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Surgical Innovations forTreating Epilepsy
Epilepsy Foundation of Arizona
Angus A Wilfong, MDFebruary 09, 2019
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Research Funding NIH/NINDS
OVID
GW Pharma
Marinus
Zogenix
Consultant LivaNova
Sunovion
Publication Royalties Up-To-Date
Patents Held Cannabidiol for FIRES
DSMB Member SLATE Trial – SLA for MTS
Disclosures
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Migraine
Parkinson’s disease
Muscular dystrophy
Autism
Stroke
Multiple sclerosis
Alzheimer’s disease
Epilepsy
Potentially Curable Neurologic Conditions
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Migraine
Parkinson’s disease
Muscular dystrophy
Autism
Stroke
Multiple sclerosis
Alzheimer’s disease
Epilepsy
Potentially Curable Neurologic Conditions
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Antiepileptic drugs (AEDs) - >30!
Epilepsy surgery
Resective
Ablative
Disconnection
Ketogenic and other diets
Neuromodulation
Vagus Nerve Stimulation (VNS - SenTiva™)
Responsive Neurostimulation (RNS - NeuroPace®)
Deep Brain Stimulation (DBS)
Treatment of Epilepsy 2019
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Mohanraj R and Brodie MJ. Eur J Neurol. 2006;13:277-282
50%
11%4%
35%
Seizure Free with FirstDrug
Seizure Free withSecond Drug
Seizure Free with ThirdDrug or multiple drugs
Refractory Population
• After adequate trials of at least 2 AEDs, overall seizure-free rates with subsequent treatment trials are dramatically decreased
n=780
Refractory Epilepsy
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Recurrent seizures/side effects (44%)
No answer (2%)
Recurrent seizures/no side effects(19%)
No seizures/side effects (17%)
Not taking AED (3%)
No seizures/no side effects (15%)
(N=760)
Report of a Roper Poll of Patients on Quality of Life. Research Triangle Park, NC: GlaxoWellcome; 1999
Living with Epilepsy
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Kwan P, et al. Epilepsia 2009; doi: 10.1111/j.1528-1167.2009.02397.x Gilliam F. Neurology 2002;58:s9-s19. Wheless JW. Neurostimulation Therapy for Epilepsy. In: Wheless JW, Willmore LJ, Brumback RA, eds. Advanced Therapy in Epilepsy. Hamilton, Ontario: BC Decker, Inc. 2008. Faught E, et al. Epilepsia 2009;50(3):501-509.
AED Trial 1 Monotherapy
Treatment Goal
• Seizure freedom
Treatment Goal
• Maximize quality of life
• Optimize Long-term seizure control
• Minimize AED side effects
• Maximize adherence
AED Trial 2 Monotherapy or Polytherapy
Newly Diagnosed Refractory Epilepsy
Epilepsy Surgery
EEG/Video monitoring
AEDs (Polytherapy) Ketogenic Diet
Neuromodulation
Treatment Goals for Epilepsy
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>1,000,000 people (35%) in US with refractory epilepsy
~3000 epilepsy surgeries per year
~4000 VNS/RNS implantsper year
A substantial number of people do not receive adequate treatment
Epilepsy prevalence in US ~3.4 million
Average duration of refractory epilepsy~20 years at time of surgery
- 150,000 new casesof epilepsy each year- 50,000 new cases ofintractable epilepsy peryear
Treatment Gap for Refractory Epilepsy
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Outcome (Class I evidence)
Wiebe, Blume, et al (NEJM 2001)
RCT: Epilepsy Surgery vs. AEDs
40 patients in each group followed for 1 year
Patients seizure-free
Surgery group – 58%
AED group – 8%
Quality of life measures: Surgery > AEDs
Complications: Surgery – 4
Death: AED – 1
Resective Epilepsy Surgery
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Craniotomy vs Laser Ablation
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Framed (>2 years old), stereotactic, avascular trajectory planning to target with 3.2 mm twist drill hole
MR FLAIR/T1 to confirm applicator entrance to target, and oblique imaging of entire trajectory
Placement of safety markers on vital nearby structures and test-dosing with laser
Ablation of target in real-time with automatic and manual shut-off
Immediate post ablation imaging (DWI/Contrast) confirming target destruction and lack of vascular injury
SLA Protocol
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Cortical Tuber in Tuberous Sclerosis
Complex
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MRI Axial FLAIR
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MRI Axial FLAIR
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Placement of Laser Fiber
Oblique Coronal plane Frame stereotaxis used to localize and place laser applicator
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Thermal Ablation of Target
Laser Dose:3 test pulses used to confirm placement of laser applicator prior to ablation.
Laser ablation: 1 exposure, 11.25 watts for 90 seconds
Estimated Damage Area:25 x 22 mm
Live Temperature Map Live Damage Estimate
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Post-Ablation Enhanced MRI
Post-contrast
Ablation Fiber
ACA
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Post-Ablation Follow-Up
15 months post-ablation
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Hypothalamic Hamartoma
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MRI Coronal & Axial FLAIR
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MRI Sagittal T1
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Thermal Ablation of Target
Laser Dose:8 watts for 51 seconds
Estimated Damage Area:Sagittal10.5 x 10 mmCoronal11.4 x 9.2 mm
Temperature limits were set to protect the hypothalamus (above) and basilar artery and optic tract (below ). The limit near the hypothalamus shut the laser off at 51 seconds.
Live Temperature Map Live Damage Estimate
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Post-Ablation Enhanced MRI
Laser Fiber
Laser Fiber
Ablation
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82% of the HH patients are seizure-free
95% of all patients are discharged home the following morning (<24-hour hospital stay)
Complications:
No cases of diabetes insipidus
No symptomatic hemorrhages or vascular injuries
No white matter or fiber tract injuries
SLA Epilepsy Outcomes
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Multifocal or generalized seizure onset
Focus of seizure-onset cannot be localized
Seizure-onset focus involves a critical brain function (eloquent cortex)
Vision
Language – expressive and receptive
Memory
Motor
Patient or family refusal
Why Can’t Surgery be Done?
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Vagus Nerve Stimulation (VNS)
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FDA approvals 1997 Initial FDA on-label indication – to reduce
seizures in patients older than 12 years with partial-onset seizures
NEW FDA on-label indication – to reduce seizures in patients 4 years old and older with partial-onset seizures
NEW VNS model 1000 - SenTiva™
Smaller, more advanced programming, wireless programming wand
VNS Therapy
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Model 102 Model 103/104 Model 105 Model 106
Generator 102 103/104 105 106 1000
Type Single Pin DemiPulse Aspire-HC Aspire-SR SenTiva
Launch Year 2002 2008 2011 2015 2017
Thickness 6.9 mm 6.9 mm 6.9 mm 6.9 mm 6.9 mm
Volume 14 cc 8 cc 14 cc 14 cc 8 cc
Weight 25 gm 16 gm 25 gm 25 gm 16 gm
Model 1000
VNS Therapy Generators
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1) Labar DR. Seizure 2004;13:392-8. 2) Garcia-Navarrete E, et al. Seizure. 2013;22(1):9-13. 3) Chayasirisobhon S, et al. J Neurol Neurophysiol 2015;6:1. 4) De Herdt V,
et al. Eur J Paediatr Neurol 2007;11:261-9. 5) Elliott RE, et al. Epilepsy Behav 2011;20(1):57-63.
Pa
tie
nts
wit
h ≥
50
%
se
izu
re
fr
eq
ue
nc
y r
ed
uc
tio
n
No medication changes were allowed during the
study period
LABAR(n=269)
57%
Mean follow-up
12 MONTHS
GARCIA-NAVARRETE
(n=43)
63%
Mean follow-up
18 MONTHS
CHAYASIRISOBHON(n=39)
64%
Mean follow-up
24 MONTHS
DE HERDT(n=138)
59%
Mean follow-up
44 MONTHS
ELLIOTT(n=436)
64%
Mean follow-up
59 MONTHS
Long-term Outcome in VNS Therapy
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Benefits of on-demand magnet stimulation
Offers more control for patients and their families
Initiates on demand stimulation May abort or decrease severity of
seizures1
May improve postictal period2
Stops stimulation Acutely manage side effects
1. Majkowska-Zwolińska et al 2012, Major and Thiele 2008, Khurana et al 2007, McHugh et al 2007, Morris 2003, Murphy et al 2003, Boon et al 2001, Wang et
al, 2009, Hammond et al, 1992. 2.Murphy et al 2003.
On-demand Magnet in VNS Therapy
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1. Morris 2003. 2. Wang et al, 2009.
62% of seizures were terminated or
diminished by on-demand magnet stimulation (N=9,482 Seizures)1
Positive Impact to Seizure
24%terminated
38%diminished
On-demand magnet stimulation terminates seizure during video-EEG
monitoring2
Evidence for On-demand Magnet Therapy
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Provides responsive stimulation to heart rate increases that may be associated with seizures.
VNS Therapy Physician’s Manual, Cyberonics, Inc. Houston ,TX.
The AutoStim Mode feature:
• Detects rapid heart rate rise
• Delivers automatic stimulation
• Has customizable parameters
to meet patients’ needs
• Works in conjunction with
normal and magnet mode
Heartbeat Sensing during OFF time
VNS Autostim Mechanism
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1. Eggleston KS, et al. Seizure 2014;23(7):496-505. 2. Jansen K, et al. Seizure 2010;19(8):455-60.
82% of patients with
epilepsy
experience rapid
heart rate
increase
associated with a
seizure1
Adapted from Carter R et al. The Human Brain Book, New York: Dorling Kindersley Limited, 2009.
Ictal discharges to areas of the brain that regulate the autonomic nervous system can impact heart rate2
Heart-Brain Connection
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38%diminished
Background Heart Rate
DetectionThreshold
@ 60%
Video depicts heart rate before, during and after two ictal events• Floating Detection Threshold automatically adjusts to the patient's underlying activity
• Threshold is customizable to individual patient needs (20-70%)
VNS Autostim Detection Algorithm
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Stimulation-associated desynchronization of focal seizure*
20% Threshold for AutoStim
Automatic Stimulation
Stimulation-associated desynchronization
Over
60% of seizures treated
ended during
automatic
stimulation
(28/46 treated seizures
from 14 patients)
Seizure Cessation in Clinical Trial
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Same patient's typical seizure progression(without VNS Therapy Automatic Stimulation)
Focal Seizure (not stimulated in this view)
Typical Seizure for Same Patient
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Software updates:
Heart rate-based seizure detection with closed-loop automated stimulation
Seizure detection incorporates rate of rise, position –prone versus supine, and bradycardia
Potentially alerts to patients at risk for SUDEP
Allows for differential stimulation parameters during daytime and nighttime
Allows for preset weekly incremental parameter introduction without having to visit clinic
Updates with SenTiva®
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VNS titration should be well tolerated by majority of patients
Expect to feel sensation in throat and may cough with each dosage increase and expect to have on-time voice hoarseness
Dose-related adverse effects typical resolve within days and voice hoarseness is typically gone within a year of treatment
For particularly sensitive patients, there are several options to maximize comfort and tolerability
Slow down rate of titration
Reduce signal frequency from 30 Hz to 20Hz
Reduce pulse width from 500 usec to 250 usec
VNS Tolerability
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For immediate control of treatment-related adverse effects – apply the magnet
Magnet can also be used as needed for control of stimulation-related voice changes
Singing in church
Giving public presentations
Surgery is a straightforward day surgery procedure that takes ~1 hour
None of the typical drug-related adverse effects – sleepy, drowsy, dizzy, mood/behavior changes, weight changes, blood, liver, renal effects, no allergic reactions
VNS Tolerability
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Need to give the therapy time – typically 2 years Important for patient and family to have accurate expectations
Unlike brain surgery, not going to wake-up seizure-free
My personal experience in children (>800) 75% of children will have at least at 50% reduction in seizures
after 2 years of therapy
11% are seizure-free
25% still have worthwhile benefit with magnet therapy, reducing drug burden, brighter and more alert, less depressed
Keep in mind that refractory epilepsy is often a progressive disease – same seizure burden 2 years later can be a dramatic positive outcome
Interpreting VNS Outcome
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Responsive Neurostimulation (RNS - NeuroPace®)
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Responsive Neurostimulation (NeuroPace®)
Detectspatient-specific patterns
Stimulatesautomatically
Monitorsbrain activity continuously
Records• Frequency, timing,
and location of electrographic activity
• Over months/years in a naturalistic setting
First closed-loop therapy system
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Cranial neurostimulator connected to one or two leads placed at seizure focus.
Responsive Neurostimulation (NeuroPace®)
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Responsive NeurostimulationPersonalized for each individual’s seizure fingerprint
Step 2: Stimulation Physician programs device to automatically stimulate in response to specific patterns, with the goal of preventing a clinical seizure.
Step 1: Detection Physician identifies and programs neurostimulator to detect patient-specific electrocorticographicpatterns.
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RNS® System Therapy Overview
• Reversible therapy, non-destructive to brain tissue• Clinical experience represents >1,700 implant years1
• No adverse cognitive effects and no chronic stimulation side effects3,5,6
• Serious adverse event rates comparable to deep brain stimulation for movement disorders6
• Provides long-term ECoG recordings that supplement clinical seizure reports and patient management
• Data obtained may complement other therapies –medications, resection/laser, etc.
• Class I Evidence and long-term follow-up studies• 72% median seizure reduction at 7 years1
• 30% achieved >90% seizure reduction2
• 16% of patients have seizure free period of > 1 year1
• Significant quality of life and cognitive improvements3,4,5
Long-term safety,
minimal side effects
Unique window to
the brain
Long-term seizure
control
1. Morrell et al., presented at AES 2016; 2. Loring DW et al., Epilepsia, 2015; 3. Meador et al., Epilepsia, 2015; 4. Heck CN et al., Epilepsia, 2014; 5. Morrell et al, Epilepsia, 2011; 6. DiLorenzo, D. et al, Journal of Neurosurgery, 2014. Enatsu, R et al, Epilepsy & Behavior, 2012.
FDA approved – 11/14/2013
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• Patients >18 years of age or older
• Refractory to two or more medications
• Partial onset seizures with 1-2 seizure foci
• Patients commonly treated with the RNS System:
– Bilateral mesial temporal onsets
– Unilateral mesial temporal onset with risks to memory or language with resection
– Onset in eloquent (functional) cortex
– Suboptimal response to VNS or epilepsy surgery
RNS System Candidates
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Median % Seizure Reduction
Heck CN, et al. Epilepsia, 2014. Bergey GK, et al. Neurology, 2015.
Responsive Neurostimulation
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Safety and tolerability
• No stimulation-related adverse effects
• Infection rate
3.7% - mostly soft tissue
• Implant-related hemorrhage rate
2.7% - vast majority were asymptomatic
Responsive Neurostimulation
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RNS System data can reveal trends in detections over time
Supplement Clinical Seizure Reports
Line shows trend in number of long episodes over time
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Help Assess Effects of Adjunctive Medication
Year
Dete
ctions p
er
day
Added a new medication
This patient showed sustained reductions in epileptiform activity with levetiracetam.
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11 patients presumed unilateral; 7/11 (64%) had bilateral electrographic seizures
71 patients presumed bilateral, 9/71 (13%) had only unilateral
electrographic seizures
Lateralization of seizures of MTL onset[King-Stephens et al., Epilepsia, 2015]
In 20% of patients, the presumed lateralization determined by prior diagnostic testing changed after chronic ambulatory ECoG monitoring.
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Personal experience
What would I do if I developed epilepsy:
Try one or two drugs
See if I could have surgery, preferably with laser ablation
Then obtain Neuromodulation therapy
VNS
RNS
What Would I Do?
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Refractory epilepsy can be a catastrophic disease
Management should focus on maximizing quality of life – stopping seizures, minimizing adverse effects
Ability to identify refractory patients early in the disease course is possible – after 2 AED failures
Non-pharmacologic treatments should be considered as soon as AEDs fail, especially potentially curative ones
Exciting and innovative new treatment options are rapidly emerging
Conclusions
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Thank-you!