Douglas Labar, MD, PhDBrain and Nerve Stimulation

ProgramWeill-Cornell Medical Center

Neuromodulation for Epilepsy

Device characteristics and technical considerations

Vagus nerve stimulation

3

The VNS Therapy System(Cyberonics)

4

VNS, MRI and diathermy

MRI/diathermy safety

recommendations

Head or extremity scan only; coil

= transmit/receive

Set output + magnet to zero mA

before scan

No MRIs on patients with lead

breaks

No diathermy (shortwave,

microwave, ultrasound) on VNS

patients

Physician’s Manual. Houston, TX: Cyberonics, Inc.

Mechanisms of action

Vagus nerve stimulation

8

Vagus Nerve Projections to the CNS

9

Locus Coeruleus Lesions Block the Effects of VNS (Krahl et al. 1998)

Krahl S, et al. Epilepsia. 1998;39:709-714.

VNS seizure rate response and thalamic blood flow

• 11 partial epilepsy patients received VNS

• Upon initial VNS activation, each had 015-H20-PET cerebral blood flow scans

• Increased thalamic blood flow bilaterally upon initial VNS activation correlated with subsequent decreased seizures during 3 months of treatment (p<0.01)

(Henry et al. 1999)

108.9 ms

169.6 ms

VNS OFF

VNS ON

VNS activation prolongs transcranialmagnetic stimulation cortical silent period

Dean et al. 2001

Efficacy

Vagus nerve stimulation

VNS therapy clinical trial: E053 months seizure reduction

Handforth A, et al. Neurology. 1998;51:48-55

P=0.04

0

10

20

30

Mean Decrease in Seizure Frequency Versus Baseline

Low (n=102) High (n=94)

Reduct

ion (

%)

15%

28%

VNS long-term seizure controlresponse rates increase over time (E01-E05)

0

10

20

30

40

50

Last Visit Carried Forward (n=440)

3 months 1 year 2 years 3 years

Morris et al., Neurology. 1999;53:1731-1735.

Patients with >50% Reduction in Seizures

Pati

en

ts (

%)

23.0%

42.7%

43.2%

36.8%

15

VNS Therapy: 12 Year Outcomes†

*Last visit carried forward (LVCF)†Simple partial seizures, complex partial seizures, and secondarily generalized tonic clonic seizures

Uthman BM, et al. Neurology. 2004;63:1124-1126.

-22%-26%

-28%-25%

-30%

-42%

-49%-52%-55

-50-45

-40

-35

-30

-25

-20

-15

-10-5

0

6 Months(n=47)

1 Year(n=47)

2 Years(n=38)

3 Years(n=35)

5 Years(n=30)

7 Years(n=17)

10 Years(n=17)

12 Years(n=12)

Time

Mean

% C

han

ge in

S

eiz

ure

Fre

qu

en

cy*

Adverse effects

Vagus nerve stimulation

0

10

20

30

40

50

60

70

Hoarseness Cough Paresthesia Dyspnea*3-month results (high stimulation only, n=152). Physician’s Manual, VNS

Therapy Pulse Model 102 Generator, Cyberonics, Inc.; June 2002. †Year 1, 2, and 3 results (all study patients, n=440). Morris GL III, Mueller WM.

Neurology. 1999;53:1731-1735.

VNS therapy tolerability: Short- andlong-term adverse effects (E01-E05)

Pati

en

ts (

%)

Month 3*

Year 1†

Year 2†

Year 3†

VNS Complications in Children

84 implants, patients < 19 years old

3 infections requiring explant3 superficial infections which resolved with antibiotics

2 revision surgeries due to lead fractures

(Smyth et al., 2003)

VNS and SUDEP:No increase

VNS SUDEP rate=4.1/1000 patient years

Resective surgery candidates SUDEP rate=9.3/1000 patient years

(Annegers et al., 2000; Dasheiff et al., 1986)

VNS OR lead test + asystole

8 cases of asystole during intraoperative lead test

2 completed surgery, 6 surgery stopped

No morbidity or mortalityAll with lead test current 1.0 mANow 103 and 104 lead test

current is 0.25 mA; no recurrence( Ali et al., 2004; Tatum et al., 1999; Asconape et

al.,1999)

VNS + Sleep Apnea(Malow et al., 2000)

PSGs on 4 VNS patients (1 with OSA)

More apnea and hypopnea during “on” phase of duty cycle

1 OSA patient, VNS increased AHI from 4 to 11.3/hour

3 non-OSA patients, all AHI < 5/hour

No apnea/hypopnea with VNS at 20 Hz

Efficacy: Why do seizure rates decline with longer VNS exposures?

Synergism with antiepileptic drugs?

Vagus nerve stimulation

VNS +/- AED changes: 1 year follow-up (Labar 2002)

% sz change0

10

20

30

40

50

60

Levi. Added n=151

Oxcarb. Added n=46

Zono. Added n=71

Same AEDs n=269

VNS and AED Reduction

Patient category VNS Case-matched control

Total number of patients

21 21

AED dose reduced 10 (48%) 2 (10%)

AED number reduced 9 (43%) 0 (0%)

Failed additional AED 4 (19%) 12 (57%)

Mean follow-up=13.2 months(Tatum et al., 2001)

Efficacy: Why do seizure rates decline with longer VNS exposures?

Stimulation settings, or other device-related changes?

Vagus nerve stimulation

Current [as tolerated]On time [30 sec] Off time [5 mins]Frequency [30 Hz] Pulse width [500 usec]

“no data…that these are optimal parameters”

Patient magnet-activated stimulation settings:

Current, on time, pulse width

Vagus nerve stimulationProgrammable functions [initial]

VNS for 1 year in 269 patients on unchanged AEDs: Changes in duty cycles (Labar 2004)

Duty cycle change, 3 mo vs. 12

mo

Number of

patients

Median % change szs @ 3 months

Median % change szs

@ 12 months

Off > 3.0 min/Off > 3.0

min

174 -45% -63%

Off > 3.0 min/Off < 1.8

min

71 -40% -50%

Off < 1.8 min/Off < 1.8

min

21 -67% -80%

Randomized trial of 3 initial VNS stimulation settings (DeGiorgio et al.,

2005)

Treatment A

Treatment B

Treatment C

On/Off time

7 sec/18 sec

30 sec/30 sec

30 sec/3 min

# Patients 19 19 23

Mean current, mA

0.87 0.80 0.93

50% responder rate

31.6% 31.7% 26.1%

Responsive VNS?E03 magnet activated stimulation study

Seizure changes

Improved Not Improved

Treatment group

52.5% of seizures 47.5% of seizures

Control group 40.7% of seizures 59.3% of seizures(Morris 2003)

Efficacy: How to improve?

Select best patient responders

Vagus nerve stimulation

The following patient clinical features did not correlate with

VNS responsiveness:

Epi. duration Age Epi. onset age Prior epi. surgery # prior AEDs Concomitant AEDs

Epi. syndrome Gender Seizure rate # current AEDs # seizure types

Labar 2002

32

Earlier Use of VNS Therapy Reduction in Seizure Frequency at 3 Months

Reduction in Seizure Frequency, %

Renfroe JB and Wheless JW. Neurology. 2002;59(suppl 4):S26-S30.

% o

f Pa

tients

*

†

*P=.001; †P<.001

50 75 90 100

EA (n = 120)Control (n = 2785)

0

10

20

30

40

50

60

51% 50%

35%

28% 26%

14% 15%

4%

Figure 1. Vagus nerve stimulation (VNS) efficacy in the mature adult.

Sirven J et al. Neurology 2000;54:1179-1182

45 patients > 50 years of ageA=3 months, all patients B=12 months, study patients

©2000 by Lippincott Williams & Wilkins

Many AED side effects

Predictable aura

Epilepsy duration < 5 years

Should I recommend VNS?Yes-for patients with…

Poor AED compliance

Co-morbid depression

> 50 years old (on multiple meds)

Should I recommend VNS?Yes-for patients with…

Sleep apnea

Known to need body MRIs

Public speaker, vocalist ?

Should I recommend VNS?No-for patients with…

Check seizures + side effects, then:

Select settings case-by-case

Adjust stimulation monthlyEfficacy:

think duty cycle?

How do I manage VNS settings?No specific stimulation is superior

Check seizures + side effects, then:

Adverse events: think current, pulse width ?Patient discomfort has no

benefit

End of battery life considerations?

How do I manage VNS settings?No specific stimulation is superior

Thanks to her for helping us out

Video: A vagus nerve stimulator patient’s experiences

Therapies “in the pipeline”

Neuromodulation for Epilepsy

Transcutaneous VNS (auricular)(Stefan et al., 2012)(Cerbomed)

Transcutaneous VNS (auricular)(Stefan et al., 2012)

Transcutaneous VNS for 1 hour three times per day

5/7 patients had less seizures in months 7-9 compared with baseline

2/7 patients had more seizures in months 7-9 compared with baseline

Trigeminal Nerve Stimulation for Epilepsy (DeGiorgio et al., 2006)(NeuroSigma)

EpilepsiaVolume 47, Issue 7, pages 1213-1215, 19 JUL 2006 DOI: 10.1111/j.1528-1167.2006.00594.xhttp://onlinelibrary.wiley.com/doi/10.1111/j.1528-1167.2006.00594.x/full#f1

©2009 American Academy of Neurology. Published by LWW_American Academy of Neurology. 2

Figure

TRIGEMINAL NERVE STIMULATION FOR EPILEPSY: LONG-TERM FEASIBILITY AND EFFICACY.DeGiorgio, Christopher; Murray, Diana; Markovic, Daniela; Whitehurst, Todd

Neurology. 72(10):936-938, March 10, 2009.DOI: 10.1212/01.wnl.0000344181.97126.b4

Figure Adjusted mean daily seizure rate across timeBars indicate standard error = 0.64.

Responsive Neurostimulator(Morell 2011)(Neuropace)

Deep Brain Stimulation for Epilepsy (Fisher et al., 2010)(Medtronic)

48

Seizure Frequency Reduction to 1 Year, Anterior Thalamic Stimulation

-90%

-70%

-50%

-30%

-10%

10%

30%

Baseline Operative Month 1-2

Month2-3

Month 3-4

Month 4-5

Month 5-6

Month 6-7

Month 7-8

Month 8-9

Month 9-10

Month 10-11

Month 11-12

Month 12-13

1-month grouping

Me

dia

n t

ota

l s

eiz

ure

fre

qu

en

cy

pe

rce

nt

ch

an

ge

fro

m b

as

eli

ne

Active (n=43)

Control (n=43)

Blinded Phase Unblinded Phase

Randomization Control starts stimulation

Includes subjects with at least 70 days of diary in each 3-month period (ie, Mo 1-4, Mo 4-7, Mo 7-10, and Mo 10-13)(Fisher et al., 2010)

Thanks for your attention.