The document discusses several topics related to neuroendocrinology and the menstrual cycle in females with epilepsy: 1. It describes the interaction between the nervous system and endocrine system, and how hormones can impact seizure frequency in females. 2. Several phases of the menstrual cycle are outlined, and how hormone fluctuations in these phases can influence seizures. 3. Issues females with epilepsy may face related to their reproductive health, bone health, and mental health are summarized. 4. Treatment approaches for catamenial epilepsy are provided, though it is noted this condition remains difficult to control.

1. Samir M Mounir
Lecturer of Pediatrics
Minia University

4.  They differ in regards to both structure and function
 Aristotle (850 B.C.) claimed that males did not "receive
their soul" until 40 days post gestation and females did
not until 80 days.
 Emil Huschke (1854): Frontal lobe size
 Continuum not ended

9.  Interaction between the nervous system and the
endocrine system, even at the level of cells and how
they communicate.
 They act together in a process called neuroendocrine
integration, to regulate the physiological processes.
 Hypothalamus, controls secretion of pituitary gland
hormones and maintains homeostasis, regulating
reproduction, metabolism, eating and drinking
behavior, energy utilization, osmolarity and blood
pressure.
 Ernst and Berta Scharrer are credited as co-founders
the neuroendocrinology

10. Steroid hormones and brain development
Estrogen receptors and gonadal hormone receptors in brain
Estrogen and the female brain
Testosterone and the male brain
Oxytocin and Vasopressin
Neurotransmitters: Differ in male vs female brain

11.  Epilepsy phenotype-genetic
syndromes may remit or
arise
 Changes in AED
pharmacokinetics
 Compliance/seizure

12.  The regular natural change that occurs in the female reproductive system (specifically
the uterus and ovaries) that makes pregnancy possible
 Premenstrual syndrome ( 20 to 30% of women): Symptoms affecting qualify life: Acne,
tender breasts, feeling tired, irritability and mood changes
 Women with neurological and behavioral conditions may worsen at about the same
time during each menstrual cycle (Migraine, epilepsy and depression) may due to
hormonal effects on CNS or thyroid
 The menstrual cycle is fundamentally a neurological event, characterized by a dynamic
interaction of brain neuroendocrine glands and the reproductive end organs.
(Towanabut et al.,1998)
 Menarche: The first period (twelve and fifteen)
 Duration: (21 to 45 days in young women) and (21 to 35 days in adults) an average of
28 days) Menstruation stops occurring after menopause (between 45 and 55 years of
age). Bleeding usually lasts around 2 to 7 days

13.  The menstrual cycle is governed by hormonal
changes.
 The ovarian cycle consists of the follicular phase,
ovulation, and luteal phase
 The uterine cycle is divided into menstruation,
proliferative phase, and secretory phase

14. Menstrual cycle phases:
 The follicular phase: Days 4-10
 The ovulatory phase: Days 11-16
 The luteal phase: Day 17-day 3 of the next cycle.

16.  From Latin: adolescere meaning "to grow up”
 Dictionary: The period in human development that occurs
between the beginning of puberty and adulthood
 Medical Dictionary: The period between the onset of puberty
and the cessation of physical growth; roughly from 11 to 19 years
of age
 Legal Dictionary: That age which follows puberty and precedes
the age of majority; it commences for males at fourteen, and for
females at twelve years completed, and continues till twenty-one
years complete.
 Encyclopedia: Time of life from onset of puberty to full
adulthood. The exact period of adolescence, which varies from
person to person, falls approximately between the ages 12 and 20
and encompasses both physiological and psychological changes

18. ????
◦ Choice of medications
◦ Substance abuse
◦ Sleep deprivation
◦ Compliance to medications
◦ Driving
◦ Sports safety
◦ Choice of profession

20.  Epilepsy prevalence rates are higher in developing
countries.
 Sex differences are not fully established except in
childhood absence epilepsy and juvenile myoclonic
epilepsy (common in girls)
 Social stigma attached to epileptic females In
developing countries
 Females experience changes in seizure frequency and
severity in relation to different phases in the
reproductive cycle: during puberty, over the menstrual
cycle, and during pregnancy and the menopause

21.  Katamenios = “monthly”
 The tendency for increased seizures related to the
menstrual cycle, this may begin with hormonal
fluctuations at menarche and continue during the
menstrual cycle
 Newmark & Penry (1980) defined catamenial epilepsy as
epileptic seizures occurring in women of fertile age
exclusively or significantly more often during a 7-day
period of the menstrual cycle beginning 3 days before
menstruation and ending 4 days after its onset. Seizure
exacerbation also can occur less frequently at other phases
of the menstrual cycle.

22.  There are about 50 million people with epilepsy worldwide,
and approximately 40% of them are females.
 In 1/3 (10% to 70% according to definition criteria) of female
patients there is substantial relationship between seizures and
menstrual cycle
 it is reported that up to one third of female patients with
intractable complex partial seizures may have this condition.
Seizures that tend to cluster in relationship to menstrual periods:
 High levels of estrogen
 Low levels of progesterone
 Fluid and electrolyte imbalance
 Psychological Stress
 Decrease in levels of AEDs

23.  The cause is unknown. May be an epileptogenic process or an exacerbation of
existing epilepsy. No validated model to prove either hypothesis.
 Female hormones change the excitability of the brain and alter the threshold for
seizures
 Changes in estrogens and progesterone (P) levels are the key factor in seizure
exacerbation in both normal females and in females with menstrual
irregularities.
 Estrogens (in particular estradiol (E)) have potent acute and chronic
proconvulsant effects. They exert an excitatory effect on neurons by stimulating
the N-methyl-D-aspartate (NMDA)- type glutamate receptor.
 Progesterone by its chronic effects hyperpolarizes neurons, acting via its
metabolites (allopregnanolone, often referred to a “neurosteroid) as an agonist at
the γ- aminobutyric acid (GABA)-a receptor with a potency almost a
thousandfold greater than that of pentobarbital and greater than the most potent
benzodiazepine, nitroflurazepam.

24.  The catamenial pattern was not affected by the type
of seizure, or its etiology.
 In a normally menstruating female, the surge of
serum estrogen levels at the time of ovulation may be
associated with increased seizure tendency; as may
the fall in serum progesterone levels just before and
during menstruation.
 Seizures in anovulatory cycles increase the infertility.
 Gonadal steroid changes may affect some AEDs
metabolism and serum levels

25. C1 – just before menstruation (steep decline in progesterone)
C2 – just before ovulation ~day 14 (steep elevation in estrogen)
C3- in second half of menstrual cycle
 Anovulatory cycles (ovulation does not occur) are more frequent in women
with epilepsy
 C1 and C3 are associated with a decrease in progesterone levels, while C2
sees an increase in the level of estrogen.
 Frequency of GTC seizures was found to be higher in anovulatory cycles,
which were also associated with an increase in the serum E/P ratio.

26.  History and Clinical Examination
 Seizure diaries
 Hormonal assay

27.  Difficult to control
 Seizure frequency was occasionally decreased at the
menopause or after oopherectomy.

28.  Currently there is no specific treatment for this neuroendocrine condition. Several AEDs
are used.
 Drugs may affect a female’s hormones.
 Bromides were tried by Locock in 1857.
 Acetazolamide became available in n the 1950s, with conflicting views on its
effectiveness.
 Increase in doses of antiseizure medications during particular time of menstrual cycle
(monitor serum levels to avoid under or overdosing).
 Perimenstrual intermittent use of AEDs.
 Clobazam 10 (5-30) mg at night perimenstrually is the simplest and most useful method.
• If this fails, acetazolamide perimenstrually.
• Lastly, hormonal manipulation was considered as a therapeutic intervention. The aim is
either to increase relative progesterone concentrations or to convert anovulatory to
ovulatory cycles.
 Hormonal manipulation (for those with regular menses) could be considered with
perimenstrual medroxyprogesterone, depot progestogen therapy or clomiphene.

29.  Menstrual Irregularities
 Fertility
 Cosmetic side effects
 Bone Disease
 Mental Health
 Sexual Dysfunction
 Contraception and AED’s
 Pregnancy
 Lactation
 Menopause

30.  Including: PCOS, hyperandrogenism, multiple ovarian cysts, anovulatory cycles,
hirsutism and obesity.
 Estimated to occur in one third of epileptic females as compared with 12 to 14%
of females in the general population.
The prevalence of PCOS in epileptic females (4% : 19%)
 Symptoms: Hirsutism, acne. male pattern balding and/or male distribution of
body hair,,,,
 Syndrome is twice as common in women with epilepsy
 Valproic acid causes features similar to PCOS
AEDs have an impact on the menstrual cycle (May be reversible)
 Especially if younger than 20 years,
 With high seizure frequency
 Polytherapy
 Valproate than carbamazepine or lamotrigine

31. Women with epilepsy have fewer children( possible explanations):
 Choice (fear of having child with birth defect)
 Sexual dysfunction
 Women with epilepsy have more frequent anovulatory cycles
 PCOS
 Both epilepsy and AEDs can target the limbic system,
hypothalamus, pituitary, peripheral endocrine glands, liver and
adipose tissue.
 Seizures and/or epilepsy may disrupt hypothalamic function at the level
of GnRH neuronal network leading to endocrine disorders.
 Temporal lobe epilepsy and chronic changes in LH pulse frequency
affecting fertility
Some AEDs decrease efficacy of birth control pills and other hormonal
birth control This may result in birth control failure and unplanned
pregnancy

32.  May lead to poor compliance and loss of seizure control.
 Connective tissue effects & coarsening of features: PHT & PB
 Hirsutism and gingival hyperplasia: PHT
 Hair loss and acne: VPA
 Weight gain: VPA, PGB, GBP, CBZ
 weight loss: Topiramate
 Weight change (important consideration)
◦ Leads to health hazards
◦ Impairs body image and self-esteem
◦ Leads to noncompliance
 Mechanisms unclear

33. Gain Neutral Loss
Valproate Lamotrigine Topiramate
Gabapentin Levetiracetam Zonisamide
Carbamazepin Phenytoin Felbamate
Pregabaline Lacosamide

34. Antiepileptic drugs associated with bone disease
 Phenobarbital, primidone, phenytoin and Carbamazepine
◦ Associated with bone loss and fractures
 Valproate
◦ Associated with bone loss
 Lamotrigine
◦ Not associated with bone loss
 Limited information on new drugs
 More severe with polytherapy and prolonged use

35. Prevention and Treatment:
- Ca, ALP, 25-hydroxy vit D measurement yearly
- Baseline bone density scan
- Eexercise, balanced diet, stop smoking, moderate
caffeine
- Calcium and vitamin D supplements
- Refer for possible treatment to endocrinologist if:
- Osteopenia/osteoporosis
- Abnormal calcium or vit D levels
- Fracture

36.  Psychiatric comorbidity is high in patients with epilepsy (Disease
And/or Drug).
 Increased risk in females, possibly due to the physiological
changes associated with menstruation, pregnancy and menopause.
 The overall prevalence rate (20–60%)
 Depression has a particularly high prevalence rate
 Psychosis has a temporal relationship with seizures and may be
peri-ictal, ictal, postictal and interictal.
 Careful consideration in selection of antidepressants and
antipsychotics due to the effects of on seizure threshold and
interaction with anticonvulsants.

38.  Much has been learned about this
disease, but there is much more
that is yet to be learned.