DEEP BRAIN STIMULATION: MOVING TOWARD A CLINICALLY EFFICIENT AND AVAILABLE THERAPY Peter Konrad, MD PhD Director, Functional Neurosurgery Vanderbilt University

Disclosures I will be discussing off-label use of DBS devices and technology and will indicate when this is the case Consulting: Medtronic Neurological, FHC Inc. Research support: NIH, DoD, Medtronic Neurological Financial interest: CMO, Fiduciary: Neurotargeting CMO: GSCII

Therapy that works Evidence for its effectiveness Class I data (PD primarily) Number of papers Symptomatic benefit Diseases that are presently approved Parkinson’s (1,000,000) Essential Tremor (5,000,000) Dystonia (Humanitarian Use) OCD (Humanitarian Use) PrevelancePts in treatment% Refractory% DBS candidates PD0.0036%82,98525% (20,746)70% (14,522) ET %4,14920% (830)50% (415) Dystonia0.0057%NA5-50% (3000)? (300?) * US data per National Parkinson’s Found, NINDS, Movement Disorders Society VU Regional Population: 22.8 Million

Potential for Future PAIN (Neuropathic) Depression Epilepsy Obesity Substance abuse Cluster Headaches ANY focal circuitry pathology Cingulum – Depression Ant Capsule - OCD Vim – Tremor Vc - Pain GPi – Dystonia, rigidity STN – Dyskinesia, tremor, DA effects PVG / PAG – Pain

Total Implanted DBS Patients Courtesy Medtronic Neurological TREMOR Universal frames, MER, Unilateral; Lead-IPG 8+ hours DYSTONIA (HUD) PD MRI (Asleep) Probabilistic atlas MER +/- < 4 hours Frameless; Commercial MER, Bilateral; Lead – 3D – IPG < 6-8 hours OCD (HUD)

Vanderbilt Experience Frameless 2 nd Func Nsgn Konrad Neimat

Steps towards clinical efficiency: Patient selection (Case Conference) Parkinson’s disease: Psychological co-morbidities: Gpi vs STN DA effects: STN Tremor alone vs other symptoms: Vim vs STN Essential tremor: Vim: unilateral / bilateral implant Dystonia: Gpi vs STN Cervical dystonia DYT1 Generalized Affiliated Movement Specialists Regional Population: 22.8 Million

Steps towards clinical efficiency: OR Efficiency DBS lead implantation OR time reduction (institutional cost / physician time) Imaging needs (CT versus MRI versus both) Radiology department time (MRI Guided implants) ICU versus ward admission IPG implantation (physician / institutional revenue) OR time Single versus dual IPG Rechargeable IPG (inadequate payment)

Steps towards clinical efficiency: Programming One hour per DBS lead: initial visit Several follow up visits: 30 min Need for telemetry based follow up Patient diaries (motor, QoL indexes) between visits needed to quantify effect of therapy Smart Guided programming Remote patient adjustment Quantify DBS impact on daily activity Sensor development Drug / activity diary QoL assessments Reduce time to measure and effect change

Steps towards greater availability: Referral flow Who is the prescriber of the therapy? Community Neurologist Psychiatrist? Anesthesiologist? Neurosciences center? Why would they continue to refer patients? Belief in therapy Marketing advantage among competing groups Desire for comprehensive expertise How to create Smart referrals? Educate on patient selection How to reduce unhappy end-users Improve implant management in the hands of programmer Make it easier, document effective and ineffective management strategies Reduce return rates to surgical centers for therapy re-assessments

Steps towards greater availability: Technology Leaps NANS I 3 : Forum to discuss device platform / industry needs FDA: Time to reach transformative technology release – decades Failure to demonstrate RCT evidence Enrollment need? Does RCT generate best data for device efficacy and safety? Statistical n: useful if large, normal distribution not realistic with device categories? Are devices necessarily coupled with disease? Should FDA label every approved device for a specific disease (thereby requiring every new application for disease to be retested for approved sales in the US? New Platforms needed for technology to grow. Wireless technology Body-wide Power supply for devices Biologic Interface for smaller electrodes / neural interface

2020? Evidence based targeting OR time < 2 hours Intraoperative neurophysiology +/- > 30% cases done under anesthesia Multiple leads / contacts with field shaping Smarter programming: less time, more customized therapy Atlas New patient Rigid + Non-Rigid Registration

Summary DBS is a beneficial technology: Parkinson’s disease, essential tremor, dystonia, OCD Market growth now attracts more than one company Prescribers (neurologists): becoming comfortable with technology – but poor penetration Implanting centers: sophistication emerging that improves efficiency and safety profile Future: Reduced discomfort for procedure (awake vs asleep) More robust tolerance for lead placement Wider range of applications believed