Treatment of Epilepsy with Implanted Devices: …az9194.vo.msecnd.net/pdfs/121201/101.03.pdfTLE...
Transcript of Treatment of Epilepsy with Implanted Devices: …az9194.vo.msecnd.net/pdfs/121201/101.03.pdfTLE...
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Treatment of Epilepsy with Implanted Devices: What Are
Indications and Benefits? 11/30/2012
Barbara C. Jobst, MD
Dartmouth-Hitchcock Epilepsy Center
Geisel School of Medicine at Dartmouth
American Epilepsy Society | Annual Meeting
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Disclosure
Name of Commercial
Interest
Neuropace, Inc Pfizer, Inc
Lundbeck Inc
UCB, Inc
NIH, CDC
American Epilepsy Society | Annual Meeting 2012
Type of Financial Relationship
Research Support
Fellowship Support Research / Advisory committee
Research Support
Research Support
The use of unapproved devices will be discussed
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Esther
• 30 yo woman with intractable seizures since age 15
• History of treated Hodgkin disease after the onset of seizures
• Tried all available AEDs including progesterone
• osteoporosis: • during a seizure fell down the stairs and acquired a C4 fracture,
• previously three clavicular fractures due to seizures
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Esther seizure #1
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Esther seizure #2
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Esther seizure #3
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Interictal EEG
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MRI
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Questions about Esther
• Is it a focal or generalized syndrome ?
• When to go to a device?
• Which device?
• What are realistic expectations about a device?
• What is the role of a callosotomy versus a device?
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Learning Objectives
American Epilepsy Society | Annual Meeting 2012
• Know the indications for implanted devices for epilepsy
• Know about the efficiency of implanted devices such as the VNS, DBS and RNS
• Weigh the risks and benefits of devices in bilateral epilepsy syndromes
• Know about principles of stimulator programming
• Assess the benefits of VNS and callosotomy in generalized epilepsies
• Inform about future developments and plot a visionary path for the future
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Algorithm
Algorithm = a procedure for solving a problem or accomplishing some end especially in a finite number of steps (Merriam- Webster dictionary)
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Epilepsy surgery
58.0%
73.0%
83.0%
56.0%
57.0%
66.0%
8.0%
0% 20% 40% 60% 80% 100%
TLE controlled
early TLE controlled
TLE retrospective 3 years
TLE retrospective 10 years
Frontal lobe surgery
Epilepsy surgery overall
Medical treatment
Efficacy
seizure free
(Wiebe 2001, Engel 2012, Yoon 2003, Lazow 2012, Spencer 2005) 12
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Devices : Electrical Stimulation
Amplitude Pulse width Frequency Intermittent – Continuous Responsive
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Vagus Nerve Stimulation (VNS)
• 7-60 seconds ON, • Up to 180 min OFF • 0.25mA-3.5mA • 1 Hz-30 Hz • pulse width 130- 1000µs • Typical settings:
30 sec ON, 5 min OFF 1.0-1.5 mA, 20 Hz, 250 µsec,
• Rapid cycling 21 sec on, 1.8 min off
• Battery life 5-10 years • Magnet for extra stimulus,
usually at higher current
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Device versus another medication? (double blind evidence)
6.0%
2.0%
2.0%
8.0%
0.0%
1.0%
37.1%
39.0%
44.3%
32.6%
25.4%
27.9%
0% 20% 40% 60% 80%
levetiracetam
lacosamide
ezogabine
eslicarbazepine
VNS EO3
VNS EO5
Efficacy
median sz reduction seizure free
6.1%
17.0%
26.8%
18.8%
1.7%
1.0%
0% 20% 40% 60% 80%
levitiracetam
lacosamide
ezogabine
eslicarbazepine
VNS EO3
VNS EO5
Tolerability
discontinued (AEs)
(Ben-Menachem 1994, 2007, 2010, French 2011, The Vagus Nerve Stimulation Group 1995, Handforth 1998) 16
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Device versus another medication?
39.6%
64.0%
46.0%
51.0%
59.2%
38.6%
35.0%
59.0%
63.8%
11.7%
9.0%
8.3%
0% 20% 40% 60% 80%
levetiracetam …
VNS 4 years
VNS 1 year
VNS > 1 year
VNS mixed …
Efficacy
seizure free
Responders > 50%
median sz reduction
Not reported
17.0%
4.5%
2.5%
3.7%
0.5%
0.2%
1.9%
0% 20% 40% 60%
removal
lead fracture
infection
hoarseness
dysphagia
vocal cord paralysis
pain
Tolerability
(Ben-Menachem 2003, De Giorgio 2000, De Herdt 2007, Elliot 2011,)
“50% of patients have 50% less seizures”
Not reported
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(observational studies)
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Device versus another medication? (Clinical Reality or The Art of Medicine)
• Side effects: cognition, sedation vs hoarseness
• Psychiatric considerations: depression, memory
• Patient preference
• Seizure severity or frequency
• Health care system
• The “magic of a device”
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The “magic” of a device
• Expectation determines the therapeutic response as well as the brain physiology (single neuron firing and dopamin release)
• Sham surgery is thought to have an even greater response
6.8%
10.0%
17.5%
0.8%
15.2%
11.3%
0.0%
0.0%
0.0%
1.0%
0.0%
0.0%
0% 20% 40% 60% 80%
levitiracetam
lacosamide
ezogabine
eslicarbazepine
VNS 03
VNS 2
Placebo response
seizure free mean sz reduction
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The “magic” of a device II: Neuromodulation
Efficacy increases with prolonged use
(Elliot 2011)
Cave: Enriched population
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60%
38%
21% 21%
29%
8% 12%
8%
19%
6% 4% 3% 2% 2% 0% 3%
0%
10%
20%
30%
40%
50%
60%
70%
Hoarseness Cough Paresthesia Dyspnea
Month 3
Year 1
Year 2
Year 3
(Morris 1999).
VNS Long-Term Adverse Effects
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VNS in different populations
55.0%
20.6%
17.0%
43.3%
60.0%
50.5%
50.0%
21.0%
26.0%
43.8%
68.7%
55.1%
7.0%
5.0%
0.0%
10.1%
5.1%
0% 20% 40% 60% 80%
medical refractory
Lennox-Gastaut
Epileptic encephalopathies
Generalized
Children
Postsurgical
Efficacy
seizure free Responders > 50% median sz reduction
(Jobst 2010, Majoie 2005 , Holmes 2004, Alexopoulos 2006, Amar 2004 ) 23
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Trends in VNS response
• Children of younger age seem to respond more favorably
• Epilepsy duration seems to have a inverse relationship with favorable response
• Possibly tuberous sclerosis and trauma respond more favorably than other pathologies
• Generalized tonic-clonic seizures may be a negative predictor of a favorable response
• Simple partial seizures tend to respond the best
Engelot 2011
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? Future: transcutaneous stimulation
Auricular branch of the vagus nerve
Trigeminal stimulation
(TNS)
N=10 data in 7 Safety in psychiatric trial for tinnitus 5/7 decreased seizure frequency No patient >50% seizure reduction
Monarch®
Nemos ®
(Stefan 2012, DeGiorgio 2009 )
N=13 data in 12 66% mean seizures reduction 5/12 responders
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Seizure reduction
Seizure reduction
Seizure reduction
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DBS principle
• Intermittent or continuous
• Amplitude 0-10.5 V
• Pulse width 60-450 µs
• Frequency 2-250 Hz
• Battery life ~ 3 years
• Modulation of limbic circuits
Target: anterior nucleus of the thalamus
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SANTE
N=108
Implantation effect
(Fisher 2010)
Amplitude 5V Pulse width 90 µs Frequency 140 Hz 1 min ON - 5 min OFF
GEE: mean percent difference -17%, (p=0.038) last month -29% (p=0.0016)
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Long term data- DBS- SANTE
43.0%
54.0%
67.0%
7.4%
12.7%
0%
20%
40%
60%
80%
1 year
2 year
3 year
Sz free lon
g term
Seizure reduction
median sz reduction
Responders > 50%
seizure free
NR NR
0.0%
16.4%
18.2%
12.7%
0.5%
4.5%
0% 20% 40% 60%
Blinded phase withdrawal
Withdrawal
Paresthesias
Infection
Pain
Hemorrhages non-clinical
Tolerability
(Fisher 2010)
NR =not reported
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Special populations- SANTE
• Temporal lobe epilepsy: median seizure reduction was significant compared to other neocortical epilepsies
• Complex partial seizures and most severe seizures improved significantly
• Current European Registry: Medtronic Registry for Epilepsy (MORE) may help to identify specific patient populations.
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? Future: hippocampal stimulation
• In small case series the hippocampal stimulation seems to be effective
• Controlled Randomized Stimulation Versus Resection (CoRaStiR) still ongoing in Europe
(Boon 2007, clinicaltrials.gov, Suthana 2012)
Hippocampal stimulation may improve memory
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Seizure reduction
Seizure reduction
Seizure reduction
Seizure reduction
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Responsive stimulation: RNS®-System
• 0.5-10 mA (< current density of 3µC/cm2)
• 100-200 Hz
• Responsive single pulses
• Battery life 3 years
Restricted to investigational use only by US law 33
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Responsive Stimulation Single pulses delivered after individualized seizure detection, delivered
multiple times per day
Detection and Stimulation up to 5 times
• Stimulation targeted at seizure onset zone
•Overall current delivered is low as only single pulses are delivered
Restricted to investigational use only by US law
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Alternative implantations
Neocortical stimulation: (only 8 electrodes are connected)
Hippocampal and neocortical stimulation
Restricted to investigational use only by US law 35
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RNS®- System: double blind data
N=191
Implantation effect
*
(Morrell 2011)
GEE: mean percent difference -37.9%, (p=0.012) last month evaluation period -41.5% (p=0.008)
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Long term treatment trial
(Jobst 2011, Bergey 2011) 37
5 years 7 years 3 years 2 years
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Long term data- RNS®-System
7.1%
15.0%
0%
20%
40%
60%
80%
2 year
Sz free lo
ng term
Seizure free
seizure free
0.2%
3.0%
5.1%
9.0%
2.1%
0% 20% 40% 60%
Explantion
Paresthesias
Infection
Pain
Hemorrhage
Tolerability
(Morrell 2011) 38
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RNS®-System in different populations
• No difference between mesial temporal or other location
• No difference whether previous epilepsy surgery
• No difference whether one or two seizure foci
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? The future: Responsive treatment
Responsive treatment could evolve into
- improved electrical seizure abortion
- improved technology treating directly at seizure focus
local drug delivery
local cooling
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The future: Seizure Risk Alerting Devices
Records, analyzes, and archives real-time, ambulatory iEEG data from 16 contacts N= 15 for safety Modulation of life style and acute treatment (Courtesy Mark Cook)
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Where do devices fit in
• Bitemporal epilepsy
• Epilepsy with > 1 seizure focus
• Seizure onset eloquent regions
• Failed surgery
• Generalized epilepsies
• ? Additive effects
• Lower complication rate
• Basis for further development such as target drug delivery, cooling, stimulation, seizure detection
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Seizure reduction
Seizure reduction
Seizure reduction
Seizure reduction
Seizure reduction
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Device versus callosotomy (CC)
40.0%
79.0%
50.0%
79.9%
66.7%
77.8%
0% 20% 40% 60% 80%
VNS
CC
Responder rates
Tonic-atonic GTC all seizures
VNS n=21 CC n=50
(Nei 2006)
8.0%
21.0%
0% 20% 40% 60%
VNS
CC
Tolerability
complications
CC VNS
Death Status Infection Hemiparesis Gait difficulties Disconnection syndrome DVT
Site infection Defective battery
Class I: CC 17% --VNS 0% 44
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Seizure reduction
Seizure reduction
Seizure reduction
Seizure reduction
Seizure reduction
Seizures
Seizure reduction
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The patient: Esther
• She had a VNS implanted.
• Could not tolerate it because of choking sensations.
• Multiple medication changes were unsuccessful.
• Finally had callosotomy.
• Significant reduced generalized tonic seizures with falling, but still has continued seizures
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Seizure reduction
Seizure reduction
Seizure reduction
Seizure reduction
Seizure reduction
Seizures
Seizure reduction
SYNDROME
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Thank you
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Quality of life and co-morbidities
Overall QOLIE
Depression Memory/ Cognition
medications ? ++/-- --
VNS + ++ neutral
DBS + -? ?
RNS + neutral +
callosotomy ? ? --
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Summary Devices RNS -System DBS VNS TNS
Target Cortical: varies according to seizure
focus
Anterior nucleus
thalamus
Ascending vagus nerve
Trigeminal nerve
Type of stimulation Closed loop: responsive Open loop scheduled
Neurostimulator Cranially implanted Pectorally implanted Not implanted visible
Stimulation time/ day
Approx. 5 min Hours-Continuous
Programming changes
Adjusted to clinical and electrographic response
According to clinical response
Information from device
Device data, detections, electrocorticogram
Device data
Physician data review
At programming and online access to stored
data
At programming
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