Patent Abstract:
the present invention relates to a method of prevention and treatment of narrowing of cerebral blood vessels after subarachnoid hemorrhage , and in particular , to a method of applying electrical energy through electrical stimulation electrodes particularly positioned in the cervical region of a patient to affect the sympathetic tone of the blood vessels supplying the brain .

Detailed Description:
cerebral vasospasm is a serious complication that occurs following an aneurysmal subarachnoid hemorrhage ( sah ). its presentation and demographics have already been established [ 1 , 2 ], but the complete understanding of its pathophysiology remains unclear . the aim of treatment usually is to maintain uninterrupted brain oxygenation using multimodality approaches [ 3 , 4 ]. spinal cord stimulation ( scs ) is an accepted method of treatment of chronic refractory pain due to central and peripheral problems [ 5 , 6 ]. the effects of cervical scs on cerebral blood flow ( cbf ) are well known based on experimental investigations [ 7 - 14 ], and its vasodilatory effect on peripheral arteries is widely used in clinical settings in treatment of peripheral vascular disease [ 15 ]. possible indications for the treatment of cerebrovascular conditions and brain tumors are now under investigation with initial results appearing quite promising [ 16 - 20 ]. the inventors have discovered that the location of scs along the axis of the cervical spinal cord correlates with the prophylactic and therapeutic effects of this modality on cerebral vasculature , specifically on management of the sah related arterial vasospasm . fig3 is schematic view of one embodiment of a spinal cord stimulator 30 that can be used to practice the invention . fig3 shows an electrical impulse generator 32 . the electrical impulse generator 32 may incorporate a controller or any suitable processor 38 . the electrical impulse generator 32 may be any suitable spinal cord stimulator that provides an electrical impulse to the spine . for example , electrical impulse generator 32 may comprise a single stimulation lead 34 or may comprise a plurality of stimulation leads . the electrical impulse generator 32 is operatively coupled to a stimulation lead 34 having an implantable electrode portion 36 , wherein the electrical impulse generator 32 is arranged to deliver the predetermined electrical signal to the electrode portion 36 . the implantable electrode portion 36 may be any suitable electrode including : intravascular , transcutaneous , intracutaneous , patch - type , cuff - type , tape - type , screw - type , barb - type , metal , wire , balloon - type , basket - type , umbrella - type or suction - type electrodes . guided or steerable catheter devices comprising electrodes may be used alone or in combination with the implantable electrode portion 36 . for example , a catheter comprising one or more wire , metal strips or metal foil electrodes or electrode arrays may be inserted adjacent the spine . the implantable electrode portion 36 may be oriented in any fashion along the catheter device , including longitudinally or transversely . various techniques such as ultrasound and fluoroscopy may be used to facilitate positioning of the electrodes . all or a portion of the implantable electrode portion 36 may be placed in any suitable manner for providing stimulation to the spine . the stimulation lead 34 may be placed invasively or non - invasively . in one embodiment , all or a portion of the implantable electrode portion 36 is implanted adjacent the spine . alternatively , all or a portion of the implantable electrode portion 36 is implanted adjacent specific vertebrae . as set forth in fig4 , the spinal cord is divided into specific neurological segments . the cervical spinal cord is divided into eight levels ( c1 - c8 ) and contributes to different functions in the neck and arms . in one embodiment , the implantable electrode portion 36 is implanted in the cervical spinal region at the c1 - c3 level . in another embodiment , the implantable electrode portion 36 is implanted in the cervical spinal region at the c3 - c5 level . in some embodiments , the implantable electrode portion 36 comprises a single contact so that electrical stimulation can be carried out on one specific area ( or contact point ) of the spinal cord . in some embodiments , the implantable electrode portion comprises multiple contacts ( 36 a - 36 j ) so that electrical stimulation can be carried out on more than one area ( or contact points ) of the spinal cord simultaneously or sequentially . for example , in some embodiments , a first group of contacts is disposed adjacent a first desired implant location adjacent an upper cervical spinal region of the subject and a second group of contacts is disposed adjacent a lower cervical spinal region of the subject and the electrical impulse generator 32 is activated to deliver the desired electrical signal to only the first group of contacts based on the presence of cerebral vasospasm and activating the electrical impulse generator 32 to deliver the electrical signal to only the second group of contacts based on the absence of cerebral vasospasm . in other embodiments , the electrical impulse generator 32 is activated to deliver the desired electrical signal to both the first and second groups of contacts . in one embodiment , electrical stimulation is carried out at both the c1 - c3 and c3 - c5 levels . alternatively , the implantable electrode portion 36 is / are a guided or steerable electrode which allows its position to be adjusted during the medical procedure . different electrode positions are accessible through various access openings along the spinal cord . the implantable electrode portion 36 may be positioned endoscopically through a percutaneous port , through an incision in the spine , placed on the skin or in combinations thereof . the present invention includes various electrodes , catheters and electrode catheters suitable for spinal cord stimulation . in one embodiment of the present invention , the location of the implantable electrode portion 36 is chosen to elicit maximum stimulation to the spinal cord while preventing current spread to adjacent tissues . furthermore , a non - conductive material such as plastic may be employed to sufficiently enclose the electrodes of all the configurations to shield them from the surrounding tissues and vessels , while exposing their confronting edges and surfaces for positive contact with the spinal cord , or the spinal cord coverings . in some embodiments , the electrical impulse generator 32 incorporates a neuro stimulator 42 . for example , fig3 shows a nerve stimulation lead at 44 . electrodes used to stimulate a nerve such as the vagal nerve may be , for example , non - invasive , e . g ., clips , or invasive , e . g ., needles or probes . the application of an electrical stimulus to the right or left vagal nerve may include , but is not limited to bipolar and / or monopolar techniques . different electrode positions are accessible through various access openings , for example , in the cervical or thorax regions . nerve stimulation lead 44 may be positioned through a thoracotomy , sternotomy , endoscopically through a percutaneous port , through a stab wound or puncture , through a small incision in the neck or chest , through the internal jugular vein , the esophagus , the trachea , placed on the skin or in combinations thereof . electrical stimulation may be carried out on the right vagal nerve , the left vagal nerve or to both nerves simultaneously or sequentially . the present invention may include various electrodes , catheters and electrode catheters suitable for vagal nerve stimulation to temporarily stop or slow the beating heart alone or in combination with other heart rate inhibiting agents . nerve stimulation implantable electrodes 46 may be endotracheal , endoesophageal , intravascular , transcutaneous , intracutaneous , patch - type , balloon - type , cuff - type , basket - type , umbrella - type , tape - type , screw - type , barb - type , metal , wire or suction - type electrodes . guided or steerable catheter devices comprising electrodes may be used alone or in combination with the nerve stimulation implantable electrodes 46 . for example , a catheter comprising one or more wire , metal strips or metal foil electrodes or electrode arrays may be inserted into the internal jugular vein to make electrical contact with the wall of the internal jugular vein , and thus stimulate the vagal nerve adjacent to the internal jugular vein . access to the internal jugular vein may be via , for example , the right atrium , the right atrial appendage , the inferior vena cava or the superior vena cava . the catheter may comprise , for example , a balloon which may be inflated with air or liquid to press the electrodes firmly against the vessel wall . similar techniques may be performed by insertion of a catheter - type device into the trachea or esophagus . additionally , tracheal tubes and esophageal tubes comprising electrodes may be used . nerve implantable electrodes 46 may be oriented in any fashion along the catheter device , including longitudinally or transversely . various techniques such as ultrasound , fluoroscopy and echocardiography may be used to facilitate positioning of the electrodes . if desired or necessary , avoidance of obstruction of blood flow may be achieved with notched catheter designs or with catheters which incorporate one or more tunnels or passageways . in some embodiments , the spinal cord stimulation described herein is administered to a subject in need thereof for a period of time selected from the group consisting of 30 minutes , 1 hour , 2 hours , 3 hours , 4 hours , 6 hours , 8 hours , 12 hours , 24 hours , 2 days , 3 days , 4 days , 5 days , 6 days , 7 days , 8 days , 9 days , 10 days , 11 days , 12 days , 13 days , 14 days , 15 days , 16 days , 17 days , 18 days , 19 days , 20 days , 21 days , or longer if warranted by the subject &# 39 ; s condition . the implantable electrode portion 36 may be in communication with a controller 38 as shown in fig3 . the controller 38 may thus be used to process the pulses being transmitted from the implantable electrode portion 36 . the controller 38 may store information about the pulses being generated . the controller 38 may also be used to control or monitor the level or duration of spinal stimulation that occurs . electrical impulse generator 32 may incorporate one or more switches to facilitate regulation of the various components by the surgeon . one example of such a switch is a foot pedal . the switch may also be , for example , a hand switch , or a voice - activated switch comprising voice - recognition technologies . the switch may be incorporated in or on one of the surgeon &# 39 ; s instruments , such as surgical site retractor , or any other location easily and quickly accessed by the surgeon . electrical impulse generator 32 may also include a display 40 . electrical impulse generator 32 may also include other means of indicating the status of various components to the surgeon such as a numerical display , gauges , a monitor display or audio feedback . electrical impulse generator 32 may also include one or more visual and / or audible signals used to prepare a surgeon for the start or stop of spinal cord stimulation and / or cardiac stimulation . any commercially - available spinal cord stimulator can be used as the electrical impulse generator to practice the invention . in one embodiment , the electrical impulse generator 32 is a commercially - available neurostimulation device more commonly used for the management of chronic pain and include the synergy , intrel , restore , restore - advanced , restore - prime , prime - advanced , restore - ultra , x - trel , and mattrix neurostimulation systems from medtronic , inc . the percutaneous leads and electrodes in this system are either quadripolar ( 4 contacts ), such as the pisces - quad , pisces - quad plus and the pisces - quad compact , verify , or octapolar ( 8 contacts ) such as the octad , octad compact and the octad subcompact lead - electrode system . the surgical leads themselves are quadripolar , such as the resume ii lead - electrode system , the resume tl lead - electrode system and the on - point pns lead - electrode system , or octapolar , such as the specify lead - electrode system , the 2 × 4 hinged lead - electrode system , or hexadecimapolar ( 16 contacts ), such as specify 5 - 6 - 5 lead - electrode system , to create multiple stimulation combinations and a broad area of paresthesia . these neurostimulation systems and associated lead - electrode systems are described in u . s . pat . nos . 6 , 671 , 544 ; 6 , 654 , 642 ; 6 , 360 , 750 ; 6 , 353 , 762 ; 6 , 058 , 331 ; 5 , 342 , 409 ; 5 , 031 , 618 and 4 , 044 , 774 , each of which is incorporated herein by reference . other commercially available systems that may useful for the practice of this invention as described herein include the rechargeable precision spinal cord stimulation system ( advanced bionics corporation , sylmar , calif . ; which is a boston scientific company ) which can drive up to 16 electrodes ( see e . g ., u . s . pat . nos . 6 , 735 , 474 ; 6 , 735 , 475 ; 6 , 659 , 968 ; 6 , 622 , 048 ; 6 , 516 , 227 and 6 , 052 , 624 ); the genesis , genesis xp , eon , eon mini and renew spinal cord stimulators available from advanced neuromodulation systems , inc . ( plano , tex . ; see e . g ., u . s . pat . nos . 6 , 748 , 276 ; 6 , 609 , 031 and 5 , 938 , 690 ); and the vagus nerve stimulation ( vns ) therapy system available from cyberonics , inc . ( houston , tex . ; see e . g ., u . s . pat . nos . 6 , 721 , 603 and 5 , 330 , 515 ). electrical impulse generators may also be classified based on their source of power , which includes : battery powered , radio - frequency ( rf ) powered , or a combination of both types . for battery powered electrical impulse generators , an implanted , non - rechargeable or rf - recharged battery is usually used as the source of power . the battery , an optional rf - receiving coil and the leads with their electrodes are all surgically implanted and thus the electrolytic device , other than the optional transmitting coil , is completely internal . the settings of the totally implanted electrical impulse generator can be controlled by the patient through an external magnet . the lifetime of the implant , when powered by a non - rechargeable battery , is generally limited by the duration of battery life and ranges from two to four years depending upon usage and power requirements . for rf - powered electrical impulse generators , the radio - frequency is transmitted from an externally worn source to an implanted passive receiver , which charges usually an implanted rechargeable battery , but may optionally charge a capacitor , such as an electrochemical supercapacitor . since the source of power for the transmitting coil can be the grid , or a readily rechargeable battery , or a replaceable non - rechargeable battery , the radio - frequency system provides greater power and can power electrodes generating electrochemically a greater amount or flux of the pain - relieving oxidant or its precursor ; or it can power a greater number of oxidant generating electrodes ; or it can power electrodes having a greater area at which more oxidant is generated . specific earlier disclosed examples include an electrical impulse generator that has a battery power source contained within to supply power over an eight hour period in which power may be replenished by an external radio frequency coupled device ( see , for example , u . s . pat . no . 5 , 807 , 397 , incorporated herein by reference ) or an electrical impulse generator which is controlled by an external transmitter using data signals and powered by radio frequency ( see , for example , u . s . pat . no . 6 , 061 , 596 , incorporated herein by reference ). in one embodiment , the electrical impulse generator generates an impulse frequency within the range of 2 - 3 , 000 hz . in other embodiments , the impulse frequency generated is selected from the group consisting of 2 , 5 , 25 , 50 , 100 , 150 , 200 , 250 , 300 , 350 , 400 , 450 , 500 , 550 , 600 , 650 , 700 , 750 , 800 , 850 , 900 , 950 , 1000 , 1100 , 1200 , 1300 , 1400 , 1500 , 1600 , 1700 , 1800 , 1900 , 2000 , 2100 , 2200 , 2300 , 2400 , 2500 , 2600 , 2700 , 2800 , 2900 , 3000 hz or more or any range therebetween . the superior cervical ganglion serves as the most important source of sympathetic input to the brain . although most of the ganglion is formed by branches of the first four cervical nerves , the sympathetic part is formed by preganglionic fibers that originate from the lateral column at the upper thoracic levels , leaving the spinal cord with the thoracic spinal nerves , traveling through the sympathetic chain until they reach the superior ganglion , where they synapse with postganglionic nerves [ 21 ]. accompanying the internal carotid artery , the sympathetic nerves enter the skull . because of the difference in growth rate between the spinal cord and the bony spine , the upper level of the thoracic spinal cord is located at the level of c7 . it seems quite clear that morphologic changes occur in the cerebral vessels after sah , and the inflammatory response and local chemical agents are responsible for the induction of vasospasm [ 22 ]. the sympathetic system also plays an important role in the pathogenesis of this process [ 23 , 24 ]. interestingly , this has been indirectly supported by yasargil [ 24 ] who suggested separating the vessel wall from the adventitial sympathetic nerve plexus during the surgery for aneurysm repair . naredi et al . [ 25 ] found increased sympathetic activity in patients with nontraumatic sah . the total body norepinephrine spillover into plasma was approximately 3 fold higher after 48 h compared to the control groups . further supporting this explanation for vasospasm origin , the higher levels were present between the 7th and 10th days after bleeding right around the empirically observed peak incidence of vasospasm occurrence . the numbers returned to normal in approximately 6 months of follow up . trying to decrease of influence by the environmental factors , one of the control groups was formed by patients under clinical investigation for refractory pain that underwent catheterization in the intensive care unit . the effects of cervical sympathectomy on vasospasm were demonstrated by faleiros et al . [ 26 ]. the authors submitted rabbits to sah by injection of autologous blood into the cisterna magna . the diameter of the basilar artery after the hemorrhage was analyzed by angiography in animals with bilateral sympathectomy of the superior cervical ganglion alone , bilateral sympathectomy of the superior plus inferior cervical ganglion , and control groups . the sympathectomy of the superior cervical ganglion seemed to protect the animals from vasospasm . treggiari et al . [ 23 ] performed cervical sympathetic blockade to treat nine patients with clinical cerebral vasospasm confirmed by angiography . they observed improvement in cerebral perfusion in all angiograms after the blockade , even though the caliber of the vessels did not change . the authors attributed this to a decreased peripheral resistance . one patient died of complications of initial hemorrhage and other 2 died from consequences of severe vasospasm . the main concern with the scientific explanation of the cbf augmentation with scs is the lack of clear understanding of the mechanisms for vasospasm development and resolution . it is possible that more central , medullary mechanisms are responsible for immediate vasospasm after sah [ 31 ] and for subsequent vasodilatation needed for vasospasm treatment . at the same time , pure sympathetic pathways that originate in lower cervical spinal cord or in the cervicothoracic junction and travel through the sympathetic ganglion to the cerebral vessels along the wall of the carotid arteries may be responsible for development of delayed vasospasm that results in major post - sah morbidity . the experimental and initial clinical data do support the idea that upper cervical scs facilitates cbf in patients with vasospasm and improved outcome . superior cervical sympathectomy , on the other hand , seems to prevent vasospasm from development . clinical results of takanashi and shinonaga [ 19 ] suggest possible augmentation in cbf that may be used as treatment for vasospasm , and not as its prophylaxis , contrary to what is postulated in the title of their publication . animal data seem to support this concept as well [ 11 ]. however , in order to prevent the delayed vasospasm , one needs to create functional sympathectomy , either by literally removing or blocking the sympathetic ganglia or by applying scs to the lower segments of the cervical spinal cord . based on the thorough literature review , we hypothesize that in order to prevent the sah - related delayed vasospasm , scs should target the lower cervical segments , but once the vasospasm is present , the patient may receive additional benefit and possibly improve clinical outcome by cbf augmentation and treatment of the vasospasm by stimulation of the upper cervical spinal cord . at this point it is difficult to say whether scs interacts with the lateral column of the medulla at those parameters that are normally used for pain treatment , but due to the limited data it would be impossible to exclude this possibility . benefits of vasospasm prevention have not yet been established since there were no studies comparing results in patients at risk of vasospasm that received or did not receive scs before the vasospasm starts . if this is turns to be true and poses no additional risk to the patient , dedicated placebo - controlled randomized clinical studies in humans will be required to prove our hypothesis . we suggest implanting longer electrode arrays that would cover both lower and upper cervical segments . lower cervical scs may then be used during the first 5 - 6 days after the sah for true vasospasm prophylaxis and the additional 10 - 14 days of scs to the upper cervical segments to treat vasospasm in those who develop it despite the prophylactic scs application . cervical spinal cord stimulation after acute aneurvsmal subarachnoid hemorrhage . the following example establishes the feasibility and safety of prolonged cervical spinal cord stimulation ( scs ) in the setting of acute aneurysmal subarachnoid hemorrhage ( asah ), as well as to evaluate clinical effects of cervical scs in a small group of selected asah patients . the study was undertaken in preparation for a larger scale randomized trial of scs for prevention of cerebral arterial vasospasm following asah . material and methods : a single arm non - randomized prospective study of cervical scs in asah patients was performed in university of illinois at chicago . standard percutaneous 8 - contact scs electrodes were implanted under an investigational device exemption protocol in 12 consecutive patients that satisfied the following inclusion criteria : ( 1 ) age 18 - 65 , ( 2 ) angiography - confirmed asah within 3 days prior to the electrode implantation , ( 3 ) hunt / hess ( h & amp ; h ) grade 2 - 4 , ( 4 ) fischer grade 2 - 4 , ( 5 ) no history of previous cervical spine surgery , and ( 6 ) ability to obtain informed consent from the patient or family . all electrodes were inserted using percutaneous approach under general anesthesia immediately upon completion of the definitive surgical or endovascular procedure to secure the ruptured aneurysm . scs was then delivered for the soonest of either 14 consecutive days or until the patient &# 39 ; s discharge . daily vital signs , laboratory values , transcranial doppler , computed tomography and angiography results were recorded along with the information on presence of clinical vasospasm and all interventions aimed at vasospasm prevention and treatment . results : mean age of implanted patients was 49 years ( range — 27 - 62 ), average h & amp ; h grade — 2 . 9 , average fisher grade — 3 . 3 . three had aneurysms coiled and 9 — clipped . one patient developed multisystem failure and expired on post - operative day 11 . in two patients , electrode was inadvertently pulled out on days 7 and 13 after the implantation . there were no complications related to the electrode insertion or to scs during the entire study period . the angiographic vasospasm was observed in 6 out of 12 patients , and clinical vasospasm — in 2 out of 12 ; no patient suffered any vasospasm - related neurological complication . both incidences were smaller than predicted based on the patients &# 39 ; fisher and h & amp ; h grades . conclusion : the data presented herein demonstrates that cervical spinal stimulation is both a safe and feasible approach for treatment . our data indicate that despite high level of acuity in patients after asah , general severity of medical condition , impaired level of consciousness , frequent patient re - positioning , need in multiple tests and variety of monitors , scs electrodes may be safely implanted and maintained for the two - week period . all of the above u . s . patents , u . s . patent application publications , u . s . patent applications , foreign patents , foreign patent applications and non - patent publications referred to in this specification and / or listed in the application data sheet , are incorporated herein by reference , in their entirety . from the foregoing it will be appreciated that , although specific embodiments of the invention have been described herein for purposes of illustration , various modifications may be made without deviating from the spirit and scope of the invention . 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