priority seizure recordings are prioritized for transmission, whenever they are recorded, and the regular recordings are secondarily prioritized. In this way, the safe recording of seizures, which are the most important information of the stereo-EEG diagnostic examination, is ensured, and the risk of their loss due to coincidence with the transmission of regular stereo-EEG recordings of lower clinical interest is avoided. Examples of the above embodiment are presented in Figures 6 to 8. Figure 6 shows an example of asynchronous transmission of stereo-EEG data, where during the asynchronous transmission of regular background stereo-EEG data, between the 20th and 25th minute, a seizure occurs and is detected. As a result, the transmission of background stereo-EEG data is interrupted, the stereo-EEG data of the seizure is recorded in the stereo-EEG data recording subunit (7), and then transmitted progressively over a period of 25 minutes via the wireless asynchronous stereo-EEG data transmission subunit (9), with the same wireless asynchronous transmission method applied to the regular background stereo-EEG data. After the transmission of the priority stereo-EEG data containing the seizure has ended, and as long as no other seizure has occurred in the meantime, the cycle of recording and transmitting new regular background stereo-EEG data continues.

Figure 7 shows an example of asynchronous transmission of stereo-EEG data, where during the asynchronous transmission of regular background stereo-EEG data two seizures occur within a short period of time between them. For the first seizure, the same procedure as shown in Figure 6 and described above is carried out. In this example, the second seizure occurs between 20 and 25 minutes after the onset of the first seizure. The asynchronous transmission of the first seizure is not interrupted but continues. The stereo- EEG data of the second seizure is recorded in the secondary memory buffer B2 of the stereo-EEG data recording subunit (7). After the end of the asynchronous transmission of the stereo-EEG data of the first seizure, the asynchronous transmission of the stereo-EEG data of the second seizure begins. After the transmission of the second epileptic seizure stereo-EEG data has ended, and as long as no other seizure has occurred in the meantime, the cycle of recording and transmission of new regular background stereo-EEG data continues.

Figure 8 shows an example of asynchronous transmission of stereo-EEG data, where during the asynchronous transmission of regular background stereo-EEG data three seizures occur within a short period of time between them. For the first two seizures, the same procedure as shown in Figure 7 and described above is carried out. In this example, the third seizure occurs between 15 and 20 minutes after the onset of the second seizure, and while its asynchronous transmission has already begun. The asynchronous transmission of the second seizure is not interrupted but continues. The stereo-EEG data of the third seizure is recorded in the primary memory buffer Bl of the stereo-EEG data recording subunit (7). After the end of the asynchronous transmission of the stereo-EEG data of the second seizure, the asynchronous transmission of the stereo-EEG data of the third seizure begins. After the third seizure's stereo-EEG data has been transmitted, and as long as no other seizure has occurred in the meantime, the cycle of recording and transmitting new regular background stereo-EEG data continues.

Figure 9 shows an example of asynchronous transmission of stereo-EEG data, where during the asynchronous transmission of regular background stereo-EEG data, between the 20th and 25th minute, an increase in temperature above safety limits is detected in one or more temperature sensors (14, 15) by the temperature monitoring subunit (11). As a result, the transmission of regular background stereo-EEG data is interrupted until the temperature is back within safety limits. After the temperature levels have returned within safety limits, and as long as no increase in another temperature sensor(s) has been detected beyond safety limits in the meantime, the cycle of recording and transmitting new regular background stereo-EEG data continues.

It should be emphasized here that the entire process of wireless asynchronous transmission of regular and priority stereo-EEG data is a process unsupervised by the patient, freeing him from any obligation to engage with the proposed system for long-term intracranial stereo-EEG during the ambulatory conduct of his daily life.

In a preferred embodiment, the implantable long-term stereo-EEG device (4) comprises a central control unit (12), comprising either a special-purpose integrated circuit or a general-purpose processor, and is designed to execute a pre-installed program from a built-in memory and based on this it arbitrates all the subunits of the long-term stereo- EEG device both in terms of the data use and the conditional states of the system. The central control unit typically incorporates a real-time clock, based on which it synchronizes the stream of stereo-EEG data and the control process sequences of the peripheral subunits.

The central control unit (12) of the stereo-EEG device (4) is also responsible for controlling the wireless asynchronous stereo-EEG data transmission subunit (9). The central control unit is interconnected with the seizure detection subunit (8) from which it receives a flag byte every time a seizure is detected in the stereo-EEG signal. Upon seizure detection, the central control unit (12) interrupts the asynchronous transmission of regular background stereo-EEG data taking place in the wireless asynchronous stereo- EEG data transmission subunit (9) and initiates priority asynchronous transmission of the seizure stereo-EEG data (Figure 6). If a second or a third seizure occurs during the asynchronous transmission of the first seizure, the central control unit (12) directs the seizure data to the secondary memory buffer B2 (Figure 7) and the primary memory buffer Bl (Figure 8), respectively. Once all seizure stereo-EEG data have been asynchronously transmitted, the central control unit (12) returns the wireless asynchronous stereo-EEG data transmission subunit (9) to its regular background stereo-EEG data asynchronous transmission mode (Figure 5).

The central control unit (12) is also interconnected with the temperature monitoring subunit (11) from which it receives another flag byte every time one of the temperature sensors (14, 15) detects an increase in temperature beyond safety limits. Upon detection of increased temperature beyond safety limits, the central control unit (12) interrupts the asynchronous transmission of regular background stereo-EEG data taking place in the wireless asynchronous stereo-EEG data transmission subunit (9) and places it in halt transmission mode (Figure 9). The central control unit (12) returns the wireless asynchronous stereo-EEG data transmission subunit (9) to its regular background stereo- EEG data asynchronous transmission mode once the temperature returns within safety limits.

According to one embodiment, the long-term intracranial stereo-EEG system of the present invention further includes an external stereo-EEG data storage device (17) (Figure 10) for receiving and storing the data recorded by the implantable long-term stereo-EEG device (4). The external stereo-EEG data storage device (17) potentially can be carried in a backpack (16) to allow the patient to be ambulatory throughout the stereo-EEG implantation and go about their daily life normally, without particular restrictions. The advantage of storing the data in an external device, compared to storing it in the implantable device (4), is that it allows storing large amounts of data. Said device (17) may include an alert button (19), which may be connected to the external stereo-EEG data storage device (17) via an external cable (18), for use by the patient when experiencing subjective warnings (epileptic auras) indicating that a seizure is imminent. This way, the patient marks the moment of epileptic aura, which further facilitates the clinical evaluation of the recordings.

According to one embodiment (Figure 11), the external stereo-EEG data storage device (17) comprises a wireless asynchronous stereo-EEG data acquisition subunit (20) to receive data from the implantable long-term stereo-EEG device (4). According to a preferred embodiment, the external stereo-EEG data storage device (17) includes a stereo- EEG data storage subunit (21), where said data comprise the set of regular and priority recordings transmitted by the implantable long-term stereo-EEG device (4) via the wireless asynchronous stereo-EEG data acquisition subunit (20). In a further embodiment, the external stereo-EEG data storage device (17) includes an alert recording subunit (22), which incorporates a real-time clock and on the basis of which it records the time points of aura occurrence as reported by patients by pressing the alert button (19).

According to a preferred embodiment, the external stereo-EEG data storage device (17) includes a stereo-EEG data output subunit (24) (Figure 11), which allows the stored stereo-EEG data to be read and retrieved from an external computer device of the supervising physician/epileptologist or the EMU of the hospital unit conducting the stereo- EEG investigation.

The external stereo-EEG data storage device (17) may include a wired battery charging subunit (23), which is responsible for charging the energy units of the external stereo-EEG data storage device (17) from an external power source via cable (25).

According to another embodiment, the long-term intracranial stereo-EEG system of the present invention further comprises an external wireless charging device (26). As schematically depicted in the embodiment of Figure 12, the implantable long-term stereo- EEG device (4) may be wirelessly charged by the external wireless charging device (26). Preferably, the implantable long-term stereo-EEG device (4) includes a wireless battery charging subunit (10), which registers battery energy levels and mediates wireless charging from the dedicated external wireless charging device (26). According to one embodiment (Figure 13), the external wireless charging device (26) comprises a wired charging subunit (29), which is responsible for charging the energy units of the external wireless charging device (26) from an external power source via cable (30). According to a preferred embodiment, the external wireless charging device (26) comprises a wireless communication unit (27), which is exclusively coupled to the wireless battery charging subunit (10) of the implantable long-term stereo-EEG device (4) and serves the exchange of charging data between the two subunits. In a further embodiment, the external wireless charging device (26) comprises a wireless charging control subunit (28), which, based on the data received from the wireless communication subunit (27), controls a switch configuration (31) that mediates the connection of the wired charging subunit (29) with the induction coil (32) and perform the wireless charging. In this way, the power of the implantable long-term stereo-EEG device (4) can be renewed at regular intervals either by the patients themselves or by their caregivers/guardians, which significantly reduces the need for patients to undergo multiple battery replacement surgeries.

According to another embodiment, the long-term intracranial stereo-EEG system of the present invention further includes an external parameterization device (33) for updating system parameters the implantable long-term stereo-EEG device (4) (Figure 14). Preferably, (Figure 15), the external parameterization device (33) includes a central control unit (35), comprising either a special purpose integrated circuit or a general purpose processor, designed to execute pre-installed programs from built-in memory . The central control unit (35) typically incorporates a real-time clock, on the basis of which it synchronizes the sequences of information exchange and control procedures between peripheral subunits within the external parameterization device (33), described below.

According to the embodiment of Figure 14, the external parameterization device (33) may include a wireless system data communication subunit (34), arbitrated by the central control unit (35) and exclusively coupled to the wireless system parameter exchange subunit (13) of the implantable long-term stereo-EEG device (4) which allows an authorized user to wirelessly transmit updated system parameters to the implantable longterm stereo-EEG device (4), in order to support the orderly, smooth and intended operation of the implantable long-term stereo-EEG device (4).

According to the embodiment of Figure 14, the external parameterization device may include a pre-installed system commands subunit (36), with built-in memory containing the operating system of the external parameterization device (33), which provides a graphic user interface to the authorized user and manages the hardware resources of the external parameterization device (33).

According to the embodiment of Figure 14, the external parameterization device may include a random access memory subunit (37) that interfaces with the central control unit (35). The random access memory subunit (37) allows the central control unit (35) to temporarily store information relevant to its ongoing operation, as well as manage the memory requirements of the processes embedded in the installed operating system when they are activated. The external parameterization device may include a display interface subunit (38) (Figure 14) that interfaces with the central control unit (35) and the pre-installed system commands subunit (36) containing the operating system, and serves as the interface of the authorized user with the long-term stereo-EEG device (4) for inputting and viewing information related to the system parameters.

The external parameterization device may include an external input-output subunit (39) (Figure 14) that interfaces with the central control unit (35) and the pre-installed system commands subunit (36) containing the operating system, for the purpose of exchanging local system information with authorized external devices of the manufacturer. The external parameterization device may include a battery control subunit (40) (Figure 14) that interfaces with the central control unit (35) and the pre-installed system commands subunit (36) containing the operating system, for the purpose of controlling the energy reserves of the battery of the external parameterization device (33).

Claims

1. A system for long-term intracranial stereo-electroencephalography (stereo-EEG), for determining the epileptogenic zone of a patient, comprising: an implantable long-term stereo-EEG device (4); and at least one intracranial stereo-EEG depth electrode (2) connected to the long-term stereo- EEG device (4), wherein said at least one electrode (2) is surgically implantable within the patient's brain parenchyma (1); wherein said long-term stereo-EEG device (4) is designed to perform regular EEG background recordings and priority epileptic seizure recordings in real time and transmit them in an asynchronous manner.

2. The system according to claim 1, wherein the implantable long-term stereo-EEG device (4) comprises a wireless asynchronous stereo-EEG data transmission subunit (9), which is designed to receive real-time stereo-EEG data and to transmit them in an asynchronous manner, in a process unsupervised by patients.

3. The system according to claim 1 or 2, wherein each regular or priority stereo-EEG recording is transmitted over a period that is at least two times, three times, four times, five times or six times longer in duration than that of the stereo-EEG recording.

4. The system according to claim 3, wherein each regular or priority stereo-EEG recording is performed for a period of five minutes and is transmitted asynchronously over a period of 10, 15, 20 or 25 minutes.

5. The system according to any one of the preceding claims, wherein the wireless asynchronous stereo-EEG data transmission subunit (9) is designed to process the stereo- EEG data before its transmission, in such a way that priority epileptic recordings are transmitted at highest priority whenever they are detected, and regular recordings take secondary priority.

6. The system according to any one of the preceding claims, wherein the implantable longterm stereo-EEG device (4) comprises a temperature monitoring subunit (11) which is connected to a group of one or more temperature sensors (14) placed on the chassis of the long-term stereo-EEG device and/or to another group of one or more temperature sensors (15) placed on the subunits of the long-term stereo-EEG device; and wherein said temperature monitoring subunit (11) is designed to stop the transmission of said data if the temperature exceeds predefined safety limits.

7. The system according to any one of the preceding claims, wherein the implantable longterm stereo-EEG device (4) further comprises a seizure detection subunit (8) which is designed to read the real-time stereo-EEG data in order to identify seizure patterns in the recorded stereo-EEG signals.

8. The system according to any one of the preceding claims, further comprising an external stereo-EEG data storage device (17) which is designed to wirelessly receive and store the set of regular and priority stereo-EEG recordings transmitted asynchronously from the implantable long-term stereo-EEG device (4); said storage device (17) being optionally arranged to be worn by the patient.

9. The system according to claim 8, wherein said external stereo-EEG data storage device (17) includes an alert button (19) designed to allow the patient to mark the moment of occurrence of an epileptic aura.

10. The system according to claim 9, wherein said external stereo-EEG data storage device (17) further comprises an alert recording subunit (22) which incorporates a realtime clock and is designed to record the times of aura manifestation entered by the patient by pressing the notification button (19).

11. The system according to any one of the preceding claims, wherein said system further comprises an external wireless charging device (26) designed to be wirelessly coupled to the implantable long-term stereo-EEG device (4) for non-invasive charging of its battery through electromagnetic induction.

12. The system according to any one of the preceding claims, wherein said system further comprises an external parameterization device (33), designed to be wirelessly connected to the long-term stereo-EEG device (4) in order to exchange system information with and install operating parameters in the long-term stereo-EEG device (4).