ruben kuzniecky, md
DESCRIPTION
New Developments in Diagnosis and Treatment of EpilepsyTRANSCRIPT
New Advances in the Management of Epilepsy
Ruben Kuzniecky, MDProfessor of NeurologyCo-Director, NYU Epilepsy CenterNYU School of Medicine
Outline Seizure Detectors New Therapies near approval Emerging treatment technologies
Focal brain cooling Silk-based brain implants Convection-enhanced drug delivery Optical neural control Laser ablation Subdural drug infusion
Epilepsy Seizures Identification
The Challenge : Many Seizures are unrecognized by Patients and CaregiversInjuries and SUDEP may be decreased by alarm systems
For LRE seizures without secondary Generalization the range of unrecognized seizures is between 50% to 63%.
For Seizures that are or become GTC the rate is between 10-20%. Left Temporal lobe seizures with SGTC were unrecognized by 100% of patients in one study.
Outpatient studies using AEEG have reported unrecognized seizures ranging from 7-38%.
Competitive Landscape
Low
Medium
High
Roaming Space
Reliability (Miss , FAR)
EPI-CARE (Denmark) ~ €1,000
Medpage (UK) $495 (In the US)Vigil-Aid (Australia) ~ $ 300
Bracelet sets(under development)
EpiLert (Israel)
SmartWatch (US)
Bed-mattress sets(no FDA)!!
OutdoorsHomeBed Room
“Epi-Care”Danish Care Technologies (sold in UK by Emfit)
About Epi-Care3000Thoroughly tested and safe alarm for seizures or motile activity at night. Memory function which saves the time of any detected seizure. Adjustable sensitivity to detect seizures on both small children and adults. Possibility of detecting smaller seizures but only to warn when major ones occur. When a seizure occurs, alarms can be transmitted wireless to a pager.
Epilepsy Alert Devices
Epi-care retail price 1620 €
Epilepsy Alert Devices
Medpage Seizure Alarm , Manufactured by Easylink (UK)
Detecting nocturnal convulsions: Efficacy of the MP5 monitor’, Seizure, April 2009 , Carlson C., Arnedo V., Cahill M., Devinsky O.,
64 subjects.5 of 8 (63%) T-C Sz were detected.269 False positive alarms.
Medpage Model MP5Radio Pager
The Medpage® MP5 is used by hospitals, care homes and families worldwide for the detection of convulsive seizures and when used in accordance with the instructions for use will provide a fast response to on-going seizures of the Tonic-Clonic (Grand Mal) type.
Epilepsy Alert Devices
Portable Systems
• EpiLert by BioLert (Israel)– Portable– Wireless Connection– Detection Algorithm for GTC Sz
• SmartWatch by Smart Monitor (USA)– Portable– Wireless– Detects GTC Sz and Myoclonic Seizures
SmartWatch
7/8 seizures detected. Non-seizure movements detected 204 times in 40 pts
Lockman J et al. Epilepsy & Behavior 2011
‘EpiLert Vx’ Set-up
Tests Objectives:
1. Recording of Seizures and Movements
2. Performance Verification VsV Hospital’s Video/EEG
3. Demonstration of EpiLert’s ‘Seizures ID’ Algorithm
MovementSensor
Radio Link
Laptop computer
Video & EEG Recording
Thinkpad - -Sz Recording- -Sz Identification
Disk Storage
Interim results of tests at NYU M.C. & Tel Aviv Sourasky M.C.Study Group: 30 patients; 15 pt had a total of 22 Sz episodes.
19 of 22 episodes longer than 30sec
3 of 22 episodes shorter than 30sec
True Positive all 19 Sz episodes detected = 100% Detected 1 of 3 = 33%
False Negative 0 Missed 2 of 3 = 66%
False Positives 8 false alerts during ~1700 hours monitoring (all F.P. during awake state)
BioLert’s Epilepsy Alert Device
Kramer U, Kipervasser S, Shlitner A, Kuzniecky R. J of Neurophysiology 2011
Seizure Detection Systems
• There is societal need for these devices• Technology mature and available to integrate
into GPS, mobile phones, beepers• Current systems detect GTC sz.• False alarm is MAIN issue for patient use• Cost is likely to make it commercial• May have applications for drug trials, etc
Medtronic SANTE TrialStimulation of Anterior Thalamus for Epilepsy
• Electrodes surgically placed in the thalamus, a deep part of the brain, on both sides
• Stimulation every 5 minutes• Strength and duration of
stimulation can be adjusted• Like Vagus nerve stimulator,
patient can “trigger” stimulation for an aura or seizure
Stimulating Electrode, 4 contactsElectrode (4 contacts)
Results of stimulation
(sham)
Deep Brain Stimulation Study
• Treatment worked better for people with epilepsy from the temporal lobe, and did not work as well in those with frontal, parietal and occipital epilepsy.
• Treatment worked just as well after surgery and VNS.• The infection rate was 10.9 % and the rate of
asymptomatic intracranial hemorrhage was 1.3 % per lead implant.
• There was a significantly higher incidence of spontaneously self-reported depression, memory impairment, and anxiety in the active group compared to the control group during the blinded phase,
Responsive Neurostimulator
• Designed to detect abnormal electrical activity in the brain and to deliver small amounts of electrical stimulation to suppress seizures before there are any seizure symptoms.
• Electrodes are placed within the brain or rest on the brain surface in the area of the seizure focus (where seizures start).
• Designed to continuously monitor brain electrical activity from the electrodes and, after identifying the "signature" of a seizure's onset, deliver brief and mild electrical stimulation with the intention of suppressing the seizure.
RNS with Leads
RNS
Anthony Murro, M.D.Medical College of Georgia
RNS Primary Effectiveness Endpoint Results
BlindedEvaluation
Period
Mean % Change in Seizure Frequency: GEE Estimate [95% CI]
Treatment Sham p-value1
Entire Blinded Evaluation Period
(N=191)
-37.9%[-46.7%, -27.7%]
-17.3%[-29.9%, -2.3%]
0.012
Month 1(3 months post-op)
-34.2%[-44.1%, -22.6%]
-25.2%[-37.1%, -11.1%]
0.307
Month 2(4 months post-op)
-38.1%[-47.3%, -27.3%]
-17.2%[-30.5%, -1.3%]
0.021
Month 3(5 months post-op)
-41.5%[-52.0%, -28.7%]
-9.4%[-29.5%, 16.4%]
<0.0011 p-value of group-by-time interaction in GEE model
Brain Cooling Project
Animal Data Indicates that cooling can stop seizures in animals
• Thermal energy (cooling) abates seizures at ~ 21°C
• Compared to electrical currents (ECs), thermal energy:• A) Has a higher therapeutic ratio
(cooling does not trigger seizures)• B) Relies only on one parameter (T),
instead of many (frequency, amplitude, pulse width, pulse shape, etc.)
• C) Is neuro-protective
Focal brain cooling for seizure control
• Objective: To lower the temperature of amygdala and hippocampus (~1 ci of brain tissue) to 16oC in 30 seconds maximum
• Strategy: Computer-based design of optimal cooling probe using realistic real-time thermal diffusivity in brain tissue
Focal brain cooling: Ivan Osorio
SAW senses brain temperature; cooling probes
Implantable device transmits signals to DSP and activates pump
External Wearable DSP receives signals, detects seizures, warns, and controls cooling probes
InletOutlet
NeedleThermocouple
Inlet manifold
Outlet manifold
5
10
15
20
25
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35
40
0 10 20 30 40 50 60
Probe diameter 0.6 mm
Measurement (BIOFIL)Computation (ANL)
Time (sec)
Arrays of distributed probes deliver sufficient thermal energy to decrease the temperature of amygdala and hippocampus from 37oC to 20oC in 30s.
Tissue disruption/loss caused by insertion of this probe is considerably less than that caused by ablative surgery.
The cooling probe is scalable
• Objective: To lower the temperature of neocortical seizure focus
• Progress• Developed implantable fluid-based
cooling and recording grid for use during invasive mapping
• In dogs, the device was capable of cooling the cortical surface to the mid-20s°C
Focal brain cooling: Steven Rothman
Focal brain cooling: Steven Rothman
Most recent version of cooling grid for use during invasive mapping. A. View from bottom; B. View from top. Fluid enters the central bladder and cools the cortex beneath the central 16 of 64 cortical contacts. Scale in A is 1 cm.
• Rationale • Adenosine is an endogenous
anticonvulsant of the brain that terminates seizures
• Adenosine deficiency is a pathological hallmark of epilepsy (in rodents and humans)
• Adenosine augmentation prevents pharmacoresistant seizures
Silk-based brain implants: Detlev Boison
Anti-ictogenic and anti-epileptogenicactivity of silk-based adenosine delivery
Fig. 1
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Adenosine release [ng/day]
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Adenosine release
Control
Adenosine
Seizure suppression
Anti-epileptogenesis
Days after polymer implantation
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Distinction of seizure suppression and anti-epileptogenesis
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Averaged daily adenosine release in vitroA
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1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45 47 49 51 53 55 57
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day 4 day 6day 5 day 8day 7 day 18 day 21day 20day 19Days after implantation (6 stimulations / day)
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Suppression of Kindled Seizures
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Szybala et al., (2009) Exp. Neurol. 219:126-35
Silk-based adenosine delivery
Wilz et al., (2008) Biomaterials, 29:3609-16
Nanofilm drug layer
Nanofilm silk layer
+
Silk fibroin shell
Encapsulated adenosine
Microspheres
Aqueous silk fibroin solution
Porous scaffold
Silk fibroin/porous scaffold Encapsulated adenosine Silk + adenosine macroscale film Silk fibroin nanofilms Adenosine nanofilms
Silk fibroin microsphere shell
4 3 2
1
Implantation before onset of kindling: suppression of kindling epileptogenesis
Implantation into fully kindled rats: seizure suppression
Potential advantages of this approach
•long-lasting therapeutic benefit (>3 months) after short term (10 days) delivery• avoidance of systemic and central side effects by focal application• exploitation of novel pharmacological principle that is based on neurochemical rationale• adenosine is already FDA approved (supraventricular tachycardia)• silk is already FDA approved (e.g. for sutures)• prior experience with I.T. infusion of adenosine to treat chronic pain• safety, because adenosine is endogenous anticonvulsant subject to rapid metabolic clearance• potential for the prevention of epileptogenesis• silk-based adenosine delivery is also of potential use for: chronic pain, amyotrophic lateral sclerosis, Alzheimer’s disease, autism, and schizophrenia
• Rationale • Convection-enhanced delivery
(CED) is a novel drug-delivery technique that uses positive hydrostatic pressure to deliver a fluid containing a therapeutic substance by bulk flow directly into the interstitial space within a localized region of the brain parenchyma
Convection-enhanced drug delivery
• Rationale • CED circumvents the BBB and
provides a wider, more homogenous distribution than bolus deposition (focal injection) or other diffusion-based delivery approaches
• CED could represent an alternative to resective surgery in the treatment of focal epilepsies that are resistant to oral AEDs
Convection-enhanced drug delivery
x x
[Rogawski MA. Convection-enhanced delivery in the treatment of epilepsy. Neurotherapeutics 2009;6:344-351.]
Convection-Enhanced Delivery — An Alternative to Epilepsy Surgery?
• Recent results • A single, localized CED infusion of
botulinum toxin B over a 20-minute period provided more than 2 months of seizure protection in the rat kindling model of epilepsy
• At therapeutic doses, no untoward toxicities were observed
Convection-enhanced toxin delivery (Rogawski)
• CED technical challenges• Large-diameter delivery cannulas
used today limit efficiency, have limited precision, and can cause mechanical trauma
• “Reflux” – movement of therapeutic away from the target back along the outside wall of the delivery cannula
Optimizing CED of drugs (Cunningham)
• Array of multiple microcannulas strategically positioned to deliver therapeutic• Reflux is minimized by reducing the
delivery cannula diameter 5-10x• Capable of simultaneous
electrophysiological recording and delivering light
• Status• Stereotactic surgical planning
software and instrumentation are near completion
Optimizing CED of drugs (Cunningham): The CED SYStem (CEDSYS) solution
Glioblastoma multiforme
Sustained Infusion
CEDSYS microcannula arrayConventional Delivery Cannula
SEDSYS Strategy: Miles Cunningham
• Objective • Transiently silence specific
targeted cells, or drive specific neurons, using light to halt seizures while minimizing side effects
Optical neural control: Ed Boyden
Results to date
Arch
Chow, Han, et al., (2010)Nature 463:98-102
I. Invented optogenetics –drive/silence neurons with light
ChR2
Boyden et al. (2005) Nature Neuroscience 8(9):1263-8
Halo
Han and Boyden (2007)PLoS ONE, 2(3): p. e299
II. Began primate testing –no cell death or immune reaction
Han et al., 2009 Neuron 62(2):191-198; new manuscript in preparation.
III.Created wirelessly-powered prosthetics forsafe, long-term light delivery
Zorzos et al. (2010) Optics Letters 35(24):4133-5; two other manuscripts in preparation
Bill Hoffman. CEO. Visualase, Inc. 713-275-2063 [email protected]
Minimally Invasive MRI-guided Laser Ablation of Epileptogenic Foci
Visualase is FDA cleared for use in soft tissue. It is not FDA approved for treating any specific disease or condition.
Visualase is FDA cleared for use in soft tissue. It is not FDA approved for treating any specific disease or condition.
Target Area
FiberLaser fiber is placed in target tissue. Placement confirmed with MR.
Laser energy is delivered under MR thermography visualization.
Post-Tx MR confirms ablation zone
Thermal Ablation
Laser Ablation Procedure, in Neurosurgery
1
2
3
Visualase is FDA cleared for use in soft tissue. It is not FDA approved for treating any specific disease or condition.
Current Status
IP: 6 Patents issued, 10 patents pending. 400k lines of proprietary code (software) Regulatory: 510(K) Clearance for soft tissue ablation in neurosurgery (and other specialties) Development: Product is fully developed and has been safely used to ablate ~100 brain tumors and, under IRB, to ablate Epileptogenic foci in two patients
Reimbursement: Significant reimbursement already exists.
Clinical:•General: multiple peer reviewed animal studies•Brain: early clinical experience in brain mets, NEUROSURGERY, July 2008. Follow up study submitted for publication, mid-2011
•Prostate: several early case reports published in European Urology, several studies ongoing, multi-center trial to commence in 2011
•Epileptogenic foci ablation: Several investigators have submitted protocols to IRB
Financial: •Visualase is venture funded•Adequate funds through early-mid 2012, Series B funding late 2011, strategic partners and VC
Acknowledgements• Ed Boyden, Massachusetts Institute of Technology
([email protected])• Miles Cunningham, Harvard Medical School
([email protected])• Detlev Boison, Legacy Research Institute
([email protected])• Bill Hoffman, Visualase, Inc.
([email protected])• Ivan Osorio, University of Kansas Medical Center
([email protected]) • Michael Rogawski, University of California, Davis
([email protected])• Steven Rothman, University of Minnesota Medical School
GBU 28
Current Approach Selective Therapy
F-16 USAF
Why drug delivery to CNS?
Why drug delivery to CNS?
• Many patients with refractory epilepsy are not candidates for surgery, and are not helped by AEDs
• It is estimated that about 200,000 patients in the U.S. are not candidates for currently available epilepsy surgery.
• There is still a large unmet need • Because it seems to work!!!!!!!
From: Ludvig et al., Epilepsia 2006
Epidurallydelivered pentobarbital can terminatefocal neocorticalseizures in rats
226 mM of PB
Suppression of focal neocorticalEEG spiking in the seizure focus,in epilepsy patients
(From: Madhavan, Kuzniecky et al., 2008, Epilepsy Research)
Design of the first generation SPD, a “hybrid neuroprosthesis”, for the treatment of focal neocortical epilepsy affecting ~ 150,000 people in US (based on US Patent #6,497,699 to Ludvig and Kovacs in 2002)
Device hardware & software
(We consider the SPD developed if:- it is fully implantable,
- it properly executes all minipump functions, - it effectively transmits/receives data and instructions,
- it can be powered by a single battery for at least 4 years)
Subdural strip Dual minipump
Microcontroller, side 1 Microcontroller, side 2
SPD hardware
(From: Medveczky et al., in preparation for J. Neurosci. Meth.)
Anesthesia during surgery Quiet wakefulness in home-cage
Moving around during memory task
Ketamine sedation for minipump refilling
Eating during memory task
Effect of subdural (ipsilat.) Ach delivery
Ipsi-lateral
Contra-lateral
Frontal cortical subdural EEG recordings transmitted by the SPD RF module
Chewing artifacts
sec
420 μV
Antiepileptic efficacy
- it is able to completely prevent the occurrence of focal neocortical seizures,
- and it can maintain this efficacy for long periods without the induction of tolerance)
Basic properties of the muscimol solution delivered with the SPD
Amanita Muscaria— GABA A agonist
Termination of Ach-inducedfrontal cortical EEG seizures by 1.0 mM muscimoldelivered via the SPDin a bonnet macaque
Long-term periodic muscimol deliveryinto the primate frontal cortex via the SPD prevents focal seizures
3H-muscimol autoradiography with thionin counterstaining: coronal section from the brain of a rat subjected to epidural 3H-muscimol exposure for 1 hour
(Histology/autoradiography made at NeuroScience Associates, by Dr. Robert Switzer)
Device safety
SPD safety can be quantified if its long-term use is not accompanied with:
- neurological symptoms- cognitive, emotional and motivational impairment- abnormal neocortical EEG and cell firing patterns- systemic side effects- infection)
Acquisition of spatial memory tasks by macaque monkeys before SPD implantation
(Test described in: Ludvig et al., 2003; Behav. Brain Res.)
(HPLC assay made at Stanford Research Institute by Dr. Jacqueline Vazquez-DeRose)
EEG effects of subdural Ach and muscimol applications with the SPD;local and systemic concentrations of the applied muscimol
Conclusions
In its present state, the muscimol-delivering SPD implant can prevent focal neocortical seizures in primates for many months without apparent side-effects or tolerance.
Animals tolerate the device and drug without major problems.
Many Challenges remain ahead:
EngineeringSafety in humans
Key team members in 2011
Neuroscience studies : Nandor Ludvig, M.D., Ph.D. (Program Director ) Hai M. Tang, M.D. (animal experiments)
Shirn L. Baptiste, B.S. (animal experiments) Carol Novotney, D.V.M. (veterinary consultation at SUNY)
Jacqueline Vazquez-DeRose , Ph.D. ( HPLC at Stanford Res. Inst.)Robert Switzer, Ph.D. (autoradiography at NeuroScience Assoc.)
Engineering studies: Geza Medveczky, M.S. (hardware and software at NYU)H. Jonathan Chao, Ph.D. (hardware at NYU Poly)N. Sertac Artan, Ph.D. (hardware and software at NYU Poly)Sandor Toth, M.S. (hardware and software)
Clinical studies: Ruben I. Kuzniecky, M.D. (epileptology) Orrin Devinsky, M.D. (epileptology) Jacqueline A. French, M.D. (epileptology) Chad Carlson, M.D. (epileptology) Neurosurgery studies: Werner K. Doyle, M.D. (implantation)
John G. Kral, M.D., Ph.D., (general surgery consultation at SUNY)
Industrial partners: Cygnus (control unit manufacturing)DocXS Biomedical (subdural strip manufacturing)