Epilepsy is the most common medical neurologic disease that affects dogs, and also commonly affects people. Epilepsy is a neurological disorder involving repeated, spontaneous seizures also called fits or convulsions. These seisures are generally caused by unusually excited or interrupted electrical signals in the brain. Symptoms can vary from periods of staring or inattention, loss of consciousness or violent convulsions. The type of seizure a person has depends on a variety of things, such as the part of the brain affected and the underlying cause of the seizure.The standard epileptic drugs phenobarbital and bromide fail to adequately control close to one-third of all epileptic dogs. These dogs are referred to as refractory epileptics. Despite the introduction of several new and effective anticonvulsant drugs for dogs within the last 10-15 years, there are still limited options for treating refractory epilepsy in dogs, and many epileptic dogs are euthanized because of uncontrolled seizures combined with adverse drug side effects. A surgically implantable device that applies high frequency electrical stimulation to deep brain structures (deep brain stimulation, or DBS) has demonstrated efficacy in human epilepsy, but has not been investigated in dogs. The PI and colleagues have developed a DBS unit specifically for use in dogs with uncontrolled epilepsy.
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Research Study Proposal
Title: Evaluation of a Surgically Implantable Deep Brain Stimulator (DBS) Device in Dogs with Refractory Canine Epilepsy.
Name of Principal Investigator:
Curtis W. Dewey, DVM, MS
Department of Clinical Sciences
College of Veterinary Medicine
Ithaca, NY 14853
Idiopathic epilepsy is the most common medical neurologic disease affecting dogs, and approximately 25%-30% of these patients are refractory to the standard epileptic drugs phenobarbital and potassium bromide. Even with improved drug options for canine epilepsy today, there remains a substantial subset of epileptic dogs that have uncontrolled seizures despite treatment with multiple anticonvulsant medications. In addition to the financial and emotional burden imposed on dog owners by the need to administer multiple drugs to these patients, many of these dogs display undesirable side effects associated with this polypharmacy approach. In a recent prospective investigation, it was shown that epilepsy in dogs does have a negative impact on lifespan, similar to the situation in people. The most common reason for euthanasia of epileptic dogs is lack of drug efficacy; and the side resulting from these drugs often contributes to the decision to euthanize. Several surgical treatment options are reported in people aimed at reducing seizure frequency in refractory epileptics, the method with most promise appearing to be that of high frequency deep brain stimulation (DBS). Mechanisms via which DBS treatment may provide an anticonvulsant effect are unknown, but theories include: 1) depolarization blockade 2) synaptic inhibition 3) synaptic depression, and 4) stimulus-induced disruption/modulation of pathologic network activity (i.e., desynchronization of depolarizing shift). Based on the overwhelming success of deep brain stimulator (DBS) therapy for humans with Parkinson's disease, this modality has been applied to people with refractory seizures with promising results. In addition to the success of DBS as an antiseizure treatment method, side effects of this surgery are uncommon and mild when they occur. After several years of investigation and preparation, the PI has developed, in conjunction with a group of engineers on campus (Dr. Carl Batt's group in Stocking Hall), a surgically implantable DBS unit specifically for dogs. In addition, the feasibility of implanting the stimulating thalamic electrodes into the canine brain has been demonstrated in canine cadaver heads using CT guidance. The procedure is readily accomplished, and requires between 15 and 20 minutes of operative time. The purpose of this investigation is to evaluate the efficacy of a canine DBS unit in 10 refractory epileptic dogs. These will be dogs satisfying the criteria for idiopathic epilepsy (including brain imaging [CT or MRI] with normal results) that are receiving at least two anticonvulsant drugs (with drug levels within therapeutic range) and are experiencing more than 4 seizures per month. The 3 month pre-, and 3 month post-DBS seizure frequency will be compared. The responder rate (dogs with at least a 50% seizure reduction) will be calculated and the overall seizure reduction will be compared between time periods using a Wilcoxon signed rank test (p<0.05). For those dogs with a reduction in seizure frequency associated with DBS therapy, owners will be requested to have the DBS unit turned off (by the investigators) for an additional 3 months. If seizure frequency increases above baseline (pre-DBS “on”) period during this “off” period, the unit will be immediately turned back on. Otherwise, the seizure frequency for the DBS “off” period will be compared with that of the DBS “on” period.
Epilepsy is a very common and serious disorder of dogs. The standard epileptic drugs phenobarbital and bromide fail to adequately control close to one-third of all epileptic dogs. These dogs are referred to as refractory epileptics. Despite the introduction of several new and effective anticonvulsant drugs for dogs within the last 10-15 years, there are still limited options for treating refractory epilepsy in dogs, and many epileptic dogs are euthanized because of uncontrolled seizures combined with adverse drug side effects. A surgically implantable device that applies high frequency electrical stimulation to deep brain structures (deep brain stimulation, or DBS) has demonstrated efficacy in human epilepsy, but has not been investigated in dogs. The PI and colleagues have developed a DBS unit specifically for use in dogs with uncontrolled epilepsy. To be included in the study, dogs will have to satisfy the criteria for idiopathic epilepsy, which includes having had normal brain imaging (computed tomography [CT] or magnetic resonance imaging [MRI]). Only dogs receiving at least two anticonvulsant drugs (with steady-state levels within therapeutic range) and with average seizure frequencies of at least 4/month (with at least 12 seizures within the 3 month period immediately preceding DBS treatment) will be eligible for inclusion. Owners of potentially eligible dogs will need to have adequate pre-treatment seizure logs for at least 3 months prior to instituting DBS therapy. At the end of the 3-month period, the effectiveness of DBS therapy will be evaluated by comparing the treatment period to the previous 3-month time period. The number of “responders” (minimum of 50% seizure reduction with DBS) and the overall seizure reduction will be calculated. Any adverse side effects associated with the surgical procedure and/or stimulation will be recorded. Monthly recheck examinations will be done during the DBS treatment period, to evaluate for any potential adverse effects. On a volunteer basis, owners of dogs with seizure reduction during the 3-month DBS “on” period will be asked to have the DBS unit turned off by the investigators for an additional 3 months. If seizure frequency increases above baseline (pre-DBS “on”) period during this “off” period, the unit will be immediately turned back on. Otherwise, the seizure frequency for the DBS “off” period will be compared with that of the DBS “on” period.
Significance of Research
Refractory idiopathic epilepsy is a serious problem in dogs. Despite the increase in number of useful drugs for dogs with epilepsy over the years, many uncontrolled epileptics are euthanized because of poor seizure control often combined with adverse drug side effects. Surgical options for epilepsy in dogs have not been extensively investigated. Corpus callosotomy and brain resection are relatively impractical approaches, and vagus nerve stimulation has already been shown to be ineffective in epileptic dogs. The recently reported success of DBS therapy in human epilepsy has resulted in a large ongoing placebo-controlled prospective study in this species. If DBS therapy is successful in dogs as well, it may not only increase the lifespan of the refractory epileptic dog, but may improve the quality of life for such patients and their owners. Also, if successful, the next step would be to develop a closed or “on-demand” system that only provides electrical stimulation when an impending seizure is sensed.
Background of Research and Preliminary Work
Deep brain stimulation (DBS) has proven to be a very effective surgical treatment option for people with Parkinson’s disease. In recent years, evidence has accumulated attesting to the potential effectiveness of DBS for a variety of other brain disorders in people, including idiopathic epilepsy refractory to medical therapy. To date, all of the reports concerning DBS in human epileptics have been small uncontrolled case series. However, the positive preliminary results of these small reports (40%-90% seizure reduction) have prompted a large double-blinded, randomized prospective investigation of DBS for human epilepsy which is currently ongoing. No work has been done regarding this mode of therapy for canine epileptics. The PI and colleagues have developed a DBS unit specifically for canine use, which includes the impulse generator, lead connectors, and implantable thalamic electrodes. This device is remotely programmable once implanted, so the settings can be altered if necessary. The PI has also investigated the coordinates for thalamic electrode placement via three dimensional reconstructed CT images of canine cadaver heads. Finally, the PI has demonstrated the feasibility of thalamic electrode insertion in canine cadaver heads.
The main objective of this clinical trial is to evaluate the efficacy of a surgically implantable deep brain stimulator (DBS) unit for dogs with refractory idiopathic epilepsy. Other objectives include describing any potential side effects of DBS use in dogs as well as owner compliance with monthly recharging of the impulse generator’s battery. In addition, we intend to decrease anticonvulsant drug doses (and attendant side effects) for dogs that exhibit a substantial reduction of seizures following DBS therapy.
Description of Research Design, Methods, and/or Tools
Ten adult, client-owned dogs suffering from refractory idiopathic epilepsy will be used for this study. In addition to satisfying general criteria for idiopathic epilepsy (i.e., seizure onset between 1-5 yrs of age, normal interictal period, normal bloodwork), all dogs will require normal results of brain imaging (CT or MRI) and be experiencing a minimum average of four generalized seizures/month despite being treated with at least two anticonvulsant drugs (with serum concentrations within the therapeutic range). Owners will sign a client consent form and will also fill out a questionnaire that will inquire, among other things, whether or not the owner is considering euthanasia because of the severity of the seizure disorder. Only dogs whose owners have kept detailed seizure logs will be considered for inclusion. Each dog will be anesthetized according to standard clinical protocols and the DBS unit will be surgically implanted. Proper insertion of the thalamic electrodes will be verified by CT, and appropriate placement of the impulse generator and transcutaneous battery charger plate will be verified via postoperative skull radiographs or CT (using a spiral multi-slice scanner-no metal artifact on images). During anesthetic recovery, EEG monitoring will be used to confirm a "driving response" once the DBS unit is activated (remotely from a laptop device in the room). The DBS parameters will be set at a frequency between 90-180 Hz, in the 1-3.5 V range and modified if necessary. After 3-7 days of hospitalization (depending on rate of postoperative recovery), dogs will be sent home with their owners with instructions to catalog all seizure frequency as previously done. Owners will be instructed not to change the patients' medications for the ensuing three months unless an increase in seizure frequency is verified; if an increase in seizure frequency occurs, the DBS unit will be considered a failure and other drugs (if possible-we suspect that many if not all of these dogs will have tried all available drugs) will be attempted. Owners will also be taught how to recharge the DBS unit transcutaneously (monthly). Each dog will serve as its own control, and post-DBS seizure frequency (3 mos) will be compared with pre-DBS seizure frequency (3 mos). The number of responders (50% or more seizure reduction after DBS implant) will be recorded and the overall response to DBS therapy will be analyzed via a Wilcoxon signed rank test (p<0.05). After the 3 month evaluation period, drug reduction may be attempted in those dogs who respond. On a client volunteer basis, the dogs that did respond will have their DBS units turned off and seizures counted for a subsequent 3 mos. If seizure frequency increases during this "DBS off" period, the unit will be turned back on immediately.
Expected Outcomes and/or Potential Application(s) to Dogs
It is expected that the DBS unit will result in a significant reduction of seizure frequency in the majority of dogs that receive this therapy. If this expectation is realized, this mode of therapy will have widespread practical applicability to dogs with refractory idiopathic epilepsy.
Anticipated Problems or Obstacles
Potential exists for intraoperative (e.g., hemorrhage) and postoperative (implant-related infections). Enrolling sufficient patients within a reasonable period of time may also be a problem, but involving both Cornell and Long Island Veterinary Specialists will increase the case numbers and shorten the time to complete the study.
Curtis W. Dewey, DVM, MS (Principal Investigator)-Dr. Dewey is currently an Associate Professor of Neurology/Neurosurgery at the Cornell University Hospital for Animals. He is the chief of the Neurology/Neurosurgery service. Dr. Dewey is board-certified by the American College of Veterinary Surgeons and the American College of Veterinary Internal Medicine (Neurology). Dr. Dewey is a nationally and internationally recognized speaker. In addition to being author or coauthor on many journal articles and textbook chapters, he has also published a comprehensive textbook, entitled “A Practical Guide to Canine and Feline Neurology”, the second edition of which is due to be published in the Fall of 2008. Much of Dr. Dewey’s past and present work involves management of seizures in dogs and cats. Dr. Dewey will be in charge of the execution of this proposed project, including presentation of the resultant data at a major veterinary meeting (e.g., ACVIM Forum), and writing the manuscript for publication in a peer-reviewed veterinary journal (e.g., JAVMA).
1. Dewey CW. Anticonvulsant therapy in dogs and cats. Vet Clin Small Anim 36: 1107-1127, 2006.
2. Dewey CW. New maintenance anticonvulsant therapies for dogs and cats. In: Bonagura, JD (ed): Kirk’s Current Veterinary Therapy XIV. Philadelphia, Saunders, in press, 2008.
3. Dewey CW, Barone G, Smith K, Kortz GD. Alternative anticonvulsant drugs for dogs with seizure disorders. Vet Medicine 99: 786-793, 2004.
4. Berendt M, Gredal H, Ersboll AK, Alving J. Premature death, risk factors, and life patterns in dogs with epilepsy. J Vet Intern Med 21: 754-759, 2007.
5. McIntyre CC, Savasta M, Walter BL, Vitek JL. How does deep brain stimulation work? Present understanding and future questions. J Clin Neurophysiol 21: 40-50, 2004.
6. Andrade DM, Zumsteg D, Hamani C, et al. Long-term follow-up of patients with thalamic deep brain stimulation for epilepsy. Neurology 66: 1571-1573, 2006.
7. Kerrigan JF, Litt B, Fisher RS, et al. Electrical stimulation of the anterior nucleus of the thalamus for the treatment of intractable epilepsy. Epilepsia 45: 346-354, 2004.
8. Boon P, Vonck K, DeHerdt V, et al. Deep brain stimulation in patients with refractory temporal lobe epilepsy. Epilepsia 48: 1551-1560, 2007.
9. Benabid AL. What the future holds for deep brain stimulation. Expert Rev Med Devices 4: 895-903, 2007.
10. Pereira EAC, Green AL, Nandi D, Aziz TZ. Deep brain stimulation: indications and evidence. Expert Rev Med Devices 4: 591-603, 2007.
11. Hodaie M, Wennberg RA, Dostrovsky JO, Lozano AM. Chronic anterior thalamus stimulation for intractable epilepsy. Epilepsia 43: 603-608, 2002.
Charges per dog:
• Implant = $800.00
• Anesthesia (approximately 4 hours) = $515.00 (without propofol CRI for maintenance)
• Surgery - craniotomy $ 1020.00 plus OR suite bundle fees (approximately) $450.00
• Screws/implants = $ 242.00 per 5 screws
• Brain with or without contrast CT = CT is $534.00 plus contrast $75.00- 100.00 and room use fee $250.00 Total per dog = $884.00
• ICU fee (7 days) = $ 2300.00
• EEG = $112.00
• Recheck Appointments once a month for 6 months = $60.00 per visit ( $360.00 for 6 months)
• Sedation for radiographs on rechecks = $ 41.00 per visit ($123.00 for 3 months)
• Radiographs = $ 109.00 for 2 view skulls films ($327.00 for 3 months)
• Pharmacy = $ 206.00 (Fentanyl CRI, Fentanyl patch, cefazolin, cephalexin, gabapentin)
Total cost per dog: $7,339.00
Total Study Cost (10 dogs): $73,390.00
From the time of funding availability, it will likely take 1-2 years to gather all the pertinent information from 10 dogs. However, if statistical significance is achieved with less than this number, the project will be curtailed in order to facilitate publication of the findings. It is estimated that analysis of the data and preparation of an abstract should take no more than one month. The resultant publication for a peer reviewed journal should be ready for submission within an additional 2-3 months. The project should be complete within 2 to 4 years of funding.
Current Funding Sources for Research on Related Research Topics
None, other than faculty start-up funds at the discretion of the principal investigator.
Pending Funding Sources for Research on Proposed Topic and Related Research Topics
The PI and colleagues currently have no funding for this particular project and have used start-up funds for the preliminary work (e.g., cadaver CT surgery, DBS prototype assembly).