Epilepsy Across the Reproductive Years
Blanca Vazquez, MDDirector of Clinical Trials
Director of International ProgramNYU Epilepsy CenterNYU Medical Center
New York, NY
Epilepsy in Women
•Hormonal contraception
1•M
enstrual cycle regularity
2
•Fertility and ovulatory function
3
•Pregnancy/breastfeeding
4
•Sexuality
5
•Bone health
6
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
Video EEG Monitoring
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)
Treatment Goals for Epilepsy*
* Kwan P, et al. Epilepsia 2009; doi: 10.1111/j.1528-1167.2009.02397.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. 2008. Faught E, et al. Epilepsia 2009;50(3):501-509.
AED Trial 1 Monotherapy
Treatment Goal Seizure freedom
Treatment Goal Maximize QoL
Long-term seizure control Minimize AED side effects
Maximize adherence
AED Trial 2 Monotherapy or Polytherapy
Newly Diagnosed Refractory Epilepsy
Video EEG
Epilepsy SurgeryVNS Therapy
AEDs (Polytherapy) Ketogenic Diet
Considerations in Epilepsy Management
Age andGender
Seizure Frequency
Underlying Pathology
Comorbidities
Medication Side Effects
Syndrome vs
Seizure Type
LiverGonads
Hypothalamus
Pituitary
EstrogenProgesteroneTestosterone
LH/FSH
GnRH
Amygdala
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
Reproductive Problems and AEDs
Problem Associated with some AEDs
Polycystic ovaries Mixed reports
Sex hormone level alterations
Yes
Menstrual cycle abnormalities
Yes
Anovulatory cyclesFertility
YesYes
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)
Duncan S. Epilepsia. 2001;42(suppl 3):60-65.
Clinical Features of PCOS Hyperandrogenism
♀ Symptoms may
include:−Hirsutism
−Acne−Male pattern balding
and/or male distribution of body hair
Lobo RA, et al. Ann Intern Med. 2000;132:989-993.
Hirsutism
Acne
Evaluation of Ovulatory FailurePredictors
• 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):704-711.
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
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
Family Planning for Women on Antiepileptic Drugs (AEDs): Interaction With Hormonal
Contraception
Possible Interaction No InteractionCarbamazepine GabapentinFelbamate LacosamideOxcarbazepine* LevetiracetamPhenobarbital TiagabinePhenytoin ValproateTopiramate*ZonisamideLamotrigine
*At higher dosage.
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;38:1082-1088.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; 1997:179-187.
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
PREGNANCY & EPILEPSYClinical 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
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
1. Yerby MS, et al. Epilepsia. 1985;26:631-635.2. Frederick J. Br Med J. 1973;2:442-448.3. Kohler HG. Lancet. 1966;1:267.4. Bjerkedal T, Bahna SL. Acta Obstet Gynecol Scand. 1973;52:245-248.5. Waters CH, et al. Arch Neurol. 1994;51:250-253.
Major Malformations Associated with Commonly Used AEDs
Drug Phenytoin PhenobarbitalValproic
Acid Carbamazepine
Cardiac defects
Yes Yes Yes
Orofacial clefting
Yes Yes Yes
GU defects Yes Yes
NT defects Yes Yes
Dysmorphic syndrome
Yes Yes Yes Yes
GU=genitourinary; NT=neural tube
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
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
Risk Factors for Major Malformations
• Polytherapy• High AED plasma concentrations• Mechanisms
– Toxic metabolites– Folic acid deficiency– Epoxide metabolites– Free-radical formation
Managing Pregnancy and Epilepsy
• Verify need for AED– Diagnosis– Surgical lesions– Remission
• Determine “best” AED for individual patient• Preconception teaching• Preconception supplementation
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;327:1832-1835
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
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
1. Zahn CA, et al. Neurology. 1998;51:949-956.2. Quality Standards Subcommittee of the American Academy of Neurology. Neurology.
1998;51:944-948.
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
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):781-791.
Effects of AEDs on Body Weight
Gain Neutral Loss
Valproate Lamotrigine Topiramate
Gabapentin Levetiracetam Zonisamide
Carbamazepin Phenytoin Felbamate
Pregabaline Lacosamide
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):781-786.Farhat G,et al. Neurology. 2002;58(9):1348-1353.Pack AM, et al. Epilepsy Behav. 2003;4(2):169-174.Sato Y, et al. Neurology. 2001;57(3):445-459.Valimaki MJ, et al. J Bone Miner Res. 1994;9(5):631-637.
Intractableseizures
Excessivedrug burden
Neurobio-chemicalchanges Unsatisfactory
quality of life
Restrictedlifestyle
Dependentbehavior
Psychosocialdysfunction
Cognitivedecline
Increasedmortality
Dimensions of Refractory Epilepsy
Kwan P and Brodie MJ. Seizure. 2002;11:78.
Overall quality of life is a fundamental measure ofsuccessful treatment in patients with epilepsy