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

1

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

2

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

3

Esther seizure #1

4

Esther seizure #2

5

Esther seizure #3

6

Interictal EEG

7

MRI

8

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?

9

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

10

Algorithm

Algorithm = a procedure for solving a problem or accomplishing some end especially in a finite number of steps (Merriam- Webster dictionary)

11

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

13

Devices : Electrical Stimulation

Amplitude Pulse width Frequency Intermittent – Continuous Responsive

14

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

15

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

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)

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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19

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

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

31

Seizure reduction

Seizure reduction

Seizure reduction

Seizure reduction

32

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

Alternative implantations

Neocortical stimulation: (only 8 electrodes are connected)

Hippocampal and neocortical stimulation

Restricted to investigational use only by US law 35

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)

36

Long term treatment trial

(Jobst 2011, Bergey 2011) 37

5 years 7 years 3 years 2 years

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

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

40

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

42

Seizure reduction

Seizure reduction

Seizure reduction

Seizure reduction

Seizure reduction

43

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

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

46

Seizure reduction

Seizure reduction

Seizure reduction

Seizure reduction

Seizure reduction

Seizures

Seizure reduction

SYNDROME

47

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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