1 1...motor frontal (2 cm) 1.3 (yrs) 100% 3 20 focal cortical dysplasia left parietal focal cortical...

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Clinical Compendium

22

1. Nair et al., Presented at AES 2018.

2. Estimates for longevity were derived from medium stimulation utilization (mAh/day) found in the clinical trial.

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Personalized therapy at the neural level

28% of patients achieved seizure freedom for ≥ 6 months1

> 8 year battery life with theNext-Gen RNS® System2

44

Unprecedented insight, now with > 8 year battery life

THE NEXT-GEN RNS SYSTEM

World’s only brain-responsive neurostimulator

Simpler, faster access to Your Window to the Brain™

• Twice the battery life

• Twice the data

THE RNS NEUROSTIMULATOR (RNS-320) THE RNS TABLET

544

Specific CPT® Code for ECoG Review with the RNS System, starting in 2019

AES Information Sessions: Saturday & Sunday @ 10:00am (Room 341, 3rd Floor)

2019 RNS SYSTEM CPT® CODING UPDATE

NEW code for ECoG review from an implanted brain neurostimulator

• Only applicable to the RNS System at this time

• Providers can bill separately for ECoG review

• Coding guidelines allow the code to be billed once per patient per 30 days, when medically necessary

Programming codes are changing for neurostimulators

• Two new programming codes for the RNS System (will replace current coding)

For more information, contact our reimbursement manager: Allie D’Accurzio (650) 933-3047 adaccurzio@ neuropace.com

New!

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TABLE OF CONTENTS

SECTION 1

Largest Prospective Study in the History of Neuromodulation1:

Long Term Outcomes from 9 Year Prospective Study

SECTION 2

Novel Approaches for Treating Epileptogenic Zones:

Neocortical Broad Onsets

Neocortical Onsets with Depth Leads

Partial Resection + RNS

Lateralization for MTL Resection

SECTION 3

Discovery of Potential ECoG Biomarkers:

Correlates of Clinical Seizures

Forecasting Clinical Seizures

Correlates of Cognition

Correlates of Depression

SECTION 4

Presentation Schedules:

Innovation Pavilion

Posters

Relevant Special Interest Groups

1. The RNS System Long-Term Treatment (LTT) Study represents the largestprospective clinical study in the field of neuromodulation with 9 year follow-up data

Largest P

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SECTION 1

Largest Prospective Study in the History of Neuromodulation1

8

SUMMARY:

• Study includes >1,895 patient implant years

• 75% median seizure reduction and a responder rate of 73% (≥50% reduction in seizures)

• 28% of patients seizure free for 6 months or longer at some time over the 9 years

• 35% had a ≥90% reduction in their seizures during their last 6 months of follow-up at 9 years

• Sustained significant improvements in Overall QOL, Epilepsy Targeted and Cognitive subscales

• Treatment remained safe over time with a risk of infection of 4.1% per procedure

SIGNIFICANCE:

This is the largest multicenter prospective study in the field of neuromodulation with 9-year follow-up data, and supports the long-term efficacy and safety of the RNS System for treatment of medically intractable focal seizures

Nine-year prospective safety and effectiveness outcomes from the long-term treatment trial of the RNS System

LARGEST PROSPECTIVE STUDY IN THE HISTORY OF NEUROMODULATION

Dileep Nair, RNS System Investigators

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Median Percent Reduction in Seizure Frequency & Responder Rate

Year 3

Res

po

nder

Rat

e (+

/- 9

5% C

I)

≥35% of subjects had ≥90% reduction in seizures at 9 years

At Least 90-days Diary Data

Constant Cohort

n=21

2

0

100

90

80

70

60

50

40

30

20

10

n=19

9

n=19

0

n=17

8

n=16

3

n=16

3

n=14

7

n=16

0

n=15

9

n=15

7

n=15

6

n=15

5

n=15

7

n=15

4

Year 4 Year 5 Year 6 Year 7 Year 8Year 3

Med

ian

% R

educ

tio

n in

Sei

zure

F

req

uenc

y (+

/- IQ

R)

n=21

2

0

-100

-90

-80

-70

-60

-50

-40

-30

-20

-10

n=19

9

n=19

0

n=17

8

n=16

3

n=16

3

n=14

7

n=16

0

n=15

9

n=15

7

n=15

6

n=15

5

n=15

7

n=15

4

Year 4 Year 5 Year 6 Year 7 Year 8 Year 9 Year 9

No

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SECTION 2

Novel Approaches for Treating Epileptogenic Zones

12NOVEL APPROACHES FOR TREATING EPILEPTOGENIC ZONES Neocortical Broad Onsets

SUMMARY:

• Neocortical seizure onsets localized toone “regional” (broad) area of cortex aredifficult to treat with resective surgery

• 12 patients who had one “regional”seizure onset zone were treated withthe RNS System at UCSF. The twodepth and/or cortical strip leads wereon average 3.3 cm apart (range: 1.2cm -6.0cm).

• An 80% median percent seizurereduction and a responder rate (≥50%reduction) of 83% was achieved

RNS System treatment in patients with regional neocortical seizure onsetsBrandy Ma, Emily Mirro, Robert Knowlton, Edward Chang, Vikram Rao

This is a retrospective review.

No

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1312RNS System Patient Example Showing Lead Placement & Regional Onset Zones

Seizure onset zone

Subdural grid electrode

Resection

NeuroPace Cortical Stip Lead electrode

Seizure Reduction for 12 Regional Onset Patients Treated with the RNS System

Patients who had concurrent resection

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SUMMARY:

• Depth leads can be the preferred RNS System lead placement strategy for neocortical seizure onsets when cortical strip leads are not feasible or the localization was done with Stereo EEG depth electrodes

• Sixteen (16) patients were implanted using this method in multiple different areas of the neocortex

• Patients who had 6 months or greater follow-up data (13/16) had a median seizure frequency reduction of 65% (mean: 59%, range: 0-100%)

• There were no functional deficits as a result of placing depth electrodes, and there were no side effects from neocortical responsive brain stimulation from the RNS System

Anatomic early electrographic seizure onset localization and clinical response with responsive neurostimulation of depth leads placed in neocortex Allen Ho, Jonathon Parker, Emily Mirro, Babak Razavi, Kai Miller, Dora Hermes, Matthew Markert, Gerald Grant, Jaimie Henderson, Casey Halpern

NOVEL APPROACHES FOR TREATING EPILEPTOGENIC ZONES Neocortical Onsets with Depth Leads


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Depth Lead Implant Locations (n=31)

Occipital Depth Lead Entry CT-MRI Fusion

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BACKGROUND:

• The RNS System can be used concurrently with a resection such that treatment is extended to an unresectable area of the seizure focus

• Three patients at Stanford had a concurrent resection with RNS placement

RESULTS AFTER INITIATION OF RNS SYSTEM THERAPY:

• All three patients had electrographic and clinical seizures after resection

• Two patients became seizure free and the third patient reported less frequent (62.5% reduction) and less severe seizures

• In these cases, the RNS System provided an additional response to complement a palliative resection

Concurrent resection and RNS System placement: 3 casesBabak Razavi, Emily Mirro, Lawrence Shuer

NOVEL APPROACHES FOR TREATING EPILEPTOGENIC ZONES Partial Resection & RNS


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ETIOLOGY MRI RESULTS

NEUROPACE LEAD

LOCATION

LOCATION OF PARTIAL RESECTION

DURATION OF RNS SYSTEM TREATMENT

% SEIZURE

REDUCTION*

1 26Focal

Cortical Dysplasia

Right Parietal Focal Cortical Dysplasia Type

IIb

Sensory Parietal 1.3 (Yrs) 100%

2 20Focal

Cortical Dysplasia

Left Frontal Focal Cortical Dysplasia Type

IIb

Motor Frontal (2 cm) 1.3 (Yrs) 100%

3 20Focal

Cortical Dysplasia

Left Parietal Focal Cortical Dysplasia Type

Ia

MotorLeft parietal (up to motor

strip)1.4 (Yrs) 62.50%

PAT

IEN

T

AG

E

*Compared to pre-RNS System treatment baseline

Results After Initiation of RNS System Therapy

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BACKGROUND:

• After bilateral MTL ambulatory monitoring with the RNS System, 21 patients at 17 epilepsy centers had MTL resections

• The average time treated with the RNS System before resection was 42 months (range: 8-117 months), and average post-resection follow-up was 37 months (range: 7-101 months)

RESULTS:

• The median seizure reduction for all 21 patients was 100% (mean: 90%, range: 50-100%)

• 15 of 21 patients (71%) were free of clinically reported disabling seizures

• 8 of the 15 seizure free patients had only unilateral seizure onsets stored by the RNS System prior to resection, and the remaining 7 had bilateral seizures with an average of 90% from the resected side

• 19/21 patients continued to be treated with the RNS System

CONCLUSION:

Long-term ambulatory ECoG monitoring of bilateral mesial temporal lobes with the RNS System can potentially lead to an efficacious resective or ablative procedure

Outcomes after mesial temporal lobe resection following long-term ambulatory recording by the RNS System

NOVEL APPROACHES FOR TREATING EPILEPTOGENIC ZONES Lateralization for MTL Resection

Lawrence Hirsch, Emily Mirro, Vincenta Salanova, Cornelia Drees, Mesha-Gay Brown, Ricky Lee, Toni Sadler, Elizabeth Felton, Paul Rutecki, Hae Won Shin, Eldad Hadar, Manu Hegde, Vikram Rao, Lilit Mnatsakanyan, Deepak Madhavan, Terek Zakaria, Anli Liu, Christianne Heck, Janet Greenwood, Jeffrey Bigelow, Dileep Nair, Andreas Alexopoulos, Jonathan Edwards, Nadia Sotudeh, Ruben Kuzniecky, Ryder Gwinn, Michael Doherty and Martha Morrell


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SECTION 3

Discovery of Potential ECoG Biomarkers


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BACKGROUND:

• RNS System “Long Episodes” are eventsthat include prolonged detected activity,frequently electrographic seizures

• This analysis evaluated Long EpisodeECoGs stored by the RNS System forpatients in whom the Long Episodes werevalidated as electrographic seizures

• Long Episode timing was compared toclinical seizure diary reports in 124 patients

RESULTS:

• Long Episode and clinical seizure eventstended to co-occur, suggesting that,for some patients, the RNS System mayprovide an objective assessment ofclinical seizure burden

Electrographic events recorded by a responsive neurostimulator may provide an objective assessment of clinical seizure burden

DISCOVERY OF POTENTIAL ECOG BIOMARKERS Correlates of Clinical Seizures

David Spencer, Mark Quigg, Nathan Fountain, Beata Jarosiewicz, Tara Skarpaas, Martha Morrell


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Figure 1: Cross-correlation between Long Episodes (LEs) and patient-reported clinical seizures (CSs) in all patients

Figure 1: All Patients

Patient 3: LE:ES Concordance = 0.90

Co

rrel

atio

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effici

ent

Dai

ly S

eizu

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oun

tD

aily

Sei

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Co

unt

LE C

oun

tLE

Co

unt

Time lag (days)

1

-10 10-5 50

0.5

0

-0.5

LEs after seizuresLEs before seizures

Days

Days

Patient 2: LE:ES Concordance = 0.50

Patient 2: Moderate relationship between LEs and CSs and low concordance between LEs and electrographic seizures (ESs)

Patient 3: Good relationship between LEs and CSs and high concordance between LEs and ESs

22

BACKGROUND:

• Recent studies using chronic intracranial ECoGhave yielded evidence that epilepsy is a cyclicaldisorder

• Using chronic ECoG from the RNS Systemand clinical seizure diary reports, interictalepileptiform activity (IEA) cycles were analyzedfor 16 RNS System patients

RESULTS:

• All patients were found to have circadian andmulti-day (“multidien”) IEA cycles, the latterwith patient-specific periodicities ranging from7 to 33 days

• This extends previous findings on the phase-relationship between electrographic seizuresand IEA cycles recorded with chronic ECoG byshowing that a similar relationship exists forclinical seizures

• This small series corroborates an emerging viewthat suggests seizures are not random events,and suggest that it may be possible to forecastclinical seizure risk on the scale of days withdata obtained from the RNS System

Clinical seizures cluster in relation to cycles of interictal epileptiform activity Maxime Baud, Thomas Tcheng, Vikram Rao

DISCOVERY OF POTENTIAL ECOG BIOMARKERS Forecasting Clinical Seizures


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Twenty months of IEA data from one representative patient showing IEA cycles in relation to clinical seizure reports is shown in (a) and (b). Then Figure (c) shows a significant phase locking of clinical seizures occurring in the upward peak of these IEA cycles.

24

BACKGROUND:

• Brain-responsive neurostimulation was provento not cause neurocognitive deficits and topossibly improve neuropsychological functionassociated with the area being treated (Loringet al., Epilepsia 2015)

• Improvements in neuropsychological functionwere not correlated with changes in clinicallyreported seizures, but higher verbal memoryscores were associated with lower left temporalspikes (Loring et, al, AES, 2017). This analysisexamines other electrographic features thatcould be possible biomarkers for cognitiveimprovement.

RESULTS:

• For neocortical patients, changes over timein delayed recall (AVLT and BVMT) wereinversely correlated with alpha power anddirectly correlated with beta power

• In contrast, for patients with MTL epilepsy,changes in cognitive scores (BVMT) over timewere directly correlated with theta powerand inversely correlated with low and highgamma power

David Loring, Kimford Meador, Beata Jarosiewicz, Tara Skarpaas, Martha Morrell

Interictal ECoG features correlate with cognitive outcomes in individuals with epilepsy

DISCOVERY OF POTENTIAL ECOG BIOMARKERS Correlates of Cognition


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BACKGROUND:

• Patients treated with the RNS System showed an improvement in the presence and severity of symptoms of depression in the clinical trials (Meador et al., Epilepsy & Behavior 2015)

• Changes in Beck Depression Inventory (BDI-II) mood scores and ECoG features over time were assessed to determine if there was an associated electrographic biomarker

RESULTS:

• Analysis of RNS generated electrographic data revealed that changes in mood suggestive of depression were associated with higher theta power overall, higher interictal spike rates in the neocortex, and lower gamma power in the MTL

• These electrographic features could potentially be targeted with brain-responsive neurostimulation to improve mood

Interictal ECoG features correlate with depression in individuals with epilepsyBeata Jarosiewicz, Tara Skarpaas, David Loring, Kimford Meador, Andres Kanner, and Martha Morrell

DISCOVERY OF POTENTIAL ECOG BIOMARKERS Correlates of Depression


2626

SECTION 3

Presentation Schedules

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SATURDAY, DEC. 1

Welcome12:30–12:40pm

(10 min)Martha Morrell, MD

Final Results of the NeuroPace 9-year Long Term Treatment Trial

12:40–12:55pm (15 min)

Dileep Nair, MD

Impact of Treatment with the RNS System on Neurocognition and Mood

12:55–1:10pm (15 min)

Martha Morrell, MD

RNS System in Combination with Other Epilepsy Therapies

1:10-1:25pm (15 min)

Lawrence Hirsch, MD

Q&A Discussion1:25–2:00pm

(35 min)All

SUNDAY, DEC. 2

Welcome12:30–12:40pm


Potential Biomarkers of Epilepsy12:40-1:00pm


Insights into Seizure Timing1:00–1:20pm

(20 min)Vikram Rao, MD, PhD

Q&A Discussion1:20–1:30pm

(10 min) All

Innovation Pavilion

28

PRESENTATION TITLE AUTHOR DATE POSTER #

Lateralization for MTL resection Hirsch et al Dec. 1 1.336

Correlates of Depression Jarosiewicz et al Dec. 2 2.046

MTLE SZ Onset Morphology Nune et al Dec. 2 2.048

Correlates of Cognition Loring et al Dec. 2 2.049

Seizure Forecasting with Recurrent Neural Networks

Arcot Desai et al Dec. 2 2.05

MTLE Lateralization Weber et al Dec. 2 2.051

Scientific Posters

Posters are located in the Convention Center, Hall H, First Floor

2928P

resentation S

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4

PRESENTATION TITLE AUTHOR DATE POSTER #

Forecasting Clinical Seizures Rao et al Dec. 2 2.052

Neocortical Broad Onsets Ma et al Dec. 2 2.073

Long Term Outcomes from 9 Year Prospective Study

Nair et al Dec. 2 2.075

Neocortical Onsets with Depth Leads

Ho et al Dec. 2 2.076

Partial Resection + RNS Razavi et al Dec. 2 2.315

Correlates of Clinical Seizures Spencer et al Dec. 3 3.092

SPECIAL INTEREST GROUP LOCATION DATE TIME

SEEGConvention Center

Room 281Nov. 30 6:00PM-7:30PM

Engineering/NeurostimulationConvention Center

Room 195Dec. 1 7:00AM-8:30AM

Epilepsy SurgeryConvention Center

Room 261Dec. 1 7:00AM-8:30AM

Scientific Posters

Relevant Special Interest Groups

30

Indication for Use

The RNS® System is an adjunctive therapy in reducing the frequency of seizures in individuals 18 years of age or older with partial onset seizures who have undergone diagnostic testing that localized no more than 2 epileptogenic foci, are refractory to two or more antiepileptic medications, and currently have frequent and disabling seizures (motor partial seizures, complex partial seizures and / or secondarily generalized seizures). The RNS® System has demonstrated safety and effectiveness in patients who average 3 or more disabling seizures per month over the three most recent months (with no month with fewer than two seizures), and has not been evaluated in patients with less frequent seizures.

Contraindications

The RNS® System is contraindicated for patients at high risk for surgical complications, with medical devices implanted that deliver electrical energy to the brain, and those who are unable (or do not have the necessary assistance) to properly operate the NeuroPace® Remote Monitor or Magnet. For patients with an implanted RNS® System the following medical procedures are contraindicated:

• Magnetic Resonance Imaging (MRI) --The RNS® System is MR Unsafe

• Electroconvulsive Therapy (ECT)

• Transcranial Magnetic Stimulation (TMS)

• Diathermy procedures (any treatment that uses high-frequency electromagnetic radiation, electric currents or ultrasonic wavesto produce heat in body tissues)

Warnings and Precautions

The RNS® System is not compatible with non-NeuroPace leads and/or pulse generators. Electrical shock may occur with incorrect use of the Programmer or Remote Monitor. Do Not Resterilize and Do Not Reuse the implantable products.

Clinical Use

The RNS® System should only be implanted at Comprehensive Epilepsy Centers by neurosurgeons with adequate experience in the implantation of subdural and stereotactic implantation of intraparenchymal electrodes and in the surgical treatment of intractable epilepsy. The RNS® System should only be used by neurologists and neurosurgeons with adequate experience in the

management of intractable epilepsy and in the localization of epileptic foci. They must complete a NeuroPace® RNS® System training program and demonstrate specific expertise related to epilepsy, video-EEG monitoring, interpretation of electrocorticograms (ECoGs), the pharmacology of antiepileptic medications and selection of patients for epilepsy surgery. In some instances Neurologists who meet the experience and certification requirements but do not practice at Comprehensive Epilepsy Centers could be qualified by NeuroPace to provide post-implant programming.

Surgical

Implantation of the RNS® System and associated surgical procedure risks may cause, but are not limited to, infection, intracranial hemorrhage, tissue damage, temporary pain at the implant site, CSF leakage, seroma, and paralysis.

RNS® System and Therapy

The safety and effectiveness has not been studied in pregnant women. The effects of long-term brain stimulation are not completely known. Strong electromagnetic interferences (EMI) can result in serious patient injury or death, damaged brain tissue, loss or change in symptom control,

NEUROPACE® RNS® SYSTEM BRIEF STATEMENT

3130N

euroP

ace® RN

S® System

Brief S

tatement

Refer to the product labeling for a detailed disclosure of specific indications,

contraindications, warnings, precautions and adverse events.

© 2018 NeuroPace, Inc. All rights reserved. NeuroPace and RNS are trademarks of NeuroPace, Inc.

NeuroPace, Inc. 455 N. Bernardo Ave. Mountain View, CA 94043. NP 180218 Rev 1 / Rev. date: 2018-11

reoperation, stimulation to turn on or off, a return of symptoms, or a momentary increase in stimulation felt by the patient. In addition EMI, such as security screening devices and radio frequency identification, can result in delivering the programmed stimulation to the patient and appear as sensing artifacts on the ECoG recordings. The RNS® System could interact with implanted cardiac devices and result in inappropriate device response or device damage. Additional surgical procedures can result from battery malfunction, electrical short, open circuit, lead fracture, lead insulation failure, damage as a result of head trauma, or lead migration. Severe brain tissue damage can result from exposure to battery chemicals if the Neurostimulator is ruptured or pierced due to outside forces. The patient must collect data from the Neurostimulator once a day and send data to the PDMS once a week.

Medical Environment

Electrolysis on the head and neck should be avoided. Prior to the administration of Extracorporeal Shock Wave Lithotripsy or high radiation sources the administering physician should consult with the physician prescribing the RNS® System. Read the user manual to understand the steps to be taken before, during and after computerized Tomography (CT) scans.

Potential Adverse Events

Serious adverse events occurring in ≥ 2.5% of patients and those of particular relevance reported during the RNS® System clinical studies include EEG monitoring, infection, change in seizures, medical device removal, death, device lead damage or revision, antiepileptic drug toxicity, hemorrhage, psychiatric events, status epilepticus and seizure-related injury. Refer to the product labeling for a detailed disclosure of other reported adverse events.

NEUROPACE® RNS® SYSTEM BRIEF STATEMENT

32

© 2018 NeuroPace, Inc. All rights reserved. NeuroPace and RNS are trademarks of NeuroPace, Inc.

NeuroPace, Inc. 455 N. Bernardo Ave. Mountain View, CA 94043. NP 180218 Rev 1 / Rev. date: 2018-11

Clinical Compendium

1 1...motor frontal (2 cm) 1.3 (yrs) 100% 3 20 focal cortical dysplasia left parietal focal cortical...

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