Download Identifying Candidates for VNS Therapy®

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
1
• Hormonal contraception
2
• Menstrual cycle regularity
3
• Fertility and ovulatory function
4
• Pregnancy/breastfeeding
5
• Sexuality
6
• Bone health
Epilepsy – What Can We Do?
DIAGNOSIS
THERAPY
•
•
•
History
Neuroimaging
•
•
Electrophysiology
•
•
•
•
•
EEG is mainstay
High density EEG
Magnetoencephalography
Intracranial EEG
•
•
•
•
Cognitive Assessments
•
•
Neuropsychological testing
Wada procedure
•
•
Vagus Nerve Stimulator
Deep Brain Stimulation
Reactive Neurostimulation
Immunomodulation
•
•
•
fMRI – BOLD changes
SPECT – perfusion
PET – glucose metabolism or other ligands
Anti-epileptic drugs
Neuromodulation
•
•
•
“Functional” Imaging
•
•
•
•
MRI is mainstay
AEDs
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®)
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®)
Gabapentin (Neurontin®)
Topiramate (Topamax®)
Zonisamide (Zonegran®)
Key: Generic (Brand Names)
Treatment Goals for Epilepsy*
Newly Diagnosed
Refractory Epilepsy
AED Trial 1 Monotherapy
Video EEG
AED Trial 2 Monotherapy
or Polytherapy
Epilepsy Surgery
VNS Therapy
AEDs (Polytherapy)
Ketogenic Diet
Treatment Goal
Treatment Goal
Seizure freedom
Maximize QoL
Long-term seizure control
Minimize AED side effects
Maximize adherence
* 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.
Considerations in
Epilepsy Management
Underlying
Pathology
Age and
Gender
Syndrome
vs
Seizure Type
Comorbidities
Medication
Side Effects
Seizure
Frequency
Reproductive Endocrine Axis
Disturbances
• Hypothalamus
Amygdala
Hypothalamus
GnRH
Pituitary
LH/FSH
Liver
Gonads
Estrogen
Progesterone
Testosterone
– 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
Polycystic ovaries
Sex hormone level
alterations
Menstrual cycle
abnormalities
Anovulatory cycles
Fertility
Associated with
some AEDs
Mixed reports
Yes
Yes
Yes
Yes
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 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):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
Carbamazepine
Felbamate
Oxcarbazepine*
Phenobarbital
Phenytoin
Topiramate*
Lamotrigine
*At higher dosage.
No Interaction
Gabapentin
Lacosamide
Levetiracetam
Tiagabine
Valproate
Zonisamide
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.
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.
bCramer
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 & 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
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.
2.
3.
4.
5.
Yerby MS, et al. Epilepsia. 1985;26:631-635.
Frederick J. Br Med J. 1973;2:442-448.
Kohler HG. Lancet. 1966;1:267.
Bjerkedal T, Bahna SL. Acta Obstet Gynecol Scand. 1973;52:245-248.
Waters CH, et al. Arch Neurol. 1994;51:250-253.
Major Malformations Associated
with Commonly Used AEDs
Phenytoin
Phenobarbital
Valproic
Acid
Cardiac
defects
Yes
Yes
Yes
Orofacial
clefting
Yes
Yes
Yes
GU defects
Yes
Drug
Yes
NT defects
Dysmorphic
syndrome
Yes
GU=genitourinary; NT=neural tube
Carbamazepine
Yes
Yes
Yes
Yes
Yes
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
Breastfeeding and AEDs
1.
2.
•
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;51:949-956.
Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 1998;51:944-948.
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
Valproate
Neutral
Lamotrigine
Loss
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.
Dimensions of Refractory Epilepsy
Intractable
seizures
Neurobiochemical
changes
Excessive
drug burden
Cognitive
decline
Unsatisfactory
quality of life
Increased
mortality
Restricted
lifestyle
Overall quality of life is a
fundamental measure of
successful treatment in
patients with epilepsy
Psychosocial
dysfunction
Dependent
behavior
Kwan P and Brodie MJ. Seizure. 2002;11:78.