Epilepsy Therapies Symposium

Innovations in Epilepsy Treatment:

Are We on the Cusp of a Paradigm Shift?
to Status

Symposium Co-Chairs:

Cynthia Harden, M.D.

and

Jerry Shih, M.D.

Monday, December 4, 2017

Convention Center – Ballroom A/B

5:45 – 8:15 p.m.

EDUCATION CREDITS
Accreditation
The American Epilepsy Society is
accredited by the Accreditation Council
for Continuing Medical Education
(ACCME) to provide continuing medical
education for physicians.
AMA Credit Designation Statement
The American Epilepsy Society designates this live
activity for a maximum of 26.5 AMA PRA Category 1
Credits™. Physicians should claim only the credit
commensurate with the extent of their participation in
the activity.
International Credits: The American Medical Association
has determined that non-U.S. licensed physicians who
participate in this CME activity are eligible for a
maximum of 26.5 AMA PRA Category 1 Credits™.
Physician Assistants: AAPA accepts certificates of
participation for educational activities certified for AMA
PRA Category 1 Credits™ from organizations accredited
by ACCME or a recognized state medical society.
Physician assistants may receive a maximum of 26.5
hours of Category 1 credit for completing this program.
Continuing Education for Nurses and
Pharmacists
Jointly provided by AKH, Inc.,
Advancing Knowledge in
Healthcare, and the American
Epilepsy Society.
Nurses: Advancing Knowledge in Healthcare is
accredited as a provider of continuing nursing
education by the American Nurses Credentialing
Center’s Commission on Accreditation. This activity is
awarded 26.5 contact hours.
Pharmacists: Advancing Knowledge in
Healthcare is accredited by the
Accreditation Council for Pharmacy
Education as a provider of continuing
pharmacy education.
Select portions of this Annual Meeting are approved for
pharmacy CE credit. Specific hours of credit for
approved presentations and the Universal Activity
Numbers assigned to those presentations are found
elsewhere in the program materials. Criteria for success:
credit is based on documented program attendance
and online completion of a program evaluation/
assessment.
AES ANNUAL MEETING | meeting.aesnet.org
If you have any questions about this CE activity relative
to nursing and/or pharmacy CE, please contact AKH, Inc.
at service@akhcme.com.
Maintenance of Certification
The American Board of Psychiatry and Neurology has
reviewed the 71st Annual Meeting—American Epilepsy
Society and has approved this program as part of a
comprehensive epilepsy program, which is mandated by
the ABMS as a necessary component of maintenance of
certification.
Claiming CME Credit and CME Certificates
Attendees who registered in the following categories
may claim CME or CE for the meeting: physician, health
care provider, trainee, one-day, and two-day. Meeting
registration includes credit claiming. There is no
separate fee to claim CME/CE.
Attendees will receive an emailed notification to access
the online evaluation and credit claim system.
The evaluation and credit claim system will remain open
through Tuesday, February 27, 2018. Evaluations and
credit claims must be completed by this date in order to
record and receive your CME/CE certificate.
Attendance Certificate/International Attendees
A meeting attendance certificate will be available at the
registration desk for international meeting attendees on
Tuesday, December 5, 2017.
Resolution of Conflicts of Interest
It is the policy of the American Epilepsy Society to
ensure balance, independence, objectivity, and scientific
rigor. All persons involved in the selection, development,
and presentation of content are required to disclose any
real or apparent conflicts of interest. In accordance with
the ACCME Standards for Commercial Support of CME,
AES implemented the mechanism of prospective peer
review of this CME activity, to identify and resolve any
conflicts. Additionally, the content of this activity is
based on the best available evidence.
42 DECEMBER 1-5, 2017 | WASHINGTON, D.C.
EDUCATION CREDITS
Unapproved Use Disclosure
AES requires CME authors to disclose to learners when
products or procedures being discussed are off-label,
unlabeled, experimental and/or investigational (not FDA
approved); and any limitations on the information that is
presented, such as data that are preliminary or that
represent ongoing research, interim analyses, and/or
unsupported opinion. This information is intended solely
for continuing medical education and is not intended to
promote off-label use of these medications. If you have
questions, contact the medical affairs department of the
manufacturer for the most recent prescribing
information. Information about pharmaceutical
agents/devices that is outside of U.S. Food and Drug
Administration approved labeling may be contained in
this activity.
Self Assessment
in Epilepsy
VOLUMES 1-4
Created by fellow epileptologists and neurologists—
members of AES—these self-assessment activities
provide continuing medical education, lifelong
learning, and career development. Also use these
activities to fulfill Maintenance of
Certification (MOC) requirements.
Visit the SAE Zone during the meeting to
take advantage of meeting discounts for
self-assessment activities. Details on page 121.
Get details at
a e s n e t . o r g /s a e
AES ANNUAL MEETING | meeting.aesnet.org
Disclaimer
This CME activity is for educational purposes only and
does not constitute the opinion or endorsement of, or
promotion by, the American Epilepsy Society.
Reasonable efforts have been taken to present
educational subject matter in a balanced, unbiased
fashion and in compliance with regulatory requirements.
However, each activity participant must always use his
or her own personal and professional judgment when
considering further application of this information,
particularly as it may relate to patient diagnostic or
treatment decisions including, without limitation, FDA-
approved uses and any off-label, investigational, and/or
experimental uses.
Continuing Education
in Epilepsy
Access continuing education and professional
resources from AES all year long, including:
Webinars
Online courses
Handouts
Self-Assessment
Learn more at
a es ne t.o rg/p ro fe ss iona l_ ed ucati on
43 DECEMBER 1-5, 2017 | WASHINGTON, D.C.
OVERVIEW
This symposium focuses on challenges and innovations in epilepsy treatment. While epilepsy surgery for
refractory epilepsy continues to be underutilized, minimally invasive techniques for localizing and treating focal
epilepsy are making epilepsy surgery more attractive to patients due to their relative safety and tolerability in
terms of discomfort and length of hospital stay. Genetic testing in adults with seizures can aid in the diagnosis
and treatment of focal epilepsy. The specific sequence and duration of treatment for immune-related epilepsy
is rarely discussed in detail, particularly in association with the causative antibody. Although there is abundant
literature on this topic, healthcare providers are still seeking more detailed guidance on the treatment
approaches of this difficult clinical entity. Finally, the initial and second choice of AEDs remains complex.

LEARNING OBJECTIVES
Following participation in this symposium, learners should be able to:
Discuss all technical approaches, inclusive of minimally invasive tools (stereo-EEG, standard depth electrodes,
subdural grids and strips, mapping for eloquent cortex with each technique, cortical resection, stereo-EEG
thermos-ablation, laser ablation and responsive neurostimulator placement), and delineate the limitations and
advantages of each
• Formulate a possible epilepsy surgical plan that incorporates all technical approaches including the
aforementioned minimally invasive tools
• Appropriately select focal epilepsy patients for genetic testing; describe how to prioritize and select the
genetic test(s) and develop treatment strategies implicated by the genetic results
• Formulate a treatment sequence for immune-related epilepsies, depending on response, with incorporation
of the duration of each treatment course, according to the best available information
• Identify the AEDs to be used earlier in the course of treatment based on effectiveness, side effect profile, and
cost

TARGET AUDIENCE
Neurologists, epileptologists, nurse practitioners, physician assistants, nurses, pharmacists

PROGRAM
Co-chairs: Cynthia Harden, M.D. and Jerry Shih, M.D.

Introduction
Cynthia Harden, M.D.

Debate: Should Staged Epilepsy Surgery Start with Minimally Invasive Approaches?
Saadi Ghatan, M.D. and Jeffrey P. Blount, M.D.

Testing and Treating for Focal Genetic Epilepsies

Piero Perucca, M.D.

The What, When, How, and How Much When Treating Immune-related Epilepsy?
Sarah E. Schmitt, M.D.

Debate: Should the Latest Generation of AEDs be Used the Earliest?

Madeline Fields, M.D. and Korwyn Williams, M.D., Ph.D.

Conclusion
Jerry Shih, M.D.
EDUCATION CREDIT
2.5 CME credits

Nurses may claim up to 2.5 contact hours for this session.

Pharmacy Credit
AKH Inc., Advancing Knowledge in Healthcare approves this knowledge-based activity for 2.5 contact
hours (0.25 CEUs). UAN 0077-9999-17-047-L01-P. Initial Release Date: 12/4/17.

COMMERCIAL SUPPORT ACKNOWLEDGEMENT

This educational activity is supported in part by educational grants from Eisai Inc. and UCB Inc.

FACULTY/PLANNER DISCLOSURES
It is the policy of the AES to make disclosures of financial relationships of faculty, planners and staff involved in
the development of educational content transparent to learners. All faculty participating in continuing medical
education activities are expected to disclose to the program audience (1) any real or apparent conflict(s) of
interest related to the content of their presentation and (2) discussions of unlabeled or unapproved uses of
drugs or medical devices. AES carefully reviews reported conflicts of interest (COI) and resolves those conflicts
by having an independent reviewer from the Council on Education validate the content of all presentations for
fair balance, scientific objectivity, and the absence of commercial bias. The American Epilepsy Society adheres
to the ACCME’s Essential Areas and Elements regarding industry support of continuing medical education;
disclosure by faculty of commercial relationships, if any, and discussions of unlabeled or unapproved uses will
be made.

FACULTY / PLANNER BIO AND DISCLOSURES

Jeffrey Blount, M.D.
Jeffrey P. Blount is Professor and Chair of Pediatric Neurosurgery at the University of Alabama at Birmingham
(UAB) and Children's of Alabama. He is the Surgical Director of the Comprehensive Pediatric Epilepsy Program at
Children's of Alabama. He completed undergraduate studies at Washington and Lee University, medical school
at the University of Rochester and Neurosurgery residency at the University of Minnesota. His interest in
Epilepsy Surgery started while working with Robert Maxwell MD PhD at the MINCEP epilepsy group and was
further developed in further studies at the National Hospital for Neurology and Neurosurgery at Queen Square
UK and during his fellowship in Pediatric Neurosurgery at the Hospital for Sick Children, Toronto, Ontario,
Canada.

Jeffrey Blount discloses he has no financial relationships to disclose relevant to this activity.

Madeline Fields, M.D.

Madeline C. Fields, MD is an associate professor of neurology at The Mount Sinai Hospital. She is co-director of
the Mount Sinai Epilepsy Center.

Madeline Fields discloses she has no financial relationships to disclose relevant to this activity.

Saadi Ghatan, M.D.

Saadi Ghatan, MD, is Director of Epilepsy Surgery and Pediatric Neurosurgery in the Mount Sinai Health System
in New York City, and Site Chair of Neurosurgery at Mt Sinai West and Mt Sinai St Luke';s Hospitals. He is a
graduate of Princeton University and the University of Washington School of Medicine, and did his residency at
the University of Washington, with Fellowships at Atkinson Morley';s Hospital in Wimbledon, England, Pediatric
Neurosurgery at Seattle Children';s, and neurodevelopmental research at the Institute of Child Health in
London, England. Dr Ghatan has special interest in less invasive diagnostic and neuromodulatory therapeutic
approaches, in order to increase access to and utilization of surgery for children and adults with refractory
seizures.

Saadi Ghatan discloses he has no financial relationships to disclose relevant to this activity.

Cynthia Harden, M.D.

Cynthia L Harden MD is Professor of Neurology at the Icahn School of Medicine at Mount Sinai. Dr. Harden
graduated from the University of Wisconsin Eau Claire campus with a Bachelor of Science in Chemistry and from
the University of Wisconsin Medical College in Madison, Wisconsin with her medical degree. Her neurology
residency was undertaken at Mount Sinai Hospital. She had a long career at Weill Cornell School of Medicine
and became Professor of Neurology there in 2007. She is currently Chairperson of the Guideline Development,
Dissemination and Implementation Subcommittee of the American Academy of Neurology and Chair of the
Epilepsy Section of the AAN. She is chair of the American Epilepsy Society Clinical Research Committee.

Cynthia Harden discloses receiving the following support: Up-to-date, Wiley: Royalties

Piero Perucca, M.D.

Piero Perucca, MD, FRACP, is Consultant Neurologist at the Royal Melbourne Hospital and Senior Research
Fellow at Monash University, Melbourne, Australia. He trained at the University of Pavia, Italy; Columbia
University, USA; Montreal Neurological Institute, Canada; and the University of Melbourne, Australia. His main
areas of interest are the genetics of epilepsy, the pharmacological and surgical treatments of epilepsy, and
genetic and electrophysiological biomarkers of epilepsy outcome.

Piero Perucca discloses he has no financial relationships to disclose relevant to this activity.

Sarah Schmitt, M.D.

Sarah Schmitt, MD is currently an associate professor and vice chair of education in the Department of
Neurology at the Medical University of South Carolina. She completed both a neurology residency and a clinical
neurophysiology fellowship at the University of Pennsylvania, and subsequently joined the faculty of the
University of Pennsylvania as an Assistant Professor of Neurology from 2009-2015. She also served as the
Medical Director of the EEG Laboratory and the Director of Long Term Monitoring from 2009 - 2015. In 2015,
she joined the faculty of the Medical University of South Carolina as an Associate Professor of Neurology. Her
clinical and research interests include ICU EEG monitoring and autoimmune epilepsy.

Sarah Schmitt discloses receiving the following support: SAGE Therapeutics: Salary

Jerry Shih, M.D.

Dr. Shih is Professor of Neurosciences and Division Chief of Epilepsy at University of California, San Diego. He
received his bachelor';s degree from the Johns Hopkins University in 1980. He received his medical degree from
the University of California, Los Angeles School of Medicine, and completed neurology residency and
epilepsy/clinical neurophysiology fellowship at UCLA. Dr. Shih was Director of the Epilepsy Program and
Associate Professor of Neurology at the University of New Mexico, School of Medicine. He then became
Associate Professor of Neurology at Mayo College of Medicine and Director of the Comprehensive Epilepsy
Program at Mayo Clinic Florida. His early research was on the use of MEG in the evaluation of epilepsy. His
current research is utilizing brain-computer interfaces to control external devices

Jerry Shih discloses receiving the following support: Eisai, Inc: Honoraria; MDMag: Honoraria
Korwyn Williams, MD, PhD
Korwyn Williams, MD, PhD is a staff neurologist/epileptologist at Phoenix Children';s Hospital in Phoenix
Arizona. He is also a Clinical Assistant Professor, Department of Child Health at the University of Arizona College
of Medicine (Phoenix), as well as a Assistant Professor of Neurology at the College of Medicine, Mayo Clinic. He
has a particular interest in status epilepticus and EEG in the ICU.

Korwyn Williams discloses he has no financial relationships to disclose relevant to this activity.

CME REVIEWERS
Vinita Acharya discloses receiving the following support: Lundbeck LLC (Spouse/Partner): Consulting, Other
Financial or Material Support, travel expenses; Sunovion (Spouse/Partner): Honoraria, Other Financial or
Material Support, travel expenses to meeting; UCB Pharma (Spouse/Partner) : Honoraria

Timothy Ambrose discloses he has not financial relationships to disclose relevant to this activity.
Susanta Bandyopadhyay discloses he has not financial relationships to disclose relevant to this activity.

PHARMACY/NURSE PLANNERS
Gigi Smith, PhD, RN, CPNP-PC: No financial relationships to disclose relevant to this activity.
Dorothy Caputo, MA, BSN, RN - Lead Nurse Planner of AKH: No financial relationships to disclose relevant to this
activity.
Dorothy Duffy, PharmD - Pharmacy Reviewer of AKH: No financial relationships to disclose relevant to this
activity.

AKH STAFF / AES STAFF

AKH staff and planners: No financial relationships to disclose relevant to this activity.
AES staff and planners: No financial relationships to disclose relevant to this activity.

CME claim for Physicians and participation – Deadline: February 28, 2018
Visit https://www.aesnet.org/annual_meeting/program/ce_cme or watch your email for the notification and
link.

For assistance, contact Experient Customer Service:

800-974-9769 (US and Canada)
001-847-996-5892 (International)
aes@experient-inc.com
Hours: Monday – Friday, 8:00 a.m. – 5:00 p.m. (CT)
AES needs your feedback. Don’t forget to complete the session evaluations along with your credit claim.

CE claim for Nurses and Pharmacists – Deadline: January 16, 2018

Visit http://www.akhcme.com/akhcme/pages/2017AES or watch your email for the notification and link.
For assistance, contact AKH at jgoldman@akhcme.com.

DISCLAIMER
Opinions expressed with regard to unapproved uses of products are solely those of the faculty and are not
endorsed by the American Epilepsy Society or any manufacturers of pharmaceuticals.
 11/29/2017

Disclosure
Innovations in Epilepsy Treatment: Are
We on the Cusp of a Paradigm Shift?
Name of Type of
Commercial Interest Relationship
Cynthia L. Harden, MD, FAES
Mount Sinai Health System
• Wiley, Up‐to‐Date • Royalties
New York, NY

Learning Objectives
Four Domains Involved in Healthcare:
Improved Health and Quality of Life for patients
• Learn about the concept value‐based pricing is a goal of all sectors
• Understand what health care consumers state is important
Patients
to them
Healthcare
systems/
doctors

Insurance
companies

Industry

Do you ask your patients what they want What matters most to patients? Strong therapeutic
alliance, not relief of disease state (2016 Survey of 1800
from you as a provider? consumers)

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 11/29/2017

What matters most for three of these Profit is paramount for three of these,
domains? Profit cont’d
• Insurance companies‐most revenue is from investing
Patients
resources therefore there is an incentive to payout less for
healthcare to conserve investable margin
Healthcare
systems • Industry‐needs to sell products at highest profit margin and strategy
is to promote branded products as improvements on what has come
Insurance
companies before‐interface with physicians consists of ”patients will get
better/feel better”
• Healthcare systems/doctors‐need to see large numbers of
Industry patients, and do inpatient and outpatient procedures; nonprofits
reinvest any profit into system

Value‐based pricing could benefit patients by

Developing concept: Value‐based pricing improving outcomes, driving down costs, but
(VBP) in pharmaceuticals maintaining profit for Industry and Insurance
• The financial risk of treatment is shared between pharma and
payers sectors
• Focus is on appropriateness of use and outcomes
• Necessary pre‐conditions for VBP
– Measurable outcomes
– No generic alternatives
• Helpful preconditions for VBP
– Concerns by clinicians and payer re: effectiveness
Added value for
patients = Appropriateness of
treatment
X Outcomes ÷ Costs over
the full cycle of care

– Highly competitive market

– Actual or potential sales volumes are significant “It is essential to drive down transaction costs through smart measurement
processes..” from 2016 KPMG International Cooperative

Which sectors actually financially benefit from improved If patients have better outcomes due to more
health outcomes, especially if new treatments are actually effective treatments, who will probably
“better”, with (or without) use of VBP?
Better health outcome=profit Better outcome≠profit
benefit financially (green) and who is at risk of
• Insurance companies‐disease • Healthcare systems/doctors‐ not benefitting (red)?
resolution and less use of spin‐off
resources for disease complications ”outcome‐based” reimbursement Patients
such as ER visits and effectiveness of true
• Industry‐products develop “cache” “outcome‐based” marketing are
of effectiveness among patient and Insurance Healthcare

providers and use is increased not established companies systems‐

• Patients‐usually if disease state is

improved, individual productivity
may improve, and complications Industry
and ER visits are less; but not if
they cannot afford brand
medication that works for example

2
 11/29/2017

Problem #1: What matters most to physicians? It is Problem #1: What matters most to physicians? It is
complicated.. physicians also have some altruism in seeking to complicated.. physicians also have some altruism in seeking to
improve health, which may conflict with the profit‐seeking improve health, which may conflict with the profit‐seeking
goal of health care systems goal of health care systems
• It is a professional
Patients
indulgence and a
Healthcare humanistic privilege to be Healthcare
Insurance Doctors “big‐hearted” and care Doctors
companies systems systems
about people, to help
people and to make strong
relationships whether it is
Industry
mostly neurotic or not

Problem #2: Patient‐centered outcomes as they exist Problem #2: Patient‐centered outcomes as they exist
do not inform development of outcome‐ based do not inform development of outcome‐ based
policies Patients
policies Patients Patients
Patients stating they
stating they stating they  Should we be more paternalistic and stating they
Patients want to want relief want to
want relief tell patients what they should want have a nicer
from disease have a nicer from disease
experience, instead of the “touchy‐feely” state experience,
state etc
Insurance
companies
etc experience?
 Are patients completely correct that
they need a warm experience to
develop the therapeutic alliance and
Doctors Healthcare move toward wellness?
Industry
systems
 We must acknowledge a huge
knowledge asymmetry that makes
patients feel vulnerable.

Value‐based pricing strategies attempt to connect goal

of industry and insurance companies (effective care
leading to profit) to improved patient health
outcomes
• The financial risk of treatment is shared between
pharma and payers to improve outcome for patients
– Where is the fourth sector, doctors and healthcare systems?
– Is success of VBP even possible without the therapeutic
alliance that patients want and doctors need?
If healthcare systems could integrate into the VBP
model, this may strategy to achieve goals of all
sectors….
– Doctors carry out their hippocratic oath, their altruistic need
and health care systems profit
– Insurance may profit but manage risk
– Industry may profit and achieve earlier adoption of their new
and expensive products
– Patients (mentioned last but not least) have access to
potentially more effective treatments, which they access
earlier, with less financial strain effected through a strong
therapeutic alliance with their providers

3
 11/29/2017

Thanks
• Just leaving you with some thoughts on a paradigm
shift…

Impact on Clinical Care and Practice

• First point
• Sub‐point 1
• Sub‐point 2

• Second point

• THIS SLIDE SHOULD COME AT THE END OF YOUR

PRESENTATION, TAKE HOME MESSAGES

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 11/29/2017

Disclosures and Credits

Early Surgery With
• Disclosures: Consultant to NeuroPace
Minimally Invasive • Credits:
Techniques: PRO – Pediatric and Adult Epilepsy Teams

Saadi Ghatan, MD
Mount Sinai Health System
New York, NY

DECEMBER 4, 2017

The Underserved Epilepsy Population Barriers to Surgery

Patients with Medically

Intractable • FEAR: brain surgery carries a NEGATIVE societal bias
Epilepsy:1,000,000
• INVASIVE MONITORING: with intracranial electrodes is often
required for diagnostic purposes prior to resection – causing concerns
over patient tolerability and safety during hospital stay
Patients Referred
to Level 3, 4
Epilepsy Centers: • IRREVERSIBILITY: resective procedures combined with the
220,000 uncertainty of outcome can be a major barrier in patient’s decision to
undergo surgery and the practitioner’s willingness to refer the patient
to an epilepsy center

Patients
Undergoing
Epilepsy Surgery:
Gumnit RJ, Labiner DM, Fountain NB, et al.; 3000
Data on Specialized Epilepsy Centers, 2012

Early Surgery with Less Invasive 1). Stereo EEG Increases Utilization of
Techniques will Lead to Better Utilization Successful Epilepsy Surgery
and Outcomes
Rationale for SEEG:
• Comprehensive intracranial recording method
1).Stereo EEG increases surgical access without • Robotic Navigation eases efficiency and safety of lead placement
sacrificing diagnostic accuracy • Patient/Advocate satisfaction
2).Laser Interstitial Thermal Therapy can be a
better ablative option when focal epilepsy is
found, leading to greater utilization
3).Neurostimulation provides diagnostic and
therapeutic advantages that did not
previously exist
Photo courtesy P. Kahane

1

Robotic SEEG
Early evidence of LITT safety, efficacy:
• MTLE
63.8% 1yr seizure freedom (n=56)
67.4% 1yr seizure freedom for MTS (n=32)
neuropsychological outcome: no decline in naming
(dominant) and facial recognition (non‐dominant)
BUT possible decline in memory
~6% overall complication rate
• HH
90% seizure freedom at 6 mo FU (n=10)
Neuromodulation for Epilepsy
Responsive Neurostimulation
̶ FDA approved since late 2013
̶ Adjunctive treatment for
pharmacoresistant partial
onset seizures with 1 or 2 foci
for patients 18 or older
11/29/2017
2). Laser Interstitial Thermal Therapy
(LITT) can be less invasive and more
• Map both hemispheres
• Sample deep structures appealing, where ablative procedures are
• Evaluate epileptogenic indicated
networks and zones
• Less painful, less invasive
• Safe
LITT 3). Neurostimulation (NS) for Epilepsy
is an attractive and effective option
• Vagus Nerve Stimulation (VNS):
̶ FDA approved since 1990’s, >100,000 implants in US
̶ Extracranial reversible procedure
̶ Widely offered as palliative treatment across all etiologies and age groups
̶ Limitations: variable therapeutic benefit, lack of ability to tailor treatment
to seizure type/ brain region involved in cases of suboptimal results
• Deep Brain Stimulation (DBS‐NS):
̶ Continuous bilateral stimulation to treat temporal lobe seizures
̶ Common targets: anterior thalamic nuclei, centro‐median thalamic nuclei,
subthalamic nuclei, direct hippocampal stimulation
̶ Approved in Europe since 2010 as an adjunctive treatment for partial onset
seizures in adults
North RY et al. Neurosurg Clin N Am 28:545‐557, 2017
Wilfong AA and Curry DJ Epilepsia 54 (Suppl.9):109‐114, 2013
Drane DL et al. Epilepsia 56(1):101–13, 2015
Jermakowicz W et al. Epilepsia 58(5):801–10, 2017
Responsive Neurostimulation System
• Targets and facilitates
understanding of both
epileptogenic zone and network
• Real‐time, chronic recordings of
electrical activity
• Modulatory rather than
destructive
2
 11/29/2017

Long Term Efficacy of RNS Sudden Unexpected Death in Epilepsy

Median follow‐up 6.8 years; 1716 patient implant years
72% median % seizure
reduction
Responder rate 66.5% (95% CI
59.4‐72.8%)
25% had seizure reductions of
≥ 93%
29% had at least one seizure
free period of ≥ 6 months
(SUDEP) in RNS patients
Anticipated SUDEP rate
Medically intractable epilepsy 5.9 / 10001 patient years
Patients with intractable epilepsy
randomized to placebo arm of 6.1 / 10002 patient years
AED trials
Candidates for epilepsy surgery 9.3 / 10003 patient years
2.0 / 10004 stimulation years
RNS System treated patients
(95% C.I. 0.7‐5.2)

From Morrell, et al. AES 2016

1Nashef et al., 1995
From Morrell, et al. AES 2016 2Ryvlin et al., 2011
3 Dasheiff, 1991
4 Devinsky, Kapur et al., 2016; presented at AES

Early surgery with less invasive techniques will

Robotic SEEG‐RNS increase utilization of epilepsy surgery without
sacrificing safety or quality
Illustrative Case: Overcoming Fear From maximally invasive evaluation and
irreversible treatment ▶ The SEEG‐LITT and SEEG‐
• PATIENT: NS options represent a
29yo F, refractory hyper‐motor seizures, normal MRI, few events shift in paradigm for the
ever captured on VEEG, no localizing value, normal interictal field of epilepsy surgery
findings, long history of struggling with decision to undergo
invasive monitoring and possible resection

• WHY RNS?
L insular epilepsy with secondary focus in L SMA was
diagnosed with bifrontal SEEG coverage ‐ unresectable

• WHERE TO PLACE THE LEADS?

depth electrode in L insula and cortical strip over L SMA

• Advantage of SEEG‐RNS?
diagnose seizures originating in deeper structures
direct evidence for RNS depth electrode placement To less invasive evaluations with modifiable and
less invasive option in a case of fear presenting a even reversible, neuromodulatory, and
barrier to treatment diagnostic treatments

3
 11/29/2017

Disclosure
Early Surgery with Minimally Invasive
Name of Type of
Techniques: Con Commercial Interest Relationship
Jeffrey P. Blount MD • none • none
Department of Neurosurgery
University of Alabama at Birmingham

Minimally invasive technologies … the

Learning Objectives
fairy tale...
• First objective: understand limitations of minimally invasive • Briefly asleep…
techniques in epilepsy surgery • No hair cut....
• Second objective: temper the delusional fantasies projected • Tiny incisions....
by Dr. Ghatan and restore a mature, balanced viewpoint of • No blood loss....
the proper role of this emerging technology… • Doesn’t hurt….
• Perfectly safe...
• Perfect 3D view of where life alterning medically resistant
epilepsy is coming from....
• LITT:
– Laser= cool, who doesn’t like that??
– No OR….just like a scan...

Premises of Minimally Invasive Surgery‐

SEEG limitations‐ data
monitoring
• Technical
• Localization equivalent or better than other strategies for electrode – Depth of reach of electrodes= 2 mm; results in narrow corridors of recognized
based localization of hyperactivty
– Ictal onset – From there process is to extrapolate known projection pathways to define “the
– Spread/ projection pathway network”
– Adjacent eloquent cortex • Conceptual‐ i.e. Defining “the network”
– Adequately and equivalently informs the resective strategy – Vague, in vogue
• Safe – Non‐contiguous
• Less painful – 3D challenges
• Cost Effective – Fundamental mission of invasive electrodes is to define the surgical resection to
result in seizure freedom
• More attractive to patients and families – Spatial mapping of eloquence is elusive, challenging to many epileptologists and
– May aid in recruiting referrals for epilepsy surgery that is o/w considered too surgical teams
frightening, risky or invasive

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 11/29/2017

SEEG limitations‐ the unreported and

unspoken
• Complications less rare than reported
– Hemorrhage
• Epidural – from pushing dura away
• Intraparenchymal
• Risk is the pial vessels tethered at entry point by arachnoid‐ NOT
the large perforant vessels defined on angiography
– Angio provides relative safety but there still are focal events
– Malpositioned electrodes

Jonas
• Venous ooze noted out anchor bolt with placement of 8th (right side) cleared with irrigation. Decision
made to abort placement of remaining electrodes and take pt for CT.
• Drapes removed, pupils noted to be equal. Pt transferred to stretcher, and R pupil noted to be blown.
Pt taken emergently to scanner, where stat CT demonstrated hyperacute right SDH.

Jonas Hypothalamic Hamartoma

• Pt emergently brought back to OR for removal of all SEEG electrodes, right frontal craniectomy, SDH
evacuation. Active bleeding identified from small cortical vein.
• Pt taken directly from OR for post‐op CT which demonstrated good SDH evacuation with resolution
of mass effect/midline shift.

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Temporal lobe epilepsy

“Finally, future research needs to

assess the clinical significance of
declines in famous face recognition
and naming.”

Mullin World
Neurosurgery, 2016.

Premises of Minimally Invasive Surgery‐

LITT limitations‐ data
ablation
• Focal ablation is as effective as resection
– At disrupting epileptogenic networks

• Effect is as lasting as ablation

Hypothalamic Hamartoma

Use this slide format only for

large graphics or images

3
 11/29/2017

Periventricular Heterotopia LITT limitations‐ the unreported and

Stereotactic laser ablation of epileptogenic unspoken
periventricular nodular heterotopia • Costs‐ expensive initial capital
Yoshua Esquenazi, Giridhar P. Kalamangalamb,Jeremy D. Slater, Robert C. Knowlton, Elliott Friedman,
Saint‐Aaron Morris, Anil Shetty, Ashok Gowdad, Nitin Tandon
– Disposables 15‐20K/case
2 cases‐
Safe
Conclusion: MRgLITT possesses significant potential
as a minimally invasive technique for ablation of
• Complications
Initially seizure free, PVNH, and more generally, as an adjunct in the – Misplaced electrodes
then recurrent seizures surgical management of lesional epilepsy. In this
1‐ then sz free with study we demonstrate the safety, feasibility and
– Hemorrhage
med limited efficacy of MRgLITT in PVNH‐associated – Hyperthermic injury/spread
2‐ seizure free after epilepsy, though its long‐term efficacy will be
further IM and ATL revealed as more centers adopt the technology in
– Mechanical malfunction
the future.

CLINICAL ARTICLE
J Neurosurg 126:1238–1245, 2017
COSTS: Capital approx $400,000
Complication avoidance in laser interstitial thermal
therapy: lessons learned Laser ablation therapy: An alternative treatment for medically
Rachel Pruitt, BS,1 Alexander Gamble, DO,2 Karen Black, MD,1,3 Michael Schulder, MD,1,2 and
resistant mesial temporal lobe epilepsy after age 50
Ashesh D. Mehta, MD, PhD1,2
1Hofstra Northwell School of Medicine, Hempstead; and Departments of 2Neurosurgery and 3Radiology, North Shore University
Waseem H, Osborn K , Schoenberg M, Kelley V, Bozorg A, Cabello
Hospital, Manhasset, New York
D,
OBJECTIVE Complications of laser interstitial thermal therapy (LITT) are underreported. The authors discuss how they
have modified their technique in the context of technical and treatment-related adverse events. Benbadis S, Vale F
TABLE 3. Complications in the literature
OR charges (USD) AMTL MRgLITT
No. of Patients (%)
Mean 63,991 89,759
Cause Total Transient Permanent
Range 55,255 to 76,716 79,184 to 106,687
Malposition 4 (1.6) 3 (1.2) 1 (0.4)
Catheter passage 4 (1.6) 1 (0.4) 3 (1.2) Total hospitalization charges
LITT treatment 43 (17.7) 33 (13.6) 10 (4.1) (USD)
Technical 0 (0) 0 (0) 0 (0) Mean 98,471 119,818
Total 51 (20.1) 37 (15.2) 14 (5.6)
Range 86,594 to 122,199 99,303 to 140,586

Premise of Minimally Invasive Strategy‐

Neurostimulation
• Neurostimulation offers effective alternative
strategy when ablation or resection carries too
much risk for disabling neurologic injury
• Safe
• Effective
• Cost Effective

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Impact on Clinical Care and Practice

Minimally invasive techniques are highly promising but the

appropriate role and domain is still being defined‐
• Regional lesions
• MTE‐ tradeoffs of efficacy/memory (?)
• No role in broad cortical dysplasias
• Localized lesions:
• Highly focal well localized ictal regions
e.g periventricular nodular heterotopias….
• Small, focal lesions in difficult regions
e.g. Hypothalamic hamartomas

5
 Epilepsy Therapies Symposium

The Use of Genetic Testing in Focal Epilepsies

Piero Perucca, MD, FRACP

The Royal Melbourne Hospital, Monash University
Melbourne, Australia

Slides not available

 11/29/2017

Disclosure
How to Approach Treatment for Immune Name of Type of
Epilepsy Commercial Interest Relationship
Sarah Schmitt, MD • SAGE Therapeutics • Salary support
Medical University of South Carolina

Learning Objectives Case example

• Describe how antigen sites influence a patient’s response to
therapy
• Describe approaches to treatment for commonly
encountered forms of autoimmune epilepsy
• Understand the unique treatment challenges presented by
GAD and thyroid‐associated antibodies
• Understand the role of neoplasms and their treatment in
• 24 year old previously healthy woman
• 7 month history of ~ sz 5‐6 times per week
• Tx: LTG 250 mg BID and LEV 1500 mg BID  no
improvement
• Previous trial of TPM also unsuccessful
• EEG  bilateral independent temporal lobe
seizures
• MRI shows T2 signal changes left > right
hippocampus
• LP  + NMDA‐R antibodies

the treatment of autoimmune epilepsy

Autoimmune seizures and epilepsy Autoimmune seizures and epilepsy

• Classic picture = limbic encephalitis Increasing recognition of autoimmunity in drug resistant

• Acute / subacute presentation
• Psychiatric disturbances
• Memory / cognitive complaints
• Seizures (often multifocal) or status epilepticus
• Mild CSF pleocytosis
• MRI  signal changes in limbic structures
epilepsy
• May not have “classic” features of limbic encephalitis
• Chronic disease course
• Memory / cognitive complaints subtle or absent
• Predominant complaints = seizures and epilepsy
• Seizures more likely to occur daily (81%)
• More likely to be multifocal (38%)
Quek AML et al. Arch Neurol 2012 May;69(5):582‐93.

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Autoimmune seizures and epilepsy 160

Articles on autoimmune epilepsy + seizures
140

Antibody Incidence 120

NMDA‐R 1,2,3 2‐4% 100

LGI1 / CASPR2 1,2,3,4,5 5‐12%

80

Glycine‐R 1,3 3‐6% NMDA‐R Ab case

series published

GAD 1,2,5 2‐13% 60

“VGKC” Ab case
series published

First clinical case

40 series of anti‐Hu
encephalomyelitis

20 Dalmau J, et al. Medicine 1992, 71:59–72

1
Brenner T et al. Epilepsia 2013 Jun;54(6):1028‐35. Vincent A, et al. Brain. 2004 Mar;127(Pt 3):701‐12
Dalmau J, et al. Ann Neurol. 2007 Jan;61(1):25‐36.
2 Dubey D et al. Jama Neurol 2017 Apr 1; 74(4):397‐402.
3 Ekizoglu E et al. Epilepsia 2014 Mar;55(3):414‐22. 0
4 Majoie HJ et al. Epilepsy Res 2006 Oct;71(2‐3):135‐41 1980 1981 1982 1983 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016
5 McKnight K et al. Neurology 2005 Dec 13;65(11):1730‐6. * Pubmed articles containing “autoimmune” or “antibody” and “epilepsy” or “seizure”

Conventional therapy and autoimmune epilepsy: Conventional therapy and autoimmune epilepsy:
Antiseizure drugs Surgery
Antibody Reported outcomes
CASPR2 One Engel III
Antibody Rate of excellent response to antiseizure drugs
GAD Four Engel II, three Engel III, five Engel IV
GABAB‐R 17%
Hu One Engel I
GAD 14%
LGI1 Two Engel I, one Engel IV
Hu 0%
Ma 2 One Engel II, one Engel III
LGI1 7%
Summary • 16% Engel I (seizure free)
• 52% Engel II or III (rare seizures,
worthwhile improvement in seizures)
Honnorat J et al. Neurology 2013 Jun 11;80(24):2226‐32.
Irani SR, et al. Ann Neurol. 2011 May;69(5):892‐900.
• 32% Engel IV (no improvement)
Malter MP, et al. Seizure 2015 Aug;30:57‐63.
Petit‐Pedrol M, et al. Lancet Neurol. 2014 Mar;13(3):276‐86.
Almeida V et al. Epileptic Disord. 2012 Sep;14(3):345‐8.
Carreño M et al. Epilepsy Res. 2017 Jan;129:101‐105.
Malter MP, et al. Seizure 2015 Aug;30:57‐63.
Quek AML et al. Arch Neurol 2012 May;69(5):582‐93.

Categorizing autoantibodies by target antigens Intracellular antigens versus cell surface antigens
• Intracellular antigens :
Intracellular Antigens Synaptic receptor antigens Other cell surface proteins • Less likely to respond to immunotherapy
Amphiphysin AMPA receptor CASPR2
• Most have strong association with neoplasms (except GAD)
CRMP‐5 (aka CV2) GABAA receptor* DPPX* • Likely cytotoxic T‐cell response  neuronal loss (possible
GAD GABAB receptor LGI1 exception: amphiphysin)
Hu (ANNA‐1) GluRε2*
Ma2 (aka Ta or PMNA‐2) Glycine receptor*
mGluR5* • Cell surface antigens (synaptic receptor and other plasma membrane
NMDA receptor bound proteins):
• More robust immunotherapy response
• More variable association with neoplasm
• Antibodies may lead to receptor internalization, downregulation
Bien CG et al. Brain 2012; 135: 1622‐1638. Manto M et al. Orphanet J Rare Dis 2010; 5:31.
Dalmau J, Rosenfeld MR. Lancet Neurology 2008; 7: 327‐40. Petit‐Pedrol M, et al. Lancet Neurol. 2014 Mar;13(3):276‐86.
* Not available through commercial panels in the United States Geis C et al. Brain 2010; 133: 3166‐3180. Toledano M, Pittock SJ. Semin Neurol 2015; 35: 245‐58.

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Treatment Limitations Treatment approach: intracellular antigens

• NO randomized controlled trials • For Hu, Ma2, CRMP‐5, amphiphysin:
– Identify and treat underlying malignancy (present in ~90% of patients)
• Data largely anecdotal, observational – Immunotherapy response rate:
Antibody Response rate

• Few comparison between treatment regimens Amphiphysin 36%

CRMP‐5 (CV2) 38% (stabilized or improved)
• Treatment regimen may be limited by: Hu (ANNA‐1) 0‐4%

• Access to IV therapies Ma2 64% (vs. 36% without)

• Insurance restrictions Dalmau et al. Brain 2004 Aug;127(Pt 8):1831‐44.

Dalmau J, et al. Medicine 1992, 71:59–72
Murinson CC, Guarnaccia JB. Neurology 2008; Dec 9;71(24):1955‐8
Sillevis Smitt P, et al. J Neurol. 2002 Jun;249(6):745‐53.

Treatment approach: intracellular antigens Treatment considerations: IVIg

• For Hu, Ma2, CRMP‐5, amphiphysin:
1st line immunosuppressant trial:
Methylprednisolone
500‐1000 mg / day x 5
days
AND / OR
Typically administer more
IVIg 2 g/kg divided over
2‐5 days slowly in patients with CHF,
ALTERNATIVE
If unable to tolerate
IVIg, plasma exchange
QOD x 4‐10 tx
• Rate of infusion correlates with incidence of adverse reactions
• Headaches, rhinitis, nasal congestion common
• Also risk of:
Consider foregoing in • Anaphylactic / hypersensitivity reactions
patients with poorly • Thrombosis  consider monitoring high‐risk pts in infusion center or
controlled DM hospital
• Renal failure  monitor creatinine
• TRansfusion Associated Lung Injury (TRALI)  ANA, CXR in pts with new
pulm complaints
pts > 55 • Transfusion Associated Circulatory Overload (TACO)
• Other strategies to minimize adverse reactions:
• Premedicate with acetaminophen, diphenhydramine
Bien CG. Epilepsia. 2013 May;54 Suppl 2:48‐55.
Dalmau J et al. Lancet Neurol. 2011 Jan;10(1):63‐74.
Suleiman J, Dale RC. Dev Med Child Neurol. 2015 May;57(5):431‐40.
• Hydration
Toledano M et al. Neurology 2014 May 6;82(18):1578‐86.
Toledano M, Pittock SJ. Semin Neurol 2015 Jun;35(3):245‐58.
Wong‐Kisiel LC et al. Can J Neurol Sci 2012 Mar;39(2):134‐44.
Cherin P et al. Autoimmun Rev. 2016 Jan;15(1):71‐81.

Treatment approach: intracellular antigens Treatment considerations: cyclophosphamide

• For Hu, Ma2, CRMP‐5, amphiphysin: • Risk of:
– If no response in 2‐3 weeks, consider therapy targeting cytotoxic T‐cell • GI side effects (dose related)
response: • May affect fertility (consider involving endocrinology for reproductive age
women)
Oral • Reversible alopecia
• Cardiac arrhythmias, CHF (monitor on telemetry during infusion)
cyclophosphamide 2
• Leukopenia, neutropenia (max 8‐12 days post‐infusion)
mg / kg / d • Hemorrhagic cystitis  increase fluid intake by 1‐2 L (IV or po)
• Pneumonitis
– Study  20 patients with intracellular antibodies randomized to PLEX + • Infections
cyclophosphamide vs. PLEX alone • Prophylaxis against P. jirovecii
– 60% improvement in cyclophosphamide arm, 30% PLEX alone • TMP/SMX 800/160 three times week
• TMP/SMX 400/80 daily
– BUT side effects  60% of CTX pts dropping out
Stern A, et al. Cochrane Database Syst Rev. 2014 Oct 1;(10):CD005590.
Vernino S, et al. Neuro Oncol. 2004 Jan;6(1):55‐62. Vodopivec I et al. Semin Neurol Sep;34(4):467‐78.

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Cyclophosphamide & intracellular antigens: Treatment approach: plasma membrane antigens

Weighing the risks and benefits For AMPA‐R, GABAA‐R, GABAB‐R, Glycine‐R, NMDA‐R, GluR5, GluRε2, LGI1, CASPR2,
DPPX Abs:
• Identify and treat underlying malignancy (if appropriate)
• Initial treatment trial:
Methylprednisolone Consider foregoing in
500‐1000 mg / day x 5 patients with poorly
days controlled DM
• Toxicity of
AND / OR
• Premorbid health cyclophosphamide
status • Need for other Typically administer more
IVIg 2 g/kg divided over
• Severity of chemotherapy 2‐5 days slowly in patients with CHF,
neurologic agents pts > 55
impairment • Relatively low alternative
• Cancer prognosis response rate If unable to tolerate Bien CG. Epilepsia. 2013 May;54 Suppl 2:48‐55.
IVIg, plasma exchange Dalmau J et al. Lancet Neurol. 2011 Jan;10(1):63‐74.
Suleiman J, Dale RC. Dev Med Child Neurol. 2015 May;57(5):431‐40.
QOD x 4‐10 tx Toledano M et al. Neurology 2014 May 6;82(18):1578‐86.
Toledano M, Pittock SJ. Semin Neurol 2015 Jun;35(3):245‐58.
Wong‐Kisiel LC et al. Can J Neurol Sci 2012 Mar;39(2):134‐44.

Early maintenance therapy: Treatment considerations: long term glucocorticoids

In clinical responders:
Steroids:
(1) 500‐1000 mg IV methylprednisolone
weekly
‐or‐
(2) Prednisolone or prednisone po 1‐2
mg /kg/d x 8‐10 weeks then taper over
1‐2 months
Bien CG. Epilepsia. 2013 May;54 Suppl 2:48‐55.
Dalmau J et al. Lancet Neurol. 2011 Jan;10(1):63‐74.
Suleiman J, Dale RC. Dev Med Child Neurol. 2015 May;57(5):431‐40.
IVIg:
(1) Weekly 0.4 gm/kg IVIg x 6‐12 weeks
followed by taper over 3‐6 months
‐or‐
(2) Monthly 1‐2 gm/kg IVIg (divided over
2‐5 days) x 3 months followed by taper
over 3‐6 months
Toledano M et al. Neurology 2014 May 6;82(18):1578‐86.
Toledano M, Pittock SJ. Semin Neurol 2015 Jun;35(3):245‐58.
Wong‐Kisiel LC et al. Can J Neurol Sci 2012 Mar;39(2):134‐44.
• Avoid NSAID use ( peptic ulcer risk)
• Glucose monitoring in patients at risk
• Osteoporosis risk:
• Vitamin D 800 IU / day
• Calcium between 1000 – 1500 mg / day
• Increased risk for opportunistic infections
• Prophylaxis against P. jirovecii
• TMP/SMX 800/160 three times week
• TMP/SMX 400/80 daily
American College of Rheumatology Ad Hoc Committee on glucocorticoid‐
induced osteoporosis. Arthritis Rheum. 2001; 44(7): 1496‐503.
Gabriel SE et al. Ann Intern Med. 1991;115(10):787.
Stern A, et al. Cochrane Database Syst Rev. 2014 Oct 1;(10):CD005590.

What defines a “clinical response?” How long to wait for a clinical response
• For patients with limbic encephalitis: • For limbic encephalitis:
• > 50% seizure reduction • Absence of early response  transition to second line therapy
after 10‐14 days
‐or‐
• Earlier tx with 2nd line agents (rituximab / cyclophosphamide) 
• Improvement in modified Rankin score by ≥ 1 improved outcome

• For patients with epilepsy alone: • For epilepsy:

• > 50% seizure reduction • May not see significant seizure reduction for several weeks
• Look for some improvement within 4‐6 weeks
• For responders, median time to seizure freedom 10 months

Dalmau J et al. Lancet Neurol. 2011 Jan;10(1):63‐74.

Toledano M, Pittock SJ. Semin Neurol. 2015 Jun;35(3):245‐58 Quek AML et al. Arch Neurol 2012 May;69(5):582‐93.

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Second line therapy Treatment considerations: rituximab

Rituximab: • Infusion reaction in 2 hours is common  MONITOR
375 mg/m2 IV weekly x 4 INFUSION
doses • HA, fever, chills, rhinitis
• Mild angioedema, sensation throat / tongue swelling
AND / OR • Bronchospasm, severe hypotension can occur
• Risk of late onset neutropenia
Cyclophosphamide:
• Risk of hepatitis B reactivation  test before, during tx
750 mg/m2 IV Q4‐6 weeks
• Low risk of P. jirovecii pneumonia  no need for
Or prophylaxis
Dalmau J et al. Lancet Neurol. 2011 Jan;10(1):63‐74
1.5‐2 mg/kg po Q4‐6 weeks Davis R, Dalmau J. Epilepsia 2013 Sep;54 Suppl 6:46‐9.
Barreto JN et al. Am J Hematol 2016;91(11):1113
van Vollenhoven RF, et al. J Rheumatol. 2015;42(10):1761‐1766.

Chronic maintenance therapy Treatment considerations: mycophenolate

• Can be used to maintain remission when weaning steroids, IVIg • Teratogenic with REMS program,
• Usually maintain for one year, then attempt wean – Patient should sign consent form  2 forms birth control
• Can consider earlier wean for LGI1 (lower risk of recurrence), NMDA‐R with
• Risk of:
tumor s/p rsxn
– GI side effects: 20‐50%
Mycophenolate
– Rash, increased infection
600 mg/m2 po BID, – Myelosuppression with low cell counts
up to 2g/d • Check CBC, CMP before starting, q2 weeks while
OR titrating, then every other month
Azathioprine
Dalmau J et al. Lancet Neurol. 2011 Jan;10(1):63‐74.
1‐3mg/kg po QD Wong SH et al. J Neurol Neurosurg Psychiatry 2010; 81: 1167‐9. Gerosa M et al. Expert Opin Drug Saf. 2014 Dec;13(12):1591‐9.
Omair MA et al. PLoS One. 2015 May 1;10(5):e0124205.
Mycophenolate mofetil (Cellcept®) [package insert]. Roche Laboratories Inc. Nov. 2000
Velo Garcia A et al. Expert Opin Drug Saf. 2016 Aug;15(8):1041‐54.

Treatment considerations: azathioprine Controversial antibodies: Glutamic acid decarboxlase (GAD)

• Check for TPMT levels before use • Can present with several clinical phenotypes:
– Low levels  dramatically increased risk of myelosuppression – Stiff person syndrome (most common: 36‐40%)
– 86% of deficient patients  myelosuppression – Cerebellar ataxia (28%)
• Other risks: – Insulin dependent diabetes mellitus (18%)
– GI upset, nausea vomiting (10‐20%)
– Less common: rash, transaminitis, stomatitis – Seizures / epilepsy (7%)
• Pregnancy category D: reports of IUGR, preterm labor – Limbic encephalitis (7%)
• Increased risk of malignancy including skin cancer  advise patient to • Response to immunotherapy: poor to fair
protect skin – 8‐10% full recovery
• Check CBC, CMP before starting, q2 weeks while titrating, then every – 27‐55% improvement with 17% relapsing
other month – 8% mortality
Dayalu P, Teener JW. Semin Neurol. 2012 Nov;32(5):544‐9.
Higgs JE et al. Pharmacogenomics 2010 Feb;11(2):177‐88. Gagnon MM, Savard M. Can J Neurol Sci 2016 Jul;43(4):486‐93.
Malter MP, et al. Seizure 2015 Aug;30:57‐63.
Levy RA et al. Autoimmun Rev. 2016 Oct;15(10):955‐63. Saiz A, et al. Brain. 2008 Oct;131(Pt 10):2553‐63.
Wagner M et al. Cochrane Database Syst Rev. 2015 Dec 3;(12):CD007746. Vianello M,et al. Autoimmunity. 2008 Feb;41(1):66‐73.

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Controversial antibodies: GAD GAD antibody: treatment algorithm

• Controversy if GAD antibodies are directly pathogenic Assess GAD Ab
– Intracellular antigen titer levels
– > 15% with GAD antibodies  no neurologic disease
• Low titers present in 1% of population If titer ≥ 2000 U/mL,
If titer ≤ 2000 U/mL, Methylprednisolone
• Co‐occurs with many autoimmune diseases no clear indication for 500‐1000 mg / day x 5
treatment days then prednisone po
• Seen in 80% of type 1 DM 1‐2 mg /kg/d
– 19% have other autoantibodies
If no response to If partial / incomplete
– May be markers of pathogenic T‐cell mediated autoimmune response methylprednisolone response, trial of IVIg 2
• GAD Abs can affect hippocampal neuron firing after 6 weeks, wean
steroids, stop
g/kg divided over 2‐5 d
or
immunotherapy PLEX QOD x 4‐6 tx

Saiz A, et al. Brain. 2008 Oct;131(Pt 10):2553‐63.

Dayalu P, Teener JW. Semin Neurol. 2012 Nov;32(5):544-9.
Gagnon MM, Savard M. Can J Neurol Sci 2016 Jul;43(4):486‐93. Gagnon MM, Savard M. Can J Neurol Sci 2016 Jul;43(4):486‐93.
Meinck HM et al. J Neurol Neurosurg Psychiatry 2001; 71: 100‐03. Malter MP, et al. Seizure 2015 Aug;30:57‐63.
Vianello M, et al. Autoimmunity. 2008 Feb;41(1):66‐73.

Thyroid peroxidase antibodies and seizures Thyroid peroxidase antibodies and seizures
• Also known as “Hashimoto’s encephalopathy” or “steroid‐responsive encephalopathy

•
associated with autoimmune thyroiditis” (SREAT)
Multiple nonspecific clinical features:
• Clinical significance of thyroid peroxidase Ab unclear
–
–
Tremor
Stroke like symptoms
– TPO Ab in ~10% of healthy adults & children
–
–
Myoclonus
Sleep changes
– > 60% of patients with sx initially attributed to TPO Abs 
– Behavioral abnormalities other antibodies (GABAA, GABAB, LGI1, NMDA‐R)
– Seizures

•
– Ataxia
Defined by:
• Antibody titer does not correlate with sx
– Thyroid peroxidase (TPO) antibodies (less common: thyroglobulin antibodies)
– Response to immunotherapy (usually steroids) • Diagnosis requires response to immunotherapy

Alink J, de Vries TW. Acta Paediatr. 2008 Apr;97(4):451-3.

Berger I, et al. Acta Paediatr. 2010 Dec;99(12):1903-5.
Doğan M, et al. J Pediatr Endocrinol Metab. 2011;24(1-2):75-80.
Lee J et al. Brain Dev. 2017 Aug 4.
Tüzün E, et al. Neurol India. 2011 Jan-Feb;59(1):47-50
Zois C, et al. Thyroid. 2003 May;13(5):485-9.

Treatment of Thyroid peroxidase Abs and seizures The cancer conundrum: who to screen, how to screen
Methylprednisolone 500‐
1000 mg day x 5 days then
then prednisone po 1‐2 mg • Neurologic sx precede cancer diagnosis in 70% of patients
/kg/d up to 80 mg/d
antibodies
– 70‐80% will have a positive screening for cancer on initial assessment
If no response, wean
steroids, halt
If partial response, PLEX
QOD 4‐10 tx
If good response,
transition to steroid • Intracellular antigens except GAD (Hu, Ma2, CRMP‐5) 
immunotherapy sparing agents
strong association with cancer
Often reserved for Rituximab 375 mg/m2 Mycophenolate 600
Azathioprine 1‐3
• Some antigens only weakly associated with cancer (GAD,
more severe or hard‐ IV weekly x 4 doses; mg/m2 po BID, up to
to‐wean pts may repeat if indicated 2g/d
mg/kg po QD glycine‐R, LGI1, GABAA‐R)

Maas A et al. Pediatr Neurol 2017 Jan;66:28‐31
Marshall GA et al. J Neuropsychiatry Clin Neurosci. 2006 Winter;18(1):14‐20.
Olmez I et al. J Neurol Sci, 331 (2013), pp. 67‐71
Gadoth A et al. Ann Neurol 2017 Jun; 82(1): 79-92. Petit-Pedrol M, et al. Lancet Neurol. 2014 Mar;13(3):276-86.
Graus F, Dalmau J. Curr Opin Neurol. 2007 Dec;20(6):732-7. Spatola M et al. Neurology. 2017 Mar 14;88(11):1012-1020.
Höftberger R, et al. Neurology. 2013 Oct 22;81(17):1500-6. Van Soderen A et al. Neurology. 2016 Oct 4;87(14):1449-1456.

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Neoplasms and antibodies Neoplasm screening: High, intermediate risk antibodies

Antibody Association with neoplasm Most common neoplasm(s)

Hu (ANNA‐1) > 90% SCLC, other

CRMP5 (CV2) > 90% Thymoma, SCLC, other
Ma2 (Ta) >90% Testicular CA, non‐SCLC High risk
Amphiphysin >90% SCC, breast
mGluR5 >90% Hodgkins lymphoma
High risk antibodies CT Chest,
AMPA‐R (GluR1/2) 60‐70% Thymoma, breast, SCLC, ovarian teratoma Repeat PET scan Q6
(Ma1, Ma2, Hu, abdomen, pelvis; If negative, whole
NMDA‐R Varies by age: 56% if > 18 Ovarian, testicular teratoma months for up to 4
Intermediate risk amphiphysin, colonoscopy, body PET scan
y.o., 9% if < 9 y.o. years
mGluR5, CRMP5) mammogram
GABAB‐R 50% SCLC
DPPX 30% B‐cell lymphoma
CASPR2 20% Thymoma, lymphoma
LGI1 10‐30% Thymoma, SCLC, lymphoma
If Ma2 or NMDA‐R Abs,
GLYCINE RECEPTOR 20% Thymoma, lymphoma Low risk ovarian / testicular US; if
negative or ambiguous,
GABAA‐R 20‐30% Thymoma
consider CT abdomen /
GAD‐65 <5% Thymoma pelvis
Gadoth A et al. Ann Neurol 2017 Jun; 82(1): 79-92. Petit-Pedrol M, et al. Lancet Neurol. 2014 Mar;13(3):276-86.
Graus F, Dalmau J. Curr Opin Neurol. 2007 Dec;20(6):732-7. Spatola M et al. Neurology. 2017 Mar 14;88(11):1012-1020. Matsuhisa A, et al. Clin Nucl Med. 2012 Jan;37(1):39-43.
Höftberger R, et al. Neurology. 2013 Oct 22;81(17):1500-6. Van Sonderen A et al. Neurology. 2016 Oct 4;87(14):1449-1456. . Vatankulu B, et al. Rev Esp Med Nucl Imagen Mol. 2015 Aug 7.
Titulaer MJ, et al. Eur J Neurol. 2011 Jan;18(1):19-e3.

Neoplasm screening: Low risk antibodies Impact on Clinical Care and Practice

• Target antigen dictates immunotherapy treatment response

• Antibodies to intracellular antigens are less responsive, and may
Low risk antibodies Consider PET scan only if warrant less aggressive therapy
CT Chest / abdomen / other sx suggestive of
(LGI1, GAD, GABAA‐R,
pelvis malignancy (e.g., • Antibodies to plasma membrane antigens are more likely to
Glycine‐R) and over 55
hemoptysis, weight loss) respond to treatment

If pt under 55 with GAD • Neoplasm identification and treatment is also a crucial

antibodies, may limit
screen to CT Chest (to
component to treating patients
look for thymoma)

Matsuhisa A, et al. Clin Nucl Med. 2012 Jan;37(1):39-43.

Vatankulu B, et al. Rev Esp Med Nucl Imagen Mol. 2015 Aug 7.
Titulaer MJ, et al. Eur J Neurol. 2011 Jan;18(1):19-e3.

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Disclosures
The Early Use of the New AEDs in the None
Course of Epilepsy if Cost is Not a
Consideration
Madeline C. Fields, MD
Associate Professor
The Mount Sinai Hospital

Learning Objectives
“Not everything that can be counted counts,
• Benefits of newer anti‐seizure medications
• Specifically Lacosamide (LCM), Eslicarbazepine acetate
and not everything that counts can be
(ESL), Brivaracetam (BRV), Perampanyl (PER) counted. “ – Albert Einstein
• Examine the efficacy and tolerability of the newer anti‐
seizure medications and where possible compare with their
older counterparts

Why might early use of newer anti‐seizure

Newly diagnosed/
medications be important? Child bearing potential Refractory disease
• Newly diagnosed: ~50% respond to the 1st drug
Genetics
(Kwan P 2000)
• It is possible patients might be on this anti‐ Current/ Previous anti‐
seizure medication for life Seizure type
seizure medications
• Importance of long term safety, efficacy and
tolerability Age
• Refractory patients
• New mechanisms of action Co‐morbidities
• Fewer drug‐drug interactions Other medications

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Brivaracetam

From Loscher W and Schmidt D in Nature Reviews Neurology 2012 (modified with permission from Macmilian Publishers Ltd@Bialer, M. & White, H.S. Nat.Rev.Drug Discov 9,68‐82 (2010)

LCM
Lacosamide (LCM) • Head to head non‐inferiority monotherapy trial (Baulac M
2017)
• Approved as add‐on (2007) and monotherapy (2014) for • LCM non‐inferior to CBZ‐CR in newly diagnosed epilepsy
focal onset seizures patients
• Selectively enhances SLOW inactivation of VGSC (no affect • Freedom from seizures after 6 months (LCM 74% vs
on fast inactivation) 70% CBZ‐CR)
• Maximum dose 400mg/d. Given BID. • Class I evidence for efficacy of LCM as first‐line monotherapy
• Comes as a tablet, oral solution, IV for new onset epilepsy
• No interaction with P450 enzymes
• Controlled substance

LCM non‐inferiority trial

• Note, 600mg/d not approved by FDA or EMA
because similar efficacy at 400mg/d
• LCM 600mg/d increased GI and CNS side effects
• May have been due to combination with VGSC
• Note: more seizure free days and seizure
freedom on 600mg/d

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LCM in special populations LCM in special populations

• Status epilepticus • Elderly well tolerated (Rainesalo S 2017)
• LCM vs VPA (Misra 2017) • Pediatric status epilepticus (Poddar K 2016)
• 400mg LCM vs 30mg/kg VPA
• Primary outcome is seizure cessation for 1h
• NO difference LCM vs VPA (66.7% vs 69.7%;
P=0.79)
• Secondary outcome seizure cessation 24h
• Insignificantly higher in VPA (66.6% vs 45.5%)
• Death and side effects not different

Eslicarbazepine acetate (ESL)

• Approved for adjunctive (2013) and monotherapy (2015) for
focal seizures ages 4 and up
• Acts on VGSC by enhancing SLOW inactivation
• Once a day
• Tablet (200mg, 400mg, 600mg, 800mg)
• Maximum dose 1200mg/d
• With or without food
• Whole or crushed
• No auto‐induction
• Less potential for causing phamacokinetic interactions

ESL
• Acts on VGSC by enhancing SLOW inactivation (Hebeisen 2015)
• Also exerts an effect on Ca, GABA, K, glycine (Soares‐da‐Silva 2015)
• ESL metabolized mainly to eslicarbazepine (aka S‐licarbazepine)
(94%)
• OXC metabolized to eslicarbazepine, R‐licarbazepine, OXC
• CBZ toxic metabolites (10, 11‐epoxy carbamazepine)
• ESL stereoselective metabolism avoids peak in OXC concentration
which is what causes AE (dizziness, HA)
• ESL associated with fewer neurological AE than IR OXC (Zaccara 2013)
• Retrospective, single‐center study 21 patients switched overnight from
IR OXC to ESL showed improved tolerability (Schmid 2016)
• ESL weak CYP450 inducer whereas CBZ potent enzyme inducer
ESL
• ESL efficacious in focal seizures w/wo bilateral tonic clonic
seizures (Elger et al 2007, 2009; Gil‐Nagel et al 2009, 2013;
Ben‐Menachem 2010)
• ESL may be efficacious in patients where CBZ failed (Elger
2007, 2009; Ben‐Menachem et al 2010; Halasz et al 2010)
• Mechanism of pharmacoresistance ‐ loss of use‐dependent
block on VGSC
• Pilocarpine animal model and resected hippocmapi of patients
with TLE (Doeser A 2015)
• ESL maintained use‐dependent blocking effects in human and rats
with significant add‐on effects to CBZ in human epilepsy
• ESL also inhibits T‐type Ca2+ channels, which have been shown to
be key mediators of epileptogenesis

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ESL in the Elderly

• Tried in people >65 (Costa 2014, Gomez‐Ibanez 2017)
• Multicenter, open labeled, non‐controlled or case series
• Better tolerated than OXC and CBZ
• (8.5% hyponatremia)

Dong X, Lepik IE, White J et al. Hyponatremia from oxcarbazepine and carbamazepine. 2005;65:1976‐1978

BRV
Brivaracetam (BRV) • Distinct pharmacologic profile BRV – Selective SV2A ligand
• Binding affinity to the SV2A receptor is 15‐30 fold higher than LEV (Gilard 2011)
• Approved for adjunctive therapy (2016) and monotheapy • No effect on Na, voltage‐gated K or Ca currents (LEV does) (Niespodziany 2015)
(2017) in focal onset seizures • Does not bind to the AMPA receptor (Carunchino I 2007)
• Translate into fewer clinical side effects?
• Targets Synaptic Vesical 2A (SV2A) • Possibly better crossing over the blood brain barrier
• Lipophilic
• NO titration necessary • Diffusion permeability across cell membranes superior to LEV (Chanteaux 2015)
• Comes as tablet, oral solution, IV • (In rat model of self sustaining status epilepticus) BRV rapidly enters the brain
when combined with low‐dose diazepam. In these rats fewer chronic
spontaneous recurrent seizures up to 1 year after treatment suggesting disease‐
modifying effect (Wasterlain 2009)
• Translate into anti‐epileptogenicity?
• Faster onset of action
• Translate into better management of acute seizures?
• Low plasma protein binding
• Metabolized non‐cytochrome P450 (neither inhibitor nor inducer)
• Only finding modest increase in CBZ‐epoxide when BRV given with CBZ (Stockis 2015)

Efficacy of BRV vs LEV for refractory focal

MOOD: BRV vs LEV
seizures (RFS)
• No head to head trial
• Indirect comparison (Lin 2016) • LEV ~13% adult patients behavioral side effects (French
• Maximum efficacy middle‐dose for both BRV and LEV (BRV 100mg, LEV 2000mg) 2001). Probably more.
• Higher dose (BRV 200mg, LEV 3000mg) did not show higher efficacy than middle
dose
• Open label, prospective, exploratory study switching LEV
• No statistical differences at all dose levels but trend toward better efficacy of LEV to BRV (Yates 2015)
• 20% patients on BRV also on LEV which may be taking up the position on the
SV2A ligand
• Effects of LEV use (Klein 2015, Ryvlin P 2014): LEV –naive populations BRV
more efficacious. Greater treatment effect in patients who discontinued LEV
due to AE than insufficient efficacy
• Shorter treatment time with BRV
• BRV higher incidence of dizziness
• Concomitant LEV increase risk of AE in BRV treated patients
• BRV typically not titrated

4

MOOD: BRV vs LEV
• 29 patients
• 93% (27/29) meaningful reduction in behavioral
adverse events (BAE) (1 patient slight worsening,
1 patient marked worsening BAE)
• 62% (18/29) freedom from BAE. Typically took
15 days
• Number of partial onset seizures similar to
baseline during LEV treatment
Black Box
PER Problems
• Metabolized through primary oxidation (CYP3A4
and CYP3A5)
• Inducers CBZ, OXC, PHT affect the metabolism of
PER resulting in lower plasma concentrations
(increase in clearance of PER) (Brodie 2013)
11/29/2017
Perampanel (PER)
• First in class noncompetitive AMPA antagonist
• Monotherapy for focal seizures or add on for
generalized tonic‐clonic seizures
• Tablet and liquid
• Once daily dosing
PER Performance
• Efficacy and tolerability RCT (French et al
2012,2013; Krauss eta al 2012)
• Efficacy and tolerability of adjunct PER (Glauser
2015)
• Greater efficacy when patients taking fewer baseline
anti‐seizure medications
• Presence of focal to bilateral tonic clonic seizures
• Unknown etiology (vs CNS infection)
• Patient taking non‐inducer anti‐seizure medications
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PER for PGTC Budget impact PER

• Budget impact of an insurance company adopting PER for the
• Only 4 anti‐seizure medications approved to treat
treatment of focal onset seizures and generalized seizures (Tremblay
generalized tonic‐clonic seizures: LTG, LEV, TPX, VPA 2017)
(Rheims 2014) • Calculated by comparing direct medical costs and societal costs
• Multicenter RCT in patients with PGTC (French 2015) • Direct medical (physician visits, ER visits, hospitalizations)
• Patients receiving up to 3 anti‐seizure medications • Societal = direct medical + indirect (productivity loss from absenteeism
• Reduction in seizure frequency ‐76.5% (vs placebo and presenteeism)
‐38%, p<0.0001)
• >50% seizure responder rate 64% (vs placebo 40%,
p=0.0019)
• Seizure freedom rate 31% (vs 12% placebo)

Response rate
• Applied weighted rate of seizure freedom
• Prevalence of focal seizures and PGTC in the population (31% and
19%)
• Seizure freedom on PER
• Direct medical, indirect costs and annual costs associated with
PER decrease with decreasing seizure frequency
• Drug costs estimated to increase every year but costs offset
by decrease in direct medical and indirect costs
• Conclusion: if a health plan of 1 million members adopts PER cost
would be minimal and societal costs close to neutral

Indirect comparisons Case

• ESL vs LCM (Brigo 2016) • The year is 1983. Lauren is 7 months old and develops a febrile illness then
• No significant difference in efficacy/ tolerability between add‐ status epilepticus. Fast forward 17 years, the year is 2000. She is still
on treatment of either drug having 25 seizures a day, tried every anti‐seizure medication on the market,
• BRV vs LCM, ESL, PER – no significant difference in add‐on ketogenic diet, experimental therapies, resective surgery. Her mom hears
treatment (Brigo 2016) of LEV and she becomes seizure free.
• Possibly better tolerability of high dose BRV than high dose ESL
and PER (lower AE’s but no difference in withdrawing)
• LEV vs ESL, LCM, PER, BRV (Zhu 2017)
• Not inferior to LEV in efficacy
• BRV similar tolerability to LEV
• ESL, LCM, PER possibly worse tolerability

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• Ben‐Menachem E, Mameniskiene R, Quarato PP, et al. Efficacy and safety of brivaracetam for partial‐onset seizures in 3 pooled clinical studies. Neurology 2016;87:314‐23.
• Berkovic SF, Knowlton RC, Leroy RF, et al. Placebo‐conrolled study of levetiracetam in idiopathic genealized epilepsy. Neurology 2007;69:1751‐60.
• Biton V, Montouris GD, Ritter F, et al. A randomized, placebo‐controlle dstudy of topiramate in primary generalized tonic‐clonic seizures. Topiramate YTC Study Group. Neurology 1999;52:1330‐1337.
•

“Keep trying, keep trying. Don’t give up.

Biton V, Sackellares JC, Vuong A, et al. Double‐blind, placebo controlled study of lamotrigine in primary generalized tonic‐clonic seizures. Neurology 2005;65:1737‐43.
• Brodie MJ, Mintzer S, Pack AM, et al. Enzyme induction with antiepileptic drugs: cause for concern? 2013 Epilepsia 54:11‐27.
• Carunchino I, Pieri M, Ciotti MT, Albo F, Zona C. Modulation of AMPA receptors in cultured cortical neurons induced by the antieileptic drug levetiracetam. Epilepsia 2007; 48:654‐62.
• Chanteaux H, Kervyn S, Gerin B, et al. In vitro pharmacokinetic profile of brivaracetam reveals low risk of drug‐drug interaction nrestriced brain permeability. Epilepsy Curr 2015;15:2.310.
• Chung S, Sperling MR, Biton V, et al. Lacosamide as adjunctive therapy for partial‐onset seizures: A randomized controlled trial. 2010;51:958‐67.
• Costa R, Oliveira C, Lopes N et al. Safety and efficacy of eslicarbazepine acetate treatment in elderly patients. Epilepsia 2014;55:112.

Never give up. •

•
•

•
French J, Edrich P, Cramer JA. A systematic review of the safety profile of levetiracetam: a new antiepileptic drug. Epilepsy Res 2001: 47:77‐90.
French J, Krauss GL, Wechsler RT, et al. Perapanel for tonic‐clonic seizures in idiopathic generalized epilepsy. Neurology 2015;85:950‐57.
Gillard M, Fuks B, Leclercq K, Matagne A. Binding characteristics of brivaracetam, a selective, high affinity SV2A ligand in rat, mouse and human brain: relationship to anti‐convulsant properties. Eur J
Pharmacol 2001;664:36‐44.
Glauser T, Laurenza A, Yang H, et al. Efficacy and tolerability of adjunct perampanel based on number of antieppileptic drugs at baseline predictors of efficacy: A phase III post‐hoc analysis. Epilepsy
Research 2015;119:34‐40.

Keep trying, keep trying. Don’t give up. •

•

•
•
Gomez‐Ibanez A, Serratosa JM, Guillamon E, et al. Efficacy and safety of eslicarbazepine‐acetate in elderly patients with focal epilepsy: Case seeries. Seizure 2017;48:53‐56
Hebeisen S, Pires N, Loureiro AI et al. Eslicarbazepine and the enhncement of slow inactivation of voltage‐gated sodium channels: a comparison with caramazepine, oxcarbazepine and lacosamide.
Neuropharmacology 2016;89:122‐35
Jeavons PM, Clark JE. Sodium Valproate in treartment of epilepsy. Br Med Jour 1974;2:584‐6.
Klein P, Schiemann J, Sperling MR, et al. A randomized, double‐blind, placebo controlled, multicenter, parallel0group to evaluate the efficacy oand safety of adjunctive brivaracetam in adult patients with

Never give up.”

uncontrolled partial‐onset seiuzres. Epilepsia 2015;56:1890‐8.
• Kwan P, Brodie MJ. Early identification of refractory epilepsy. NEJM 2000;342:315‐9
• Kwan P, Trinka E, Van Paesschen W, Rektor I, Johnson ME, Lu S. Adjunctive brivaracetam for uncontrolled focal and generalized epilipsies: rsults of a phase III, double‐blind, randomized, placebo‐
controlled, flexible dose trial. Epilepsia 2014;55:38‐46.
• Lin Z, Shaoping L, Hua L, Xiaoyi Z. Levetiracetam vs. brivaracetam for adults with refractory focal seizures: A meta‐analysis and indirect comparison. Seizure 2016;39:28‐33.
• Nicolas JM, Hannestad J, Holden D, et al. Brivaracetam, a selective high‐affinity synaptic vesicle protein 2A (SV2A) ligand with preclinical evidence of high brain permeability and fast onset of action.

‐Yo gabba gabba

Epilepsia 2016;57:201‐2019.
• Misra UK, Dubey D, Kalita J. Comparison of lacosamide versus sodium valproate in status epilepticus: A pilot study. Epilep Behav 2017;76:110‐113.
• Niespodziany I, Andre V, Leclere N, et al. Anticonvulsant properties of brivaracetam are not mediated by its effects on voltag‐gated sodim channels. Epilepsy Curr 2014; 14:1.204.
• Niespodziany I, Lukyanetz EA, Matagne A, et al. Brivaracetam does not modulate the major ionic conductances in neurons. Epilepsia 2015;56:192‐193.
• Poddar K, Sharma R, Ng YT. Intravenous Lacosamide in Pediatric Status Epilepticus: An Open‐Label Efficacy and Safety Study. Pediatr Neurol. 2016 Aug;61:83–6.
• Rainesalo S, Makinen J, Raitanen J, et al. Clinical management of elderly patients with epiepsy; the use of lacosamide in a single center setting. Epilep Behav 2017;75:86‐89.
• Rheims S, Ryvlin P. Pharmacotherapy for tonic‐clonic seizures. Expert Opin Pharmacother 2014;15:1417‐26. Ryvlin P, Werhah KJ, Blaszczyk B, et al. Adjunctive brivaracetam in adults with uncontrolled
focal epilepsy: results froma double‐blind, randomized, placebo‐controlled trial. Epilepsia 2014;55:47‐56.
• Schmid E, Kuchukhidze G, Kirschner M, et al. Overnight switching form oxcarbazepine to eslicarbazepine acetate: an observational study. 2016 Acta Neurol Scand
• Sperling MR, Abou‐Khalil B, Harvey J, et al. Eslicarbazepine acetate as adjunctive therapy in patients with uncontrolled parital‐onset seizures: Results of a phase III, double‐blind, randomized, placebo‐
controlled trial. 2015;56:244‐253.Soares‐da‐Silva P, Pires N, Bonifiacio MJ, eta l. Eslicarbazepine acetate for the treatment of focal epilepsy: an update on its proposed mechanism of action. Pharmacol Res
Perspect 2015;3.
• Stockis A, Cchanteaux H, Rosa M, et al. Brivaracetam and carbamazepine interaction in healthy sugjects and in vitro. Epilepsy Res 2015;113:19‐27.
• Wasterlain CG, Suchomelova L, Matagne A, et al. Short‐term and long‐term effects of brivaracetam in an animal model of status epilepticu. Epilepsia 2009;50:042.
• Yates SL, Fakhoury T, Liang W, Eckhardt K, Borghs S, D’Souza J. An open‐label, prospective, exploratory study of patients with epilepsy switching from levetiracetam to brivaracetam. Epi and Behav
2015;52:165‐68.
• Zaccara G, Giovannelli F, Maratea D, et al. Neurological adverse events of neew generation sodium blocker antiepileptic drugs. Meta‐analysis of randomized, double‐blinded studies with eslicarbazepine
acetate, lacosamide and oxcarbazepine. Seizure 2013;22:528‐36.
• Zhu LN, Chen D, Xu D, et al. Newer antiepileptic drugs compared to levetiracetam as adjunctive treatments for uncontrolled focal epilepsy: An indirect comparison. Seizure 2017;51:121‐132

Impact on Clinical Care and Practice

• Newer anti‐seizure medications are as efficacious and often

more tolerable when compared to older anti‐seizure
medications
• More favorable phramokinetics
• Improved drug interaction profiles
• Provide more options for our medically refractory patients

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Disclosure
The Early Use of the New AEDs in the Course of Epilepsy, if Cost
is a Consideration Name of Type of
Commercial Interest Relationship
Korwyn Williams, MD, PhD • None • None
Phoenix Children’s Hospital

Learning Objectives
• Health care spending concerns us all
• High cost/spending does not equate to higher quality care
• How do we balance the costs and benefits of expensive
therapies

4alken.com/why_alken.php

www.kff.org/report‐section/health‐care‐costs‐a‐primer‐2012‐report/ www.commonwealthfund.org/publications/fund‐reports/2014/jun/mirror‐mirror

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Payors of health care costs want to bend this curve Shifting from volume to value: CMS’ four categories of
payment models
Many stakeholders are involved
• Government Moving from category 1 to category 4 involves two
• Private insurance shifts:
1. Increasing accountability for both quality
• Employers
and total cost of care.
• Pharmacy managers 2. 2. A greater focus on population health
• Patients management as opposed to payment for
specific services.”

multimedia.3m.com/mws/media/1340264O/hccs‐and‐shift‐to‐value‐based‐
reimbursement‐white‐paper.pdf

Prevalence and cost of epilepsy in Sweden – a register‐

based approach
• While the prevalence of epilepsy remained about the same, the total cost of epilepsy
increased
• Direct medical costs rose from 36% of the estimated total cost in 2005 to 60% in 2011.
• The corresponding pharmaceutical cost as a share of total healthcare costs increased
from ~0.5% in 2005 to ~1% in 2011.
How to Address Prescription Prices?
Prices are higher in the US than around the world.
Different countries employ different mechanisms to control drug prices
• UK sets a threshold of ₤20,000‐30,000 per quality‐adjusted year of life (QALY) before
covering a medication
• Germany, Canada, Australia use some version of cost‐effectiveness, comparative
effectiveness, & comparative drug pricing in deciding on coverage.

Acta Neurol Scand 131 (1), 37‐44, 2015

2

What Does This Mean for Providers?
We are not actuaries, health
economists , or social scientists!
And yet, we direct a large amount of
health care spending.
If we don’t play a role in managing
resources, others (non‐clinicians) will
make those decisions for us
(Hint, they already have with
prior authorizations, restricted
formularies, etc.)
www.123rf.com/stockphoto/wagging_finger.html
Is Newer Better?
Cost Comparison
• Perampanel 8 mg QD ($860/month)
• Eslicarbazepine 200 mg tab QD
($880/month)
• Briviact 100 mg tabs, 2 tabs BID
($2100/month)
• Lacosamide 200 mg tabs BID
($843/month)
11/29/2017
Trends in Antiepileptic Drug Use in Children and Adolescents
With Epilepsy
• The annual prevalence of valproic acid use declined from 42.4% in 1999 to 26.5% in 2009
• The prevalence of carbamazepine use declined from 37.1% to 10.2%.
• The prevalence of levetiracetam use increased from 5.1% to about 32.0% in 2009
• The prevalence of oxcarbazepine use increased from 1.3% to 19.1%.
• Since 2008, levetiracetam (29.6%) has replaced valproic acid (27.8%) as the most
commonly used AED in children and adolescents with epilepsy.
• The prevalence of diazepam use increased from 11.6% to 28.1%.
Pediatr Neurol. 2017 Sep;74:32‐40
Should the new AEDs be used early in the
course of epilepsy?
For the purpose of this discussion, consider these agents:
• Brivaracetam
• Perampanel
• Eslicarbazepine
• Lacosamide
What Are Factors To Consider in Medication Choices?
• Effectiveness?
• 50% reduction? 75% reduction? 90% reduction? Seizure‐freedom?
• Are they more effective in reducing seizures than other agents ( Phase III
• Oxcarbazepine 60 tabs 600 mg trials in this country are placebo‐controlled )?
($48/month)
• Cost?
• Lamotrigine 200 mg BID ($104/month) • Medication itself? Overall healthcare spending? Indirect costs such as
unemployment, abseentism) ? Quality of life ? (Cost‐effectiveness trials are
• Levetiracetam 1000 mg BID ($16/month) typically retrospective and variably consider: QALY (the cost of a year of
perfect health), seizure‐freedom, >50% reduction, adverse events, mortality,
“quality of life”)?
• Serious, costly, and rare, adverse events are difficult to calculate
www.drugs.com/price‐guide/ (accessed 10/21/17)
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What Are Factors To Consider in Medication Choices? Side‐effects of antiepileptic drugs: The economic burden
The total societal costs of common side‐effects in 2012 are estimated to be € 20,751 per patient
• Beneficiaries?
per year:
• Payors
• Health‐care costs
• Hospital/clinics (may participate in the cost‐sharing in managing chronic conditions)
• Patient & family care
• Pharmacy benefit managers
• Productivity losses
• Pharmaceutical companies (invested heavily in research, development, and
• Behavioral
marketing)
• Cognitive
• Patients/Families (share prescription costs and high prices are associated with poor
• Cosmetic
adherence)

Seizure 23 (2014) 184–190

Are Cost‐Effectiveness Studies the Answer?

Cost‐effectiveness calculates the monetary value of all project costs for a intervention, but
considers the output in non‐monetary terms (lives saved, illnesses prevented or years of life
gained).

The result is the cost per case prevented or cost per year of life gained.

Some limitations in trying to solve a multi‐dimensional problem:

‐often based on randomized trial data (divorced from real‐life practice due to short duration, rigid
protocols)
‐often depend on what is being measured (eg, absenteeism from work vs hospitalizations vs 50%
seizure reduction vs quality of life)
‐depends on the costs involved, which can change over time and depending on location

The American Journal of Managed Care, 4(9):S501‐509, 1998

A double‐blind study comparing oxcarbazepine and carbamazepine

in patients with newly diagnosed, previously untreated epilepsy.

Effectiveness from a Historical Perspective • No significant difference in seizure frequency between oxcarbazepine and
carbamazepine

• oxcarbazepine caused significantly fewer 'severe' side effects than carbamazepine;

• global evaluation of tolerability demonstrated a trend towards the better tolerability

of oxcarbazepine

Epilepsy Res. 1989 Jan‐Feb;3(1):70‐6.

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Clinical effectiveness, tolerability and cost‐effectiveness of newer

drugs for epilepsy in adults: a systematic review and economic
evaluation
• There was little ,good‐quality evidence to support:
• the use of newer monotherapy or adjunctive therapy AEDs over older drugs, or
• the use of one newer AED in preference to another.
• No consistent or statisticall significant differences between drugs for clinical
effectiveness, safety and tolerability.
The clinical effectiveness and cost‐effectiveness of newer drugs for
children with epilepsy. A systematic review
• “Gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate and
vigabatrin are no more effective but may be somewhat better tolerated than the older
agents, and so the cost effectiveness for early use will depend on the trade‐off between
effectiveness and tolerability.”

• Combination therapy involving new AEDs may be cost‐effective at a threshold

willingness to pay per quality‐adjusted life year (QALY) greater than £20,000.

Health Technol Assess 2005;9(15) Health Technol Assess 2006;10(7).

A Cost‐Effectiveness Decision Model for Antiepileptic Drug Treatment

in Newly Diagnosed Epilepsy Patients
• Seizure‐freedom varied from 64% (VPA–CBZ strategy) to 74% (LTG–VPA strategy).
• LTG–VPA was more effective than the least expensive strategy CBZ–VPA (€ 975), but at higher
costs (€6,000) per additional effectively treated patient.
• In the UK’s National Institute for Health and Care Excellence (NICE) guidance, the “newer” AEDs
like LTG are recommended for people
• who have not benefited from conventional AEDs,
• for whom the older drugs are unsuitable because of contraindications, interactions,
• of childbearing potential.
Assessing the cost‐effectiveness of new pharmaceuticals
in epilepsy in adults: the results of a probabilistic decision model
The analysis showed that, on the basis of existing evidence, for newly diagnosed patients with
partial seizures, carbamazepine and valproate are likely to be the most cost‐effective mono‐
therapies. Carbamazepine is likely to be the most cost‐effective 2nd‐line monotherapy for
refractory patients, and oxcarbazepine would probably be the most cost‐effective adjunctive
therapy for refractory patients if the willingness to pay for additional health benefits is greater
than 18,000 pounds per quality‐adjusted life year (QALY).

Med Decis Making. 2005 Sep‐Oct;25(5):493‐510.

International Society for Pharmacoeconomics and Outcomes Research
(ISPOR) 10(3): 173–182, 2007
www.nice.org.uk/TA076guidance

Proportion of Lennox‐Gastaut patients using seizure‐

The cost‐effectiveness of newer drugs as add‐on therapy for
related health care pre‐/post‐clobazam
children with focal epilepsies

Older (PHT, CBZ, VPA) and newer (OXC, TPM, GBP, TGB) AEDs are similar in terms of drug retention Administrative claims reviewed from 2010‐2014 with
rates and the average time in ‘good’ treatment outcomes. In terms of cost, the results indicate a Presumed Lennox‐Gastaut syndrome
consistent increase in cost (compared to older AEDs) when all of the newer AEDs are considered. The
decision analysis results indicate that there are no important health benefits from the use of newer Concluded that increased prescription costs were
AEDs when used as add‐on therapy. “mostly offset” by reduced utilization

(NB, one of the authors worked for manufacturer of

Seizure (2007) 16, 99—112 clobazam)

J Mark Access Health Policy. 2017;

5(1): 1318691.

5

Culmination of these studies: Newer not
more effective than older medications
NICE Guidance
• Offer carbamazepine1 or
lamotrigine as first‐line
treatment to children, young
people and adults with newly
diagnosed focal seizures.
https://www.nice.org.uk/guidance/CG137
Evidence of effectiveness of AEDs
Eslicarbazepine
• Maximum reduction in seizure
frequency was 43% (20% for
placebo)
Epilepsia. 2009 Mar;50(3):454‐63
Evidence of effectiveness of new AEDs
Perampanel
• Maximum reduction in seizures
(over placebo) was 31% (11% for
placebo)
• ≥50% responder rate (over
placebo)was 35% at 8 mg/d
(18% for placebo).
Neurology. 2012 May 1;78(18):1408‐15
• Offer levetiracetam,
oxcarbazepine or sodium
valproate3 (provided the cost of
levetiracetam falls to at least
50% of June 2011 value), if
carbamazepine and lamotrigine
are unsuitable or not tolerated.
Oxcarbazepine
• Maximum reduction in seizure
frequency was 50% at 2,400
mg/day (8% for placebo)
FDA label for Trileptal (adult study) [accessed
10/22/2017]
Topiramate
• Maximum reduction in seizure
frequency was 48% (13% for
placebo)
• ≥50% responder rate placebo
was 47% at 400 mg/d (18% for
placebo).
Neurology. 1996 Jun;46(6):1684‐90
11/29/2017
Lacosamide in a medically refractory cohort in Belgium
Over a 24‐month period, standard anti‐epileptic drug therapy plus lacosamide led to a reduction
of seven seizures, an increase of 0.038 quality‐adjusted life‐years and a cost decrease of € 3,619
per patient compared with standard therapy alone. Using a willingness to pay of € 30,000 per
QALY the net monetary benefit of standard anti‐epileptic drug therapy plus lacosamide
amounted to € 4,754. The probability of standard anti‐epileptic drug therapy plus lacosamide
being cost effective was 97.3%, 99.8%, 99.9% and 100% at 6, 12 , 18 and 24 months, respectively.
Evidence of effectiveness of new AEDs
Lacosamide Lamotrigine
• Maximum reduction in seizure • Maximum reduction in seizure
frequency was 36% (20% for frequency was 36% (8% for
placebo) placebo)
• ≥50% responder rate placebo • ≥50% responder rate placebo
was 46% at 400 mg/d (26% for was ~30% at 500 mg/d (rate for
placebo). placebo not stated).
Neurology. 1993 Nov;43(11):2284‐91.
Epilepsia. 2009 Mar;50(3):443‐53
Evidence of effectiveness of new AEDs
Brivaracetam Levetiracetam
• Maximum reduction in seizures • Maximum reduction in seizures
(over placebo) 24% (over placebo) 23%
• ≥50% responder rate was 39% at
• ≥50% responder rate was 40%
at 100 mg/d (20% for placebo). 3,000 mg/d (14% for placebo).
FDA label for Keppra (study 3) [accessed 10/22/2017]
Neurology. 2016 Jul 19;87(3):314‐23
6
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Efficacy, safety, and tolerability of lacosamide monotherapy versus

controlled‐release carbamazepine in patients with newly diagnosed Levetiracetam vs. brivaracetam for adults with refractory focal
epilepsy: a phase 3, randomised, double‐blind, non‐inferiority trial. seizures: A meta‐analysis and indirect comparison

An indirect‐comparison meta‐analysis of 13 trials (over 3000 patients)

For newly diagnosed adults with LEV might have a slightly higher efficacy with a lower probability of dizziness compared with
BRV for patients with refractory focal seizures.
focal epilepsy, lacosamide was
demonstrated to be non‐inferior to
carbamazepine CR, with similar
rates of treatment‐emergent
adverse events and retention rates

Lancet Neurol. 2017 Jan;16(1):43‐54. Seizure. 2016 Jul;39:28‐33

Efficacy and tolerability of brivaracetam compared to

lacosamide, eslicarbazepine acetate, and perampanel as adjunctive treatments in Newer antiepileptic drugs compared to levetiracetam as adjunctive
uncontrolled focal epilepsy: Results of an indirect comparison meta‐analysis of RCTs. treatments for uncontrolled focal epilepsy: An indirect comparison

• Meta‐analysis of indirect comparisons of 24 RCTs (n=8540 patients)

• Meta‐analysis of randomized • Compared to LEV, ESL, LAC and BRV did not show significant difference in efficacy at
controlled trials demonstrated all dose levels.
• Compared to LEV, PER showed lower 50% response rates and seizure‐free rates at
no difference between the 4
the highest effective recommended dosages.
agents in responder rates, • Treatment‐emergent adverse events and withdrawal rates due to adverse events of
seizure freedom, or LAC and PER were higher than LEV at the highest effective recommended dosages
discontinuation rates in • Overall AE rates from ESL were higher than LEV.

medically refractory patients

Seizure. 2016 Nov;42:29‐37
Seizure. 2017 Oct;51:121‐132.

A common reference‐based indirect comparison meta‐analysis

of eslicarbazepine versus lacosamide as add on treatments for focal Conclusions
epilepsy
Patient well being Resource usage
Adjunctive ESL or LCM in patients with focal epilepsy and compared with placebo in 8 • Appropriate agent • Cost is a many‐headed hydra:
studies. Following outcomes were considered: ≥50% reduction in seizure frequency; seizure
• Easy to adhere to – Medication costs
freedom; treatment withdrawal for any reason; ≥25% increase in seizure frequency.
• Well tolerated physically and – Provider visits
Indirect comparisons adjusted for dose‐effect showed no difference between ESL and LCM
behaviorally – Hospitalizations for seizures/side‐
for responder rate, seizure freedom, and withdrawal rates. effects/injuries
• Well tolerated financially – Surveillance studies

Epilepsy Res. 2016 Nov;127:12‐18

7
 11/29/2017

Impact on Clinical Care and Practice

• Our patient’s well being is our primary responsibility

• Be deliberative about the most appropriate choice
• Available information is imperfect, but experience shows us that:
• the same percentage of patients remain medically refractory
with the second generation of anti‐epileptic drugs.
• the phase III trials for the newest anticonvulsants did not prove
to be any more effective in medically refractory populations
• Indirect comparisons have not demonstrated improved
tolerability
• Newer (and more expensive) does not always mean
better