The present invention relates to an apparatus and methods for the treatment of brain affections like brain tumors as well as brain diseases and disorders like Alzheimer disease or Parkinson disease.

Background Art

In the last decades, the academic and clinical knowledge and understanding of brain processes and diseases have considerably improved and so have the medical and surgical treatments of such pathologies. One field of brain medicine which has particularly developed is the field of neuromodulation techniques, which consists in affecting brain areas with a physical stimulation like an electric current or a magnetic field to treat a neurological disorder. Among neuromodulation techniques, DBS (for "Deep Brain Stimulation") with electrical probes, TES (for "Transcranial Electrical Stimulation") and TMS (for "Transcranial Magnetic Stimulation") are well known and exemplified in literature.

Recently, it has been proposed in WO 2006/092061 Al implantable devices to cause lasting change in neural functions through several types of physical stimulation (mechanical impulsion on cortex, electrical deep brain stimulation, drug infusion, for neurological deficit rehabilitation). It has also been suggested in WO 2009/067323 Al devices for creating a skull/brain interface, which devices (implantable into the skull) are totally passive windows or channels permeable to external physical means (electric ionic current, radiofrequency...) in order to neuromodulate brain activity for movement disorder/epilepsy pathologies.

In the field of brain cancer treatment, such neurostimulation techniques are not efficient. The treatments applied to this pathology remain the same as those contemplated for any kind of cancer, i.e. chemotherapies and/or surgical ablation of tumors when it is possible without irreversible or lethal damaging of the brain.

Surgical treatments of the brain require open surgical procedures on the skull of patients. Such open surgical procedures comprise a craniotomy, which includes performing a bone flap.

To do so, the surgeon firstly performs a trepanation in the skull by piercing several burr holes, and secondly unsticks the durra matter underneath. After that, the surgeon then performs the craniotomy by using a saw going from one burr hole to the other. Burr holes are usually 10 to 12 mm diameter each. The fragmented bone chip of each burr hole is kept and used at the end of the surgery to fill bone defects, which suffer poor, long- term, ossification. At the end of the surgical procedure, the bone flap is repositioned and fixed either with trans-skull stitches or with titanium micro plates. The bone defect area are filled up either with a synthetic copolymer or with bone powder obtained from the drilling of the burr holes at the beginning of the procedure.

These craniotomy procedures are heavy to support for the patients and leave irreversible traumas in the skull.

Ultra keyhole surgical procedures don't require performing a bone flap, but only a burr hole. This burr hole can be very slight (4 mm diameter) in cases of stereotactic biopsy, but can be a larger (between 8 to 12 mm diameter) for endoscopic procedures required for partial ablation of tumors.

Where chemotherapeutic treatments are concerned, these treatments include administration of highly active drugs to the patients. Unfortunately, these drugs are not specifically active onto the tumors but also have considerable negative effects in the whole body of patients, with very unpleasant side-effects like nausea, hair loss etc...

For some years now, high intensity ultrasounds have shown to be a relevant physical mean to treat tumors by their capacities to thermo coagulate the tissue (high intensity ultrasounds). However, in the brain, such ultrasound treatments are by now ineffective due to the skull barrier that absorbs and diffracts ultrasounds waves.

Description of the invention

The present invention aims at providing a new way of treatments for brain tumors and other brain disorders.

The invention particularly aims at providing less traumatic methods and devices for the treatment of brain tumors and/or disorders.

Another goal of the invention further focuses on providing treatments for brain tumors and disorders, which can precisely be active at the tumors' locations in the brain with no or limited effect on the rest of the brain or body of the patient.

According to a first aspect, the invention proposes an apparatus for the treatment of a brain affection, in particular brain tumor, characterized in that it comprises at least one MRI compatible implantable generator for implantation into a burr hole performed in the skull of a patient, said implantable generator comprising:

a casing having at least an upper wall, and a lower wall connected together by a peripheral wall,

- a treating device positioned into said casing to induce brain affection treatment through its lower wall into the brain, and

means for fastening the implantable casing into the skull,

said apparatus further comprising:

a power controller to supply electricity to the treating device of the implantable generator and to set its working parameters, and

connecting means to connect the power controller and the treating device of the implantable generator. The apparatus according to the invention is dedicated to the treatment of brain diseases and disorders by means of emissions with the treating device directly into the brain. The implantable generator is designed as MRI compatible to avoid MRI acquisition distortion in order to preserve the qualities of recurrent MRI controls.

According to a first embodiment of the invention, the treating device of the apparatus comprises means for generating ultrasound waves into the brain.

Preferably, said treating device comprises at least one ultrasound transducer. Still preferably, the treating device comprises highly efficient transducers such as High-Intensity Focused Ultrasound (HIFU) ultrasound transducers.

According to another feature of the apparatus of the invention, the ultrasound transducers comprise piezoelectric elements chosen into the group formed by: piezo-composite elements, piezo-ceramic elements, C-MUT elements.

In an alternative embodiment of the apparatus of the invention, the treating device comprises at least one light emitter, such as at least one electroluminescent diode, replacing the ultrasound transducer(s) or in addition to said transducer(s).

The apparatus of the invention is designed for treating brain affections by means ultrasound and/or light waves into an area of the brain where treatment is required. To ease emission and diffusion of the ultrasound and/or light into the brain, the lower wall of the implantable casing of the apparatus is advantageously permeable to light and/or ultrasound waves.

According to another characteristic of the apparatus of the invention, said implantable generator comprises connecting plugs to accommodate the connecting means and assure connection between the power controller and the treating device.

In still a preferable embodiment of the invention, the connecting plugs are transdermic plugs held into the upper wall of the casing of the implantable generator and comprise an isolating coating preventing contact with the patient's skin.

Preferably, the connecting means comprises transdermic needles suitable for plugging into the connecting plugs through the patient's skin, said transdermic needles being coated with an isolating material except at their tip for contacting the treating device connectors through the connecting plugs.

The use of transdermic needles as electrical connections between the power controller and the implantable generator avoids MRI incompatibility issues of the apparatus of the invention. The implanted patient can be easily disconnected from the power controller to follow MRI tests during or after treatment.

According to the invention, said power controller and said connecting means are implemented into said casing and said power controller comprises wireless programmable means, and for instance radiofrequency communication means. The apparatus then also comprise advantageously a transcutaneous wireless remote control for programming and setting said wireless programmable means.

In a preferred embodiment of the apparatus of the invention, the power controller is implemented onto an electronic card or an integrated circuit.

Advantageously, said casing of the implantable generator is made of non ferromagnetic material to guaranty MRI compatibility and prevent MRI signal artefact and diffraction. Preferably, said implantable generator is made of an isolating material. Moreover, the fastening means of the casing preferably comprises tabs formed on the edge of the upper wall of said casing, the tabs comprising screw holes for receiving anchoring screws.

According to a second aspect, the invention also relates to a method for treating brain affections, characterized in that it comprises the steps of:

- performing at least one burr hole into the skull of a patient, - implanting into said at least one burr hole an implantable generator of an apparatus according to one of claims 1 to 16,

- surgically close the skin and let it heal

- when needed for a treatment procedure, connecting the implantable generator to the power controller by means of the connecting means of said apparatus,

supplying power with the power controller to said generator to activate the treating device of said generator, and

treating an area of the brain located beneath the implantable generator by emission of physical waves with the implantable generator's treating device, and

unplug the connecting means when treatment is complete. The method of the invention can be carried out at the end of a traditional neurosurgical procedure. The implantable generator is introduced in burr holes performed in the skull of a patient, when needed in holes performed for a craniotomy procedure just before the skin closure of the patient. Such generator emit physical waves such as ultrasounds and/or light for treating the brain and specifically an area of the brain previously accessed by the surgeon to treat a brain pathology, and for example a tumor. It can be used either in a thermal destruction way, particularly for tumor treatment but also at a lower energy to modulate cerebral activities in the case of brain disorder pathologies.

According to a first preferable embodiment for the method of the invention, the treating device of the implantable generator comprises an ultrasound emitting device and in that the physical waves are ultrasound focused or non focused waves transmitted to the brain for treating brain affections.

The emission of ultrasound waves proves particularly efficient in the treatment of tumors. The generator and its treating device being implanted into the patient's skull, the ultrasounds emitted in the brain are not be absorbed nor diffracted by the skull since they are positioned in the thickness of the skull it self and the waves are directed and diffused through the brain for direct treatment of tumors or other pathologies.

In a second and alternative embodiment for the method of the invention the implantable generator comprises a light emitting device and in that the physical waves are focused or non focused light waves transmitted to the brain for treating brain affections. The use of light as treating stimulus may be advantageous to address some specific diseases or trauma of the brain, which cannot be treated by ultrasounds.

With respect to the first embodiment for the invention previously presented and contemplating the use of ultrasound transducers, the method of the invention further includes, in a preferred way of implementation, the step of intravenously injecting a drug in the blood of a patient before or during ultrasound emission in the brain, said drug comprising therapeutic agents coated with ultrasound sensitive release or carrier agents, and then emitting ultrasound waves with the implantable generator into the brain once the drug treatment has diffused in the patient's blood to release the therapeutic agents only into the area of the brain to be treated.

In cases of tumor lesions, intravenous systemic chemotherapy is usually administered after surgery such as Temodal (Registered Trademark), Avastin (Registered Trademark).... Such drugs have systemic undesirable consequences. Instead of administering those drugs intravenously in the whole organism, the method of the invention proposes coating such drug with ultrasound sensitive release agents so that the drug can be released only when it enters the ultrasound field emission. By this mean, the active drug is only released in the brain area to be treated and doesn't affect the rest of the organism.

The drug injected is preferably MRI-visible so that its release within the brain can be monitored by MRI during or after the ultrasound emission treatment performed according to the method of the invention.

The possibility foreseen by the method of the invention of using an ultrasound emission together with an ultrasound sensitive drug release agent or carrier (i.e. nanoparticles) is real breakthrough in the field of brain affection treatments as it allows for the first time to reduce the shortcomings and side-effects of usual drug chemotherapeutic treatments. Indeed, ultrasound emission induces a loco regional release of drugs coated or added with ultrasound sensible release agents such as nanoparticles or liposomes for example.

Moreover, the implementation of ultrasound waves directly within the brain according to the invention allows definitive sonoporation of the underneath cerebral tissue to increase drug input.

Another advantage of the method of the invention relates to the possibility of modification of electrophysiological brain activity by mechanical stress, sonoporation, or hyperthermia through ultrasound emission for the treatment of specific brain disorders or diseases. For example, a loco regional sono-destruction or decomposition of pathological abnormal molecular deposit can be carried out by ultrasound emission according to the method of the invention for the treatment of Alzheimer disease patients.

On the practical side of the method of the invention, the axis of the burr hole drilled in the patient's skull is preferably directed towards the area to be treated in the brain.

The method of the invention also contemplates drilling several burr holes in the patient's skull, each accommodating an implantable generator, said holes and generators being positioned in a specific fashion, for example concentric fashion, with regard to the area of the brain to be treated. This helps concentrating the effects of the treatment all around the area to be treated for a better and faster efficiency of the treatment.

Preferably, positioning of the burr hole(s) and implantable generator(s) is carried out in the method of the invention by stereotaxy, for instance at the end of a regular tumor biopsy procedure, by using existing craniotomy burr hole(s). Description of the accompanying drawings

The apparatus and method of the present invention will be further described in detail below with reference to the accompanying unique Figure showing a preferred embodiment and implementation of the invention.

Description of a preferred embodiment of the invention

The enclosed Figure 1 is a section view of a human skull 1 covering the brain 2 and into which a burr hole 3 has been drilled to perform a regular craniotomy. The burr hole 3 receives an implantable generator 4 fastened to the skull 1 by means of bone screws 5. The implantable generator 4 is part of an apparatus for the treatment of brain affections, which also comprises an extraneous power controller PwC to supply electricity the implantable generator 4 and to set its working parameters, and connecting means 6 to connect the power controller PwC and the implantable generator 4.

The implantable generator 4 is formed of a casing 7 made of a MRI compatible and biocompatible material such as plastic, preferably in a cylinder shape having at least an upper wall 8 and a lower wall 9 connected by a circular peripheral wall 10. Said casing 7 accommodates a treating device 11 designed for emitting physical waves directly into the brain 2 through the lower wall 9 of the casing 7 to induce brain affection treatment. The casing 7 advantageously comprises anchorage means, for example as represented in the form of peripheral tabs 12 with hole(s) for receiving the bone screws 5 to fix the implantable generator 4 to the skull 1.

It is a very important characteristic of the present invention that said implantable generator 4 is in its entirety made of non ferromagnetic material to insure MRI compatibility and to prevent MRI signal artefact and diffraction.

The treating device 11 located in the casing 7 comprises means for emitting high intensity physical waves into the brain through the lower wall 9 of the casing when the implantable generator 4 has been positioned in the burr hole 3 in the skull 1.

In the embodiment represented in the accompanying Figure 1, the treating device 11 is made of an ultrasound generator comprising at least one, and preferably several therapy ultrasound transducers 13 applied onto the inner face of the lower wall 9 of the casing 7 of the implantable generator 4, said therapy ultrasound transducers 13 being connected by wires 14 to connecting plugs 15 fixed to the upper wall 8 of the casing 7 and into which power supply connectors 16 of the power controller PwC can fit.

According to the invention, the therapy ultrasound transducers 13 are preferably piezoelectric elements chosen into the group formed by piezo- composite elements, piezo-ceramic elements or C-MUT elements. These piezoelectric components are commonly used in the medical field to realize ultrasound transducers.

The therapy ultrasound transducers 13 and the power controller PwC are configured to allow HIFU (for High Intensity Focused Ultrasound) techniques for the treatment of brains affections, and for instance brain tumors. Such HIFU techniques provide for brain affections the same advantages as for the treatments of other tumors located in the body, i.e. rapid and precise heat treatment and/or ablation of tumorous tissues with limited heat diffusion around the focus point of the ultrasounds.

In addition to the therapy ultrasound transducers 13, the ultrasound generator can advantageously comprise at least one imaging ultrasound transducer 17 designed for echo-imaging of the brain 3, said imaging transducer 17 being connected to the power controller PwC to work at a different frequency from the therapy ultrasound transducers 13 and to produce echo-imaging onto a monitor implemented in or connected to the power controller PwC.

The therapy and imaging ultrasound transducers 13, 17 of the implantable generator 4 of the invention are not necessarily plane and they can be curved so as to easily focus the ultrasound waves they emit onto the area of the brain to be treated or imaged. Preferably, the therapy transducers 13 are positioned so that their focusing axes are all merging into a same focusing point, which is located into the imaging plane of the imaging transducer 17.

It is therefore possible with the apparatus of the invention to treat a brain affection by ultrasound emission while in the same echo-imaging the area of the brain being treated, for example to monitor correct focusing of the therapy ultrasounds emitted by the therapy ultrasound transducers 13.

The ultrasound transducers 13, 17 are connected by wires 14 to connecting plugs 15 of the ultrasound generator. These connecting plugs 15 are located within the implantable casing 7 and are adapted to accommodate connecting rods 16 from the power controller PwC to power the ultrasound transducers 13, 17.

According to the invention, the connecting plugs 15 are preferably transdermic plugs held into the upper wall 8 of the casing 7 of the implantable generator 4 and comprise an isolating coating 18 preventing contact with the patient's skin. In addition, the connecting rods 16 are transdermic needles 19. These needles are suitable for piercing the patient's skin and the upper wall 8 of the implantable casing 7 before plugging into the connecting plugs 15 inside the implantable generator 4. The upper wall 8 of the casing 7 is preferably made of an isolating concealable material 20 like Silastic®, from the silicone manufacturer Dow Coming. This material can easily and automatically reseal when the needles are withdrawn from the implantable generator 4. Thus, the upper wall 8 forms a sealing gasket between the treating device 11 in the casing 7 and the biological fluids and tissues of the patient's head.

Advantageously, the transdermic needles 19 are coated with an isolating material 21, for instance wax or plastic on their entire length except at their tip 22 so that an electric contact can be established at their tip within the connecting plugs 15 to power the implantable generator 4 without electric burns in the patient's skin. As represented in the accompanying drawing, the connecting plugs 15 are held within the casing 7 of the implantable generator 4, just beneath the upper wall 8 of the casing, formed by a thick plate of sealing material 18 or by a self-sealing membrane.

The embodiment of the invention represented in Figure 1 depicts a bipolar connection between the power controller PwC and the implantable generator 4 by two transdermic needles 19. However, unipolar connection by means of a single transdermic needle together with a ground secondary connection is also possible.

Alternatively, the invention also considers a variant embodiment into which the power controller PwC and connecting means are not separate from the implantable generator but implemented directly into the casing receiving said generator. To fulfil this design, the power controller PwC then advantageously comprises wireless programmable means and is also preferably implemented onto an electronic card or in the form of an integrated circuit including wireless communication means to be remotely controlled by an operator, surgeon, doctor, or nurse for example, who sets the working parameters of the implantable generator to perform treatment of the patient's brain by means of a transcutaneous remote control based on radiofrequency for example.

It should be noted that in the present detailed description the apparatus of the invention is described according to a preferred embodiment comprising a treating device located in an implantable casing and comprising ultrasound transducers to emit ultrasound waves into the brain to perform brain affections treatments. However, the reference to ultrasound transducers as active elements of the treating device should not be interpreted as limitative and the invention contemplates the use of other emitting techniques as a replacement of ultrasounds, and particularly the use of light emission by means, for example, of electroluminescent laser diodes positioned in the implantable generator instead of ultrasound transducers, the lower wall of the casing then being light translucent. The apparatus of the invention, as described hereinbefore, is aimed at providing a solution for treating brain affections and particularly brain tumors in complements to regular craniotomies by emitting physical waves such as ultrasound or light waves directly is the area of the brain affected. The invention therefore proposes a complementary method of treatment of such brain affections.

The method of the invention essentially consists in positioning at the end of a traditional neurosurgical procedure (craniotomy debulking or keyhole biopsy) at least one implantable generator 4 of the apparatus previously described in a burr hole 3 practised in a patient's skull 1 just before the skin closure of the patient. Alternatively, it can also be carried out without previous neurosurgical procedure. In that case, burr holes 3 are drilled directly in the patient's skull 1 with the aim of implanting the generators 4 of the apparatus of the invention. The exact positioning of the burr holes 3 to drill in the skull are then preferably determined prior to drilling by stereotaxy.

Once the implantable generator 4 has been implanted in a burr hole 3, it can be secured to the skull 1 on its edges by bone screws 5 introduced in the peripheral tabs 12 of the casing 7 containing the implantable generator 4.

The cranial skin is then sutured over the implantable generator 4 secured in the burr hole 3 and let heal before any further action.

When the skin in the patient's head has heeled, treatment of brain affections can then be carried out. To that aim, the implantable generator 4 is connected to the power controller PwC by means of transdermic needles 19 implanted through the head's skin in the upper wall 8 and connecting plugs 15 of the implantable generator 4, which is power supplied in that way. The treating device 11 in the implantable generator 4 is then activated through the power controller PwC of the apparatus, which the surgeon or practitioner carrying out the treatment has previously set to specific treatment parameters. Once the treating device 11 has been activated, physical waves are thus emitted in the patient's brain 2 to treat the brain area located just beneath the implantable generator 4 in the patient's skull.

Emission of the physical waves in the brain to complete treatment lasts a predetermined time. Once treatment is finished, the practitioner just unplugs the transdermic needles 19 from the implantable generator 4 and the patient's head.

The treatment method of the invention preferably uses ultrasounds as physical waves emitted in the patient's brain. Thus, the treating device 11 of the implantable generator preferably comprises ultrasound transducers capable of emitting, under command of the power controller, ultrasound focused or non focused waves.

Such ultrasound emission in the brain, and specifically in the area of the brain that may have been operated by the surgeon where the pathology was such as tumors, are not absorbed nor diffracted by the skull since they are positioned in the thickness of the skull 1 it self. The effect of ultrasound waves is therefore not affected by the skull and the affected brain area focused can be treated, particularly in the case of brain tumors, like any other organ pathologies already addressed by ultrasound therapy today, with corresponding effects.

The method of the invention thus allows local ablation of tissues, for instance tumorous tissues of the brain 2. It can also allow modification of electrophysiological brain activity by mechanical stress, sonoporation, or hyperthermia by ultrasound emission, or a loco regional sono destruction/decomposition of pathological abnormal molecular deposit.

In cases of tumor lesions, intravenous systemic chemotherapy is usually administered after surgery. Such drugs have systemic undesirable consequences for the patients.

To reduce these undesirable effects, the method of the invention further includes the step of intravenously injecting a drug in the blood of a patient before or during ultrasound emission in the brain, said drug comprising therapeutic agents coated with ultrasound sensitive release/carrier agents. In that way, the active drug is only released in the organism, and precisely only where the brain affection to be treated is located when ultrasound waves transmitted with the implantable generator 4 into the brain reach encounter the coated therapeutic agents which have diffused in the patient's blood. By this mean, the active drug is only released in the tumor region and doesn't affect the rest of the organism.

Moreover, ultrasound emission can also induce a loco regional release of ultrasound sensible release/carrier agents such as nanoparticles, or liposomes for example. Still preferably, if the drug injected in the patient's body is MRI-visible, its release within the brain can advantageously be monitored by MRI during or after the ultrasound emission treatment according to the method of the invention after connection of the implantable generator 4 of the apparatus of the invention to its power controller PwC. Such MRI monitoring is possible with the apparatus and methods of the invention as the implantable generator 4 doesn't contain any ferromagnetic material and the transdermic needles 19 used as connecting mains are coated with an isolating material.