Ruben Kuzniecky, MD

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New Developments in Diagnosis and Treatment of Epilepsy

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  • Steve for this slide hit return every second, six times.This animates the targeting and distribution of CEDSYS.Note that infusion from each microcannula occurs simultaneously. But I could only get the program to do one injection at a time(!)
  • Ruben Kuzniecky, MD

    1. 1. New Advances in the Management of Epilepsy<br />Ruben Kuzniecky, MD<br />Professor of Neurology<br />Co-Director, NYU Epilepsy Center<br />NYU School of Medicine<br />
    2. 2. Outline<br />Seizure Detectors<br />New Therapies near approval<br />Emerging treatment technologies<br />Focal brain cooling<br />Silk-based brain implants<br />Convection-enhanced drug delivery<br />Optical neural control<br />Laser ablation<br />Subdural drug infusion<br />
    3. 3. Epilepsy Seizures Identification<br />The Challenge :<br />Many Seizures are unrecognized by Patients and Caregivers<br />Injuries and SUDEP may be decreased by alarm systems<br />For LRE seizures without secondary Generalization the range of unrecognized seizures is between 50% to 63%.<br />For Seizures that are or become GTC the rate is between 10-20%. Left Temporal lobe seizures with SGTC were unrecognized by 100% of patients in one study.<br />Outpatient studies using AEEG have reported unrecognized seizures ranging from 7-38%.<br />
    4. 4. Competitive Landscape<br />High<br />Medium<br />Low<br />Outdoors<br />Home<br />Bed<br />Room<br />Reliability (Miss , FAR)<br />Bracelet sets<br />(under development)<br />EpiLert(Israel)<br />SmartWatch(US)<br />EPI-CARE (Denmark) ~ €1,000 Medpage(UK)$495 (In the US)<br />Vigil-Aid (Australia) ~ $ 300<br />Bed-mattress sets<br />(no FDA !!)<br />Roaming Space<br />
    5. 5. Epilepsy Alert Devices<br />“Epi-Care”<br />Danish Care Technologies (sold in UK by Emfit)<br />About Epi-Care3000<br />Thoroughly tested and safe alarm for seizures or motile activity at night. <br />Memory function which saves the time of any detected seizure. <br />Adjustable sensitivity to detect seizures on both small children and adults. <br />Possibility of detecting smaller seizures but only to warn when major ones occur. <br />When a seizure occurs, alarms can be transmitted wireless to a pager.<br />
    6. 6. Epilepsy Alert Devices<br />Epi-care retail price 1620 €<br />
    7. 7. Radio Pager<br />Medpage Model MP5<br />Epilepsy Alert Devices<br />Medpage Seizure Alarm , Manufactured by Easylink (UK)<br />The Medpage® MP5 is used by hospitals, care homes and families worldwide for the detection of convulsive seizures and when used in accordance with the instructions for use will provide a fast response to on-going seizures of the Tonic-Clonic (Grand Mal) type.<br />Detecting nocturnal convulsions: Efficacy of the MP5 monitor’,<br />Seizure, April 2009 , Carlson C., Arnedo V., Cahill M., Devinsky O., <br />64 subjects.<br /> 5 of 8 (63%) T-C Sz were detected.<br /> 269 False positive alarms.<br />
    8. 8. Portable Systems<br />EpiLert by BioLert (Israel)<br />Portable<br />Wireless Connection<br />Detection Algorithm for GTC Sz<br />SmartWatch by Smart Monitor (USA)<br />Portable<br />Wireless<br />Detects GTC Sz and Myoclonic Seizures<br />
    9. 9. SmartWatch<br />7/8 seizures detected. Non-seizure movements detected 204 times in 40 pts<br />Lockman J et al. Epilepsy & Behavior 2011<br />
    10. 10. Radio Link<br /><ul><li>- Sz Recording
    11. 11. - Sz Identification</li></ul>Thinkpad<br />Laptop computer<br />Movement<br />Sensor<br />Video & EEG <br />Recording<br />Disk Storage<br />BioLert’s Epilepsy Alert Device<br />Kramer U, Kipervasser S, Shlitner A, Kuzniecky R. J of Neurophysiology 2011<br />
    12. 12. Seizure Detection Systems<br />There is societal need for these devices<br />Technology mature and available to integrate into GPS, mobile phones, beepers<br />Current systems detect GTC sz.<br />False alarm is MAIN issue for patient use<br />Cost is likely to make it commercial<br />May have applications for drug trials, etc<br />
    13. 13. Medtronic SANTE Trial<br />Stimulation of Anterior Thalamus for Epilepsy<br />Electrodes surgically placed in the thalamus, a deep part of the brain, on both sides<br />Stimulation every 5 minutes<br />Strength and duration of stimulation can be adjusted<br />Like Vagus nerve stimulator, patient can “trigger” stimulation for an aura or seizure<br />
    14. 14. Electrode (4 contacts)<br />Stimulating Electrode, 4 contacts<br />
    15. 15. Results of stimulation<br />(sham)<br />
    16. 16. Deep Brain Stimulation Study<br />Treatment worked better for people with epilepsy from the temporal lobe, and did not work as well in those with frontal, parietal and occipital epilepsy.<br />Treatment worked just as well after surgery and VNS.<br />The infection rate was 10.9 % and the rate of asymptomatic intracranial hemorrhage was 1.3 % per lead implant. <br /> There was a significantly higher incidence of spontaneously self-reported depression, memory impairment, and anxiety in the active group compared to the control group during the blinded phase,<br />
    17. 17. Responsive Neurostimulator<br /><ul><li>Designed to detect abnormal electrical activity in the brain and to deliver small amounts of electrical stimulation to suppress seizures before there are any seizure symptoms.
    18. 18. Electrodes are placed within the brain or rest on the brain surface in the area of the seizure focus (where seizures start).
    19. 19. Designed to continuously monitor brain electrical activity from the electrodes and, after identifying the "signature" of a seizure's onset, deliver brief and mild electrical stimulation with the intention of suppressing the seizure. </li></li></ul><li>RNS with Leads<br />
    20. 20. RNS<br />
    21. 21. Anthony Murro, M.D.<br />Medical College of Georgia<br />
    22. 22. RNS Primary Effectiveness Endpoint Results<br />1 p-value of group-by-time interaction in GEE model<br />
    23. 23. Brain Cooling Project<br />Animal Data Indicates that cooling can stop seizures in animals<br />
    24. 24. Focal brain cooling for seizure control<br /><ul><li>Thermal energy (cooling) abates seizures at ~ 21°C
    25. 25. Compared to electrical currents (ECs), thermal energy:
    26. 26. A) Has a higher therapeutic ratio (cooling does not trigger seizures)
    27. 27. B) Relies only on oneparameter (T), instead of many (frequency, amplitude, pulse width, pulse shape, etc.)
    28. 28. C) Is neuro-protective</li></li></ul><li>Focal brain cooling: Ivan Osorio<br /><ul><li>Objective: To lower the temperature of amygdala and hippocampus (~1 ci of brain tissue) to 16oC in 30 seconds maximum
    29. 29. Strategy: Computer-based design of optimal cooling probe using realistic real-time thermal diffusivity in brain tissue </li></li></ul><li>SAW senses brain temperature; cooling probes <br />Implantable device transmits signals to DSP and activates pump<br />External Wearable DSP receives signals, detects seizures, warns, and controls cooling probes<br />Arrays of distributed probes deliver sufficient thermal energy to decrease the temperature of amygdala and hippocampus from 37oC to 20oC in 30s. <br />Tissue disruption/loss caused by insertion of this probe is considerably less than that caused by ablative surgery. <br />The cooling probe is scalable<br />
    30. 30. Focal brain cooling: Steven Rothman<br /><ul><li>Objective: To lower the temperature of neocortical seizure focus
    31. 31. Progress
    32. 32. Developedimplantable fluid-based cooling and recording grid for use during invasive mapping
    33. 33. In dogs, the device was capable of cooling the cortical surface to the mid-20s°C</li></li></ul><li>Focal brain cooling: Steven Rothman<br />Most recent version of cooling grid for use during invasive mapping. A. View from bottom; B. View from top. <br />Fluid enters the central bladder and cools the cortex beneath the central 16 of 64 cortical contacts. Scale in A is 1 cm. <br />
    34. 34. Silk-based brain implants: Detlev Boison<br /><ul><li>Rationale
    35. 35. Adenosine is an endogenous anticonvulsant of the brain that terminates seizures
    36. 36. Adenosine deficiency is a pathological hallmark of epilepsy (in rodents and humans)
    37. 37. Adenosine augmentation prevents pharmacoresistant seizures</li></li></ul><li>Anti-ictogenic and anti-epileptogenic<br />activity of silk-based adenosine delivery<br />Implantation into fully kindled rats: <br />seizure suppression<br />Implantation before onset of kindling: <br />suppression of kindling epileptogenesis<br />Szybala et al., (2009) Exp. Neurol. 219:126-35 <br />
    38. 38. Potential advantages of this approach<br /><ul><li>long-lasting therapeutic benefit (>3 months) after short term (10 days) delivery
    39. 39. avoidance of systemic and central side effects by focal application
    40. 40. exploitation of novel pharmacological principle that is based on neurochemical rationale
    41. 41. adenosine is already FDA approved (supraventricular tachycardia)
    42. 42. silk is already FDA approved (e.g. for sutures)
    43. 43. prior experience with I.T. infusion of adenosine to treat chronic pain
    44. 44. safety, because adenosine is endogenous anticonvulsant subject to rapid metabolic clearance
    45. 45. potential for the prevention of epileptogenesis
    46. 46. silk-based adenosine delivery is also of potential use for: chronic pain, amyotrophic lateral sclerosis, Alzheimer’s disease, autism, and schizophrenia</li></li></ul><li>Convection-enhanced drug delivery<br /><ul><li>Rationale
    47. 47. Convection-enhanced delivery (CED) is a novel drug-delivery technique that uses positive hydrostatic pressure to deliver a fluid containing a therapeutic substance by bulk flow directly into the interstitial space within a localized region of the brain parenchyma</li></li></ul><li>Convection-enhanced drug delivery<br /><ul><li>Rationale
    48. 48. CED circumvents the BBB and provides a wider, more homogenous distribution than bolus deposition (focal injection) or other diffusion-based delivery approaches
    49. 49. CED could represent an alternative to resective surgery in the treatment of focal epilepsies that are resistant to oral AEDs</li></li></ul><li>x<br />x<br />
    50. 50. Convection-Enhanced Delivery — An Alternative to Epilepsy Surgery?<br />[Rogawski MA. Convection-enhanced delivery in the treatment of epilepsy. Neurotherapeutics 2009;6:344-351.]<br />
    51. 51. Convection-enhanced toxin delivery (Rogawski)<br /><ul><li>Recent results
    52. 52. A single, localized CED infusion of botulinum toxin B over a 20-minute period provided more than 2 months of seizure protection in the rat kindling model of epilepsy
    53. 53. At therapeutic doses, no untoward toxicities were observed</li></li></ul><li>Optimizing CED of drugs (Cunningham)<br /><ul><li>CED technical challenges
    54. 54. Large-diameter delivery cannulas used today limit efficiency, have limited precision, and can cause mechanical trauma
    55. 55. “Reflux” – movement of therapeutic away from the target back along the outside wall of the delivery cannula</li></li></ul><li>Optimizing CED of drugs (Cunningham): The CED SYStem (CEDSYS) solution<br /><ul><li>Array of multiple microcannulas strategically positioned to deliver therapeutic
    56. 56. Reflux is minimized by reducing the delivery cannula diameter 5-10x
    57. 57. Capable of simultaneous electrophysiological recording and delivering light
    58. 58. Status
    59. 59. Stereotactic surgical planning software and instrumentation are near completion</li></li></ul><li>SEDSYS Strategy: Miles Cunningham<br />Glioblastoma multiforme<br />Sustained Infusion<br />Conventional Delivery Cannula<br />CEDSYS microcannula array<br />
    60. 60. Optical neural control: Ed Boyden<br /><ul><li>Objective
    61. 61. Transiently silence specific targeted cells, or drive specific neurons, using light to halt seizures while minimizing side effects</li></li></ul><li>Results to date<br />II. Began primate testing –<br />no cell death or immune reaction<br />Invented optogenetics –<br />drive/silence neurons with light<br />Arch<br />Chow, Han, et al., (2010)<br />Nature 463:98-102<br />Han et al., 2009 Neuron 62(2):191-198; new manuscript in preparation.<br />Halo<br />Created wirelessly-powered prosthetics for<br />safe, long-term light delivery<br />Han and Boyden (2007)<br />PLoS ONE, 2(3): p. e299 <br />ChR2<br />Zorzos et al. (2010) Optics Letters 35(24):4133-5; two other manuscripts in preparation<br />Boyden et al. (2005) Nature Neuroscience 8(9):1263-8<br />
    62. 62. Minimally Invasive MRI-guided Laser Ablation of Epileptogenic Foci<br />Bill Hoffman. CEO. <br />Visualase, Inc. <br />713-275-2063 <br />bhoffman@visualaseinc.com <br />Visualase is FDA cleared for use in soft tissue. It is not FDA approved for treating any specific disease or condition.<br />
    63. 63. Laser Ablation Procedure, in Neurosurgery<br />3<br />1<br />Fiber<br />Laser fiber is placed in target tissue. Placement confirmed with MR.<br />Target Area <br />Thermal Ablation<br />2<br />Post-Tx MR confirms ablation zone<br />Laser energy is delivered under MR thermography visualization.<br />
    64. 64. Current Status<br /> IP: 6 Patents issued, 10 patents pending. 400k lines of proprietary code (software)<br />Regulatory: 510(K) Clearance for soft tissue ablation in neurosurgery (and other specialties)<br />Development: Product is fully developed and has been safely used to ablate ~100 brain <br /> tumors and, under IRB, to ablate Epileptogenic foci in two patients<br />Reimbursement: Significant reimbursement already exists.<br />Clinical:<br /><ul><li>General: multiple peer reviewed animal studies
    65. 65. Brain: early clinical experience in brain mets, NEUROSURGERY, July 2008. Follow up study submitted for publication, mid-2011
    66. 66. Prostate: several early case reports published in European Urology, several studies ongoing, multi-center trial to commence in 2011
    67. 67. Epileptogenic foci ablation: Several investigators have submitted protocols to IRB</li></ul>Financial: <br /><ul><li>Visualase is venture funded
    68. 68. Adequate funds through early-mid 2012, Series B funding late 2011, strategic partners and VC </li></li></ul><li>Acknowledgements<br /><ul><li>Ed Boyden, Massachusetts Institute of Technology (esb@media.mit.edu)
    69. 69. Miles Cunningham, Harvard Medical School (mcunningham@mclean.harvard.edu)
    70. 70. Detlev Boison, Legacy Research Institute (dboison@downneurobiology.org)
    71. 71. Bill Hoffman, Visualase, Inc. (bhoffman@visualaseinc.com)
    72. 72. Ivan Osorio, University of Kansas Medical Center (iosorio@kumc.edu)
    73. 73. Michael Rogawski, University of California, Davis (rogawski@ucdavis.edu)
    74. 74. Steven Rothman, University of Minnesota Medical School (srothman@umn.edu)</li></li></ul><li>Selective Therapy<br />Current Approach<br />F-16 USAF<br />GBU 28<br />Why drug delivery to CNS?<br />
    75. 75. Why drug delivery to CNS?<br />Many patients with refractory epilepsy are not candidates for surgery, and are not helped by AEDs<br /> It is estimated that about 200,000 patients in the U.S. are not candidates for currently available epilepsy surgery.<br />There is still a large unmet need<br />Because it seems to work!!!!!!!<br />
    76. 76. From: Ludvig et al., Epilepsia 2006<br />
    77. 77. Epidurally<br />delivered <br />pentobarbital <br />can terminate<br />focal neocortical<br />seizures in rats<br />226 mM of PB<br />
    78. 78. Suppression of focal neocortical<br />EEG spiking in the seizure focus,<br />in epilepsy patients<br />(From: Madhavan, Kuzniecky et al., 2008, Epilepsy Research)<br />
    79. 79. Design of the first generation SPD, a “hybrid neuroprosthesis”, for the treatment of focal neocortical epilepsy affecting ~ 150,000 people in US<br /> (based on US Patent #6,497,699 to Ludvig and Kovacs in 2002)<br />
    80. 80. Device hardware & software<br />(We consider the SPD developed if:<br /> - it is fully implantable,<br /> - it properly executes all minipump functions,<br /> - it effectively transmits/receives data and instructions,<br /> - it can be powered by a single battery for at least 4 years)<br />
    81. 81. SPD hardware<br />Dual minipump<br />Subdural strip<br />Microcontroller, side 1<br />Microcontroller, side 2<br />(From: Medveczky et al., in preparation for J. Neurosci. Meth.)<br />
    82. 82.
    83. 83. Frontal cortical subdural EEG recordings transmitted by the SPD RF module<br />Ipsi-<br />lateral<br />420 <br />μV<br />Contra-<br />lateral<br />sec<br />Anesthesia during surgery <br />Quiet wakefulness in home-cage<br />Chewing artifacts<br />Moving around during memory task<br />Eating during memory task<br />Ketamine sedation for minipump refilling<br />Effect of subdural (ipsilat.) Ach delivery<br />
    84. 84. Antiepileptic efficacy<br /> - it is able to completely prevent the occurrence of<br /> focal neocortical seizures,<br /> - and it can maintain this efficacy for long periods<br /> without the induction of tolerance)<br />
    85. 85. Basic properties of the muscimol solution delivered with the SPD<br />Amanita Muscaria— GABA A agonist<br />
    86. 86. Termination of Ach-induced<br />frontal cortical EEG seizures <br />by 1.0 mM muscimol<br />delivered via the SPD<br />in a bonnet macaque<br />
    87. 87. Long-term periodic <br />muscimol delivery<br />into the primate <br />frontal cortex via <br />the SPD prevents focal seizures<br />
    88. 88. 3H-muscimol autoradiography with thionin counterstaining: coronal section from the brain of a rat subjected to epidural 3H-muscimol exposure for 1 hour<br />(Histology/autoradiography made at NeuroScience Associates, by Dr. Robert Switzer)<br />
    89. 89. Device safety<br /> SPD safety can be quantified if its long-term use is not accompanied with:<br /> - neurological symptoms<br /> - cognitive, emotional and motivational impairment<br /> - abnormal neocortical EEG and cell firing patterns<br /> - systemic side effects<br /> - infection)<br />
    90. 90. Acquisition of spatial memory tasks by macaque monkeys <br /> before SPD implantation <br />(Test described in: Ludvig et al., 2003; Behav. Brain Res.)<br />
    91. 91. EEG effects of subdural Ach and muscimol applications with the SPD;<br />local and systemic concentrations of the applied muscimol<br />(HPLC assay made at Stanford Research Institute by Dr. Jacqueline Vazquez-DeRose)<br />
    92. 92. Conclusions<br />In its present state, the muscimol-delivering SPD implant can prevent focal neocortical seizures in primates for many months without apparent side-effects or tolerance.<br />Animals tolerate the device and drug without major problems.<br />Many Challenges remain ahead:<br /> Engineering<br /> Safety in humans<br />
    93. 93. Key team members in 2011 <br />Neuroscience studies :Nandor Ludvig, M.D., Ph.D. (Program Director ) <br />Hai M. Tang, M.D. (animal experiments)<br />Shirn L. Baptiste, B.S. (animal experiments)<br /> Carol Novotney, D.V.M. (veterinary consultation at SUNY)<br /> Jacqueline Vazquez-DeRose , Ph.D. ( HPLC at Stanford Res. Inst.)<br /> Robert Switzer, Ph.D. (autoradiography at NeuroScience Assoc.)<br />Engineering studies: Geza Medveczky, M.S. (hardware and software at NYU)<br /> H. Jonathan Chao, Ph.D. (hardware at NYU Poly)<br /> N. Sertac Artan, Ph.D. (hardware and software at NYU Poly)<br />SandorToth, M.S. (hardware and software)<br />Clinical studies: Ruben I. Kuzniecky, M.D. (epileptology)<br /> Orrin Devinsky, M.D. (epileptology) <br /> Jacqueline A. French, M.D. (epileptology) <br /> Chad Carlson, M.D. (epileptology) <br />Neurosurgery studies: Werner K. Doyle, M.D. (implantation) <br /> John G. Kral, M.D., Ph.D., (general surgery consultation at SUNY)<br />Industrial partners: Cygnus (control unit manufacturing)<br />DocXS Biomedical (subdural strip manufacturing)<br />

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