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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.