Vns Therapy™ System For Weikong For Print

1

VNS Therapy™ Systemfor Epilepsy Patients

VNSSS05-11-1000-EC

Wei Gong Memorial HospitalNOV15 2007

AST

A Light on the A Light on the HorizonHorizon

The Epilepsy Patients

• Easy to Control: – 47% can be controlled

by 1 AED– Only 17% can be

controlled by added-on AED

• Difficult to Control:– 39% of Total Epilepsy

1st AED, 47%

2nd/ 3rd AED,14%

Multi-AED,3%

Difficult-to-control, 36%

Easy to Control Group Difficult toControl, 39%

Easy to Control,61%

1st line AED: CAM, DIZ, DIL etc

2nd line AED: Top, Neuro, Oxb etc

Seizure free with or without side effect

Well management:3-month prescriptionTolerant side effect

Controlled Seizure or free of seizure Satisfied and Happy PatientSatisfied and Happy Patient

Difficult to Control Group Difficult toControl, 39%

Easy to Control,61%

1st line & 2nd line AED failure

Multi-AED or Treatment-Resistant

Seizure, and AED side effect

Continue Multi-AED with side effectSurgical evaluation

Search for alternative treatment Suffer from bad QoL Unhappy patients Unhappy patients

What are patient looking for?

Quality of Life Improvement

II

Treatment’s Benefit –Treatment’s Side effect

What are patients looking for?

BQoL

SE

Easy to Control Group

Valu

e

B

QoLSE

Difficult to Control Group

Valu

e

Do we have other tools?Product Side Effect

CNS Vision Skin GU/Reproduction

Liver toxicity

Others

Carbamazepine v V

(Diplopia)

V,

S-J

Valporic Acid / Sodium

v V,

POD

V B.W.

Phenytoin v V Gum hyperplasia

Lamotrigine V Rush, S-J(A: 1/1000, C: 1/50~1/100)

Vigabatrin V Vision angle narrow

B.W.

Gabapentin V

Topiramate V Glaucoma (23/82,500)

Kidney stone (1.5%)

B.W.

VNS X X X X X x

Seizure reduction: VNS + AED

12%

26%

11%

26%20%

58%

18%25%

36%

50%

33%

54% 56%

36%43% 40%

62%

0%

10%

20%

30%

40%

50%

60%

70%

TGB OXC ZNS PGB GBP LTG TPM LEV VNS

Medium (mean) seizure reduction in adults patientsAdd-on therapy for partial refractory epilepsy

Ref: J.A. French et al. Neurology 2004, 62: 1261-1273, Welinaton A et.al, CNS Drugs 2001: 15(2):137-163; A. Gil-Nagel Rev Neurol 2005. 40(10):609-613; G Zaccara et al. Acta Neurol Scand 2006; 114:15-168;T.A. Glauser Epilepsia 1999; 40 (Suppl.5) S71-S80; P. Genton et al. Acta Neurol Scan 2006; 113:387-394

Too Good to be True?

Unique Mechanism of Action

Mechanism of Action

• VNS works by triggering the left Vagus to send electrical pulses into the brain

• The Vagus is projected througth the NTS, Locus coeruleus, Raphe magnus nuclei, Limbic structure, Hypothalamus and Thalamus.

• These neuro pathway are important for VNS’s positive effects.

III-11

Vagus Nerve Projects to Key Brainstem Regions

Henry TR. Neurology. 2002;59(suppl 4):S3-S14.

STN=spinal trigeminal nucleus; NTS=nucleus tractus solitarius; DMN=dorsal motor nucleus of the vagus; AP=area postrema; NA=nucleus ambiguus; CN-X=cranial nerve X; RF=reticular formation.

Bilateral projections on nucleus tractus solitarius (NTS)

III-12

Vagus Nerve and NTS Project to Key Brainstem Regions


KFN=Kölliker-Fuse nucleus; LC=locus coeruleus; ICH=inferior cerebellar hemisphere; RMN=raphe magnus nucleus; PBN=parabrachial nucleus; NTS=nucleus tractus solitarius.

• Parabrachial nucleus of pons has widespread cerebral projections

• Locus coeruleus supplies norepinephrine

• Raphe magnus nuclei supply serotonin

III-13

Vagus Nerve - NTS - PBNProject to Key Cerebral Regions

• Limbic structures– Amygdala– Insula

• Autonomic structures– Hypothalamus – Periaqueductal gray

• Reticular structures– Thalamus


NTS=nucleus of the tractus solitarius; PBN=parabrachial nucleus; PAG=periaqueductal gray; CNA=central nucleus amygdala; PVN=periventricular nucleus of hypothalamus; VPM=ventral posterormedial nucleus of thalamus.

Year Investigator Patients Result1992 Hammond Partial epilepsy (n=9) VNS Therapy aborted

Adults seizures (n=2) early in epileptic event 1993 Salinsky, Partial epilepsy (n=6) No statistically significant

Burcheil Adults effects on EEG

2001 Olejniczak Presurgical evaluation VNS Therapy decreased (n=1) hippocampal

spikes at Adults 30 Hz; increased at 5 Hz

2001 Koo Generalised and partial Generalised and focal onset seizures; high frequency spikes diminished during of interictal discharges;

VNS Therapy (12 months)

younger patients

VNS on Human EEG


Serial EEGs of the same patient. Above: baseline EEG showing active multifocal independent epileptiform activity.

Koo B. EEG changes with vagus nerve stimulation. J Clin Neurophysiol ; 18 (5): 434-441.

EEG 3 months after the patient received a VNS implant showing similar alternating paroxysms of spikes/spike and wave activity with periods of

spike-free intervals during the time when stimulation is off.


EEG at 1 year showing further prolongation of intervals of spike-free period.


MOA Comparison

• AED– Neurotransmitter

inhibitor– Suppress both,

epileptic and normal brain function

• Cranial Surgery– Removal of

epileptic region of brain

• VNS– Does NOT

suppress nor remove brain function

Not Only Seizure Control

• “Quality of Life of can not be maximized if we solely focus on seizure frequency and severity”

• Schachter, 26th international epilepsy congress

34%

31%

43%

40%

44%

55%

61%

Memory

Achievements

Mood

Verbal Skills

Clusters

Post-ictal

Alertness

12 Months (N=1615)

VNS Therapy Quality of Life Benefits

VNS Patient Registry: January 25, 2002Data on file, Cyberonics, Inc.

% of Registry Patients Better or Much Better*

Constant Cohort Data

* Fewer than 7% of patients reported any single measure worse

15 children study oncognition, QoL, behaviour and mood

• N=15, Mean Age=11 (4-17)

• Seizure Reduction: – 6/ 15 children showed a 50% or more reduction in seizure frequency; – 1/15 became seizure-free. – 2/15 children had a 25—50% seizure reduction. .

• QOL, Mood, Cognition– 13/15 children there was an improvement in NHS3 (National Hospital

Seizure Severity Scale)– There were no changes in cognitive functioning. – 12 showed an improvement in QOL. – 11 improved in seizure severity and mood and 5 also in depressive

parameters.

• Conclusion: This study has shown a good anti-seizure effect of VNS, an improvement in seizure severity and in QOL and a tendency to improvement over time.

Tove Hallbo¨o¨k et.al , Seizure (2005) 14, 504—513

QoL Improvement

• In addition to experiencing fewer and less severe seizures, many VNS Therapy patients and their doctors also report:

– Improvements in their mood– Increased alertness– Improved memory– Possible reduction in number and

doses of medications– Fewer visits to the emergency

room

Jerry,

44 years of age

“

”

Since the implant,

I have been able

to live a normal life free from the

side effects of medication...

My life has regained

a semblance

of normality.

Responder Rate of VNS

49%

31%

23%

39%

43%

59%

51% 50%

0%

10%

20%

30%

40%

50%

60%

70%

All E-03(3 mon)

E-05(3 mon)

X5E (15 mon)

Morris(>2 yr)

Registry (2 yr)

Renfore (3 mon)

Renfroe (3mon)

On Average, 49% of the patients are responders to VNS TherapyTotal Patient number: 4432, 50% seizure reduction responder: 2172

Seizure Free Rate

7.4%

27%

15% 13% 12%8% 8% 7% 6% 5% 5% 5%

0%5%

10%15%20%25%30%

Total patients: 7174, Seizure free: 533, Seizure free rate: 7.4%

Reduction by Seizure type• Lennox-Gastaut Syndrome: 58% reduction after 6 months

• LGS + Drop Attacks: 88% reduction after 6 months

• LGS + Absence: 81% reduction after 6 monthsFrost M. Epilepsia.2001;42(9)1148-1152.

• Tuberous Sclerosis: 50% reduction in 90% patientsParain D. Paediatric Neurology. 2001;25(3):213-216.

V d - 26

47%50%

53%50%50%

56%56%61%61%59%

0

10

20

30

40

50

60

70

(0-6) (7-11) (12-18) (19-35) (36-55)

3 months12 months

Wheless J et al. Neurology. 2002;59 (Suppl 4) S21-S25.

115/229 57/96 215/433 136/222 323/610 198/326 543/1080 349/626 477/1014 318/558

Pat

ien

ts (

%)

Patients with ≥50% Reduction in Seizures

Age (Years)

Seizure Reduction by Age Group - Wheless

VNS is more effective in patients under 18 VNS is more effective in patients under 18

SAFETYSurgical Complications

Epilepsy Clinical Studies (n=454)

• •Surgical Complication 0.5% 1

•Infection without explant 1 •Infection with explant 1 •Hoarseness/temporary vocal cord paralysis 1 •Hypoesthesia/lower left facial paresis 1

1.8%1.1%0.7%0.7%

• Mortality 0.0%

1Bruce DA, et al. Epilepsia. 1998;39(suppl 6):92-93.

SAFETYSide Effects

• Hoarseness, • Paresthesia, • Shortness of breath, • Dry cough.

– decrease with time

– only when stimulation is ON. (30sec/5min)

– can be turned off by patient

Timing for VNS Therapy1. Difficult to treat Epilepsy

2. Patient not suitable or resists cranial surgery

3. Patient suffers from poor Quality-of-Life

4. Patient suffers from mental depression, poor memory and alertness.

5. Possible drug reduction and to reduce drug side effects

VNS Case Manager Hotline

Medical / Financial Evaluation

Device Implantation(Case Manager assist)

Monthly Followup (Case Manger assist)

PATIENT SATISFACTION

•Over 70% of patients chose to get new VNS after old battery expired.

•Ben-Menachen & French, 26th international epilepsy congress

PATIENT SATISFACTIONVNS v.s. AEDs

• Continuation rates at 3 years: – VNS: 72%– Levetiracetam: 37%– Topiramate: 30%– Lamotrigine: 29%

• VNS Therapy are remarkably better than long-term continuation rates with other treatments for pharmacoresistant epilepsy

World Wide Experience – Now, over 50,000 patients have been treated with VNS Therapy

within 75 countries

What VNS can bring to your patients:• Better QoL:

– Mood improvement– Alertness increase– Memory increase

• Better Efficacy to AED but much less side effects

• 7.4% Seizure free rate

Thank you for your attention

Q&A

What are patient looking for?

Mental health

Physical function

Physical role limitation

Emotional role limitation

General health

Social function

Vitality

Bodily pain0.01 0.1 1 10 100More important to More importantClinicians to patients

Odds Ratios (95% CI)

Ref: P.M. Rothwell et.al BMJ 1997; 314:1580

VNS referring center in TaiwanNorth Taiwan:CGMHVGHCathy GH

Central Taiwan:CMMHVGH-TCCHCH

South Taiwan:CKUHCGMH-KSVGH-KS

East Taiwan:Tzu-Chi

PATIENT SATISFACTIONTestimonial

Heather, 21 years of age

VNS Therapy since 1992

I was sluggish and tired, had very few friends,

and no social life. The only options were

to add another medication or to increase the medications.

“”

Heather before VNS Therapy

« Since VNS Therapy, my whole life has been completely changed. I graduated from high school.

I have made friends and am able to have a normal life. I have a job that I love in a day care centre.

The magnet stops the seizures and also decreases the length of the seizures. Not only do I

have a new life but I feel great! »

DESCRIPTION

• Proven Treatment for Epilepsy

• Improves Quality-of-Life

• Implantable stimulator delivers 24/7 therapy

• Few Side-Effects

Mechanism of Action

World Wide Experience I

• 1985 First animal studies (J. Zabara, Temple University)

• 1988 First human implant (K. Penry, B.J. Wilder, E. Ramsay)

• 1994 European community approval for RE (CE Mark)

• 1997 US FDA commercial approval for RE

• 2002 15,000+ patients treated worldwide

• 2004 25,000+ patients treated

• 2005 FDA approval for treatment in Resistant Depression

Patient Assistance Program• VNS Easy Access Program

– Rental Program– Monthly payment + initial setting cost

• VNS Case Manager helps with– Patients Education– Program Setting– Trouble Shooting

SURGICAL PROCEDURE

Pre-Implant: Summary• Power up the fully charged computer previously

loaded with Programming Software• Attach Programming Wand (with working 9V

battery) to computer• Pre-op I.V. antibiotic administration Use computer and wand

to perform generator “Communication Check” outside of sterile field in sterile package by performing an “Interrogation”

Program in patient initials and implant date

VNS System Implant:Positioning the Patient

• Anesthesia administered

• Patient in supine position with head turned to the right

VNS System Implant: Marking the Incision Sites

Clavicle

Anterior fold of axilla incision site option

Neckincisionsite

Transverse incision site on left neck marked, in skin crease midway between clavicle and mastoid process, for electrode placement (for thick neck, vertical incision used). Transverse incision performed to “hide” scar in neck.

Incision site marked at front fold of left axilla or on left frontal chest wall aligned to the center of clavicle for generator placement

VNS System Implant: Platysma Divided

VNS System Implant: Palpating the Carotid Pulse

VNS System Implant: The Exposed Carotid Sheath

VNS System Implant: Isolating the Vagus Nerve

• Expose >3cm of nerve.• Use soft vessel loops

to gently lift nerve.• Avoid excessive

handling of nerve to prevent injury & preserve branches off the vagus.

• Avoid letting the nerve dry out.

VNS System Implant: Creation of Generator Pocket

• Incision made with creation of subcutaneous pouch superior to pectoralis major

VNS System Implant: Creating the subcutaneous

tunnel • The tunneler is inserted in the neck incision and passed to the chest incision. The bullet tip and then steel shaft are removed leaving the plastic sheath.

Tunneling Direction

VNS System Implant: Passing the Lead

• The connector pin end(s) of the lead are inserted into the sheath of the tunneling tool at the neck opening. The sheath is pulled out through the chest incision.

TunnelingDirection

VNS System Implant: Lead position after being

passed • After pulling the sheath from the chest incision, the connector pin(s) are removed. The helical electrodes remain near the neck incision.

VNS System Implant: Final Electrode/Anchor Tether

Placement

Negative Electrode

Positive Electrode

Anchor Tether

Cephalad Caudal

• Use of the integrated anchor tether helps prevent force transfer to the electrodes.

VNS System Implant: Routine System Diagnostic Test

#1• Perform a

Lead Test to make sure both components are functioning

• If Lead Test fails, check all connections.

VNS System Implant: Strain Relief Bend

VNS System Implant: Silastic Tie-Down

• Lead strain relief bend completed with lead attached to fascia using tie downs

VNS System Implant:Inserting the Pulse Generator

• Secure pulse generator with suture to prevent migration.

• Logo may face up or down.

VNS System Implant: Routine System Diagnostic Test

#2 • After the skin is closed, and before breaking the sterile field, perform a confirmatory Lead Test

• After Lead Test, perform a confirmatory interrogation to make sure that the Pulse Generator is set to 0 mA

VNS System Implant: Closure

• To minimise scarring, a subcuticular closure is recommended for both skin incisions.

Thank you !!!

Back up slide

Who can benefit from VNS Therapy?

People suffering

from difficult-to-control seizures

People with

all seizure types

People of all ages:

kids, teens, adults,

elderly

• People who are not candidates for brain surgery

• People who do not want to have brain surgery

• People who failed brain surgery

• People suffering from epilepsy who have developmental disability (MRDD)

Refractory Epilepsy Occurrence

• More than 30% of patients continue to have seizures in spite of multiple adequate trials with pharmacologic therapy. Seizures may persist in terms of frequency, severity, or duration, or in all 3 aspects.

V d - 69Frost M. Epilepsia.2001;42(9)1148-1152.

Seizure Reduction – LGS - Frost (2001)

38%

58%

0

10

20

30

40

50

60

> 50% > 75%

Seizure Reduction (n=24)

Pat

ien

ts (

%)

6 Months after implant n = 50

mean age = 13yrs

mean onset age = 1.4yrs

# of ADE before implant = 9

>50% reduction @ 1m = 42%3m = 58.2%6m = 57.9%

50% reduction in 58% of LGS patients after 6 months

V d - 70

55%

47%

0102030405060708090

100

1 m 3 m

Mea

n R

edu

ctio

n (

%)

Drop Attack Seizures

p<0.0001 p<0.0001

Seizure Reduction – Drop Attacks (LGS) - Frost

Frost M. Epilepsia.2001;42(9)1148-1152.

88%

6mp=0.0002

Data Analyzed by Drop Attack seizures

88% of Drop Attack Seizures are reduced after 6 months

V d - 71

73%

48%

0102030405060708090

100

1 m 3 m

Mea

n R

edu

ctio

n (

%)

Absence Seizures

Seizure Reduction – Absence (LGS) - Frost

Frost M. Epilepsia.2001;42(9)1148-1152.

81%

6m

Data Analyized by Atypical Absence seizures

81% of Absence seizures are reduced after 6 months

V d - 72

Seizure Reduction - Tuberous Sclerosis - Parain

• n = 10

• age range = 7 ~ 20

• mean age = 13

• 5 ~ 19 seziures/day

• Seizure duration reduction in 30% of patients

Parain D. Paediatric Neurology. 2001;25(3):213-216.

48%

90%

0102030405060708090

100

50% 90%

sei

zure

red

uct

ion

(%

)

Tuberous Sclerosis

% of patients

For TS patients, 90% of patients had 50% reduction

VNS Therapy System: Implanted Components

New ImplantsModels 102 & 302

Battery ReplacementFor Dual Cavity GeneratorModels 102R or 101 & 300

Mechanism of Action• The locus coeruleus (LC)

may be involved in anticonvulsant effect.

• Induces progressive EEG changes

• Bilateral changes in blood flow..

• Increased blood flow in the thalamus correlate with long-term seizure control

VNS Therapy System – Other Components

Recent Advances in VNS therapy

– VNS & seizure control– VNS & early treatment– VNS & drug reduction – VNS & medical cost reduction– VNS & patient satisfaction – Safety & side effects– On-going research

• In the EAR group (< 5 years after onset), 15% reported no seizures with VNS Therapy at 3 months compared with 4.4% of those in the control group.

• one patient in five reported no seizures with a loss of consciousness, and one in three with complex partial seizures reported complete control of the complex partial seizures at 3 months with earlier use of VNS Therapy.

Seizure Control – 3 months after implant

Seizure Control – 3 years after implant

An open-label, long-term study of 454 epilepsy patients using data from all 5 VNS Therapy controlled, clinical trials. The study compared the percentage of patients with seizure reductions of 50% over a 3-year period.

The percentage of patients with 50% seizure reduction was 43% at 2 and 3 years.

51% 50%

35%28% 26%

14% 15%4%

0%

20%

40%

60%

>=50% >=75% >=90% 100%

Reduction in seizure frequency at 3 months, all seizure

EAR Control

Benefit of Early VNS Treatment –

Seizure Control• Early Adjunctive Registry (EAR): n=120, VNS implant <5 yrs of 1st

onset

• Control group: n=2785, VNS implant>5 yrs of 1st onset

P=0.001

P<0.001

Ref: J.Ben Renfroe and James W.Wheless Neurology 59 (4), S26-S30, 2002

0

1000

2000

3000

4000

5000

AEDs Surgery VNS

Before treatment After treatment

ERDMC In USD

Ref: P. Boon et al. Epilepsia 43(1): 96-102, 2002

Epilepsy-related direct medical costs (ERDMC) include: Cost of AEDs Cost of visiting clinics Cost of hospital

admissions Cost of lab tests

Medical Cost Reduction Resulted by

AED / Surgery / VNS

P=0.0007

P=0.0036

VNS and Surgery both show significant decrease in ERDMCVNS and Surgery both show significant decrease in ERDMC

VNS and Medical Cost Reduction –

ICU / ER / WARD• Subject: 43

Patients• Method:

Retrospective medical record

• Sahlgenska University Hospital. Sweden -

100,000

200,000

Hopsital cost reduction from VNS

Pre-VNS 46,875 13,000 151,125

Post-VNS - 9,000 21,375

ICU ER WARD

Ref: Elinor Ben-Menachem et al. Neurology 59 (4), S44-S47, 2002

Patient Satisfaction of VNS v.s. AEDs

• Continuation rates at 3 years: – VNS: 72%– Levetiracetam: 37%– Topiramate: 30%– Lamotrigine: 29%

VNS Therapy are remarkably better than long-term continuation rates with other treatments for pharmacoresistant epilepsy

On-going Research on VNSDisease Author Subjects Key Finding

Depression Rush et al 30 patients Depression improvement

Sackeim et al 60 patients Depression improvement, smaller, response predictors

Sackeim et al Patients No adverse cognitive effects of VNS over time

Marangell et al 30 Patients Continued improvement at 1 year

Rush et al 240 Patients Ongoing

Krahl et al Rats Antidepressant effects is Porsolt Swim Test

Anxiety Group 8 Patients Ongoing

Obesity Roslin et al 10 dogs Weight reduction in chronic model

Roslin et al Patients Ongoing

Alzheimer’s dz

10 Patients Initial results promising

Migraine Ongoing

Patient IdentificationPatients who :

• Have uncontrolled seizures despite 2 adequate AED trials?

• Quality of life compromised due to uncontrolled seizures ?

• Discontinue or switch therapies frequently?

• Experience negative side effects associated AEDs?

• Are not candidates for intracranial surgery?

• Patient Identification Qualification form & Cyberonics Patient Registry

• End-of-Service Replacement

If the answer to any of these questions is “yes,” you may have patients who could benefit from VNS Therapy.

Replacement of End-of-Service Generators(video)

Replacement of End-of-Service Generators(video)

VNS Therapy Surgical Complications

Data on file. Cyberonics, Inc. Houston, TX; 2002. Data reported are for the most commonly reported surgical complications on all surgical cases including reimplants.

Post approval (n=17,019)

Infection (with and without explant)1.3%

Hoarseness/temporary vocal cord paralysis1.1%

Mortality0.0%

Device Activation–Program Settings

• Initial Activation – 2 weeks after implant• Initial program setting

• 0.25 mA output current• 20-30 Hz frequency• 250-500 µsec pulse width• ON 30 sec• OFF 5 minutes

• Adjustment:• Slowly titrate output current over 4 weeks to 0.5-1.5 mA• Reduce pulse width from 500 µsec to 250 µsec• Again, try to increase output current and decrease pulse

width

Advance Program Settings – Study Results

• High setting is more effective than Low setting– (30 sec ON, 5 min OFF, 30 HZ(0.25-3.5mA)) vs (30 sec ON,

180 min OFF, 1 HZ(0.25-3.5mA))

• Low setting were crossed over to high setting, a robust improvement in efficacy resulted: 21% to 40%

• A significant improvement in efficacy was observed when:– Duty cycle (ON/ON+OFF time) 22% – OFF time 1.1 minutes,

• A precise dose-response relationship for VNS therapy is still under investigation

Support from Cyberonic and CardioMed

• Prognosis evaluation-PIQ

• Patient education

• Financial assistance

Agenda • What is VNS

– Refractory Epilepsy– Mechanism – Picture of Product

• Recent Advances in VNS therapy

– VNS & seizure control– VNS & early adjunctive therapy– VNS & drug reduction – VNS & medical cost reduction– VNS & patient satisfaction – Safety & Side effects– Update research

• Patient Identification & Selection

• PIQ & Cyber data base

• Implant Procedure• Procedure outline

(replacement & new)• Pictures & movie• Possible complications

• Program setting• Initial settings• Adjustment

• Support from Cyberonic and CardioMed

Epilepsy-EpidemiologyEpilepsy is one of the most prevalent neurological disorders that can

be effectively prevented and treated at an affordable cost. It is the most common serious brain disorder worldwide with no age, racial, social class, national nor geographic boundaries.

• There are over 50 million sufferers in the world today, 85% of whom live in developing countries;

• An estimated 2.4 million new cases occur each year globally;

• At least 50% of cases begin at childhood or adolescence;

• 70% to 80% of people with epilepsy could lead normal lives if properly treated;

• In developing countries, 60% to 90% of people with epilepsy receive no treatment due to inadequacies in health care resources and delivery, and due to social stigma.

(Ref: http://www.who.int/mental_health/neurology/epilepsy/en/)

Cause of Epilepsy• Newborn: congenital malformation, brain injury

during perinatal or encephalitis

• Children and adolescent: injury from traumas, infections such as meningitis or encephalitis.

• Adult and elders: brain tumor and stroke

(Ref: 最新癲癇病人手冊關尚勇 2001)

Treatment Sequence for Refractory Epilepsy

Surgery evaluation before VNS?

Pulse Generator:Physical Characteristics

Model 102 Model 102R Model 101

Titanium Case

6.9 mm 52.2 mm 51.6 mm

6.9 mm 52.2 mm 51.6 mm

10.3 mm 54 mm 54 mm

Weight 25 grams 27 grams 38 grams

Header Polyurethane Polyurethane Epoxy

Power Source

Lithium Carbon Monofluoride Battery



Longevity

6 - 11 years depending on stimulation parameters



Cavity Single Dual Dual

Serial #’s

< 1,000,000 1,000,000 > 0

Pulse Generator:Programmable Parameters

Parameter Units Range Typical

Output Current milliamps 0 - 3.5 1.25

Signal Frequency hertz 1 - 30 30

Pulse Width microseconds 130 - 1000 500

Signal On-time seconds 7 - 60 30

Signal Off-time seconds/minutes 12 sec-180 min 5 minutes

Generator cycle is 24 hours per day.

Lead: The Electrodes and Anchor

Tether

--Negative Electrode

--Positive Electrode

--Anchor Tether

NOTE: Sutures are for placement, not tying.

(No metal/conducting electrode inside)

All lead models are currently available in two sizes based on helical inner diameter:

Model 302 (single pin of G102) Model 302-20 (2.0 mm)

Model 302-30 (3.0 mm)

Model 300 (dual pin of G102R, G100, G101) Model 300-20 (2.0 mm)

Model 300-30 (3.0 mm)

Lead:Physical Characteristics

Insulation: Silicone

Length: 43 cm

Resistance: 120 to 180 ohms, pin to electrode

Electrode Sizes: 2.0 and 3.0 mm inner diameter

Conductor Material: Platinum Iridium

Lead Models 300 & 302:

Please Note: Drawing is not to scale and is for informational purposes only

Vagus Nerve Schema with Lead Attachment Location

Left Vagus Nerve

Superior Cervical Cardiac Branch of Vagus Nerve

Inferior Cervical Cardiac Branch of Vagus Nerve

Superior Laryngeal Nerve

Lead Electrode Location

Thoracic Cardiac Branch Of Vagus Nerve

Left Recurrent Laryngeal nerve

Communicating Branch of Vagus Nerve to Carotid Sinus Branch of

Glossopharyngeal Nerve

Pharyngeal Branch of Vagus Nerve

Right Recurrent Laryngeal nerve

Model 100

Single Pin Connector: Model 102Prior/Fully InsertedSingle Pin Connector: Model 102Prior/Fully Inserted

Dual Pin Connector: Model 102RPrior/Fully Inserted

Model 402 Tunneler

• Contents:– 2 sleeves to

accommodate both Lead models

– Steel shaft– Steel bullet tip

Model 502 Accessory Pack• Contents:

– Hex screwdriver– 4 tie-downs– Dual pin resistor for

101, 102R– Single pin resistor for

102

Programming System Components

• A computer, Programming Software (Model 250), and Programming Wand (Model 201) communicate transcutaneously to the Pulse Generator

• Easy to use

• Used during– Surgical implant– Programming office visits

Model 201 Programming Wand• Model 201

Programming Wand• Intended for use only with

the VNS Therapy System.

• Hand-held device that transmits programming and interrogation information between a VNS Therapy Computer and the VNS Therapy Pulse Generator

Model 220 Magnets

• Provide on-demand stimulation that may help abort or lessen the intensity of an oncoming seizure

• Temporarily inhibit stimulation

• Reset the Pulse Generator (in combination with the Programming Wand)

• Test daily the functioning of the Pulse Generator

Cost Reduction after VNS Therapy

• Epilepsy-related direct medical costs (ERDMC):– Cost of AEDs

– Cost of visiting clinics

– Cost of hospital admissions

– Cost of lab testsPre- VNS

Post- VNS (2 years)

Range P value

(Wilcoxon signed rank test)

ERDMC US 8830 US 4215 US 615-11794

N=13

0.018

HP admission days

21 days 8 days 0-35 day

N=13

0.023

Ref: P. Boon et al. Acta Neurochir 141:447-453, 1999

Program Setting: Physicians Experiences

ON (sec) OFF (min) Duty Cycle (%)

30 5 10

30 3 16

30 1.8 25

30 1.1 35

21 0.8 36

14 0.4 41Duty cycle=(ON+4)/(ON+OFF) in sec

Some physicians use the following progression to find the optimal duty cycles for their patients

ERDMC between 3 TRT of Refractory Epilepsy

Parameters Before (range) After (range)

Conservatively treated patients

Cost HAD 875 (0-8494) 870 (0-6310)

Cost clinic visit 114(39-243) 93(22-132)

Cost AEDs 1305(44-6299) 1218(110-2885)

Cost lab test 230(110-386) 241(110-441)

ERDMC 2525(287-15254) 2421(387-7409)

CPS(#/mo) 12(1-30) 9(0-30)

Surgically treated patients

Cost HAD 33(0-3398) 222(0-5339)


Cost AEDs 986(84-2568) 881(90-3242)

Cost lab test 18(11-33) 18(11-33)

ERDMC 1465(205-5138) 1186(149-6393)

CPS(#/mo) 17(0-210) 2.3(0-53)

VNS-treated patients

Cost HAD 3048(0-14561) 693(0-3155)


Cost AEDs 1389(278-2307) 1498(416-2925)

Cost lab test 243(0-331) 216(0-331)

ERDMC 4826(631-16661) 2496(813-5432)

CPS(#/mo) 21(2-180) 9.3(0-60)

What is VNS• An adjunctive therapy in reducing the frequency of seizures in patients whose

epileptic disorder is dominated by partial seizures or generalized seizures, which are refractory to antiepileptic medication.

• VNS Therapy delivers stimulation via a device implanted just under the skin in the left chest area. The pacemaker-like device sends mild, intermittent electrical impulses through a lead to the left vagus nerve, which then sends signals to the brain. Each device is programmed for the individual patient, and the patient has the ability to initiate or abort stimulation with the use of a hand-held magnet.

Patient Kit

• Contents:– Patient Manual– 2 Magnets– Patient Emergency

Information Card

• To be given to patients immediately following surgery

New Benefits for 102 v.s 1001. 33% thinner2. 34% lighter3. single connector eliminate the risk of

reverse polarity4. longer battery life (2X)5. longer warranty (2yr instead of 1yr)6. faster programming7. longer shelf life

The VNS Therapy System Components

• Implement components:– Pulse Generator: Model 101, 102, 102R – Lead: Model 300, 302

• Disposable components: – Tunneler Model 402– Accessory Pack Model 502

• Programming and patient components:– Magnet Model 220

• Watch-style (220-3) and Pager-style (220-4)

– Programming WandModel 201– Programming Software Model 250 – Programming Computer

No Latex in any product

Pictures First

Patient assistance: Avenues program

• AVENUES Program

• Patient Videos

• Website: www.vnstherapy.com

• Power To Renew My Life Diary

• VNS Therapy Phone Facts Teleconferences

• Case Managers

Asystole from Lead Test in Surgery

• Incidence of asystole during routine intraoperative lead test 1 – Reported rate is estimated to be between 1 in

400 and 1 in 800 patients

– Full recovery for all patients

• Similar events were not reported in controlled, epilepsy clinical trials 2

• Reason: anatomic differences, lead placement, anesthesia, or collateral current spread? 1,3

1Data on file. Cyberonics, Inc. Houston, TX; 2002. 2Tatum WO, et al. Neurology. 1999;52:1267-1269.3Asconape JJ, et al. Epilepsia. 1999;40:1452-1454.

Program Setting: FAQ• When can I safely activate the device?Ans: 2 weeks after surgery.

• What are the most important things to remember when adjusting VNS parameters?

Ans:– monitor the patients for shortness of breath, throat

tightness/discomfort, excessive hoarseness and discomfort with swallowing.

– Follow the physician manual of Generator Sec 8 (approved by FDA)– Ensure the patient tolerance before leaving

• How do I manage side effects?Ans: Adjust pulse width first then the output current.

• What are appropriate magnet settings?Ans: Magnet settings should be programmed at 0.25 mA

higher than the around-the-clock VNS therapy. Setting the output current of magnet higher than regular.

No Side Effects from AEDs and Safe

• No side effects associated with AEDs e.g.: sleeplessness, confusion, weight gain, memory loss

• VNS Therapy is not associated with – interactivity toxicity1,2 – pharmacokinetic interactions2 – systemic neurotoxic effects2 – idiosyncratic reactions (rash, renal impairment, bone marrow

suppression etc.)2

• No evidence of impaired fertility or harm to the fetus in animal studies 3 →FDA granted approval VNS Therapy safety in women of childbearing age.

The unique safety profile of VNS Therapy can contribute to the quality-of-life for patients.4

1Henry TR. Neurology. 2002; 59 (suppl.4):S3-S14.2Gates J, Huf R, Frost M. Epilepsy & Behavior. 2001; 2:563-567.3Physician’s Manual: VNS Therapy Pulse Model 102 Generator. Houston, Texas: Cyberonics Inc.; 2003. 4Wheless JW et al. Neurology. 2002; 59 (suppl.4):S21-S25.

Program Settings: New Parameter Study Results

Group ON

(sec)

OFF

(sec)

DC

(%)

N 75%

responder

A 7 18 28% 19 5%

B 30 30 50% 19 0%

C* 30 180 14% 23 13%*The data is similar to those found in the prior study to let FDA approval: 11% (75%) in 30 sec ON and 5 min OFF If the patients has shown no response after several months, then decreasing the OFF times may be appropriate

Data on file. Cyberonics, Inc. Houston, TX

VNS chronology• 1988 EO1 Study-1st Human Implant

• 1994 European Community Approval

• 1997 5 Completed Controlled Studies (N=454)

• 1997 US and Canadian approvals

• 2004 >25,000 patients treated

Patient Selection• Limited success with any single AED or combination of AEDs2

• Response to first AED trial2

• Predictors related to intolerable side effects

• Seizure frequency before initial therapy2

• Early age at onset3

• Cause or origin of seizures2

• Electroencephalographic (EEG) factors3

• Imaging with positron emission tomography (PET)4

• Cyberonic’s Patient Registry – PIQ for predicting treatment outcome.

1Brodie MJ, Kwan P. Neurology. 2002;58(suppl 5):S2-S8.2Kwan P, Brodie MJ. N Engl J Med. 2000;342:314-319.3Ko TS, Holmes GL. Clin Neurophysiol. 1999;110:1245-1251.4Dupont S, et al. Arch Neurol. 2000;57:1331-1336.

Implant procedure of VNS system(video)Implant procedure of VNS system(video)

VNS Therapy - a breakthrough in treating difficult-to-control epilepsyVNS Therapy - a breakthrough in treating difficult-to-control epilepsy

A clinically proven epilepsy treatment

Safe and has been used in over 50,000 patients

Helps to prevent seizures

Has minimal side effects

Can improve quality of every day life

Has long-term benefits

Is easy to live with

Gives people with epilepsy a sense of control over their lives

VNS TherapyA different mechanism of actionVNS TherapyA different mechanism of action

The mechanism of action of VNS Therapy might be:

Changes in metabolism of brain areas relevant to mood regulation

Alteration of key mood-regulating brain neurotransmitters1,2

Changes in the HPA-axis3

1. George MS et al., Biological Psychiatry, 2000. 2. Dorr et al., The Journal of Pharmacology and Experimental Therapeutics, 2006. 3. O’Keane et al., Biological Psychiatry, 2005. 4. Data acquired from St. Louis University, analyzed at Medical University of South Carolina Center for Advanced Imaging Research by Xingbao Li, MD; 6 patients for 3 months of VNS Therapy, compared with baseline.

Cortical/limbic brain specificity with VNS Therapy4

Orbitofrontal cortex Left insula Mid-cingulate gyrus

Left thalamusLeft amygdala and hippocampus

Position emission tomography (PET)P<0.05 for display, no significant decreases

VNS and Drug ReductionVNS and Drug Reduction21 patients using VNS compared results to a case-matched control

group in Tampa General Hospital Comprehensive Epilepsy Center

n = 21 Dose reduction Dose remain

9 Patients w/ reduced number of AEDs

4 5

12 Patient w/ same number of AEDs

6 6

Results:1. 15 /21 patients decrease the usage of AEDs either in number or dose2. Tiagabine was the most common AED reduced.

Ref: W.O. Tatum et.al., Neurology 56: 561-563, 2001

Heather, 21 years of age


Since VNS Therapy, my whole life has been

completely changed. I graduated from high school.

I have made friends and am able to have a normal

life.

I have a job that I love in a day care centre.

The magnet stops the seizures and also decreases

the length of the seizures. Not only do I

have a new life but I feel great!

“

”

Here is what some patients are saying:

Before the VNS, I had so many seizures,

I felt like a prisoner in my own home.

Thankfully things are much better now.

“”

When I got the VNS implant, it changed my whole life.“ ”

The longer we go, the better it gets.“ ”

VNS Therapy brings seizure relief to many patientsPrevent SeizurePrevent Seizure

V d - 127Sperner J. Neuropediatrics 2002;33:A22-A23.

Seizure Reduction Increases with Time Sperner (2002)

• n = 95 in Europe

• age range = 3 ~25yrs

• mean age = 10yrs

• onset, mean = 1.2yrs

• duration, mean = 8yrs

• 86% mentally retarted

• 20% had surgery

• 23% LGS

Pat

ien

ts (

%)

Patients with ≥50% Reduction in Seizures

50%

34%

0

10

20

30

40

50

60

3 mn=42/122

12 mn=42/84

54%

24 mn=20/37

Reduction improves over time in addition to QoL improvement

Can improve the quality of every day lifeCan improve the quality of every day life

Jerry,

44 years of age

“

”

Since the implant,

I have been able

to live a normal life free from the

side effects of medication...

My life has regained

a semblance

of normality.

Kristen, 19 years of age


I was nervous about the idea of having surgery

when I first heard about VNS Therapy. But if I had

known then how much better my life would be,

I wouldn’t have waited so long to get it. And as it turned

out, the surgery was not a big deal.

I was back home in a couple of hours.

“

”

Magnetic empowerment - a unique benefit of VNS Therapy

Magnetic empowerment - a unique benefit of VNS Therapy

Brady,8 years of ageVNS Therapysince 2000

The magnet has

given us control over Brady’s seizures, where with drugs we had no control. You couldn’t put more medication in him to get his seizures to stop – you’d have to worry about overdosing. The magnet

doesn’t hurt him. He has a magnet at school

and we trained his teachers to use it.

Brady’s mum

“

”

By passing the special Magnet over the VNS Therapy device when you feel a seizure coming on, you may be able to:

Stop your seizure

Shorten your seizure

Decrease the severity of your seizure

Improve the drowsy post-ictal/

recovery period following your seizure

VNS Therapy quality of life benefitsVNS Therapy quality of life benefits

Even in patients who are not responders (less than 25% seizure change), quality of life improves

VNS Patient Registry: January 25, 2002

Data on file, Cyberonics, Inc.

24%

22%

33%

33%

52%

45%

33%

Memory

Achievements

Mood

Verbal Skills

Clusters

Post-ictal

Alertness

12 Months (N=320)

% of Registry Patients Better or Much Better

* Fewer than 8% of patients reported any single measure worse

63%55%

40%34% 36%

26% 28%22%

45%39%

59%49% 52%

37%

0%

20%

40%

60%

80%

QoL at 3 months: % of better or much better

EAR Control

P=0.003P< 0.002

Ref: J.Ben Renfroe and James W.Wheless Neurology 59 (4), S26-S30, 2002

Benefit of Early VNS Treatment –Quality of LifeBenefit of Early VNS Treatment –Quality of Life

Health & Medicine

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