New advances were presented for managing epilepsy, including seizure detection devices, new drug therapies nearing approval, and emerging neuromodulation technologies. Seizure detection devices can help identify unrecognized seizures to reduce injuries, but have issues with false alarms. Promising new therapies include focal brain cooling, silk-based brain implants delivering adenosine, and convection-enhanced drug delivery directly into the brain. Emerging technologies also show potential, such as responsive neurostimulation, optogenetics, MRI-guided laser ablation, and subdural drug infusion devices. These new approaches aim to provide more targeted treatment options for drug-resistant epilepsy.

1. New Advances in the Management of Epilepsy Ruben Kuzniecky, MD Professor of Neurology Co-Director, NYU Epilepsy Center NYU School of Medicine

2. Outline Seizure Detectors New Therapies near approval Emerging treatment technologies Focal brain cooling Silk-based brain implants Convection-enhanced drug delivery Optical neural control Laser ablation Subdural drug infusion

3. Epilepsy Seizures Identification The Challenge : Many Seizures are unrecognized by Patients and Caregivers Injuries and SUDEP may be decreased by alarm systems For LRE seizures without secondary Generalization the range of unrecognized seizures is between 50% to 63%. 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. Outpatient studies using AEEG have reported unrecognized seizures ranging from 7-38%.

4. Competitive Landscape High Medium Low Outdoors Home Bed Room Reliability (Miss , FAR) Bracelet sets (under development) EpiLert(Israel) SmartWatch(US) EPI-CARE (Denmark) ~ €1,000 Medpage(UK)$495 (In the US) Vigil-Aid (Australia) ~ $ 300 Bed-mattress sets (no FDA !!) Roaming Space

5. Epilepsy Alert Devices “Epi-Care” Danish Care Technologies (sold in UK by Emfit) About Epi-Care3000 Thoroughly tested and safe alarm for seizures or motile activity at night. Memory function which saves the time of any detected seizure. Adjustable sensitivity to detect seizures on both small children and adults. Possibility of detecting smaller seizures but only to warn when major ones occur. When a seizure occurs, alarms can be transmitted wireless to a pager.

6. Epilepsy Alert Devices Epi-care retail price 1620 €

7. Radio Pager Medpage Model MP5 Epilepsy Alert Devices Medpage Seizure Alarm , Manufactured by Easylink (UK) 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. Detecting nocturnal convulsions: Efficacy of the MP5 monitor’, Seizure, April 2009 , Carlson C., Arnedo V., Cahill M., Devinsky O., 64 subjects. 5 of 8 (63%) T-C Sz were detected. 269 False positive alarms.

8. Portable Systems EpiLert by BioLert (Israel) Portable Wireless Connection Detection Algorithm for GTC Sz SmartWatch by Smart Monitor (USA) Portable Wireless Detects GTC Sz and Myoclonic Seizures

9. SmartWatch 7/8 seizures detected. Non-seizure movements detected 204 times in 40 pts Lockman J et al. Epilepsy & Behavior 2011

11. - Sz IdentificationThinkpad Laptop computer Movement Sensor Video & EEG Recording Disk Storage BioLert’s Epilepsy Alert Device Kramer U, Kipervasser S, Shlitner A, Kuzniecky R. J of Neurophysiology 2011

12. Seizure Detection Systems There is societal need for these devices Technology mature and available to integrate into GPS, mobile phones, beepers Current systems detect GTC sz. False alarm is MAIN issue for patient use Cost is likely to make it commercial May have applications for drug trials, etc

13. Medtronic SANTE Trial Stimulation of Anterior Thalamus for Epilepsy Electrodes surgically placed in the thalamus, a deep part of the brain, on both sides Stimulation every 5 minutes Strength and duration of stimulation can be adjusted Like Vagus nerve stimulator, patient can “trigger” stimulation for an aura or seizure

14. Electrode (4 contacts) Stimulating Electrode, 4 contacts

15. Results of stimulation (sham)

16. Deep Brain Stimulation Study 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. Treatment worked just as well after surgery and VNS. The infection rate was 10.9 % and the rate of asymptomatic intracranial hemorrhage was 1.3 % per lead implant. 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,

18. Electrodes are placed within the brain or rest on the brain surface in the area of the seizure focus (where seizures start).

20. RNS

21. Anthony Murro, M.D. Medical College of Georgia

22. RNS Primary Effectiveness Endpoint Results 1 p-value of group-by-time interaction in GEE model

23. Brain Cooling Project Animal Data Indicates that cooling can stop seizures in animals

25. Compared to electrical currents (ECs), thermal energy:

26. A) Has a higher therapeutic ratio (cooling does not trigger seizures)

27. B) Relies only on oneparameter (T), instead of many (frequency, amplitude, pulse width, pulse shape, etc.)

31. Progress

32. Developedimplantable fluid-based cooling and recording grid for use during invasive mapping

35. Adenosine is an endogenous anticonvulsant of the brain that terminates seizures

36. Adenosine deficiency is a pathological hallmark of epilepsy (in rodents and humans)

39. avoidance of systemic and central side effects by focal application

40. exploitation of novel pharmacological principle that is based on neurochemical rationale

41. adenosine is already FDA approved (supraventricular tachycardia)

42. silk is already FDA approved (e.g. for sutures)

43. prior experience with I.T. infusion of adenosine to treat chronic pain

44. safety, because adenosine is endogenous anticonvulsant subject to rapid metabolic clearance

45. potential for the prevention of epileptogenesis

48. CED circumvents the BBB and provides a wider, more homogenous distribution than bolus deposition (focal injection) or other diffusion-based delivery approaches

50. Convection-Enhanced Delivery — An Alternative to Epilepsy Surgery? [Rogawski MA. Convection-enhanced delivery in the treatment of epilepsy. Neurotherapeutics 2009;6:344-351.]

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

54. Large-diameter delivery cannulas used today limit efficiency, have limited precision, and can cause mechanical trauma

56. Reflux is minimized by reducing the delivery cannula diameter 5-10x

57. Capable of simultaneous electrophysiological recording and delivering light

58. Status

62. Minimally Invasive MRI-guided Laser Ablation of Epileptogenic Foci Bill Hoffman. CEO. Visualase, Inc. 713-275-2063 bhoffman@visualaseinc.com Visualase is FDA cleared for use in soft tissue. It is not FDA approved for treating any specific disease or condition.

63. Laser Ablation Procedure, in Neurosurgery 3 1 Fiber Laser fiber is placed in target tissue. Placement confirmed with MR. Target Area Thermal Ablation 2 Post-Tx MR confirms ablation zone Laser energy is delivered under MR thermography visualization.

65. Brain: early clinical experience in brain mets, NEUROSURGERY, July 2008. Follow up study submitted for publication, mid-2011

66. Prostate: several early case reports published in European Urology, several studies ongoing, multi-center trial to commence in 2011

69. Miles Cunningham, Harvard Medical School (mcunningham@mclean.harvard.edu)

70. Detlev Boison, Legacy Research Institute (dboison@downneurobiology.org)

71. Bill Hoffman, Visualase, Inc. (bhoffman@visualaseinc.com)

72. Ivan Osorio, University of Kansas Medical Center (iosorio@kumc.edu)

73. Michael Rogawski, University of California, Davis (rogawski@ucdavis.edu)

75. Why drug delivery to CNS? Many patients with refractory epilepsy are not candidates for surgery, and are not helped by AEDs It is estimated that about 200,000 patients in the U.S. are not candidates for currently available epilepsy surgery. There is still a large unmet need Because it seems to work!!!!!!!

76. From: Ludvig et al., Epilepsia 2006

77. Epidurally delivered pentobarbital can terminate focal neocortical seizures in rats 226 mM of PB

78. Suppression of focal neocortical EEG spiking in the seizure focus, in epilepsy patients (From: Madhavan, Kuzniecky et al., 2008, Epilepsy Research)

79. Design of the first generation SPD, a “hybrid neuroprosthesis”, for the treatment of focal neocortical epilepsy affecting ~ 150,000 people in US (based on US Patent #6,497,699 to Ludvig and Kovacs in 2002)

80. Device hardware & software (We consider the SPD developed if: - it is fully implantable, - it properly executes all minipump functions, - it effectively transmits/receives data and instructions, - it can be powered by a single battery for at least 4 years)

81. SPD hardware Dual minipump Subdural strip Microcontroller, side 1 Microcontroller, side 2 (From: Medveczky et al., in preparation for J. Neurosci. Meth.)

83. Frontal cortical subdural EEG recordings transmitted by the SPD RF module Ipsi- lateral 420 μV Contra- lateral sec Anesthesia during surgery Quiet wakefulness in home-cage Chewing artifacts Moving around during memory task Eating during memory task Ketamine sedation for minipump refilling Effect of subdural (ipsilat.) Ach delivery

84. Antiepileptic efficacy - it is able to completely prevent the occurrence of focal neocortical seizures, - and it can maintain this efficacy for long periods without the induction of tolerance)

85. Basic properties of the muscimol solution delivered with the SPD Amanita Muscaria— GABA A agonist

86. Termination of Ach-induced frontal cortical EEG seizures by 1.0 mM muscimol delivered via the SPD in a bonnet macaque

87. Long-term periodic muscimol delivery into the primate frontal cortex via the SPD prevents focal seizures

88. 3H-muscimol autoradiography with thionin counterstaining: coronal section from the brain of a rat subjected to epidural 3H-muscimol exposure for 1 hour (Histology/autoradiography made at NeuroScience Associates, by Dr. Robert Switzer)

89. Device safety SPD safety can be quantified if its long-term use is not accompanied with: - neurological symptoms - cognitive, emotional and motivational impairment - abnormal neocortical EEG and cell firing patterns - systemic side effects - infection)

90. Acquisition of spatial memory tasks by macaque monkeys before SPD implantation (Test described in: Ludvig et al., 2003; Behav. Brain Res.)

91. EEG effects of subdural Ach and muscimol applications with the SPD; local and systemic concentrations of the applied muscimol (HPLC assay made at Stanford Research Institute by Dr. Jacqueline Vazquez-DeRose)

92. Conclusions 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. Animals tolerate the device and drug without major problems. Many Challenges remain ahead: Engineering Safety in humans

93. Key team members in 2011 Neuroscience studies :Nandor Ludvig, M.D., Ph.D. (Program Director ) Hai M. Tang, M.D. (animal experiments) Shirn L. Baptiste, B.S. (animal experiments) Carol Novotney, D.V.M. (veterinary consultation at SUNY) Jacqueline Vazquez-DeRose , Ph.D. ( HPLC at Stanford Res. Inst.) Robert Switzer, Ph.D. (autoradiography at NeuroScience Assoc.) Engineering studies: Geza Medveczky, M.S. (hardware and software at NYU) H. Jonathan Chao, Ph.D. (hardware at NYU Poly) N. Sertac Artan, Ph.D. (hardware and software at NYU Poly) SandorToth, M.S. (hardware and software) Clinical studies: Ruben I. Kuzniecky, M.D. (epileptology) Orrin Devinsky, M.D. (epileptology) Jacqueline A. French, M.D. (epileptology) Chad Carlson, M.D. (epileptology) Neurosurgery studies: Werner K. Doyle, M.D. (implantation) John G. Kral, M.D., Ph.D., (general surgery consultation at SUNY) Industrial partners: Cygnus (control unit manufacturing) DocXS Biomedical (subdural strip manufacturing)