therapeutic devices for epilepsy prof. robert s. fisher · orange light reversibly blocks bursting...

Therapeutic Devices for EpilepsyProf. Robert S. Fisher

1The screen versions of these slides have full details of copyright and acknowledgements

Therapeutic Devices for Epilepsy

1

Robert S. Fisher, M.D., Ph.D.Maslah Saul MD Professor

Stanford UniversityDepartment of Neurology

• In accordance with the standards of the Accreditation Council for Continuing Medical Education (ACCME), all speakers, planners and/or persons who can influence the CME content must disclose to learners any relationships with commercial interests providing products or services that are relevant to the content of the presentation

• The following individual(s) have indicated the following relationships:

Planner and faculty disclosure to learners

Name

(Alphabetical Order)Commercial Interest Nature of Relationship

2

Robert S. Fisher, M.D., Ph.D. NeuroVista, seizure prediction Stock options, consulting

SmartMonitor, seizure detection Stock options, consulting

ICVRx, drug infusion to brain Stock options

Note: No Medtronic or brain stimulation financial connections

No conflict relevant to this talk (except sponsored research to Stanford)

Famous people with seizures

Julius Caesar

DostoevskyPeter the Great Flaubert

Napolean

Van Gogh

Alfred NobelCharles V

Lord ByronLeo Tolstoy

Neil Young

Charles II Spain Charles II England

3

1%LeninJames Madison

TchaikovskyPrince John

Pope Pius IX

Blaise PascalRichard Burton

Truman Capote

Bud AbbottDanny GloverHugo Weaving

Margot HemingwayFlorence Joyner

Alan Faneca

Bobby Jones

Tony Coelho

PrinceDJ Happa Chanda Gunn



Responds to new meds = 10%

Candidate for surgery = 5%

4

Responds to old meds = 50%

Uncontrolledseizures = 35%

Epilepsy is not a solved problem

Controlled 35%

65%

5

Uncontrolled people with epilepsy number more than:

• All brain tumors

• Multiple sclerosis

Treatments for epilepsy

Medicines Surgery

6Devices

Biofeedback Ketogenic diet

Alternativetherapies



Therapeutic devices for epilepsy• VNS “Plus”

• Trigeminal stimulation

• Seizure notification

• Seizure prediction

C li

7

• Cooling

• Optical control

• Brain drug infusion

• Hybrid silicon neural implants

• Transcranial magnetic stimulation

• Electrical deep brain stimulation

Therapeutic devices for epilepsy (2)

• The existing device

• According to the Cyberonics website more than 50,000patients have been implanted

8

VNS Therapy® – future pipeline (modified slide, courtesy of Cyberonics)

Phoenix

Griffin

MRI Conditional System

Telemedicine

Sz Alert

EEG Sensing

Leadless electrode

2014

9

Future:• Rechargeable

• MRI-safe 3T

• ECG-based detect

• Burst Stimulation

• New parameters

• Telemedicine

• Remote monitoring

• Detect / predict

NXT HC

NXT SRCardiac-based detectionFlint Hills Scientific

NXT NPMicroBurst StimulationElectronic Diary

Note: Products shown above are Not Approved for Human Use

CYBX today



• VNS “Plus”




Therapeutic devices for epilepsy

The NeedIdentify responders for a VNS-like therapy, before invasive surgery

10

• Cooling

• Optical control





g y

Trigeminal nerve stimulation

1.5

2.0

2.5

Daily Seizures

11

• Can test externally

• If helpful, implant

0.0

0.5

1.0

Baseline 3 months

Supported by Epilepsy Therapy Project Christopher DeGiorgio, Neurology, April, 2009

• VNS “Plus”





The NeedNotify others when a seizure is taking place

12

• Cooling

• Optical control





a seizure is taking place



• Sensors and intelligence built-in

• Alerts caregivers via wireless, mobile phones, PDAs

• As easy as wearing a “Watch”

Smart watch

13http://www.smart-monitor.com/product.html

• VNS “Plus”




C


The NeedNotify when a seizure

14

• Cooling

• Optical control





Notify when a seizure is likely in the near future

DetectPredict1 sec

15



Raw EEG

Seizure prediction example

16

Predictors

Cumulativepredictionprobability

Wong S, Gardner AB, Krieger AM and Litt B. J. Neurophysiol. 97: 2525-2532, 2007

-30 -20 -10 0 10

Seizure prediction approaches

• EEG component frequency analysis

• EEG nonlinear “chaos theory”

• EEG synchronicity and correlation

• EEG high-frequency oscillations

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EEG high frequency oscillations

• Multiple unit responses (BrainGate/NeuroPort)

• Optical changes

• Patient behavior and awareness

• Other

• VNS “Plus”




C


18

• Cooling

• Optical control





The NeedReversible reduction of activity in a seizing region of brain



Rat hippocampal slice in 10 µM bicuculline

Cooling reduces neuronal bursting

19

Javedan S, Fisher RS, Eder HG, Smith K, & Wu J. Cooling Abolishes Neuronal Network Synchronization in Rat Hippocampal Slices; Epilepsia 43: 574-580, 2002

20From R.S. Fisher

21From R.S. Fisher



22From R.S. Fisher

Will cooling the brain be practical?

23

• Gyri vs. sulci

• Heating dissipation

• Power demands

• Safety

• Other

Computer Modeling

24

Measurement (BIOFIL)Computation (ANL)



• VNS “Plus”




C


25

• Cooling

• Optical control





The NeedControlling brain excitability by implanted fiber-optics

Optical control of excitability

26

Work of Karl Deisseroth, Stanford

• N. Pharonis contains a rhodopsin, light-sensitive protein, as in our retina; A family of rhodopsins opens various neuron channels; Make a viral vector and put the rhodopsin into neurons; Then light controls brain cell excitability

Boyden & Deisseroth, Nature Neuroscience, 2005

Fig. 1: Lake Zug from Wadi Natrun, Sahara Desert, Egypt

Optical control of excitability (2)

27Boyden ES, Zhang F, Bamberg E, Nagel G, Deisseroth K. Millisecond-timescale, genetically targeted optical control of neural activity; Nat Neurosci. 2005; 8: 1263-8

• Mouse organotypic hippocampal culture slice

• Inject viral vector with halorhodopsin chloride pump gene

• Co-label vector with yellow fluorescent protein

• Orange light activates the rhodopsin and hyperpolarizes the transfected cells



Optical control of excitability (3)

1. Orange light activates rhodopsin gene

2. Opens chloride channel

3. Hyperpolarizes transfected neuron

4. Stops neuron firing

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1. Organotypic hippocampal culture slices

2. Stimulus train induced bursting (STIB)

3. Orange light reversibly blocks bursting

Boyden ES, Zhang F, Bamberg E, Nagel G, Deisseroth K. Millisecond-timescale, genetically targeted optical control of neural activity; Nat Neurosci. 2005; 8: 1263-8

Is optical control feasible ?

• Need to localize seizure focus

• Doubly invasive:

Viral transfection

29

Fiberoptic implant

• Duration of transfection

• How many cells transfected

• Cost


• VNS “Plus”




C

30

The NeedDeliver drug to a seizure focus

• Cooling

• Optical control







Blocking epileptiform activity by AED perfusion

Ref

CannulaBMI, thenDiazepam

orVehicle

31Eder HG, Jones DB, Fisher RS. Local perfusion of diazepam attenuates interictal and ictal events in the bicuculline model of epilepsy in rats; Epilepsia 1997; 38: 516-521

LA

LM

LP

RA

RM

RP

• Ictal EEG changes were defined as rhythmical spiking at a frequency greater than one per second, sustained for at least 10 seconds

TIME TO EEG ICTAL EVENT (SECS)

Blocking seizures by AED perfusion

32

Vehicle

Diazepam

0 200 400 600 800 1000 1200

1067n = 2

107n = 7

Eder HG, Jones DB, Fisher RS. Local perfusion of diazepam attenuates interictal and ictal events in the bicuculline model of epilepsy in rats; Epilepsia 1997; 38: 516-521

Video-EEGRecording System

ProgrammableInfusion Pump

Hippocampal

From Stein & Fisher

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Hippocampal Electrodes

Injection

Cannula



seiz

ures

in 1

5 m

in

25

30

35

40

Spikes *p<0.0001

Seizures (X 100) *p<0.001

Adenosine reduces spikes and seizures

34

mM of infused adenosine

# sp

ikes

or s

10

15

20

0 30 150 300

Anschel DA, Ortega EL, Kraus AC, Fisher RS. Focally injected adenosine prevents seizures in the rat; Experimental Neurology, 2004; 190: 544-547

Subdural infusion of AEDs

35NYU Group: Nandor Ludvig, Hai M. Tang, Shirn L. Baptiste, Geza Medveczky, Jacqueline French, Werner K. Doyle, Chad Carlson, Ruben I. Kuzniecky, Orrin Devinsky

Convection-enhanced delivery

36Rogawski MA. Convection-Enhanced Delivery in the Treatment of Epilepsy;Neurotherapeutics. 2009; 6: 344–351



37


• VNS “Plus”




• Cooling

38

The NeedRenewable release of an inhibitory compound with stimulation

• Cooling

• Optical control





Stimulation-induced GABA release

39From Rickus & Irazoqui, Purdue University

GABA releasing cells on electrodes




• VNS “Plus”




C

40

The NeedNoninvasive electromagnetic brain stimulation

• Cooling

• Optical control





Transcranial magnetic stimulation

• 24 people were randomly assigned to active (1 Hz for 15 min twice daily for 1 week at 120% of motor threshold) or placebo (the coil was angled away

41

(the coil was angled away from the scalp) . . .

• (no significant difference)This study suggests that a TMS effect, if there is one, is probably short-lived and weak

TMS is FDA approved for major depression

Theodore WH, Fisher RS. Brain stimulation for epilepsy, Lancet Neurol. 2004; 3: 111–18


• VNS “Plus”




C

42

The NeedImplanted stimulationelectrodes

• Cooling

• Optical control







Caudate

Anterior thalamusCM

Hypothalamus

Subthalamus

Electrical stimulation for epilepsy

Direct Focus

43

CerebellumVagus

CM=centromedian nucleus of thalamus

Hippocampus

Brainstem

CallosumC

From R.S. Fisher

OPEN-LOOP (Medtronic) CLOSED-LOOP (NeuroPace)Responsive neurostimulation

Deep brain stimulation

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Responsive neurostimulation

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Pivotal Trial reported at AES 12/7/09

• During the last two months of the three month blinded evaluation period of the study, people in the treatment group experienced a mean percentage reduction of 29 percent in their disabling seizures compared to 14 percent reduction for those in the sham stimulation group; In the long term, open label period of the trial, . . . 47 percent of these subjects experienced a 50 percent or greater reduction in their seizure frequency (From NeuroPace web site)

Bergey, GB, et al., Epilepsia, Vol 43, Suppl 7, 2002



SANTÉ neurostimulationStimulation of the anterior nucleus of thalamus

for epilepsy

0.0%

-14.5%

-21.3%

-22.2%-25.3% -28.7%

30 0%

-20.0%

-10.0%

0.0%

10.0%

20.0%

quen

cy p

erce

nt c

hang

e m

bas

elin

e

ActiveControl

46• p=0.039 for the primary outcome, excluding 1 outlier• p=0.002 for final month, including outlier

-40.4%

21.3%

-33.9%-42.1%

-70.0%

-60.0%

-50.0%

-40.0%

-30.0%

Baseline Operative (1 month)

Month 1-2 (1 month)

Month 2-3 (1 month)

Month 3-4 (1 month)

1-month groupings

Med

ian

seiz

ure

fre

from

Blinded Phase(3-month total duration)

Fisher et al., Epilepsia 2010; 51: 899-908

SANTÉ conclusions

• Thalamic stimulation was effective; 40% vs. 15% in DB

• Suggestion of improvement over time

• By 2 years, a 56% reduction, QoLIE & severity improved

• Deaths: 1 in baseline and 4 in open-label*

47* None of the deaths were attributed to stimulation or procedure

• Hemorrhage: 4.5%, none clinically significant

• Well-tolerated

• Possible issue of depression, memory

• Not yet FDA approved

Therapeutic devices for epilepsy• VNS “Plus”




Cooling

48

• Cooling

• Optical Control




• Electrical Deep Brain Stimulation



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Chinese Fortune CookieUncle Lee's House of Szechuan

Baltimore, Maryland

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therapeutic devices for epilepsy prof. robert s. fisher · orange light reversibly blocks bursting...

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