1. Epilepsy Across the Reproductive Years
Blanca Vazquez, MD
Director of Clinical Trials
Director of International Program
NYU Epilepsy Center
NYU Medical Center
New York, NY

2. Epilepsy in Women 1 2 3 4 5 6 Hormonal contraception
Menstrual cycle regularity 3
Fertility and ovulatory function 4
Pregnancy/breastfeeding 5
Sexuality 6
Bone health

3. Epilepsy – What Can We Do?
Diagnosis
therapy
History
Neuroimaging
MRI is mainstay
Electrophysiology
EEG is mainstay
High density EEG
Magnetoencephalography
Intracranial EEG
“Functional” Imaging
fMRI – BOLD changes
SPECT – perfusion
PET – glucose metabolism or other ligands
Cognitive Assessments
Neuropsychological testing
Wada procedure
AEDs
Anti-epileptic drugs
Neuromodulation
Vagus Nerve Stimulator
Deep Brain Stimulation
Reactive Neurostimulation
Immunomodulation
Steroids
Intravenous Immunoglobulin (IVIG)
ACTH (which is probably more than just immune)
Plasma Exchange (PLEX)
Epilepsy Surgery
Diet

4. Video EEG Monitoring

5. What are some of the AEDs that are currently available?
First Generation AEDs
Second Generation AEDs
Carbamazepine (Carbatrol®,
Carbatrol® XR, Tegretol®, Tegretol XR®)
Felbamate (Felbatol®)
Gabapentin (Neurontin®)
Clonazepam (Klonopin®)
Lacosamide (Vimpat®)
Ethosuximide (Zarontin®)
Lamotrigine (Lamictal®)
Lorazepam (Ativan®)
Levetiracetam (Keppra®, Keppra® XR)
Phenobarbital (Luminal®)
Oxcarbazepine (Trileptal®)
Phenytoin (Dilantin®, Phenytek®)
Pregabalin (Lyrica®)
Primidone (Mysoline®)
Rufinamide (Banzel®)
Valproate (Depakote®, Depakene®)
Tiagabine (Gabitril®)
Topiramate (Topamax®)
Zonisamide (Zonegran®)
Key: Generic (Brand Names)

6. Treatment Goals for Epilepsy*
Newly Diagnosed
Refractory Epilepsy
AED Trial 1 Monotherapy
Video EEG
VNS Therapy AEDs (Polytherapy) Ketogenic Diet
AED Trial 2 Monotherapy or Polytherapy
Epilepsy Surgery
Goal of this slide is to distinguish the treatment goals for patients with refractory epilepsy versus newly diagnosed/surgical candidates. Seizure freedom is not the likely outcome and, therefore, other quality of life enhancing factors play more of role.
For patients still having seizures, factors other than seizure frequency are more predictive of improved quality of life
Depression
Mood
Adverse AED side effects
Treatment Goal
Maximize QoL
Long-term seizure control
Minimize AED side effects
Maximize adherence
Treatment Goal
Seizure freedom
* Kwan P, et al. Epilepsia 2009; doi: /j x Gilliam F. Neurology 2002;58:s9-s19. Wheless JW. Neurostimulation Therapy for Epilepsy. In: Wheless JW, Willmore LJ, Brumback RA, eds. Advanced Therapy in Epilepsy. Hamilton, Ontario: BC Decker, Inc Faught E, et al. Epilepsia 2009;50(3):

7. Considerations in Epilepsy Management
Underlying Pathology
Age and Gender
Syndrome vs Seizure Type
Comorbidities
Seizure Frequency
Medication Side Effects

9. Reproductive Endocrine Axis Disturbances
Hypothalamus
Altered secretion of GnRH
Pituitary
Altered LH release
Gonadal
Altered steroid metabolism/binding
GnRH=gonadotropin-releasing hormone; LH=luteinizing hormone; FSH=follicle-stimulating hormone
Hypothalamus
Amygdala
GnRH
Pituitary
LH/FSH
2001 Novartis Core T3
Martha J. Morrell M.D.
Liver
Gonads
Estrogen
Progesterone
Testosterone

10. Sex Steroid Hormones and Epilepsy
Progesterone may be an anticonvulsant
Increases inhibition at GABAA receptor
Attenuates excitation of glutamate in hippocampus
Alters mRNA for GAD and increases GABA synthesis
Estrogen may be a proconvulsant
Reduces inhibition at GABAA receptor
Alters mRNA for GAD and inhibits GABA synthesis
GABA = -aminobutyric acid; mRNA = messenger ribonucleic acid;
GAD = glutamic acid decarboxylase.
Morrell MJ. Neurology. 1999;53(suppl 1):S42-S48. Woolley CS, Schwartzkroin PA. Epilepsia. 1998;39(suppl 8):S2-S8.

11. Reproductive Problems and AEDs
Associated with some AEDs
Polycystic ovaries
Mixed reports
Sex hormone level alterations
Yes
Menstrual cycle abnormalities
Anovulatory cycles
Fertility

12. Polycystic Ovary Syndrome NIH Diagnostic Criteria
Presence of ovulatory dysfunction, polymenorrhea, oligomenorrhea, or amenorrhea
Clinical evidence of hyperandrogenism and/or hyperandrogenemia
Exclusion of other endocrinopathies (eg, Cushing syndrome, hypothyroidism, late-onset congenital adrenal hyperplasia)
PCOS: National Institutes of Health Diagnostic Criteria.
In the United States, PCOS is defined with diagnostic criteria developed by the National Institutes of Health (NIH) as an ovulatory dysfunction with clinical evidence of hyperandrogenism and/or hyperandrogenemia.3,4 For the condition to be diagnosed, related disorders, such as those that affect adrenal or thyroid function (eg, androgen-secreting neoplasms), must be excluded.1-3 The diagnosis of PCOS is generally made through a combination of clinical, ultrasonographic, and biochemical criteria.2
This definition excludes the finding of polycystic ovaries (PCO), multifollicular ovaries, or hyperandrogenism in isolation.
Outside of the United States, the diagnosis is usually based on ovarian morphology, and affected women may be further subgrouped by ovulatory status. Because the anovulatory subgroup may demonstrate more profound insulin resistance, differences in diagnostic criteria may explain many of the divergent findings between US and European studies of patients with this disorder.3
References
1. Bauer J, et al. Epilepsy Res. 2000;41:
2. Chappell KA, et al. Ann Pharmacother. 1999;33:
3. Dunaif A, et al. Annu Rev Med. 2001;52:
4. Duncan S. Epilepsia. 2001;42(suppl 3):60-65.
Duncan S. Epilepsia. 2001;42(suppl 3):60-65.

13. Clinical Features of PCOS Hyperandrogenism
Symptoms may include:
Hirsutism
Acne
Male pattern balding and/or male distribution of body hair
Hirsutism
Clinical Features of PCOS. Hyperandrogenism.
Hyperandrogenemia is a key feature of PCOS, and it may appear as hirsutism, acne, male pattern balding, and/or male distribution of body hair.1
Reference
1. Lobo RA, et al. Ann Intern Med. 2000;132:
Acne
Lobo RA, et al. Ann Intern Med. 2000;132:

14. Evaluation of Ovulatory Failure Predictors
Predictors included:
Primary generalized epilepsy
Use of valproate ever or within the past 3 years
High free testosterone
Fewer numbers of LH pulses
Valproate use in primary generalized epilepsy (19/35) was associated with:
Relatively increased free testosterone
Anovulatory cycles
Morrell M, et al. Ann Neurol. 2002;52(6):

15. AEDs and Contraception
High potential for interaction between some AEDs and oral contraceptives (OCs) since both utilize isoenzyme CYP 3A4
OCs are metabolized by liver, highly protein-bound and have low and variable bioavailability
Inducing effects of some AEDs on estradiol and progesterone may explain OC failure

16. Contraception Choices for Women with Epilepsy
Hormonal contraception
Contraceptive pills
Injectables and depots
Patches
Rings
Barrier methods
Intrauterine contraceptive devices (IUCDs)
Surgical sterilization
Natural methods

17. Family Planning for Women on Antiepileptic Drugs (AEDs): Interaction With Hormonal Contraception
Possible Interaction No Interaction
Carbamazepine Gabapentin
Felbamate Lacosamide
Oxcarbazepine* Levetiracetam
Phenobarbital Tiagabine
Phenytoin Valproate
Topiramate* Zonisamide
Lamotrigine
*At higher dosage.

18. Catamenial Seizures
Changes in seizure patterns may begin with hormonal fluctuations at menarche and continue during the menstrual cyclea,b
30%-50% have epileptic patterns that correspond to their menstrual cycleb,c
Vulnerability to seizures is highest just before and during flow and at ovulation (relatively high estrogen and low progesterone levels)
aHerzog AG, et al. Epilepsia. 1997;38:
bCramer JA, Jones EE. Epilepsia. 1991;32(suppl 6)S19-S26.
cMorrell MJ. In: Wyllie E, ed. The Treatment of Epilepsy: Principles and Practice. 2nd ed. Baltimore, Md: Williams & Wilkins; 1997:

19. Treatment of Catamenial Epilepsy
Difficult to control with AEDs
Increasing doses of AEDs premenstrually may be beneficial
Important to monitor serum levels to avoid under- or overdosing
Acetozolamide of limited benefit
Natural progesterone for women with regular menses

20. PREGNANCY & EPILEPSY Clinical Dilemma
Drugs generally contraindicated in pregnancy
Women with epilepsy are unable to stop using AEDs
Increases risk of seizures
Injury
Miscarriage
Developmental delay
Loss of job or driving privileges
Risk of cognitive decline
Complications of pregnancy and labor
Risk of congenital malformations may be increased by AED therapy

21. Pregnancy Complications in Women With Epilepsy
Eclampsia1
Increased rate of obstetric intervention (such as C-section)1
Increased birth asphyxia2
Neonatal hemorrhage3
Increased perinatal mortality2,4,5
Yerby MS, et al. Epilepsia. 1985;26:
Frederick J. Br Med J. 1973;2:
Kohler HG. Lancet. 1966;1:267.
Bjerkedal T, Bahna SL. Acta Obstet Gynecol Scand. 1973;52:
Waters CH, et al. Arch Neurol. 1994;51:

22. Major Malformations Associated with Commonly Used AEDs
Drug
Phenytoin
Phenobarbital
Valproic Acid
Carbamazepine
Cardiac defects
Yes
Orofacial clefting
GU defects
NT defects
Dysmorphic syndrome
GU=genitourinary; NT=neural tube

23. Congenital Anomalies Associated with Commonly Used AEDs
Dysmorphism ~10%
Dysmorphic features (mid-face)
Hypertelorism
Upturned nasal tip
Flat nasal bridge
Long philtrum
Full lips
Distal digital hypoplasia

24. Fetal Anticonvulsant Syndrome
Not drug specific
Features modify as child grows
Can be seen with newer as well as older AEDs
Lamotrigine, topiramate
Clinically indistinguishable from fetal alcohol syndrome

25. Risk Factors for Major Malformations
Polytherapy
High AED plasma concentrations
Mechanisms
Toxic metabolites
Folic acid deficiency
Epoxide metabolites
Free-radical formation

26. Managing Pregnancy and Epilepsy
Verify need for AED
Diagnosis
Surgical lesions
Remission
Determine “best” AED for individual patient
Preconception teaching
Preconception supplementation

27. Folate and Neural Tube Defect
Numerous studies of vitamin supplementation
Pivotal study1
Supplementation began at least 28 days before conception and continued at least until second missed menses
Fewer malformations in vitamin supplemented group (13.3 vs 22.9 per 1000)
Fewer NTDs in vitamin supplemented group (0 vs 6)
Czeizel AE, Dudas I. N Engl J Med. 1992;327:

28. Folate Supplementation
Centers for Disease Control and Prevention recommends preconceptional folic acid
0.4 mg/d for all women
4.0 mg/d for women with a history of previous NTD

29. What Is the Safest AED in Pregnancy?
No drug without risks
Maternal seizures hazardous
Valproate has an additional risk of developing an NT defect (1%–2%)
Monotherapy (seizure control)
Phenobarbital has no advantage
Choose the best AED for the seizures

30. Breastfeeding and AEDs
Assess risks and benefits for individual patients
AED concentration in breast milk related to protein binding1
PB and other sedating AEDs may cause sedation or poor feeding1
American Academy of Neurology encourages breastfeeding with close observation of baby2
Zahn CA, et al. Neurology. 1998;51:
Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 1998;51:

31. Role of Pregnancy Registries
To facilitate monitoring fetal outcomes of pregnant women1
Systematic epidemiology study2
Collection and assessment of postmarketing data on potential adverse health effects to the mother, fetus, or infant caused by exposure to a drug or other biological agent during pregnancy2
Provides information that can be included in product labeling2
Can assess suspected or unknown risks2
1Lamotrigine [product information]. Research Triangle Park, NC: GlaxoSmithKline, 2003.
2FDA Guidance for Industry: Establishing Pregnancy Registries. Draft Guidance. Accessed June 27, 2002.

32. Effects of AEDs on Body Weight
Weight change important consideration
Leads to health hazards
Impairs body image and self-esteem
Leads to noncompliance
Most data anecdotal
Actual incidence and magnitude unknown
Mechanisms unclear
Biton V. CNS Drugs. 2003;17(11):

33. Effects of AEDs on Body Weight
Gain
Neutral
Loss
Valproate
Lamotrigine
Topiramate
Gabapentin
Levetiracetam
Zonisamide
Carbamazepin
Phenytoin
Felbamate
Pregabaline
Lacosamide

34. Manifestations of Bone Disease
Osteopenia/Osteoporosis
AEDs reported as a secondary cause
Increased rates at multiple sites including hip and lumbar spine
Osteomalacia
Increased osteoid or unmineralized bone
Most studies in institutionalized persons
Confounded by poor diet, inadequate sunlight, limited exercise
Andress DL, et al. Arch Neurol. 2002;59(5):
Farhat G,et al. Neurology. 2002;58(9):
Pack AM, et al. Epilepsy Behav. 2003;4(2):
Sato Y, et al. Neurology. 2001;57(3):
Valimaki MJ, et al. J Bone Miner Res. 1994;9(5):

35. Epilepsy at Menopause Perimenopause Menopause
Fluctuations in ovarian steroid levels may exacerbate or diminish seizuresa,b
Menopause
Seizures may improveb
Improvement most likely in those with catamenial patternb
HRT with menopause may worsen seizuresb
HRT= hormone replacement therapy
aAbbasi F, et al. Epilepsia. 1999;40(2):
bHarden CL, et al. Epilepsia. 1999;40(10):

36. Dimensions of Refractory Epilepsy
Intractable
seizures
Excessive
drug burden
Neurobio- chemical changes
Unsatisfactory quality of life
Restricted lifestyle
Dependent behavior
Psychosocial dysfunction
Cognitive decline
Increased mortality
Overall quality of life is a
fundamental measure of
successful treatment in
patients with epilepsy
Dimensions of Pharmacoresistant Epilepsy
Refractory epilepsy can be classified as a condition with multi-faceted dimensions that affect a patient’s quality of life. Intractable seizures are only 1 dimension of refractory epilepsy affecting patients, including cognitive decline, dependent behavior, psychosocial dysfunction, increased mortality, excessive drug burden, and neurobiochemical changes.1 [Kwan and Brodie 2002, p 77, abstract, lines 1-3, p 78, Table 1; p 77, col 2, para 1, lines 16-19]
Reference
1. Kwan P and Brodie MJ. Seizure. 2002;11:78.
Kwan P and Brodie MJ. Seizure. 2002;11:78.