Annual Fundamentals Symposium

Epilepsy on the Consult Service

Symposium Chair:

Fred Lado, MD

and

Aradia Fu, MD

Friday, November 30, 2018

Convention Center – New Orleans Theater AB

12:30 pm – 3:00 p.m.

 ABOUT THE EDUCATION PROGRAM

Statement of Need
The need for this activity has been determined based on
identifying professional practice gaps, previous course
evaluations, and AES self-assessments. The educational content
of this activity was based upon current issues and topics provided
by the Annual Meeting Committee and membership.
Accreditation
Target Audience This activity has been planned and implemented in accordance with
Neurologists, epileptologists, pediatric neurologists, nurses, the Essential Areas and policies of the Accreditation Council for
psychologists, neuropsychologists, nurse practitioners, physician Continuing Medical Education. The American Epilepsy Society (AES)
assistants, pharmacists, researchers, and scientists. is accredited by the Accreditation Council for Continuing Medical
Education to provide continuing medical education for physicians.

Global Learning Objectives

This comprehensive educational meeting provides learners with
opportunities to:
1. Increase knowledge about the diagnosis and treatment,
including novel diagnostic methods and therapeutic modalities
of, various manifestations of epilepsy and common comorbidities
to enhance clinical practice and improve patient outcomes.
2. Be informed about the latest research developments in
epilepsy that may translate into clinical care and human
therapy in the near future.
AMA PRA Category 1 Credit™ Designation
The American Epilepsy Society designates this live educational
activity for a maximum of 29.75 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 AMA PRA Category 1 Credits™.

3. Consider the public health implications of epilepsy and the impact Physician Assistants
of the disease on patients, communities, and health systems. AAPA accepts certificates of participation for educational
activities certified for AMA PRA Category 1 Credits™ from
NOTE: Each session has its own specific learning objectives, which organizations accredited by ACCME or a recognized state
are included within the program book. medical society. Physician assistants may receive a maximum of
29.75 hours of Category 1 credit for completing this program.
Mission Statement
The American Epilepsy Society (AES) promotes research and
education for physicians and other healthcare professionals
dedicated to the prevention, treatment and cure of epilepsy.
Its continuing professional education (CPE) offers an array of
activities to assist the learner in assessing their educational needs
and expanding their knowledge, competence and performance Continuing Education for Nurses and Pharmacists
in the field of epilepsy, which leads to an improvement in the Jointly provided by AKH, Inc., Advancing Knowledge in
outcomes of care. Healthcare, and the American Epilepsy Society.
The CPE program always reinforces the fundamental components
of epilepsy care in accordance with an Epilepsy Core Curriculum,
Nurses
including quality improvement and patient safety. In addition, its
Advancing Knowledge in Healthcare is accredited as a provider
educational interventions also provide an opportunity to advance
of continuing nursing education by the American Nurses
professional practice in new and emerging areas of the specialty.
Credentialing Center’s Commission on Accreditation. This activity
In recognition of the importance of the added qualification in
is awarded 29.00 contact hours
epilepsy by the American Board of Psychiatry and Neurology as
well as the Maintenance of Certification requirements, AES is
committed to the provision of educational opportunities and
tools that aid in the certification and MOC requirements.
The expected results of AES’s program of continuing professional
development are as follows:
• The AES CPE Program fosters a culture of interprofessional Pharmacists
collaboration amongst the cadre of professionals that care for Advancing Knowledge in Healthcare is accredited by the Accreditation
persons with epilepsy. Council for Pharmacy Education as a provider of continuing pharmacy
education. Select portions of the Annual Meeting are approved
• The AES CPE Program enhances the professional practice of for pharmacy CE credit. Specific hours of credit for approved
healthcare professionals who care for persons with epilepsy. presentations and the Universal Activity Numbers assigned to select
• The AES CPE Program provides education in epilepsy therapy to presentations are found in the program materials. Criteria for success:
increase the competence of clinicians in the use of these complex credit is based on documented program attendance and online
and multi-layered options to manage epilepsy in patients. completion of a program evaluation/assessment. NOTE: Questions
regarding CE activity and reporting relative to nursing and/or
• The AES CPE Program uses educational interventions as a tool to
pharmacy please contact AKH, Inc. at service@akhcme.com.
improve the quality of care and patient safety of persons with epilepsy.

AES ANNUAL MEETING 2018 18 MEETING.AESNET.ORG

 ABOUT THE EDUCATION PROGRAM
Maintenance of Certification
The American Board of Psychiatry and Neurology has reviewed
the 72nd Annual Meeting and has approved this program as
part of a comprehensive Continuing Medical Education (CME)
program, which is mandated by the ABMS as a necessary
component of maintenance of certification.
Credit Claim
Attendees who registered in the following categories may claim
CME or CE for the Annual Meeting: physician, health care provider,
trainee, one-day, and two-day. Meeting registration includes credit
claiming. Post meeting attendees will receive an email notification
to access the online evaluation and credit claim system. The
evaluation and claim system will remain open until February 28,
2019. Evaluations and credit claims must be completed by this
date to record and receive your CME/CE certificates.
Disclosure Policy and Resolution of Conflicts of Interest
It is the policy of the American Epilepsy Society to ensure balance,
independence, objectivity, and scientific rigor. All individuals
involved in the selection, development, and presentation of
content are required to disclose any real or apparent conflicts of
interest. Conflicts of interest will be resolved by AES prior to an
educational activity being delivered to learners. In accordance
with the ACCME Standards for Commercial Support of CME, AES
implemented the mechanisms 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.
Unapproved Use Disclosure
The American Epilepsy Society 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.
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.
AES ANNUAL MEETING 2018
Annual Meeting Session Descriptions
The AES Annual Meeting offers high-quality educational
programming across diverse work settings, professional
roles, and experience levels. Whether you are just starting
with the specialty, have a limited background in epilepsy, or
are highly fluent with complex topics, you will find sessions
and content relevant to your needs.
Symposia
Provide the major educational activities at the Annual
Meeting. Topics range from clinically oriented presentations
reviewing common issues in epilepsy to more complex topics
combining basic sciences and clinical neurology. While target
audiences differ, all symposia include discussion of clinically
relevant information.
Special Interest Groups (SIG)
Offer information and networking for attendees with similar
interests, in sessions organized by AES members. Although
the sizes of SIG sessions vary, all lend themselves to active
participation and dialogue.
Special Lectures
Recognize the accomplishments of distinguished leaders
in clinical epilepsy and research. The Judith Hoyer Lecture
in Epilepsy is delivered by an AES President Emeritus. The
Lennox and Lombroso Lecture is given by an invited member
who has greatly advanced the collective understanding of
epilepsy.
Annual Course
Encourages in-depth exploration of important topics related
to epilepsy, focused on clinical care, including review of the
science underlying the topics, reviews of clinical research,
and discussion of the associated clinical implications. The
Annual Course includes a mixture of educational lectures,
clinical vignettes, and panel discussions.
Investigators Workshops
Highlight exciting developments in basic, translational, and
clinical epilepsy research in a format promoting interactive
discussion. Speakers include established and junior epilepsy
investigators, as well as researchers from other fields.
Skills Workshops
Deliver hands-on and interactive learning opportunities
in focused clinical areas or basic science research skills.
Attendance at each workshop is limited to a small number
of participants to allow optimal interaction. Advance
registration and an additional fee are required.
19 MEETING.AESNET.ORG
 American Epilepsy Society Annual Meeting
November 30 – December 4, 2018 | New Orleans, LA

INSTRUCTIONS FOR OBTAINING CE CREDIT

(NURSES AND PHARMACISTS ONLY)

NURSING
AKH Inc., Advancing Knowledge in Healthcare is accredited as a provider of continuing nursing education by the
American Nurses Credentialing Center’s Commission on Accreditation.

PHARMACY
AKH Inc., Advancing Knowledge in Healthcare is accredited by the Accreditation
Council for Pharmacy Education as a provider of continuing pharmacy education.

PLEASE NOTE: Providing your NABP e-profile # is required.

The National Association of Boards of Pharmacy (NABP) requires that all pharmacists and pharmacy technicians
seeking CE credit have an ID number issued by NABP. Pharmacy CE providers, such as AKH Inc., Advancing
Knowledge in Healthcare, are required to submit participant completion information directly to NABP with your ID
number and birth information to include month and date (not year) as a validation to this ID number. If you do not
have an ID number (this is not your license #), go to: www.MyCPEmonitor.net

TO CLAIM CREDITS:
Nursing and Pharmacy credit (per session) is based on attendance as well as completion of an
online evaluation form available at:

akhcme.com/akhcme/pages/AES

THIS MUST BE DONE BY JANUARY 15, 2019 TO RECEIVE YOUR CE/CPE CREDIT.
We CANNOT submit credit to NABP after this date.
If you have any questions, please contact AKH at jgoldman@akhcme.com.
Description
The purpose of this activity is to explore issues at the intersection of epilepsy and medical
conditions. Epileptologists must often confront diagnostic dilemmas or weigh the risk of a
seizures against the potential side effects of medications. "Epilepsy and the heart" will discuss
the effects of anticonvulsants on cardiovascular risk and of seizures on cardiac arrhythmias.
"Seizure mimickers" will discuss the differentiation of epileptic seizures from syncope.
"Medications that lower seizure threshold" will focus on consideration of the effect that
psychiatric and other medications can have on susceptibility to seizures. "Seizure management
during pregnancy" addresses the risks that seizures and seizure medications pose to pregnancy
and the risks that pregnancy may destabilize seizure control. Finally, "Epilepsy and the skin"
examines the risk factors and pathophysiology of hypersensitivity reactions causing rash and
more serious consequences related to anticonvulsant use.

Learning Objectives
Following participation in this activity, learners will be able to:
1. Comprehend and manage the cardiovascular risks of anticonvulsants
2. Identify and manage the selection of antibiotics and psychiatric medications to minimize
risk of seizures
3. Examine and differentiate seizures from syncope and distinguish different more serious
from less serious forms of syncope
4. Employ and manage anticonvulsants during pregnancy to optimize seizure control and
pregnancy outcomes
5. Evaluate and comprehend pathogenesis of skin reactions from seizures medications and
minimize the risk

Target Audience
Adult Neurologists/Clinician (MD/DO), Allied Health Professionals/Advance Practice
Providers, Clinical Trainee Student/Fellow, Pediatric Neurologists/Clinician (MD/DO)

Program
Co-chairs: Fred Lado, MD, and Aradia Fu, MD

Epilepsy and the Heart: AEDs and Cardiovascular Risk, AEDs and Arrhythmias, and Discussion
of Ictal Arrhythmia: Scott Mintzer, MD

Seizure Mimickers: Distinguishing Seizures from Syncope and Other Mimickers: Steven Pacia,
MD

Medications that Lower Seizure Threshold: How Much do Psychiatric Medications and
Antibiotics Increase Seizure?: Andreas Kanner, MD

Seizure Management During Pregnancy: Page Pennell, MD

Seizure Medications and the Skin Hypersensitivity: Arturo Saavedra, MD, PhD
Disclosures
Detailed disclosure information is available via:
• AES Annual Meeting app;
• Annual Meeting Online Final Program (https://meeting.aesnet.org/program)

Faculty Bios
Fred Lado, M.D., Ph.D.
Northwell Health
Dr. Lado is the Director of the Epilepsy Division for the Central and Eastern Regions of Northwell
Health. He chairs the AES Council on Education and serves on the AES board. Dr. Lado also
serves as the chair of the accreditation task force of National Association of Epilepsy Centers. He
obtained his MD PhD from New York University, completed residency training in neurology at
New York Presbyterian-Cornell, and clinical neurophysiology fellowship at Albert Einstein
College of Medicine - Montefiore Medical Center. He is interested in the treatment of medically
refractory epilepsy and in the use of non-invasive testing to localize the brain regions triggering
seizures.

Scott Mintzer, M.D.

Thomas Jefferson University
Scott Mintzer is Professor of Neurology at Thomas Jefferson University and Director of the
Epilepsy Monitoring Unit at the Jefferson Comprehensive Epilepsy Center. He was educated at
the University of Michigan and the University of Chicago Pritzker School of Medicine, and
completed a fellowship in Epilepsy at the University of California, Los Angeles. His main area of
research is the metabolic effects of antiepileptic drugs, particularly the impact of enzyme
induction on lipids and other vascular risk markers.

Steven Pacia, MD
Northwell
Steven V. Pacia, MD, is Vice Chair, Neurology, North Shore University Hospital and Director,
Neurology, Northwell Health Eastern Region since 2017. Dr Pacia was previously with NYU
Comprehensive Epilepsy Center and prior to this was Director of Neurology at Lenox Hill
Hospital for 12 years. Dr Pacia has been awarded a number of grants to support his research
and was the principal site investigator for the first multi center NIH fundedstudy of epilepsy
surgery. He has authored many peer reviewed articles on the diagnosis and treatment of
epilepsy and co authored the book Alternative Therapies for Epilepsy which provides an
evidence based review of complementaryand alternative therapies for care of the epilepsy
patient. He earned his Medical Degree from Medical College of Wisconsin and completed both
Residency (Neurology) and Fellowship (EEG/ Epilepsy) from Yale University School of Medicine.
Dr Pacia is board certified in both Neurology and Clinical Neurophysiology.

Andres Kanner, MD, FANA, FAAN, FAES

University of Miami, Miller School of Medicine
Dr. Andres M. Kanner is Professor of Clinical Neurology at the University of Miami, Miller School
of Medicine, and he also is the Director of the Comprehensive Epilepsy Center and Head of the
Epilepsy Division in the Department of Neurology. Before coming to Miami 6 years ago, he had
been Professor of Neurological Sciences and Psychiatry at Rush Medical College and Associate
Director of the Rush Epilepsy Center in Chicago. His research has focused in psychiatric,
pharmacologic and surgical aspects of epilepsy. He is board certified in Neurology, Psychiatry,
Epilepsy and Clinical Neurophysiology.

Natasha Watanabe, M.D.

Brigham and Women's Hospital, Harvard Medical School
Page B. Pennell, MD is Professor of Neurology at Harvard Medical School and Director of
Research for the Division of Epilepsy in the Department of Neurology at Brigham and Women’s
Hospital (BWH), with a secondary appointment in the Division of Women’s Health. She is a
clinician investigator with a focus on sex-specific outcomes in epilepsy. Dr. Pennell’s current
clinical studies focus on the effects of hormones on seizure provocation, pharmacokinetic
changes of AEDs during different reproductive phases, and maternal and fetal outcomes during
pregnancy in women with epilepsy. Dr. Pennell earned her BS in biology from Emory University,
her MD from the University of Florida, and completed her Neurology residency and
Epilepsy/Clinical Neurophysiology fellowship at the University of Michigan. She is currently
serving as the first Vice-President of the American Epilepsy Society.

Jeanne Young, MD

Lawrence Hirsch, M.D.

Yale University School of Medicine
Lawrence J. Hirsch, MD is Professor of Neurology; Chief of the Division of Epilepsy and EEG; and
Co-Director of the Comprehensive Epilepsy Center, all at Yale University School of Medicine in
New Haven, CT. He received his MD from Yale University. He then moved to The Neurological
Institute, Columbia University in New York, NY where he completed Neurology residency, a 2
year Epilepsy and EEG fellowship, and 14 years as faculty. He moved to Yale in 2011. He has
published >200 articles on topics such as EEG monitoring in the critically ill, brain stimulation for
epilepsy, antiepileptic drugs, epilepsy surgery, intracranial EEG, brain mapping, SUDEP, seizure
clusters, and more.

Aradia Fu, MD
Northwell Health
Aradia Fu is an assistant professor of neurology in the Zucker School of Medicine at
Hofstra/Northwell and attending physician at Northwell Health Comprehensive Epilepsy Center.
She earned her BS in neuroscience & BA in psychology from UCLA and her MD from University of
California Irvine School of Medicine. She completed neurology residency training at Barrow
Neurological Institute and then went to Yale New Haven Hospital for 2-year fellowship training
in clinical neurophysiology and epilepsy.
 11/28/2018

Disclosure
I (and my co‐authors) have something to disclose.
Fundamentals of Epilepsy Symposium
Detailed disclosure information is available via:
“Epilepsy on the Consult Service” • AES Annual Meeting app;
and
• Annual Meeting Online Final Program (https://meeting.aesnet.org/program)

Learning Objectives Faculty

Aradia Fu, MD Asst. Professor of Neurology, Northwell Health Epilepsy Comprehensive Center

• Explore the effects of AEDs on lipids, interactions between AEDs and Larry Hirsch, MD Professor of Neurology, Yale University; Chief, Division of Epilepsy and EEG; Co‐
Director, Yale Comprehensive Epilepsy Center
cardiac medication. Andres Kanner, MD Professor of Clinical Neurology, University of Miami, Miller School of Medicine;
• Review key features that distinguish seizures from syncope and other Director, Comprehensive Epilepsy Center and Head, Section of Epilepsy
mimickers. Fred Lado, MD PhD Director, Epilepsy Division, Northwell Health Eastern and Central Regions
Scott Mintzer, MD Professor of Neurology, Jefferson Comprehensive Epilepsy Center, Thomas Jefferson
• Review psychiatric medications that potentially lower seizure threshold. University
• Learn about management of seizure during pregnancy. Steven Pacia, MD Director, Neurology, Northwell Health Eastern Region; Vice Chairman, North Shore
University Hospital
• Discuss AEDs and risk of skin hypersensitivity, evaluate cross reactivity
Page Pennell, MD Professor of Neurology, Harvard Medical School; Director of Research, Division of
among different AEDs. Epilepsy, Brigham and Women’s Hospital
Jeanne Young, MD Asst. Professor of Dermatology, University of Virginia

Program
12:30‐12:40 Introduction of Program and Speakers Impact on Clinical Care and Practice
12:40‐1:05 Epilepsy and the heart
AEDs and cardiovascular risk, AEDs and cardiac drugs

• Making the correct diagnosis ‐ seizure vs mimickers

Speaker: Scott Mintzer

1:05‐1:30 Seizure mimickers

Distinguishing seizures from syncope and other mimickers
Speaker: Steven Pacia
• Selecting the appropriate AEDs for patients
1:30 – 1:55 Medications that lower seizure threshold • Being mindful of interaction between AEDs and other
How much do psychiatric medications and antibiotics increase seizure risk?
Speaker: Andy Kanner medications
1:55 – 2:20 Seizure management during pregnancy
Speaker: Page Pennell • Addressing management of epilepsy in a specific
2:20 – 2:50 Seizure medications and the skin hypersensitivity population – women during pregnancy
2:20‐2:40 Speaker: Jeanne Young
2:40‐2:50 Q&A with Larry Hirsch

Conclusions

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Disclosure
Epilepsy & Heart Disease:
Tips for the Consultant I have disclosures.
Detailed disclosure information is available via:
S M E , MD
PROFESSOR OF NEUROLOGY • AES Annual Meeting app;
THOMAS JEFFERSON UNIVERSITY and
PHILADELPHIA, PA • Annual Meeting Online Final Program (https://meeting.aesnet.org/program)

Learning Objectives Case: Cardiac Consultation

• To identify the impact of anticonvulsants on
cardiovascular risk markers
• To assess the potential impact of drug interactions
involving anticonvulsants on cardiac conditions
(and other health conditions)
• To appraise the role of the neurological consulant in
anticonvulsant choice
• Medicine re uests consult on 4 yo man admitted after
episode of abrupt LOC
• Hx of cryptogenic epilepsy AND cardiac dz
• Seizures began 35 yrs ago non‐specific feeling in head x 1
min unresponsive staring
• Tried one drug (?? which), switched to CB 30 yrs ago. Now on
CB ‐ER 400 BID and seizure‐free for 12 yrs

Cardiac Consultation Case (continued) Anticonvulsants are part of epilepsy

• Latest episode different than sz
• No warning; abrupt fall
• Neither has ever happened with previous seizure
• Has HTN, cholesterol, CAD, AFib, post‐herpetic neuralgia
• Couldn’t tolerate GBP; pain not well‐controlled
• Takes propranolol, amlodipine, atorvastatin, warfarin, amiodarone,
nortriptyline
• BP 1 0/ ; Cholesterol 25 ; LDL‐C 1 0; CRP 8.3
• Drugs effectively part of the disease
• Many drugs impact may differ depending on Rx
• Inducing drugs , PH , P , P M can subtantially
complicate cardiovascular & general health
1)Direct impact of inducing AEDs on cardiovascular system
2)Interactions with cardiovascular (and other) drugs

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“Switch” study:
Inducing drugs and lipids Measure
(mg/dL)
Pt group (N) On CBZ/PHT On LEV/LTG p -value
(2-tailed)

patients on
• Many cross‐sectional studies show higher chol levels in Total cholesterol All (n =38) 217 ± 43 191 ± 38 p<0.0001 CB or PHT
patients taking inducers (LoPinto‐Khoury & Mintzer 2010) crossing over to
Non-HDL chol. All (n =38) 155 ± 42 135 ± 36 p<0.0001 LTG or LEV
• Giving CB to young healthy men produced substantial
increase in total cholesterol and Lp(a) (Br mswig et al. 2003) HDL cholesterol All (n =38) 62 ± 21 56 ± 16 p=0.002

• “Switch” studies: cross patients over from CB /PHT to non‐

Triglycerides All (n =38) 142 ± 126 90 ± 47 P<0.0001 Mintzer et al,
inducers cholesterol goes down 25 mg/dL (many) Ann Neurol 200

Mean±SD values; All changes p<0.05 relative to changes in normal subjects (not shown)

Baseline
weeks post‐switch Switch to LEV/LTG Measure Pt group (N) On inducer On non-inducer p -value
➙
months post‐switch (2-tailed)
(Mintzer et al Ann Neurol 200 )
CRP (mg/L) All (n =37) 4.2 ± 5.2 2.4 ± 4.1 p=0.003
Long‐term “switch” study:
Switch to TPM Lp(a) (mg/dL) CBZ only (n=20) 33 ± 25 23 ± 18 p=0.004
(Mintzer et al Epilepsy Behav 2012) Homocysteine
Pts on CB or PHT crossing PHT only (n=13) 13.5 ± 6.4 10.5 ± 3.9 p=0.02
➘ (μmol/L)
over to LEV, LTG, or NS

Lipids measured CRP, Lipoprotein(a), and homocysteine

before switch, also appear elevated (variously) by
weeks after, and inducing drugs
months after
Decline when patients are switched to non‐
inducers

CLINICAL RELEVANCE OF Inducers & new hyperlipidemia diagnoses

INDUCED HYPERLIPIDEMIA
Q: After starting Rx for
new epilepsy, how likely is
patient to wind up on a
statin?
A: 50 more likely if
started on an inducing
anticonvulsant
• 11, 83 adults with new Dx & Rx for sz from 200 ‐200
• Followed for mean of slightly 1 year
• 0 4( ) put on non‐inducing anticonvulsant
• 1055 (11. of these) got new Dx of hyperlipidemia
• 2 1 (23 ) put on inducing anticonvulsant
• 432 (15. of these) got new Dx of hyperlipidemia (p 0.001)
• After adjustment, inducer Rx = 25% higher odds of hyperlipidemia Dx
subse uently ( 5 CI 1.10 ‐1.41, p 0.001)
Mintzer et al, AES 2018 (stop by Monday )

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Inducing agents and MI But wait, there’s more

• Olesen et al. (Pharmacoepidemiol Drug Saf 2011) ‐ vascular dz rates by AED in
• Inducers engender dozens of drug interactions
national Danish database
• Direction of interaction: reduce exposure to other drug
Found rates of MI (28 ) in VPA‐treated pts vs. CB ‐treated patients,
& rate of CV death (15 ) in LTG‐treated pts vs. CB ‐treated patients • Ex: PHT atorvasta n AUC by 54 (Bullman et al Epilepsia 2011)

• Ex: CB simvasta n AUC by 5 (Ucar et al Eur J Pharm 2004)

• Renoux et al. (BMJ Open 2015) ‐ UK GPRDatabase
Found 4 in MI in pa ents treated with inducing AEDs for 24 months,
• Expect therapeu c e ec veness
and 1 in MI among pa ents ge ng VPA impede statins from lowering lipids

Inducers and statins: functional impact Inducers’ interactions with other CV drugs
• Ca2 ‐channel blockers
• amlodipine, verapamil, ditiazem, nifedipine, nicardipine, nimodipene, others
• Antiarrythmics
• mexiletine, amiodarone, procainamide, uinidine, disopyramide
• 𝛃‐blockers
• propranolol, metoprolol
• Others
• losartan, digoxin, warfarin, rivaroxaban

Mintzer et al, Epilepsia 2018

Drugs induced by PHT, CB : Greatest Hits CB Cardiac Consultation Case (continued)

itraconazole AUC ↓90% oral contraceptives
Not a
do ycycline prednisone complete
protease inhi itors de amethasone list
• Latest episode different than sz
efavirenz vincristine All induced
tricyclic antidepressants etoposide • No warning; abrupt fall by CB 😳
upropion ‐ AUC ↓90% paclita el • Neither has ever happened with previous seizure
nefazodone cyclophosphamide
risperidone tacrolimus sirolimus • Has HTN, cholesterol, CAD, AFib, post‐herpetic neuralgia
uetiapine ‐ 5x ↑ clearance cyclosporine • Couldn’t tolerate GBP; pain not well‐controlled
clozapine ‐ levels ↓50% methotre ate
haloperidol ‐ levels ↓ over 50% meperidine • Takes warfarin, amiodarone, atorvastatin, propranolol, amlodipine,
enzodiazepines methadone levels ↓50% nortriptyline
theophylline acetaminophen
• BP 1 0/ ; Cholesterol 25 ; LDL‐C 1 0; CRP 8.3
Patsalos and Perucca, Lancet Neurol 2003

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The consultant’s job Carbamazepine Phenytoin Phenobarbital

• “The heart is not my problem ” • Eschewing these drugs should be your baseline position
but your job is to look out for the patient’s health • Infre uent exceptions (cost, pregnancy, uni ue efficacy)

• When problem is interdisciplinary, somebody needs to take
ownership
• Problem with the “specialty silos” of medical practice
• Other docs will not change anticonvulsant
☞ If you don’t fix it, nobody will ☜
• Especially dangerous for those w/ vascular dz or risk factors
• Healthy people eventually wind up taking medications
• Even if you can remember all those interactions will others??
• If already on one consider switching to non‐inducing drug

Recurrence risk after drug switch in sz‐free patients

Impact on Clinical Care and Practice
Study Group N Seizure-free Recurrent seizures
6 months after within 6 months of
switch/index date switch/index date
• Inducers significantly increase lipids & vascular risk markers
Study #1 Cases 5 (21.7%) • Inducers reduce effectiveness of statins & many other CV agents
Wang, Mintzer et al
Controls 2 (4.3%) • Poor choices for anyone with CV disease or risk factors
Epilepsia 2013

In fact, inducers probably poor choices for everyone!

Study #2 Cases 12 10 (83.3%) 2 (16.7%)
• Consider switching anticonvulsant other docs won’t do it
Finamore et al
Epilepsia 2016
Controls 36 35 (97.2%) 1 (2.8%) That’s why they consult you

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Disclosure
Syncope and Other Seizure Mimics

STEVEN V. PACIA, MD I have nothing to disclose.

VICE CHAIR, NEUROLOGY
NORTH SHORE UNIVERSITY HOSPITAL
DIRECTOR, NEUROLOGY
NORTHWELL HEALTH EASTERN REGION

Learning Objectives Differential Diagnosis

• Syncope
• 1. Generate a differential diagnosis for patients ‐ Vasovagal syncope
‐ Cardiac arrhythmia
presenting with episodic loss of consciousness ‐ Orthostatic hypertension
• Meta olic
Hypoglycemia metabolic
• 2. Differentiate migraine from epilepsy ‐Hypoxia
• Psychological
Psychogenic seizure
• 3. Understand the epidemiology and clinical ‐Panic Attack
characteristics that distinguish syncope from seizures
• Migraine
‐
‐
Confusional migraine
Migraine visual aura
•
•
A
A
‐VBI and LOC
‐Limb shaking TIA
Disorders
• Sleep Disorders
‐Narcolepsy/Cataplexy
‐Sleep Disorders
• ransient lo al Amnesia
• ransient lo al Amnesia

Pathophysiology
Migraine

• Migraine headache is a complex, recurrent headache disorder Images not available due to copyright
that is one of the most common complaints in medicine.

• In the United States, more than 30 million people have 1 or

more migraine headaches per year.

• Approximately 5 of all persons who experience migraines

are women

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fMRI Migraine with Aura PET‐ Migraine

Images not available due to copyright Images not available due to copyright

Absence MRI Visual Auras

M A E S AL A A AL S AL A A

Images not available due to copyright • monochromatic • Multicoloured ictal

• Linear, zigzag • unformed or circular (but
• Lateralization‐variable not zigzags),
between attacks; traversing • often confined to one
visual field hemi‐field.
• Onset gradual‐ 5‐20 min. • Onset more rapid (within
• Duration‐ 5‐30 min sec)
• relatively brief
(30sec‐2min)

Benign Occipital Epilepsy

Acute Confusional Migraine
Child
• Incidence in paediatric age group – 0.45‐ .8
(Verma et al BMJ 2013)

• Abrupt onset of agitation, disorientation, and

behavioral changes (minutes to hours)

• There may be no recollection of the event and

the associated headache

• Diagnosis of exclusion

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 11/28/2018

Consciousness TLOC

Images not available due to copyright

• Vasovagal

• Epilepsy

• Cardiac

Syncope vs Seizure

Video

3
11/28/2018

4
 11/28/2018

Syncope Incidence

• Vanbrabant P. et al. BMC Fam Pract. 2011 Sep 2 ;12(1):102.

Syncope Prognosis Lifetime Cumulative Incidence of Syncope

• Cardiovasc Electrophysiol. 200 Nov;1 (11):11 2‐
• In one third of .
participants, a cause • Netherlands Survey of 54 adults
for syncope could not
be assigned
• Median number of episodes was 2
• Risk of death increased
by 31 among all • Most fre uently mentioned triggers: warm
participants with environment, pain, insufficient food intake, seeing
syncope blood/venipuncture, and emotion.
• Risk of death dou led
among participants
with cardiac syncope • Cumulative Incidence of 35 (females 41 v.
males 28 )
Soteriades, E.S.. et al. Incidence and Prognosis of Syncope. N Engl J
Med 2002; 347:878-885

Cumulative Incidence of Epilepsy

Images not available due to copyright Images not available due to copyright

5
 11/28/2018

Epilepsy

Affects nearly 3.4 million Americans

Approximately 20‐ 40 medically refractory

Tongue bite significantly more likely in Seizure vs

Syncope

(Brigo, et al Seizure, 2012)

Atonic Seizure
Tonic Seizure

Video Video

Cardiac Syncope
Non‐Epileptic Seizure
• Any posture, common in bed, exertion/emotion

Video • During Exercise (still most vasovagal)

• achyarrhythmias‐ palpitations common even between attacks, long QT

(inherited and medication related)

• radyarrhythmias‐ fatigue common, carotid hypersesitivity, reflex

bradycardic (valsalva, cough, micturition)

• Structural ‐ AS, hypertrophic, LV underfilling (mitral Stenosis), pump

failure
 11/28/2018

Cardiac Syncope‐ Reliability of

Clinical Symptoms
MacCormick JM et al. Heart Lung Circ. 2011 Sep;20( ):5 3‐8. Symptoms and signs
associated with syncope in young people with primary cardiac arrhythmias.

35 consecutive unrelated gene‐positive probands with a proven cardiac

channelopathy presenting with sudden death or syncope

Dizziness or lightheadedness was the most fre uent symptom‐ 4

45 had witnessed seizure‐like activity and 40 had urinary incontinence

(Supported by Brigo et al 2012‐ no value of UI in discriminating sz, nes and syncope

Tussive Syncope

Video
 11/28/2018

Tussive Syncope

• Middle aged, overweight males

• COPD
• Possible Mechanisms‐
• High intrathoracic pressure leads to reduce CO
• VS
• Neurally mediated reflex vasodepressor‐bradycardia
response to cough

Syncope‐ Reflex (Vasovagal) VVSyncope Mechanisms

• Estimated costs of syncope related hospitalizations 2.4 billion
USD/yr

• Triggers‐ standing, hot crowded places (restaurant), emotional

trauma, pain

• Prodrome‐ light headed, nausea, sweating, palpitations,

graying/blacking of vision, muffled hearing, feeling distant

• Event‐ loss of tone, fall, clonic jerks, rare incontinence and tongue
bite, rapid recovery without confusion

• Mechanism‐ venous pooling (legs or splanchnic), Cardiac Output

falls, Bezold Jarisch Reflex (vigorous cardiac contractions suggest
over filling and increase vagal and reduced sympathetic tone.

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 11/28/2018

Bezold‐ Jarisch Reflex Pathophysiology of the vasovagal response

Images not available due to copyright
• Jardine, et al. Heart Rhythm 2018
• Teenagers and young adults‐vasodilatation or falling cardiac
output.
• The fall in cardiac output due to decrease in stroke volume as
blood is pooled in the splanchnic veins.
• Older adults‐ reduced cardiac output is the dominant
hypotensive mechanism as systemic vascular resistance
remains above baseline levels.

Orthostatic Syncope (autonomic failure)

Tilt Table Testing
Recommendations
• Loss of normal vasoconstriction response to postural fall in BP
• If diagnosis is unclear after initial
evaluation, TTT can be useful for
patients with suspected VVS
• No pallor, sweating or pulse rate changes • TTT can be useful for pts with syncope
and suspected delayed OH when initial
eval not diagnostic
• Reasonable to distinguish convulsive
• Causes‐ Neuropathy, MSA, medications syncope from epilepsy in certain
patients
• Reasonable to establish diagnosis of
• Must exclude anemia and hyponatremia pseudosyncope
• Not recommended to predict a response
to medical treatment for VVS

Myoclonic Jerks

Video
 11/28/2018

? Fencer’s Posture Vocalization

Video Video

201 Guideline for Evaluation and

Eye Deviation & Vocalization
Management of VVS
Video Images not available due to copyright

New Studies‐ ILRs New Studies‐Genetics

Sulke et al. EP Europace 201 . June 1; 12‐ 18
Implantable loop recorder (ILR) monitoring ‐ more rapid
diagnosis in unexplained syncope than usual care
ILR demonstrated a high rate of intermittent bradycardia
re uiring pacing (22 v 3 )
ILR reduced time to second syncope
Standard care resulted in more diagnostic tests
Klein,M.K. Neuroscience:Basic & Clinical 2014 Sep (144; 0‐ 5.
enetics of vasovagal syncope
• VVS patients have FH more often than controls
• Monozygous vs Dizygous twins
• Most cases complex inheritance but AD inheritance
described (one family with 30 affected individuals)

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 11/28/2018

New Studies‐ Orthostatic Training New Studies‐ Fluoxetine

• Pacing Clin Electrophysiol. 2018 Jan;41(1):42‐4 .0
• Home OT in 38 patients (13 males, age 3 .4 15.2
• uropace, 1 January 201
years). • 0/10 pts with positive ASI randomized 2:1
• Baroreflex sensitivity (BRS), heart rate variability, and to 10‐40 mg fluoxetine vs placebo
uality of life were assessed before and after months • One year follow up
of OT.
• Fluoxetine was superior to placebo in
• OT reduced symptoms and syncope in 4 patients
who trained regularly.
preventing recurrent syncope
• ?baroreceptor reactivity in upright position.
• Only 55 completed the one year program

DDD‐dual chamber demand PM Closed Loop Stimulation

Images not available due to copyright Images not available due to copyright

New Studies‐ Dual‐Chamber Pacing With Closed Loop Stimulation in

Recurrent VVS
The SPAIN Study
• JACC 201 , Baron‐Es uivas et alc
• 4 40 yes age
• 12 month crossover w/sham
stimulation
• DDD‐CLS pacing significantly
reduced syncope burden and
time to first recurrence 2 pts
with 50 reduction in syncope
reduction in syncope
Images not available due to
copyright
Conclusions
• Syncope often misdiagnosed and treated as
epilepsy
• Witnesses often unreliable in describing events
• Atonic seizures in adults‐ very unlikely,
Lifelessness at onset of event syncope
• Cumulative incidence of syncope is 10 times
greater than epilepsy
• EST ‐EKG indicated in exercise induced syncope

11
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12
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Do psychotropic and antibiotics drugs cause Disclosure

seizures? A review of the evidence.
I have something to disclose.
ANDRES M. KANNER, MD, FANA, FAAN, FAES
PROFESSOR OF CLINICAL NEUROLOGY
Detailed disclosure information is available via:
DIRECTOR, COMPREHENSIVE EPILEPSY CENTER
HEAD, SECTION OF EPILEPSY, DEPARTMENT OF NEUROLOGY,
UNIVERSITY OF MIAMI, MILLER SCHOOL OF MEDICINE, MIAMI, FL • AES Annual Meeting app;
and
• Annual Meeting Online Final Program (https://meeting.aesnet.org/program)

Learning Objectives

• To review whether psychotropic drugs have

proconvulsant properties.

• To identify which antibiotic drugs can cause seizures and

the pathogenic mechanisms associated with seizure
occurrence.

Case 1
35 year‐old woman with a 2 year history of a mixed
depressive disorder and anxiety disorder. sychotropic sychiatric
ru isorder

Three months ago she was started on the SSRI citalopram at

a dose of 20 mg/day and four weeks later the dose was
increased to 40 mg /day which resulted in the remission of
her symptoms.
Seizure

The patient was brought to the emergency room after having

been witnessed to have a GTC seizure.

In the ER, she was instructed to stop the citalopram.

1
 11/28/2018

What is the incidence of seizures in non‐epileptic patients

treated with psychotropic drugs?
Alper et al , iological sychiatry 200

Data from Food and Drug Administration (FDA) Phase II and

III clinical trials as Summary Basis of Approval (SBA) reports
that noted seizure incidence in trials of psychotropic drugs
approved in the United States between 1 85 and 2004.
Antidepressant drugs N 5,8 3 patients.

Comparison of seizure incidence among active drug and

placebo groups in psychopharmacological clinical trials and
the published rates of unprovoked seizures in the general
population.

TCAs, SSRIs and SNRIs

igher incidence of sei ures in patients exposed to
antidepressants than placebo
Antidepressant treatments associated with lower seizure incidence
relative to placebo for all SSRIs and SNRIs Clomipramine
Standardized seizure ratio: 0.48, 5 C.I. 0.3 ‐0. 1. Bupropion immediate release (IR)

The incidence of seizures among patients randomized to placebo

was 19‐fold higher than that of the general population.

Number of published studies suggesting an

effect of antidepressants on seizures in
Animal models animal models of epilepsy
Anticonvulsant effect: n 30

roconvulsant effect n

o effect n 21

2
 11/28/2018

Anticonvulsant action of hippocampal

serotonin is mediated by 5‐HT1A receptors.
Clinc ers R, et al ournal of eurochemistry, 200

The anticonvulsant effects of intrahippocampally applied 5‐HT concentrations

were evaluated against pilocarpine‐induced seizures in conscious rats.

5‐HT perfusions protected the rats from limbic seizures as long as extracellular
5‐HT concentrations ranged 80–350 increments relative to baseline levels.
Antipsychotic drugs
High extracellular 5‐HT ( 00 increases) concentrations worsened seizure
outcome.
The latter proconvulsant effects were associated with significant increases in
extracellular glutamate.

What is the incidence of seizures in non‐epileptic patients

treated with psychotropic drugs?
Alper et al , iological sychiatry 200
What is the incidence of seizures in non‐epileptic patients treated with
psychotropic drugs?
Data from Food and Drug Administration (FDA) Phase II and Alper et al , iological sychiatry 200
III clinical trials as Summary Basis of Approval (SBA) reports
that noted seizure incidence in trials of psychotropic drugs
approved in the United States between 1 85 and 2004.
Increased seizure incidence observed with
N 5,8 3 patients. antipsychotics:
clozapine
Comparison of seizure incidence among active drug and
placebo groups in psychopharmacological clinical trials and olanzapine
the published rates of unprovoked seizures in the general uetiapine
population.

CNS Stimulants and seizures

A retrospective survey of seizures associated with drug intoxication in the

San Francisco Bay area over a 2‐year period.
C timulants The leading causes of seizures were:
cyclic antidepressants in 2 ,
CNS stimulant drugs in 2 ,
antihistaminics in 14 ,
theophylline in 5

lson, earney et al 99

3
 11/28/2018

CNS Stimulants
Exacerbation of seizures reported in 0 ‐18 of study populations on
methylphenidate, but most are mild and transient, with no more than 5
stopping medication.
Studies were not placebo‐controlled. Therefore, it is not possible to
determine if the changes are related to baseline fluctuations.
Seizure exacerbation rates for atomoxetine were ‐ , but again the
numbers were too small to draw conclusions, and there are no data for
amphetamines.
Seven studies, which included patients with refractory epilepsy, indicated
that methylphenidate is probably safe.
Data collected by the pharmaceutical manufacturer of atomoxetine found
that seizures were no more prevalent in children with ADHD treated with
this drug than in children with ADHD without psychostimulant
intervention.

Methylphenidate in children with ADHD and Epilepsy Anticonvulsant action of hippocampal dopamine and
Ravi Ic owit , Can Acad Child and Adolesc sychiatry 20 5 serotonin is independently mediated y D and H
receptors
Clinc ers et al, eurochem 200

The anticonvulsant effects of intra‐hippocampally

applied DA concentrations were evaluated against
pilocarpine‐induced seizures in conscious rats.

DA perfusions protected the rats from limbic

seizures as long as extracellular DA concentrations
ranged between 0‐400 increases compared with
the baseline levels.

nticon ulsant action of hippocampal dopamine and serotonin is

independently mediated y and 5- receptors.

Clinckers et al, J Neurochem. 2004.

Co‐perfusion with the selective D(2) blocker remoxipride abolished o psychiatric disorders increase
all anticonvulsant effects.
the ris of developing epilepsy
High extracellular DA ( 1000 increases) concentrations worsened
seizure outcome.

The pro‐convulsive effects of high DA concentrations were

associated with significant increases in extracellular glutamate

4
 11/28/2018

rends in the incidence rate ratio for epilepsy versus controls ith confidence intervals for depression in the years efore
Epilepsy, Suicidality, and Psychiatric and years after epilepsy diagnosis
esdorffer et al , Ann eurol, 20 2
Disorders: A Bidirectional Association
esdorffer et al , Ann eurol, 20 2

b ective: to determine whether psychiatric disorders associated with suicide are more
common in incident epilepsy than in matched controls without epilepsy, before and after
epilepsy diagnosis.

ethods: A matched, longitudinal cohort study was conducted in the UK General Practice
Research Database.

A total of 3, 3 cases diagnosed with epilepsy between the ages of 10 and 0 years were
compared to 14,025 controls matched by year of birth, sex, general practice, and years of
medical records before the index date.

rends in the incidence rate ratio for epilepsy versus controls ith confidence intervals for an iety in the rends in the incidence rate ratio for epilepsy versus controls ith confidence intervals for suicidality in the
years efore and years after epilepsy diagnosis years efore and years after epilepsy diagnosis

rends in the incidence rate ratio for epilepsy versus controls ith confidence intervals for
Bidirectional Relationship Between Epilepsy and
psychosis in the
years efore and years after epilepsy diagnosis ADHD

Psychiatric History Preceding

the nset of
Authors ype of Study Epilepsy ontrols

esdorffer et al, Population‐ 3.5 times the history of

Arch of sychiatry 200 based Attention Deficit Disorder,
(Iceland) Inattention Type

5
 11/28/2018

nti iotics CNS isease

o Antibiotics cause sei ures

Seizures

Seizures as ad erse e ents of anti iotics idence for anti iotic-related symptomatic seizures
ru s systematic re iew
is low to ery low

Penicillins
Anti iotic Fre uency AA lass of ype of seizure ontri uting
evidence factors
Penicillin Up to 5 IV GTC Renal failure
acillin Myoclonic Brain lesions

Piperacillin IV GTC Renal failure

NCSE

Cephalosporins Carbapenems
Anti iotic Fre uency AA lass of ype of seizure ontri uting Anti iotic Fre uency AA lass of ype of ontri uting
evidence factors evidence seizure factors
mipenem Up to 5 III ‐ IV GTC Renal failure
efazolin 80 with renal IV GTC Renal failure Brain lesions
(1st generation) failure NCSE Intrathecal Epilepsy
CSE infusion Rx with
theophyline
efotiam IV GTC (one case) Mental
(2nd Generation) disorders Meropenem 1 III‐ IV GTC Renal failure
Brain lesions
eftazidime IV NCSE Renal failure; Epilepsy
(3rd generation) brain lesion treated ith
PA
efepime Up to 11 III – IV GTC Renal failure; Doripenem 1.2 III GTC Epilepsy
(4th generation) Myoclonic Brain lesion
seizures Ertapenem IV GTC Renal failure
NCSE Brain lesions
Epilepsy
ith PA
 11/28/2018

Fluoro uinolones Antibiotics and seizures

Anti iotic Fre uency AA lass of ype of ontri uting factors utter et al eurology 20 5 5 2
evidence seizure
iproflo acin ‐ III ‐ IV GTC Renal failure
Mental disorders
Epilepsy
Evidence regarding symptomatic seizures from
Concomitant fluoro uinolones:
theophyline
orflo acin ‐ IV GTC Prior seizures case reports and case series.
Mo iflo acin ‐ IV GTC Renal failure most reports for ciprofloxacin in patients with renal
SE Epilepsy
Levoflo acin ‐ IV GTC Renal failure dysfunction, prior seizures, other CNS disease or co‐
NCSE Epilepsy
administered theophylline.
atiflo acin ‐ IV GTC Renal failure
SE Epilepsy

Anti‐TB Mechanisms associated with the

development of seizures
Anti iotic Fre uency AA lass of ype of seizure ontri uting Impact on neurotransmitters
evidence factors
Decrease of GABA‐ergic activity.
ifampicin ‐ IV GTC ‐

soniazid ‐ IV GTC ‐ harmaco inetic interaction with A s

SE
CP‐450 enzyme induction (Rifampin)

Inactivation of hydratization of pyridoxal 5 phosphate, which

is the essential coenzyme of GAD for the synthesis of GABA
from glutamic acid resulting in failure of GABA synthesis
(Isonizid)

Conclusions (2)
Conclusions (1)
1) The evidence that antibiotics can cause
seizures is low.
1) With a few exceptions, antidepressant do not cause 2) Seizures can occur in the setting of high doses,
seizures when used at therapeutic doses. renal failure and CNS disease with the use of
2) With two exceptions, second generation antipsychotic certain penicillins, cephalosporins and
drugs do not cause seizures when used at therapeutic carbipenems.
doses. 3) The main pathogenic mechanism responsible
3) CNS stimulants do not appear to cause seizures when for seizures consists of interference with
used at therapeutic doses. GABAergic transmission.
 11/28/2018

Impact on Clinical Care and Practice

• With a very few exceptions, are safe in the treatment of

psychiatric disorders of patients with epilepsy as long as they
are used at therapeutic doses.

• Antibiotics of the penicillin, cephalosporin, carbipenem

families can potentially be associated with seizures
particularly in the setting of renal failure and CNS disease. Yet
the fre uency of seizures is low.

8
 11/28/2018

Disclosure
Seizure Management during Pregnancy
PAGE B. PENNELL, MD I have nothing to disclose.
PROFESSOR OF NEUROLOGY, HARVARD MEDICAL SCHOOL
DIRECTOR OF RESEARCH, DIVISION OF EPILEPSY
BRIGHAM AND WOMEN’S HOSPITAL

a nitude
Learning Objectives

• To become familiar with which AEDs carry the highest

teratogenic risk
• To become knowledgeable about other adverse neonatal
and child outcomes •
• To become familiar with gestational pharmacokinetic
principles and how to adjust AEDs during pregnancy to Pregnancy planning w/optimization of med type, dose, & FA is key
maintain maternal seizure control
Neurology N Engl J Med
PaediatrPerinatEpidemiol Adedinsewo DA, et al., Birth Defects Research (Part A) 2013.

Planned Pregnancies are Essential

AEDs: Degree of Induction of Metabolism of Hormonal
Long-Acting Reversible Contraceptives
Contraceptive Agents
(LARC)
Stron nducers ea nducers Non-inducers
pheno ar ital topiramate ethosuximide
phenytoin lamotri ine alproate
car amazepine fel amate a apentin
primidone rufinamide clonazepam
oxcar azepine clo azam tia a ine
perampanel eslicar azepine le etiracetam
zonisamide
pre a alin Copper T IUD
i a atrin
lacosamide
ezo a ine Mirena or Skyla IUD
(levonorgestrel)
Approved Quality Measure for Epilepsy

Avoid concomitant use ith the lo est dose oral contraceptive pills Contraceptive implant
D Medical Eligi ility riteria ategory ris s out eigh the enefits Davis A, Pennell PB, 2014. (etonogestrel), not w/ EIAEDs

1
 11/28/2018

Pregnancy & Postpartum Care in Women A Precise Balancing Act:

with Epilepsy Benefits versus Risks of AEDs during Pregnancy

•
•
• type amount

Clinical dilemma of minimizing teratogenic effects of AED

exposure while maintaining maternal seizure control
N Engl J Med Adedinsewo DA, et al., Birth Defects Research (Part A) 2013.

AED Pregnancy Registries

• R n international re istry of s
and pre nancy
Spina Bifida
• North merican re nancy Re istry

• pilepsy and re nancy Re istry

Day 17-18 after conception the
neural tube starts forming • ustralian re nancy Re ister
(3 days after the missed
menstrual period) • erala re nancy Re istry ndia
3
5
• harmaceutical company re istries

reatment of omen

Major Congenital Malformation Rates in EURAP: Number of offspring with MCMs for the four monotherapies
at different doses at conception (mg per day), (rate, 95% CI)
NAAPR and EURAP and other registries

NAAPR (2012) EURAP (2012‐2018) 1381

323
of M M

125
2 4

1 5
1
verall ates

35
152

153 183 333 41

2414 5 1033 4
450
182
15 2

442 145

Tomson T, et al. Lancet Neurol 2011;10(7):609-17.

Voinescu PE, Pennell PB, Seminars in Neurology, 2016, updated Nov 2018.

2
 11/28/2018

opiramate re nancy utcomes

EURAP updates, Lancet Neurology, 2018

(combined data from 21 prospective studies)

Num er reported with specific
C shown on top of the ars

Prevalence of S A and relative ris compared to lamotrigine

•
•
•
•
•

Arch Neurol Neurology Neurology

Hernandez‐Diaz S et al Ann eurol 201 ; 82:45 ‐4 5.

3
 11/28/2018

NEAD STUDY DESIGN etal xposure to alproate

ssociated with ower at e6
Mean IQs (95% Difference CIs from VPA)
adjusted for maternal IQ, AED dose, gestational age & folate:
• Multicenter prospective, parallel-group observational study with
statistical control. CBZ LTG PHT VPA
• 309 pregnant mothers with epilepsy enrolled from late 1999 to Mean IQ 105 * 108 * 108 * 97
early 2004 in USA & UK.
• Antiepileptic drug (AED) monotherapy: Difference 7 10 10
Carbamazepine (CBZ)
Lamotrigine (LTG) DCIs (3:12) (6:15) (5:16)
Phenytoin (PHT)
Valproate (VPA) # Children 93 100 56 62
• Blinded cognitive assessments:
2, 3, 4.5, & 6 y/o
Meador KJ, et al. Lancet Neurol 2013;12:244-52.
• Primary outcome: IQ at 6 y/o

ASD & Autism in Children on Women on

Dose-Dependent Effects in NEAD AED Monotherapies

Carbamazepine Lamotrigine

Phenytoin Valproate

Meador KJ, et al. Lancet Neurol 2013;12:244-52. Christensen J, et al. JAMA 2013.

May 13, 2013: FDA Drug Safety Communication:

Valproate Anti-seizure Products Contraindicated for
Migraine Prevention in Pregnant Women due to
Decreased IQ Scores in Exposed Children

No olate
• VPA’s pregnancy category for migraine use will be changed from "D"
(the potential benefit of the drug in pregnant women may be
acceptable despite its potential risks) to "X" (the risk of use in pregnant
women clearly outweighs any possible benefit of the drug).

• With regard to… epilepsy or bipolar disorder, valproate products

should only be prescribed if other medications are not effective in
treating the condition or are otherwise unacceptable. Valproate
products will remain in pregnancy category D for treating epilepsy and
manic episodes associated with bipolar disorder.

Meador KJ, et al. Lancet Neurol 2013;12:244-52.

4
 11/28/2018

ssociation of olic acid Supplementation with

ris of utistic raits In Utero
• Population-based, prospective Norwegian Cohort study
• Children exposed in utero to AED, June 1999-Dec 31, 2008
Children 18-36 mos (n=104,946; 335 exposed to AEDs)
• Folic acid 4 weeks prior to and 12 weeks after conception
• MCHAT questionnaire
• Adjustments for maternal health and SES

• AOR = 5.9 (CI 2.2-15.8) at 18 mos and AOR = 7.9 (CI 2.5-24.9) at 36
mos for the AED-no folate group compared to AED-folate group.
• Folate benefit still present but to lower degree in the WWoE
• Degree of autistic traits inversely associated with folate
concentrations (17-19 weeks GA) and folic acid doses.
• 60.4% were on folic acid >0.4 mg per day

Bjork M, Gilhus NE, JAMA Neurol, epub 12/28/2017. Neurology

•
•

Risks of Seizures versus

•

Antiepileptic Drugs
•

•
•

J Perinat Med Neurology Arch

Neurol

ffects of with G in re nancy

• Studies report that 2 -5 % of women ha e

seizure worsenin durin pre nancy compared to
aseline

• epends on se eral factors

•
•
•
•
•
•
•

5
 11/28/2018

Clearance

aily dose (m / )

concentration (m / )

Pennell PB. Neurology. 2003;61(6 Suppl 2):S35-42.

S eizure F requency

0.25

0.2

Proportion ofpatient
)/(m / )

0.15

N 3 5 samples 0.1
53 re nancies
0.05
(m /

0
1 2 3 4 5 6 7 8 9 10 PP1 PP2 PP3

M onth

Increased seizures,all-types D oubled seizures,all-types

Increased G TC S z's D oubled G TC S z's

•
•
Pennell PB, et al. Neurology, 2008. Funded by NIH P50 MH68036.
Pennell PB, et al. Neurology 2008. Supported by NIH P50 MH68036.

Post hoc Early ncreases in L learance y mean in the

st rimester

op.
219%

op
21%

Annals of Clin & Translational Neurology 2014

Birnbaum A, Pennell PB, French JA, Harden CL, P‐PEP, Annals of eurology, 2018.
 11/28/2018

Mean elative and PM learance y

Mean elative Levetiracetam learance y rimester
rimester
2.5
2
P 0.02 for each trimester P 0.05 for trimesters 2 & 3

2
Relative Clearance

1.5

Relative Clearance
1.5

1
1
O C
LEV Research Values
TPM
LEV Clinical Values
0.5 0.5
Baseline TM1 TM2 TM3 baseline TM1 TM2 TM3

Neurology .
Neurology .

atio to arget oncentration in Sz orsening

roup vs Sz Sta le mproved roup
•

•
•
•

Ohman, Epilepsia 2004; De Haan, Neurology 2004; Pennell PB, Neurology 2008.;
Neurology . Annals Clin & Trans Ngy 2014

Maternal Outcomes &

Neurodevelopmental Effects of Anti-
Epileptic Drugs

NEAD study and Breastfeeding

• re nant omen with pilepsy

• re nant healthy controls

Non-pre nant

Multiple-PIs:
Kimford Meador, MD (Stanford)
• Page B. Pennell, MD (BWH)

Obstetrics Core:
My Suggested Strategy T. McElrath (BWH), M. Druzin (Stanford)
modelin
Neonatal Core: L. Van Marter (BWH)
Semiology Core: J. French (NYU)
• Mood Core: Z. Stowe (U Arkansas)
in utero
Mea or, et al. JAMA Pediatrics, 201 .
 11/28/2018

Prescribing Patterns in
Pregnant Women with
Epilepsy at MONEAD sites ercenta e of omen remainin Seizure- ree
1 %

% 88.6%
85. % 86. %
84. %

8 %
Generalized seizures ocal seizures nclassified
7 %

6 %

5 %
Su ects

4 %

3 %
No. of

2 %

1 %

%
Seizure-free durin pre nancy/ months Seizure-free months postpartum/ next months
G G ther C NS C C ther N
olyRx onoRx
Com os

Meador KJ, Pennell PB, May RC, et al. Epilepsy & Behavior, 2018.

Chan es in re imens y eli ery/ months

P E n

Car amazepine henytoin

amotri ine
xcar azepine heno ar ital alproic acid
P E n e etiracetam
onisamide opiramate

ncreasin Ris

Impact on Clinical Care and Practice

• Preconception
• Transition to AED with favorable teratogenic profile
• Establish individual target concentration
• Lower dose of possible (e.g., after D/C of OCs,); use ER formulations BID
• Pregnancy
• Monthly AED levels for therapeutic drug monitoring
• Adjust dose for seizures, SEs, and to maintain RTC 0. 5
• Team approach with OB
• Postpartum
• Adjust dose to (slightly above) pc baseline over 2 weeks – 3 months,
• Breastfeeding plan when desired
• Educate about importance of sleep, clinical signs of medication toxicity

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ANTICONVULSANTS AND SKIN Disclosure

HYPERSENSITIVITY
JEANNE YOUNG, MD, FAAD I (and my co‐authors) have nothing to disclose.
UNIVERSITY OF VIRGINIA HEALTH SYSTEM

Learning Objectives

• Recognize some common and some less common but more serious
hypersensitivity reactions associated with anticonvulsant medications
• Distinguish between hypersensitivity reactions based on
pathophysiologic mechanisms and clinical presentation
• Identify clinical features of drug hypersensitivity reactions that could
indicate a severe cutaneous adverse reaction

Bolognia, J. L., Jorizzo, J. L., & Schaffer, J. V. (2012). Dermatology, 3e (Bolognia, Dermatology).

CELL MEDIATED (DELAYED‐TYPE) MEDICATIONS AND SKIN HYPERSENSITIVITY

• A. Th1 immune mediated reaction‐ monocytes are preferentially • Benign Exanthems • Fixed Drug Reaction
recruited and activated by IFN‐ , leading to CD8 T‐cell activation
and a pro‐inflammatory response (TNF, IL‐12) • Urticaria • DRESS
• B. Th2 immune mediated reaction‐ eosinophils are preferentially
recruited and activated in part by IL‐4, ‐5, ‐13 and eotaxin (DRESS) • Erythema Multiforme
• C. Cytotoxic immune mediated reaction‐ CD4 and CD8 T cells • SJS/TEN
with release of perforin and granzyme B and/or Fas–FasL
interactions (SJS/TEN)
• D. Neutrophil and T‐cell based immune reaction ‐ mediated via
chemokines (e.g. C CL8) and cytokines (e.g. GM‐CSF) (AGEP)

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MORBILIFORM DRUG ERUPTION

• Primary pathomechanisms
immunologic: complex and cell Photo not available Photo not available
mediated
• Erythematous macules and
papules, often confluent
• Dependent areas can have
petechial/purpura
• Low grade fever and pruritus can
be present
• iming is days after initiation
of drug, more immediate on
rechallenge

MANAGEMENT SIGNS OF SCAR

• Topical steroids, antihistamines, emollients
• Edema of the face (angioedema vs DRESS)
• /‐ Cessation of offending drug
• Pustules
• May need to “treat through”
• Vesicles
• Can re‐challenge
• Dusky or painful lesions
• Mucous membrane involvement
• Signs of systemic involvement:
(fever/eosinophilia/transaminitis/atypical lymphocytes/AKI)

URTICARIA URTICARIA VS ERYTHEMA MULTIFORME

• ‐IgE mediated reaction, Photo not available
10 drug Photos not available
• ‐Erythematous, edematous
dermal papules and pla ues
• ‐Lesions appear within
minutes to 1 hour after
drug administration
• ‐ ndividual lesions come and
go ithin hours
• ‐Angioedema 50
Shah, Kara N., Paul J. Honig, and Albert C. Yan. ediatrics11 .5 (200 ): e11 ‐e1183.

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Drug Reaction with Eosinophilia and Systemic

MANAGEMENT
• Cessation of offending drug
• Antihistamines (high dose)
• Systemic steroids
• Subcutaneous epi in life threatening
angioedema/anaphylaxis
Symptoms (DIAS, DIDMOHS)
• 1 in 10,000 exposures to drugs
• Timing 2‐ weeks after drug exposure
• Fever (85 )
• Morbiliform eruption ( 5 ) that becomes edematous,
often has follicular accentuation
• Edema of face is HALLMARK
• 10 mortality, primarily liver failure

ommon culprits

Photos not available

•
•
•
•
•

DRESS

Roujeau, Jean‐Claude, et al. ermatol inica 2 .2 (200 ): 203‐

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PATHOMECHANISMS
• Eosinophil activation induced by IL5 which is generated from drug‐
specific CD4 and CD8 T cells

• Viral reactivation is associated with DRESS (HHV / , CMV, EBV),

? Pathologically involved

• Certain HLA subtypes associated with increased risk

• Genetic polymorphisms that affect detoxification of anticonvulsants

have been identified in patients recovering from DRESS White, Katie D., et al. Allergy Clin Immunol ract (1) (2018): 38‐ .

MANAGEMENT TO IC ERYTHEMAS
• Immediate cessation of offending drug

• /‐ Steroids (no good data) • Generalized Bullous Fixed Drug Reaction

Symptoms often recur with tapering so if using, taper slowly
• Erythema Multiforme
• /‐ IVIG (no good data)
• Stevens Johnson Syndrome
• Mean time of recovery is wks
• Toxic Epidermal Necrolysis
• No clear features of poor prognosis though several suggested:
Allopurinol as the offending drug
Pancytopenias
Multiorgan involvement
CRI

FI ED DRUG REACTION
‐First exposure: 1‐2 weeks Photo not available Photos not available
‐Re‐exposure 48 hrs
‐sulfonamides, tetracycline,
barbiturates, carbamazepine
‐Erythematous to dusky pla ue
with central bulla/erosion
‐Heals with post‐inflammatory
hyperpigmentation

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PATHOMECHANISM

Photos not available • Resident CD8 T cells with effector‐memory phenotype at

the site of reaction
• IFN‐gamma, perforin, FasL
• CD4 FoxP3 regulatory T cells abundant in FDE lesions
• ? Viral influence

TO IC ERYTHEMAS EM : TYPICAL VS ATYPICAL SKIN LESIONS

• Erythema Multiforme (acral or minor) – target lesions and 0‐10
epidermal detachment, no or limited mucosal disease Photos not available
• Erythema Multiforme (disseminated or major) – target lesions and 0‐10
detachment throughout body, ( /‐Mucosal disease)

• Stevens‐Johnson Syndrome – Mucosal disease and 0‐10 detachment

• Overlap SJS‐TEN – Mucosal disease and 10‐30 detachment
• Toxic Epidermal Necrolysis ‐ 30 detachment

ERYTHEMA MULTIFORME MANAGEMENT

• Viral ‐ 0 ‐ HSV 1/2 • Treat for HSV if evidence of disease

• Drug (unusual) • Otherwise, take off drug
• CTD culprits (Rowell’s syndrome) (rare) • High risk for progression to systemic disease if
• Virus specific CD4 cells IFN‐gamma persistently exposed
• Drug specific CD8 TNF‐alpha (Kokuba, H., Aurelian, L. and Burnett, J., • If recurrent outbreaks, may consider acyclovir in absence
1 . ournal of investigative
dermatology, (5), pp.808‐815) of clinical HSV

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STEVENS‐JOHNSON SYNDROME TO IC EPIDERMAL NECROLYSIS

• Toxic Erythema with extensive mucosal involvement • 0.4‐1.3 cases/million/year

• Usually about 10 involvement • Prodrome, rapidly progressive
• May have systemic symptoms • Blistering, red, tender skin
• Must stop the offending drug immediately • Nikolsky sign
• High risk of progression into full‐thickness des uamation • 30 including genital, nasal, esophagus, intestinal tract
• Most often, inpatient admission needed and respiratory epithelium
• Role for higher dose oral steroid therapy • Glomerulonephritis, hepatitis, hematologic complications

PATHOMECHANISM

• Cytotoxic immune mediated reaction‐ CD4 and CD8 T

cells with release of perforin and granzyme B and/or Fas–
FasL interactions (SJS/TEN)
• CD8 T cells, NK cells and NK T cells‐ derived granulysin
Serum granulysin and IL‐15 may prove useful as prognostic
markers in acute SJS/TEN
White, Katie D., et al. Allergy Clin Immunol ract (1) (2018):
• Regulatory T cells are notably diminished early in the
38‐
course of SJS/TEN

PATHOGENESIS

• HLA‐B12
• HLA‐B 5801 for allopurinol
• HLA‐B 1502 for carbamazepine
• HLA‐DQB1 0 01 ocular involvement
• Infections (HSV, HIV, Mycoplasma)
• Immunizations
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Algorithm for Drug Causality in TEN score

MEDICATIONS
(ALDEN)
• Relevant exposure window (4‐28 d)
• Recent start of drug intake (without prior use)
• Drug notoriety
• Half life of active substances
Specific for SJS/TEN and re uires clear dx before
application

SCORTEN Prognosis

MANAGEMENT IMPORTANT POINTS

• Supportive care • Most drug reactions are fairly benign and “treating through”
• Immediate cessation of medication
is a potential option
• Signs/symptoms of more concerning reaction include fever,
• Treatment of culprit infections facial swelling, lymphocyte activation, blisters or pustules,
• Cyclosporine (3‐4 mg/kg/day), cyclophosphamide (100‐300 mucosal involvement, signs of systemic organ involvement
mg/day), plasmapheresis, N‐acetylcysteine (2g/ hr) • Severe cutaneous adverse reactions re uire immediate
• Steroids (?) cessation of offending medication and often hospitalization
• Thalidomide (?) • Immune and idiosyncratic mechanisms play a role in most
SCARs
• IVIG (1 g/kg/day)
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