Vagal Nerve stimulation

Amr Hassan MD,FEBN
Professor of Neurology- Cairo University
VAGAL NERVE STIMULATION

European
epilepsy
population
Prevalence of
epilepsy
Well
controlled
with AEDs2
70%
1.8 m DRE patients are
candidates for non-
pharmacological
interventions
~6m1
8.2/
1,0001 DRE
30%2
(1.8m)
DRE is a large potential non-pharmacological treatment
population
1. Available at: Epilepsy in the WHO European Union http://www.ibe-epilepsy.org/downloads/EURO%20Report%20160510.pdf. Accessed Jan 2018; 2. Mohanraj and Brodie. Eur J
Neurol. 2006;13:277–82.

Diet1 Vagus Nerve Stimulation
(VNS) Therapy®1
Ketogenic
Modified
Atkins
Low
glycaemic
Cranial
surgery1
Responsive
Neurostimulation
System (RNS) and
Deep Brain
Stimulation (DBS)2
Resective surgery
• Hemispherectomy
• Corpus callosotomy
• Multiple subpial transection
MRI laser ablation
Adapted from 1. Yusuf M & Al-Ghamdi SBA. Ind Res J Pharm Sci.2016;3:737–50; 2. Engel J. Neurology 2016;87:2483–9.
Non-pharmacological treatment options for DRE

• In addition, side-effects of this kind of surgery can be significant2
• For this reason, less invasive strategies aiming to modulate neuronal
activity of deep brain areas should be considered as an alternative2
VNS Therapy® is an alternative option
• Many patients with DRE are not candidates for surgery1
• This is either because the epileptic focus remains unidentified or located in the
functional cortex1
VNS Therapy® is an efficacious neurophysiological treatment for patients
with DRE who are unsuitable for curative resective surgery or who have
experienced insufficient benefit from such a treatment3
1. El Tahry R, et al. Seizure 2010;19:531–5; 2. Casazza M, et al. Seizure 2006;15:198–207; 3. Boon P, et al. Seizure 2011;10:448–55.

…
VNS Therapy® or palliative surgery?
Mesial temporal
unilateral
Neocortical lesional
Bitemporal/bifocal
Multifocal
Idiopathic
generalised
Generalised epilepsy
(Lennox-Gastaut type)
Candidacy for epilepsy surgery1,2 Influencing factors1,3
Suitable for epilepsy
surgery
Less suitable for
epilepsy surgery*
*Patients that are not suitable for epilepsy surgery may benefit from VNS Therapy® over other palliative treatment options2,3
…
Expected extent of seizure reduction
Risk
Comorbidities
Living situation
Patient preference
1. Available from: MedScape - Outcomes of Epilepsy Surgery http://emedicine.medscape.com/article/1185416-overview. Accessed March 2018; 2. Jenssen S, et al. Seizure
2006;15:621–9; 3. 1. Ryvlin P & Rheims S. Dialogues Clin Neurosci. 2008;10:91–103.

Focal
Temporal
1a. Mesiotemporal
1a1. Clear
unilateral
Resection RNS, YNS, DBS
(rarely)
1a2. Possibly
bilateral
Intracranial
EEG
Resection RNS
VNS
(Possibly
followed
by DBS)
1b. Extratemdoral or
Temporal neocortical
1b1. Lesional 1b2. Non-Lesional
Intracranial
EEG
Resection RNS
VNS
(Possibly
folloed by
DBS)
Benbadis et al, Epil & Behav, in Press.

Generalized
epilepsy
Genetic
Generalized
epilepsy
Lennox.
Gastaut type
VNS
(Possibly followed By
DBS)
VNS
(Possibly followed By
DBS)
Corpus
Callosotomy
(Partial to
complete)
Benbadis et al, Epil & Behav, in Press.

• VNS Therapy® usually has mild non-pharmacological side effects
• These are typically related to stimulation and are normally temporary
• Common side effects include:
– Paraesthesia
– Increased cough
– Dyspnoea
– Pharyngitis
– Voice-alteration (hoarseness)
– Swallowing difficulties
– Worsening of asthma or bronchitis
• Other somatic side effects, such as sleep apnoea, have also been reported
• VNS Therapy® should be used with caution in the presence of bilateral or left
cervical vagotomy, unipolar diathermy and patients with clinically meaningful cardiac
arrhythmias2
VNS Therapy®: Safety profile1
1. Ben-Menachem, E & French, JA. Epileptic Disord. 2005;7:S22–6; 2. VNS Therapy® Physician’s Manual, October 2017.

…sufficient evidence exists to rank VNS
Therapy® for epilepsy as effective and safe,*
based on a preponderance of Class 1 evidence†1
*Safe: A judgment of the acceptability of risk in a specified situation, e.g., for a given medical problem, by a provider with specified
training, at a specified type of facility
†Class 1 evidence: Provided by one or more well designed randomised, controlled clinical trials
1. Fisher RS & Handforth A. Neurol. 1999;53:666–9.

What is VNS Therapy®?
• VNS Therapy® is:
– An adjunctive therapy for partial and generalised seizures*
– Suitable for adults and children1
– Implanted in a simple, short outpatient procedure2
– Proven safety profile and efficacy3,4
– Easy to dose1
• VNS Therapy® is recommended by guidelines as an
adjunctive therapy in reducing seizure frequency in
children and adults with DRE who are not suitable for
resective surgery5
• A VNS Therapy® implant is a pulse generator that is
implanted under the skin and connected to the left
vagus nerve at the carotid sheath6
Left vagus nerve
Electrodes
*VNS Therapy® is not approved for these indications in all countries. Consult your label. VNS=Vagus Nerve Stimulation.
1. VNS Therapy System. Physicians manual. Available at: http://en.eu.livanova.cyberonics.com/healthcare-professionals/resources/product-training. Accessed March 2018;
2. Benifla M, et al. Childs Nerv Syst. 2006. DOI 10.1007/s00381-006-0123-6; 3. George R, et al. Neurology 1995;45:224–30; 4. Handforth A, et al. Neurology 1998;51:48–55; 5.
NICE Guideline CG137 Epilepsy. Available at: https://www.nice.org.uk/guidance/cg137. Accessed March 2018; 6. Edwards C, et al. Mayo Clin Proc. 2017;92;1427–44.
Pulse generator

How does VNS Therapy® work?
VNS Therapy® delivers an anti-convulsive effect via multiple pathways
Neurotransmitter
expression
Cerebral
blood flow
Changes in
EEG
Alters neurotransmitter
expression and release
Increases cerebral
blood flow3
↑ Noradrenaline1
↑ GABA2
↑ Serotonin2
↓ Aspartate2
↑ Thalamus
↑ Cortex
Desynchronises ictal
EEG patterns4
ANTI-CONVULSIVE
EFFECT
1. Roosevelt R, et al. Brain Res. 2006;124–32; 2. Ben-Menachem E, et al. Epilepsy Res. 1995;221–7; 3. Henry TR, et al. Epilepsia 2004;45:1064–70; 4. Koo BJ,
Clin Neurophysiol. 2001;434–41.
EEG=electroencephalogram, GABA=gamma-aminobutyric acid.

Glutamate
GAD
GABA
GABA-T
Succinic
semi-
aldehyde
Inhibitory
pre-synaptic
terminal
GABA
GATI
GABAA receptor
CI-
VNS Therapy®2
VNS Therapy®3
Post-synaptic neuron
GABAA receptor
At the inhibitory synapse1
Impaired GABA-mediated inhibition associated with
epilepsy suggests that GABAA receptors contribute
to the therapeutic efficacy of VNS Therapy®2
Neuronal inhibition in the brain is mediated
predominantly by the interaction of GABA with the
heteromeric GABAA receptor2
VNS Therapy® stimulation increases GABA levels
and density of GABAA receptors.2
The role of GABA in the anti-epileptic effect of VNS
Therapy® remains to be demonstrated2,3
Mechanism of action of VNS Therapy®: Inhibition
1. Adapted from Bialer M & White HS. Nat Rev Drug Disc. 2010;9:68–82; 2. Marrosu F, et al. Epilepsy Res. 2003;55:59–70; 3. Ben-Menachem E, et al. Epilepsy Res 1995;20:221–7.
Cl=chlorine, GABA-T=4-aminobutyrate transaminase, GAT=GABA transporter, GAD=glutamate decarboxylase.

Excitatory
pre-synaptic
terminal
Propagated
action potential
Voltage-gated
Na+ channel
Glutamate
α2δ subunit
of L-type Ca2+
channel
Ca2+, Na+
Na+(Ca2+)
AMPA and kainate
receptors
NMDA
receptor
Post-synaptic neuron
K+ K+
VNS Therapy®3
SV2A
Na+
Depolarisation
At the excitatory synapse1
VNS Therapy® has been shown to
decrease glutamate levels in patients with
DRE3
Glutamate plays a key role in normal
excitatory neuronal signalling2
Excess glutamate is associated with
recurrent seizures and is observed in
chronic epilepsy2
Mechanism of action of VNS Therapy®: Excitation
Adapted from 1. Bialer M & White HS. Nat Rev Drug Disc. 2010;9:68–82; 2. Barker-Haliski M & White HS. CSH Perspect Med. 2015;5:a022863;
3. Ben-Menachem E, et al. Epilepsy Res. 1995;20:221–7.
AED=anti-epileptic drug, AMPA=α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, Ca=calcium, Na=sodium,
NMDA=n-methyl-D-aspartate.

DRE patients
after 1 year of VNS Therapy® (n=10)
DRE patients
eligible for VNS Therapy® (n=7)
-20 0 20 40 60 80 100
GRD distribution (% change)
Seizure
frequency
reduction
GRD distribution (% change)
Seizure
frequency
reduction
-20
-5
10
25
40
55
70
85
-10 0 10 20 30
-15
-5
5
15
25
35
Changes in cortical GABAA receptor density (GRD) measured
by SPECT with the GABAA receptor agonist [123I] iomazenil
• Clinical efficacy of
VNS Therapy®
correlates with up-
regulation of GRD
in DRE
• GABAA receptor-
mediated neuronal
inhibition is
enhanced by VNS
Therapy®1
Adjunctive VNS Therapy® modulates GABAA
receptor expression1
Adapted from 1. Marrosu F, et al. Epilepsy Res. 2003;55:59–70.
SPECT=single-photon emission computed tomography
GRD : GABA receptor denisty.

VNS Therapy® reduces the inter-ictal EEG
• The inter-ictal period can be used by neurologists when diagnosing epilepsy as
an EEG trace will often show inter-ictal spiking and other abnormalities2
1. Mula M and Monaco F. Behav Neurol. 2011;24:21–5; 2. Hallböok T, et al. Seizure 2005;14:527–33; 3. Marrosu F, et al. Clin Neurophysiol. 2005;116:2026–36;
4. Koo BJ, et al. J Clin Neurophysiol. 2001;8:434–41.
VNS
Therapy®
• The power spectrum3
• Inter-hemispheric gamma band
synchronisation3
• Duration of spike-free intervals4
• Inter-ictal spikes2
• Theta synchronisation3
• Spike duration4
• Spike-and-wave activity4

Clinical evidence for VNS Therapy® in DRE
>1,000 peer-reviewed publications on VNS Therapy®
Primary focus # of articles
Effectiveness >500
Safety >150
Ease of use >30
Economics >15
Mechanism of action >250
Review articles >50
A variety of other clinical studies are currently underway in a range
of settings, including epilepsy, depression, migraine,* congestive
heart failure* and others1
There is ample evidence for the efficacy of VNS Therapy® for DRE
1. Available at: Clin Trials.gov. VNS Therapy: https://clinicaltrials.gov/ct2/results?cond=&term=vns+therapy&cntry=&state=&city=&dist. Accessed Mar 2018.
*Limited by Federal (or United States) law to investigational use. VNS Therapy is not approved or under investigation for these
indications in all countries – consult your label.

With VNS Therapy® patients experience:
Enhanced seizure
control and improved
patient outcomes
when treated early1
Sustained improvements in
seizure frequency2 and
significant reductions in seizure
severity and recovery time3–5
Significant
improvements in
quality of life
(QoL)6–8
VNS Therapy® has been shown to protect against
partial and generalised seizures
1. Renfroe BJ & Wheless JW. Neurology 2002; 59:S26–S31; 2. Elliott RE, et al. Epilepsy & Behavior 2011;20:478–83; 3. Boon P, et al. Seizure 2015;32:52–61; 4. Fisher RS, et al.
Neuromod. 2016;19:188–95; 5. Morris GL. Epilepsy & Behavior 2003;4:740–5; 6. Ryvlin P, et al. Epilepsia 2014;55:893–900; 7. Ergene E, et al. Epilepsy & Behavior 2001;2:284–7;
8. Klinkenberg S, et al. Clin Neurol Neurosurg. 2012;114:336–40; 9. Boon P, et al. Seizure 2001;10:448–55.
Improvements in
mental functioning,
mood and
behaviour9
To be updated for each country’s label

• Early treatment of DRE
patients with VNS
Therapy® has been
shown to enhance
seizure control and
improve patient
outcomes, compared
with later treatment with
VNS Therapy®
• Patients were 3x more
likely to be seizure-free
at 3 months if treated
earlier with VNS
Therapy® (p<0.001)
Early use (N=120)
25.8% 14.3%
15.0% 4.4%
p=0.001
p=<0.001
VNS Therapy® initiated within
5 years of epilepsy onset
VNS Therapy® initiated after 5 years
of epilepsy onset, mean 21 years
These patients
experienced
≥90% reduction
in seizure
frequency at
3 months
These patients
were seizure-free
at 3 months
Percentage of patients
Control (N=2,785)
Treating early is beneficial for patients with DRE1
1. Renfroe JB & Wheless JW. Neurology 2002;59:S26–S31.

• VNS Therapy® usually has mild non-pharmacological side effects
• These are typically related to stimulation and are normally temporary
• Common side effects include:
– Paraesthesia
– Increased cough
– Dyspnoea
– Pharyngitis
– Voice-alteration (hoarseness)
– Swallowing difficulties
– Worsening of asthma or bronchitis
• Other somatic side effects, such as sleep apnoea, have also been reported
• VNS Therapy® should be used with caution in the presence of bilateral or left
cervical vagotomy, unipolar diathermy and patients with clinically meaningful cardiac
arrhythmias2
VNS Therapy®: Safety profile1
1. Ben-Menachem E & French JA. Epileptic Disord. 2005;7:S22–6; 2. VNS Therapy® Physician’s Manual, October 2017.

VNS Therapy® has additional benefits
• VNS Therapy® has none of the AEs commonly associated with AEDs1
• There are no interactions between VNS Therapy®
and AEDs or other common drugs1
• VNS Therapy® side effects:2–5
- Occur mostly during stimulation2
- Decrease over time3
- Can be reduced by adjusting VNS Therapy® output parameters4
• VNS Therapy® happens automatically; adherence is not a problem5
1. VNS Therapy® Physician’s Manual, October 2017; 2. Ben-Menachem E, et al. Neurol. 1999;52:1265–7; 3. Morris GL & Mueller WM. Neurology 1999;53:1731–5; 4. Heck C, et al.
Neurology 2002;59:S31–S37; 5. Ben-Menachem E, et al. Epileptic Disord. 2005;7:S22–S26.

Summary
• VNS Therapy® involves stimulation of the vagus nerve to provide
an anti-convulsive effect in DRE1
• VNS Therapy® works in a number of ways, including:
– Altered neurotransmitter expression2,3
– ↑ cerebral blood flow4
– Altered EEG patterns5
• Effectiveness of VNS Therapy® is maintained long-term6–10 and even
increases over time,11 providing:
– ↓ Seizure frequency and severity10,12
– ↑ QoL12
– ↓ Economic burden13,14
• VNS Therapy® side effects are moderate and controllable15
1. Edwards C, et al. Mayo Clin Proc. 2017;92;1427–44; 2. Roosevelt R, et al. Brain Res. 2006;124–32; 3. Ben-Menachem E, et al. Epilepsy Res. 1995;221–7; 4. Henry TR, et al.
Epilepsia 2004;45:1064–70; 5. Koo BJ, et al. Clin Neurophysiol. 2001;434–41; 6. Labar D, et al. Seizure 2004;13:392–8; 7. Chayasirisobhon S, et al. J Neurol Neurophysiol.
2015;6:1; 8. Vonck K, et al. J Clin Neurophysiol. 2004;21:283–9; 9. De Herdt V, et al. Eur J Paediatr Neurol. 2007;11:261–9; 10. Elliott R, et al. Epilepsy Behav. 2011;20:57–63;
11. Ryvlin P, et al. Epilepsia 2014;55:893–900; 12. Orosz I, et al. Epilepsia 2014;55:1576–84; 13. Bernstein A, Barkan H, and Hess T. Epilepsy Behav. 2007;10:134–37; 14. Helmers
S, et al. Epilepsy Behav. 2011;22:370–75; 15. Ben-Menachem, E & French, JA. Epileptic Disord. 2005;7:S22–6.
LivaNova PLC, 20 Eastbourne Terrace, London, W2 6LG, UK

Drug-Resistant Epilepsy in children
of the paediatric
population have
epilepsy1
0.5–1%
• Severe epilepsy during the developmental period is detrimental to intellectual
and social maturation1
• Repeated seizures in children may lead to cognitive and behavioural impairments2
with epilepsy have drug-resistant
disease1
Up to in children
1 3
1. Elliott R, et al. J Neurosurg Pediatrics 2011;7:491–500; 2. Kanemura H & Aihara M. J Neurol Neurophysiol. 2013;S2–006.

Clinical evidence for paediatric VNS Therapy® in DRE
• The initial randomised studies of VNS Therapy® were time-limited (3-month follow
up) and demonstrated a 25%–30% decrease in seizure frequency2–4
• Subsequent non-blinded, non-randomised studies reported superior seizure control
and demonstrated efficacy, and acceptable safety for VNS Therapy® in children with
epilepsy5–10
1. Ben-Menachem E, et al. Euro J Neurol. 2015;22:1260–8; 2. Ben-Menachem E, et al. Epilepsia 1994;35:616–26; 3. George R, et al. Neurology 1995;45:224–30; 4. Handforth A, et al. Neurology
1998;51:48–55; 5. Ben-Menachem E, et al. Neurology 1999;52:1265–7; 6. Benifla M, et al. Childs Nerv Syst. 2006;22:1018–26; 7. Helmers SL, et al. J Child Neurol. 2001;16:843–8; 8. Murphy JV, et
al. J Pediatr. 1999;134:563–6; 9. Murphy JV, et al. Arch Pediatr Adolesc Med. 2003;157:560–4; 10. Patwardhan RV, et al. Neurosurg. 2000;47:1353–8; 11. FDA SSED for VNS. Available at:
https://www.accessdata.fda.gov/cdrh_docs/pdf/p970003s207b.pdf. Accessed March 2018.
In 1994, VNS Therapy® was approved in Europe for the
treatment of DRE1
FDA=Food and Drug Administration; VNS=vagus nerve stimulation.

RNS
DBS
VNS
No
Probably
(Limited
cvidence)
yes
Generalized or
Multifocal epilepsy
Yes
Yes
No
Invasiveness (intracranial)
Yes
No
No
Recording capbility
No
No
Yes
Indication for depression
Probably
Unknown
Yes
Positive effects on mood &
congition
No
Unknown
Yes
Children
No
Variable
Yes
MRI brain
Closed
(electrographic
Seizure)
Open
Open and
closed
(tachcardia)
Loop type
No
No
Yes
Side effect during stimulation
U.S. (FAD) only
U.S. (FDA),
Europe (CE-
mark), Canada,
Australia
All
Regulatory approval as of now
Green = advantage
Red = disadvantage Benbadis et al, Epil & Behav, in Press.
Yes (2020)

Effectiveness of VNS Therapy® by seizure type1,2
Adapted from 1. Cukiert A, et al. Seizure 2013;22:396–400; 2. Cukiert A, et al. Neuromodulation 2013;16:551–3.
42%
58%
17.9%
88%
42%
58%
9.3%
80%
75%
49%
• VNS Therapy® has shown to be effective in reducing daily frequency rates in myoclonic and
generalised tonic-clonic seizures in children with Lennox-Gastaut or Lennox-like syndromes
To be updated for each country’s label

AspireSR®1
The first VNS Therapy® system that provides responsive stimulation to heart-rate increases
that may be associated with seizures
The AutoStim mode feature:
• Detects rapid heart-rate rise
• Delivers automatic stimulation
• Has customisable parameters to meet patients needs
• Works in conjunction with normal and magnet mode
1. VNS Therapy System. Physicians manual. Available at: http://en.eu.livanova.cyberonics.com/healthcare-professionals/resources/product-training. Accessed May 2018

Heart-brain connection1
82%
of patients
with epilepsy experience
rapid heart-rate
increase associated
with a seizure3
Ictal discharges to areas of the brain that regulate
the autonomic nervous system can impact heart rate2
Adapted from 1. Carter R, et al. The Human Brain Book, New York: Dorling Kindersley Limited, 2009; 2. Jansen K, et al. Seizure 2010;19:455–603; 3. Eggleston KS,
et al. Seizure 2014;23:496–505;

More than 60%
of seizures treated with
Automatic Stimulation ended
during the course
of stimulation
(28/46 treated seizures)
Results: Seizure cessation
1. Data on file. LivaNova. E-36/E-37 Integrated Clinical Study Report.

Earlier stimulation correlated with shorter seizures1
R² = 0.69
0
30
60
90
120
-60 -30 0 30 60 90 120
Stimulation latency (seconds)-relative to ictal onset
N=28 seizures
ended during
stimulation, from
14 patients
Seizure
duration
(seconds)
Ictal
EEG
Onset
Earlier stimulation
Shorter seizure
Earlier
stimulation
Shorter
seizures
1. Bialer M, et al Epilepsy Research 2017;130:27–36.

Optimising AspireSR® settings
The Threshold determines the % heart-rate increase that will trigger
AutoStim (20–70%), thereby also influencing detection latency
26 sec detection latency
5 sec
20.5 sec
21 sec
16 sec
11 sec

Reduction of ictal synchronisation by acute
stimulation at seizure-onset
Ictal synchronisability
pre-VNS Therapy®
Ictal synchronisability
post-VNS Therapy®
***p<0.001
1. Ravan M, et al. 2017 IEEE Trans Biomed Eng. 2017;64:419–28; 2, Ravan M, et al. Epilepsia 2016;57(Suppl.):1–261.
Acute VNS Therapy® reduces generalisation
of seizures
pre-VNS Therapy® 105 seizures
post-VNS Therapy® 107 seizures

Seizure duration
Seizure severity
Improves QoL
Improving patient outcomes with AspireSR®*1
Long-term efficacy and safety
Detects heart rate
associated with seizures
Automatic delivery of
on-demand stimulation
*The AutoStim feature should not be used in patients with clinically meaningful arrhythmias.
1. Boon P, et al. Seizure. 2015;32:52–61.

What is the goal of dosing?
Adjust stimulation
parameters as quickly
as tolerable to reach a
therapeutic dose
Generate an action
potential on the vagus
nerve by creating a charge
Maximise
therapeutic effect
Minimise
side effects

Action potential initiation
Nerve
membrane
potential U/mV
Generator
Stimulation
20
0
-20
-40
-60
-80
-100
Time
Threshold Level
Resting Potential
Action Potential
One pulse of
stimulation
Stimulation must be high
enough for membrane potential
to reach Threshold Level
Stimulation not enough to reach
Threshold Level
When Threshold Level is met,
Action Potential is initiated
Stimulation not enough to reach
Threshold Level
1. Barker RA, Ciccetti F & Neal MJ. Neuroanatomy and Neuroscience at a Glace (2012) 4th edition. p38–89

Response to stimulation (1)1
• The position, composition of the fascicles (A, B
and C fibres) and key fascicles needed for
effective stimulation vary among patients
• The VNS Therapy® electrode will not fully
encircle the nerve (wraps approximately 270º
around it)
• If the fibres of interest are in the uncovered
region, they may require more charge for
activation
Illustration of a peripheral nerve with
fibre bundles and connective tissues
Connective tissues
Fascicle
Perineurium
Epineurium
VNS Therapy®
electrode Blood vessels
1. Helmers SL, et al. Acta Neurologica Scand. 2012;126:336–43.

VNS Therapy® electrode
Illustration showing the voltage distribution
resulting from an applied stimulus
While ramping up the stimulation
current, more and more nerve
fibres in a mixed nerve get
activated and create action
potentials.
Response to stimulation (2)1
Vagus nerve
Schematic illustration for VNS Therapy®
Stimulus
1. Hille B. Ion Channels of Excitable Membranes; Sinauer Ass. 1992. 2nd Edition.

VNS Therapy®: Stimulation parameters1
(applicable for Normal Mode; Magnet Mode; AutoStim (1)
Output Current
Amount of electrical
current delivered in a
single pulse of stimulation
Pulse Width
Duration of a single pulse
within a stimulation period
Signal Frequency
Number of pulses per
second
Pulse Width (µsec)
Output Current (mA)
Signal Frequency (Hz)

Ramp Up/Down Period
Gradual Increase/Decrease in output current intensity at the beginning/end of stimulation pulses
ON Time (sec)
Duration of time that the Generator delivers pulses at the programmed output current
OFF Time (min)
Interval between programmed ON Times (includes Ramp Up/Down periods)
Ramp
Up
Ramp
Down
(2 sec) (2 sec)
ON Time
OFF Time
(Frequencies <10
Hz do not ramp)
VNS Therapy®: Stimulation parameters1
(applicable for Normal Mode; Magnet Mode; AutoStim) (2)

Dosing parameters
Stimulation throughout the day (24 hours/day, 7 days/week) is referred to as
the Normal Mode Stimulation
Parameter Units Range
Output Current Milliamps (mA) 0–3.5
Signal Frequency Hertz (Hz) 1–30
Pulse Width Microseconds (sec) 130–1,000
Signal On-Time Seconds (sec) 7–60
Signal Off-Time Minutes (min) 0.2–180

Time
VNS Therapy® dosing: Phase 1
Ramping up Normal Mode Output Current
Output
Current
0.25 mA
0.50 mA
1.00 mA
Implantation
• Increase Normal Mode Output Current to therapeutic range as quickly as tolerable
• More frequent visits (1–2 weeks) are suggested in Phase 1
1.50 mA
2.00 mA
Phase 1: Normal Mode Output Current
≥2
weeks
Therapeutic Range: 1.5–2.25mA
(some patients may receive additional
efficacy at higher Output Currents)
Phase 2:
0.125 mA
0.375 mA
0.625 mA
Multiple 0.25 mA increases
may be made in a single visit
to reach therapeutic range
sooner; ensure patient
tolerability before making
additional adjustments

Titration process: Increasing output current
Multiple increases in output
current can be made in one
dosing session if tolerated
by the patient
Target range for a minimally
effective dose is approximately
1.5 mA – 2.25 mA
Parameter Adjustment #1 Adjustment #2 Adjustment #3 Adjustment #6
Output Current 0.25
Signal Frequency 20/30
Pulse Width 250/500
Signal ON Time 30
Signal OFF Time 5
Duty Cycle (%) 10
Magnet Output Current 0.50
Magnet Pulse Width 500
Magnet Signal ON Time 60

Output Current 0.25 0.75
Signal Frequency 20/30 20/30
Pulse Width 250/500 250/500
Signal ON Time 30 30
Signal OFF Time 5 5
Duty Cycle (%) 10 10
Magnet Output Current 0.50 1.00
Magnet Pulse Width 500 500
Magnet Signal ON Time 60
by the patient
1.5 mA – 2.25 mA

Output Current 0.25 0.75 1.50
Pulse Width 250/500 250/500
Signal OFF Time 5 5
Magnet Output Current 0.50 1.00 1.75
Magnet Signal ON Time 60 60
by the patient
1.5 mA – 2.25 mA

Output Current 0.25 0.75 1.50 2.00
Pulse Width 250/500 250/500
Signal OFF Time 5 1.8
Magnet Output Current 0.50 1.00 1.75 2.25
Magnet Signal ON Time 60 60
by the patient
1.5 mA – 2.25 mA

Typical dose-adjustment session
1. Interrogate generator
2. Adjust parameters if desired,
based on efficacy, outcome and
paying attention to patient’s
tolerability
3. Programme parameters
Perform System Diagnostic test
Always interrogate
generator as last step in session
Ensures parameters are programmed and
delivered as desired

Strategies to alleviate side effects
Reduce signal
frequency from
30 Hz to 20 Hz
Reduce the pulse
width from 500 sec
to 250  sec.
If the patient cannot
tolerate a pulse width of
250 sec, reduce output
current by 0.25 mA

Optimising dosing effectiveness
Increasing output current
beyond generating an
action potential is likely to
generate side effects and
decrease battery life, but
does not increase
effectiveness
Increasing the amount of time
VNS Therapy® is stimulating per
day may increase effectiveness
Achieved through duty cycle
adjustments

Duty Cycle
Duty Cycle
is the amount of
time stimulation is
being delivered in a
24-hour period
Standard Duty
Cycle is 10%
30 sec on;
5 min off
Maximum
recommended Duty
Cycle is 49%
21 sec on;
0.5 min off

Duty Cycle: Caution
IMPORTANT
Excessive stimulation, combination of:
• Excess duty cycle (i.e. occurs when ON time is greater than OFF time)
• High-frequency stimulation (i.e. stimulation at ≥50 Hz)
Excessive stimulation:
• Resulted in degenerative nerve damage in laboratory animals
• Excess Duty Cycle can be produced by continuous or frequent magnet activation (>8
hours)
• Continuous or frequent magnet use could lead to early battery depletion
Maximum programmable frequency is limited to 30 Hz to prevent excessive stimulation

Duty Cycle
The design prevents excessive stimulation by limiting the frequency to 30 Hz.
It is recommended that ON time is not programmed to be greater than OFF time
Off Time (Minutes)
On Time
(Seconds)
0.2 0.3 0.5 0.8 1.1 1.8 3.0 5.0 10
7 58% 44% 30% 20% 15% 10% 6% 4% 2%
14 69% 56% 41% 29% 23% 15% 9% 6% 3%
21 76% 64% 49% 36% 29% 19% 12% 8% 4%
30 81% 71% 57% 44% 35% 25% 16% 10% 5%
60 89% 82% 71% 59% 51% 38% 27% 18% 10%

Duty Cycle
Off Time (Minutes)
On Time
(Seconds)
0.2 0.3 0.5 0.8 1.1 1.8 3.0 5.0 10
7 58% 44% 30% 20% 15% 10% 6% 4% 2%
14 69% 56% 41% 29% 23% 15% 9% 6% 3%
21 76% 64% 49% 36% 29% 19% 12% 8% 4%
30 81% 71% 57% 44% 35% 25% 16% 10% 5%
60 89% 82% 71% 59% 51% 38% 27% 18% 10%

On-demand dosing parameters
Magnet Output
Current
Milliamps
(mA)
0–3.5
Magnet Pulse Width
Microseconds
(sec)
130–1,000
Magnet On Time Seconds 7–60

AspireSR® dosing parameters
Stimulation throughout the day (24 hours/day, 7 days/week)
is referred to as the Normal Mode Stimulation
Besides the Normal Mode and Magnet Mode parameter settings AspireSR has the following
extra parameters:
CBSD seizure detection ON
AutoStim Output Current Milliamps (mA)
0–2.0 (0.125)
2.0–3.5 (0.25)
AutoStim Pulse Width Hertz (Hz) 130–1,000
AutoStim On Time Seconds (sec) 30–60
Heartbeat Detection Sensitivity 1–5
Threshold for AutoStim Percentage 20–70

AspireSR® Duty Cycle with cardiac-based seizure detection
(CBSD) and AutoStim – ON
Off Time (Minutes)
On
Time
(Seconds)
0.2 0.3 0.5 0.8 1.1 1.8 3.0 5.0 10
7 58% 44% 30% 20% 15% 10% 6% 4% 2%
14 69% 56% 41% 29% 23% 15% 9% 6% 3%
21 76% 64% 49% 36% 29% 19% 12% 8% 4%
30 81% 71% 57% 44% 35% 25% 16% 10% 5%
60 89% 82% 71% 59% 51% 38% 27% 18% 10%
AspireSR® with CBSD OFF and AutoStim OFF acts like prior generator models
AspireSR® with CBSD ON and AutoStim ON:
In order to allow enough detection time between scheduled stimulation
periods, the Programming Software will not allow selection of normal mode to
programme Off Time of ≤0.8 minutes

General dosing guidelines
Always dose to
patient tolerance
and ensure that the
patient can tolerate
settings before
leaving the office
Give the patient time
to adjust to parameter
changes before making
additional adjustments
Higher magnet mode
settings can increase
tolerability of higher
settings
Frequent office visits
(every 1–2 weeks) are
suggested for the first
several months to
track patient response
and adjust stimulation
parameters

THANK YOU
amrhasanneuro@kasralainy.edu.eg

Vagal Nerve stimulation

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