Easy to Control Group 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 prescription Tolerant side effect Controlled Seizure or free of seizure Satisfied and Happy Patient
Difficult to Control Group 1st line & 2nd line AED failure Multi-AED or Treatment-Resistant Seizure, and AED side effect Continue Multi-AED with side effect Surgical evaluation Search for alternative treatment Suffer from bad QoL Unhappy patients
What are patients looking for? B QoL SE Difficult to Control Group Value B QoL SE Easy to Control Group Value
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 Medium (mean) seizure reduction in adults patients Add-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;
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
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.
Vagus Nerve Projects to Key Brainstem Regions III- 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)
Vagus Nerve and NTS Project to Key Brainstem Regions III- Henry TR. Neurology. 2002;59(suppl 4):S3-S14. KFN=K ö lliker-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
Vagus Nerve - NTS - PBN Project to Key Cerebral Regions
III- Henry TR. Neurology. 2002;59(suppl 4):S3-S14. 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.
VNS on Human EEG Year Investigator Patients Result 1992 Hammond Partial epilepsy (n=9) VNS T herapy 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 T herapy decreased (n=1) hippocampal spikes at Adults 30 Hz; increased at 5 Hz 2001 Koo Generali s ed and partial Generali s ed and focal onset seizures; high frequency spikes diminished during of interictal discharges; VNS T herapy (12 months) younger patients Henry TR. Neurology. 2002;59(suppl 4):S3-S14.
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. Koo B. EEG changes with vagus nerve stimulation. J Clin Neurophysiol ; 18 (5): 434-441.
EEG at 1 year showing further prolongation of intervals of spike-free period. Koo B. EEG changes with vagus nerve stimulation. J Clin Neurophysiol ; 18 (5): 434-441.
0.01 0.1 1 10 100 More important to More important Clinicians to patients Odds Ratios (95% CI) Ref: P.M. Rothwell et.al BMJ 1997; 314:1580
VNS referring center in Taiwan North Taiwan: CGMH VGH Cathy GH Central Taiwan: CMMH VGH-TC CHCH South Taiwan: CKUH CGMH-KS VGH-KS East Taiwan: Tzu-Chi
PATIENT SATISFACTION Testimonial 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! »
Patient in supine position with head turned to the right
VNS System Implant: Marking the Incision Sites
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
Clavicle Anterior fold of axilla incision site option Neck incision site
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.
Seizure Reduction – LGS - Frost (2001) V d - Frost M. Epilepsia .2001;42(9)1148-1152. 38% 58% 0 10 20 30 40 50 60 > 50% > 75% Seizure Reduction (n=24) Patients (%) 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
Seizure Reduction – Drop Attacks (LGS) - Frost V d - 55% 47% 0 10 20 30 40 50 60 70 80 90 100 1 m 3 m Mean Reduction (%) Drop Attack Seizures p<0.0001 p<0.0001 Frost M. Epilepsia .2001;42(9)1148-1152. 88% 6m p=0.0002
Data Analyzed by Drop Attack seizures
88% of Drop Attack Seizures are reduced after 6 months
Seizure Reduction – Absence (LGS) - Frost V d - 73% 48% 0 10 20 30 40 50 60 70 80 90 100 1 m 3 m Mean Reduction (%) Absence Seizures 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
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.
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.
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 1 st onset
P=0.001 P<0.001 Ref: J.Ben Renfroe and James W.Wheless Neurology 59 (4), S26-S30, 2002
Medical Cost Reduction Resulted by AED / Surgery / VNS 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
P=0.0007 P=0.0036 VNS 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
Ref: Elinor Ben-Menachem et al. Neurology 59 (4), S44-S47, 2002
VNS Therapy are remarkably better than long-term continuation rates with other treatments for pharmacoresistant epilepsy
On-going Research on VNS Disease 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
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
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)
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.
Epilepsy 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.
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 Lithium Carbon Monofluoride Battery Lithium Carbon Monofluoride Battery Longevity 6 - 11 years depending on stimulation parameters 6 - 11 years depending on stimulation parameters 8 - 12 years depending on stimulation parameters Cavity Single Dual Dual Serial #’s < 1,000,000 1,000,000 > 0
Pulse Generator: Programmable Parameters 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:
Ref: P. Boon et al. Acta Neurochir 141:447-453, 1999 Pre- 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
Program Setting: Physicians Experiences Duty cycle=(ON+4)/(ON+OFF) in sec Some physicians use the following progression to find the optimal duty cycles for their patients 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 41
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 clinic visit 128(66-154) 66(22-110) 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 clinic visit 146(132-265) 89(6-132) 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)
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.
No side effects associated with AEDs e.g.: sleeplessness, confusion, weight gain, memory loss
VNS Therapy is not associated with
interactivity toxicity 1,2
pharmacokinetic interactions 2
systemic neurotoxic effects 2
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 *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 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%
Changes in metabolism of brain areas relevant to mood regulation
Alteration of key mood-regulating brain neurotransmitters 1,2
Changes in the HPA-axis 3
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 Therapy 4 Orbitofrontal cortex Left insula Mid-cingulate gyrus Left thalamus Left amygdala and hippocampus Position emission tomography (PET) P<0.05 for display, no significant decreases
21 patients using VNS compared results to a case-matched control group in Tampa General Hospital Comprehensive Epilepsy Center
Results : 1. 15 /21 patients decrease the usage of AEDs either in number or dose 2. Tiagabine was the most common AED reduced. Ref: W.O. Tatum et.al., Neurology 56: 561-563, 2001 n = 21 Dose reduction Dose remain 9 Patients w/ reduced number of AEDs 4 5 12 Patient w/ same number of AEDs 6 6
Heather, 21 years of age VNS Therapy since 1992 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! “ ”
Prevent Seizure 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 patients
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
V d - Sperner J. Neuropediatrics 2002;33:A22-A23. Reduction improves over time in addition to QoL improvement Patients (%) Patients with ≥50% Reduction in Seizures 50% 34% 0 10 20 30 40 50 60 3 m n=42/122 12 m n=42/84 54% 24 m n=20/37
Can 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 VNS Therapy since 1997 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
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
Brady, 8 years of age VNS Therapy since 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 “ ”