Hippocrates noted that while epilepsy at birth tended to be resistant to cure, seizures whose origin was in later childhood tended to cease at puberty. Though many seizure disorders improve during puberty, many worsen. In patients with primarily generalized absence seizures, improvement is common; however, a small proportion goes on to develop generalized convulsive seizures at puberty (1). Benign focal epilepsy remits during puberty (2). Photo-sensitive epilepsies generally begin during puberty, as do generalized tonic–clonic seizures on awakening (3,4). Juvenile myoclonic epilepsy also begins at puberty and is more common in girls; in addition, seizures can be more frequent during menses (5). Lennox–Gastaut syndrome often worsens during puberty (6).

PHYSIOLOGY OF SEXUAL MATURATION

At puberty, the hypothalamus begins to secrete gonadotropin-releasing hormone (GnRH) (Figure 43.1). This is carried in the portal circulation to the anterior pituitary, which, in turn, releases follicle-stimulating hormone (FSH). FSH promotes the development of ovarian follicles. The ovarian follicles secrete estrogen. Luteinizing hormone (LH) is also secreted by the pituitary, but, unlike FSH, it has a pulsatile secretory pattern. It promotes maturation of the ovarian follicle and ovulation. The remaining follicular cells then become the corpus luteum, which secretes progesterone. At the point at which the corpus luteum is developed, the follicular phase ends and the luteal phase of the menstrual cycle begins. Progesterone inhibits secretion of GnRH, FSH, and LH. If there is no fertilization, the corpus luteum regresses, and estrogen and progesterone levels decline. With this decline, the GnRH secretion resumes and the cycle repeats.

THE IMPACT OF FEMALE SEX STEROID HORMONES ON SEIZURE OCCURRENCE

Neurosteroids

Neurosteroids are steroid molecules that modulate brain excitability, and therefore can influence seizure occurrence (7). Estrogen and progesterone, the primary reproductive hormones for women, both affect neuronal excitability (8,9). Estrogens potentiate epileptiform discharges on EEG recordings (10), while intravenous progesterone reduces epileptiform spikes in women with epilepsy (WEE) (11). Estrogen has a complex action on neuroexcitability via two avenues. The first is a short-latency, nongenomic effect; this action is rapid in onset, reversible, and dose-related, consistent with a neuronal membrane-mediated effect (12). The second route is a long-latency (hours to days) genomic effect. Like other steroid hormones, estrogen enters passively into the cell where it binds to and activates the estrogen receptor, a dimeric nuclear protein that binds to DNA and controls gene expression. An example of this effect is estradiol-induced increased density of agonist-binding sites on the N-methyl-D-aspartate (NMDA)-receptor complex in hippocampal cells, which occurs after two days of estradiol treatment consistent with a long-latency process (13). Overall, it appears that estrogen can be proconvulsant, although the magnitude of the effect likely varies with dose, acute versus chronic concentrations, and individual susceptibility factors. Progesterone, on the other hand, promotes neuroinhibitory effects primarily through the action of its reduced metabolite, allopregnanolone, as a positive allosteric modulator of gamma-amino-butyric acid (GABA) conductance (14–16). Cyclic surges and decrements in these hormones during the menstrual cycle alter seizure susceptibility in a predictable manner in experimental models of epilepsy (17) but, as is often the case, they have less predictable effects in the individual patient. Catamenial epilepsy is the term used when adolescent and adult women have predictable fluctuations in their seizure frequency in relationship to their menstrual cycles.

FIGURE 43.1 The hypothalamic-pituitary-ovarian axis.

FSH, follicle-stimulating hormone; GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone.

Hormone Fluctuations During the Menstrual Cycle

The average menstrual cycle is 28 days (Figure 43.2). Conventional numbering of the menstrual cycle begins with day 1 as the first day of menstrual flow. In a 28-day cycle, ovulation occurs approximately on day 14 going forward or, even more accurately with variable cycle lengths, 14 days prior to the next menstrual cycle. The menstrual cycle has two phases: the follicular phase (days 1–14) and the luteal phase (days 15–28). During the follicular phase, the ovarian follicles grow and the dominant follicle becomes the ovulatory follicle, which contains the oocyte. On day 14, the oocyte is released (ovulation) and the nondominant follicles degenerate. In the luteal phase, the dominant follicle forms the progesterone-producing corpus luteum. In some menstrual cycles, ovulation does not occur, and the progesterone levels remain quite low. Investigators have reports that anovulatory cycles occur more frequently in women with epilepsy (7). Figure 43.2 shows the fluctuation of estradiol and progesterone levels in normal menstrual cycles as well as in anovulatory menstrual cycles with an inadequate luteal phase.

The neurosteroid influences that promote enhanced seizure susceptibility in catamenial epilepsy therefore likely include: (a) premenstrual withdrawal of the anticonvulsant effects of progesterone and its metabolite neurosteroid, allopregnanolone, mediated through action on GABA_A receptors; (b) the sudden estrogen peak in the days prior to ovulation; and (c) increased frequency of anovulatory cycles due to hypothalamic-pituitary-gonadal axis dysregulation and consequent low progesterone luteal phases.

Catamenial Epilepsy

The term catamenial (from the Greek kata, by; men, month) epilepsy refers to seizure exacerbation in relation to the menstrual cycle. For adolescent females and women with epilepsy, however, there are likely individual susceptibilities to the neurophysiologic effects of the rapid estrogen spike associated with ovulation, as well as the withdrawal effects of progesterone and its metabolite, allopregnanolone. Rather than being a clearly distinct entity, adolescent and adult women with catamenial epilepsy merely have a heightened susceptibility to fluctuating hormonal levels. This increased sensitivity is supported by the fact that women who have a history of catamenial epilepsy are more likely to remain seizure-free and have seizure improvement during pregnancy, a time that both estradiol and progesterone increase dramatically and linearly throughout gestation (7).

Catamenial epilepsy has long been a recognized phenomenon. It is interesting to note that the first anticonvulsant drug, potassium bromide, was introduced to treat “hysterical epilepsy” in women. This term was previously used to describe seizures occurring during menstruation. During a presentation by Dr. Sieveking to the Royal Medical and Chirurgical Society of London on May 11, 1857, Sir Charles Locock commented that he had tried bromide for women with (hysterical or catamenial) epilepsy and had successfully prevented seizures in 13 of 14 patients treated (18). Gowers was the first of the “modern” epileptologists to recognize an association between increased seizures and menstruation (19). Turner reported in 1907, “The relationship between fits and menstruation has been well established” (20). Lennox and Cobb (21) wrote that “it is a well-known fact that many female patients frequently have seizures near their menstrual period.” Subsequent reports were primarily brief case series, and they show significant differences as to whether and to what degree catamenial epilepsy occurred.

FIGURE 43.2 Patterns of catamenial epilepsy.

Day 1 is the first day of menstrual flow and day –14 is the day of ovulation. (A) Normal cycle with normal ovulation. C1 pattern is associated with exacerbation of seizures in the perimenstrual phase, and C2 pattern is associated with exacerbation of seizures in the periovulatory phase. (B) Inadequate luteal phase cycle with anovulation. The C3 pattern is associated with exacerbations beginning day 10 of one cycle through day 3 of the next cycle.

C, catamenial seizure pattern; F, follicular phase; O, periovulatory; L, luteal phase; M, perimenstrual.

Source: Modified and reproduced with permission from Ref. (7). Harden CL, Pennell PB. Neuroendocrine considerations in the treatment of men and women with epilepsy. Lancet Neurol. 2013;12(1):72–83.

Although the phenomenon of a catamenial pattern is well described and appreciated, a precise definition of catamenial epilepsy has been elusive; the length of observation required to make the diagnosis varies widely, many studies document patterns by the retrospective recollection of seizures by patients, and various studies include women with different types of seizures and epilepsy syndromes. All of these factors have contributed to the variability in reported rates of catamenial epilepsy from 10% to 72%.

Defining and Understanding Catamenial Epilepsy

Herzog et al. (22) determined that catamenial seizures occur in three different patterns in their prospective, observational study of women with medically-refractory temporal lobe epilepsy, with uncontrolled complex partial seizures and secondarily generalized seizures (Figure 43.2). They statistically derived the patterns of seizure occurrence throughout the menstrual cycle, and found a near doubling of seizure frequency during three specific portions of the menstrual cycle. Approximately 33% of the women in their study met criteria for at least one catamenial pattern. Some women displayed more than one pattern. The perimenstrual pattern (C1) was the most common and defined as maximum seizure frequency during the perimenstrual phase (days –3 to +3); the periovulatory pattern (C2) was the second most frequently observed pattern, with maximum seizure frequency during the ovulatory phase (days +10 to –13); and the third pattern occurred with anovulatory cycles, noted as the luteal phase pattern (C3), with increased seizure frequency throughout all phases other than the mid-follicular phase (day +10 of one cycle to day +3 of the next cycle) (Figure 43.2). The proposed criterion from this study, that is, doubling of the average daily seizure frequency during predefined menstrual cycle phases, has become the most widely accepted clinical definition in use. However, applying the criterion to an individual cycle is most accurate when it is determined if a cycle is ovulatory or anovulatory (through basal body temperature tracking or day 21 progesterone levels), and is often a requirement for clinical research studies.

The effective treatment of catamenial epilepsy requires precise analysis in the individual adolescent female patient if a catamenial pattern is present, and if yes, which pattern(s) (Figure 43.2)? Some patients have more than one pattern, and the categorization can be improved if markers of ovulation are also assessed by a day 21 progesterone level, LH surge test kits (available over the counter), or by basal body temperature tracking. The first two methods are expensive and not always practical, and the latter is difficult to track accurately on a daily basis over extended periods of time. The present author suggests keeping calendars of menstrual bleeding onset, and seizures by frequency and type, for a minimum of three cycles in order to confirm if a catamenial pattern exists and which one; determination if any cycles were anovulatory is of added benefit. Once a diagnosis of catamenial epilepsy has been established, it is helpful to determine into which catamenial pattern(s) (C1, C2, or C3) the individual patient belongs, and what the level of C1 seizure exacerbation is. Adding to the difficulty of these assessments is the fact that many adolescents in the general population have irregular menstrual cycles, and this is likely even more frequent in adolescent females with epilepsy. Additionally, all of the descriptions of catamenial epilepsy patterns and treatments are in the setting of no systemic hormonal contraceptives

Treatment Options for Catamenial Seizure Patterns

Attempts to use hormonal supplementation for women with catamenial epilepsy has met with mixed results. The use of medroxyprogesterone (MPA) in a pilot study resulted in seizure reduction in 7 of 14 treated women, with overall seizure reductions of approximately 30%. Limitations of this study include that it was open-label, included a variety of seizure types, and had a small number of subjects (23). Other concerns to consider are that MPA has been linked to a higher risk of osteoporosis, as have many antiepileptic drugs (AEDs) (24). Additionally, after cessation of MPA, endogenous hormones can fluctuate more dramatically for several months and, thus, could lead to seizure exacerbation as well as prolonged return to normal fertility. Although no controlled clinical trials are published, some clinicians use a similar strategy of shutting down normal cyclic sex steroid hormone release by prescribing a continuous oral contraceptive pill.

Acetazolamide (AZ) has been used to treat catamenial epilepsy for several decades, although it still has not been evaluated in a randomized trial. Effectiveness at 250 to 500 mg daily from 3 to 7 days prior to menses has been reported (25,26).

Clobazam is the only benzodiazepine formally studied for the treatment of catamenial epilepsy. In a small, double-blind, placebo, crossover study, clobazam (20–30 mg/day) appeared superior to placebo (27). For each subject, the investigators delineated the 10-day period during which several seizures occurred each month for the preceding 6 months, with all beginning sometime between day 7 to day –2. Treatment would begin 2 to 4 days before that individual set point. In many of the patients, treatment was begun earlier than planned because of unpredictable onset of menstruation or the cluster of seizures. In 14 of 18 patients, clobazam was preferred compared to placebo, and many subjects even had complete seizure control during the 10-day treatment phase. However, seizure counts over the entire menstrual cycle were not reported, and in this author’s experience, taking away the catamenial pattern sometimes results in spreading out the same number of seizures more evenly over the whole menstrual month. Clobazam side effects were of low frequency and severity. Other types of benzodiazepines have not been studied formally for the treatment of catamenial epilepsy.

Temporarily increasing the patient’s usual AEDs at specific times in a menstrual cycle is another reasonable, empirical approach, although it is not studied in a formal way. Some AEDs are more likely to be effective and tolerated with this approach; however, phenytoin should not be used in this manner due to the risk of toxicity associated with its nonlinear kinetics.

Herzog and colleagues introduced the concept and tested the hypothesis that cyclic progesterone use may be beneficial for focal seizure control in women with epilepsy. Natural progesterone, unlike synthetic progestins, is metabolized to allopregnanolone, the neurosteroid with anticonvulsant properties. One of the barriers to administration is that progesterone cannot be administered in a typical pill formulation. Two small open-label studies in adult women with focal epilepsy administered natural progesterone as a vaginal suppository or an oral lozenge during certain phases of the menstrual cycle according to the catamenial pattern (28,29). These studies were followed by an NIH-funded, randomized, double-blinded, placebo-controlled multi-center clinical trial (30). Although there was no difference in the primary outcome of the rates of women who had more than 50% seizure reduction (responder rates), and this was still true when considering the catamenial and noncatamenial subjects separately, the authors did find that there were differences in responder rates (37.8% vs. 11.1%, P < 0.05) in the women with a C1 level greater than or equal to 3. In other words, if the average daily seizure frequency was greater than or equal to 3 during menstrual days −3 to +3 compared to the other days of the month, then those subjects were more likely to experience seizure reduction with cyclic progesterone lozenges as adjunctive therapy to traditional AEDs. For women who had a C1 seizure increase of eight-fold or greater, the percent reduction in seizure frequency was approximately 70%. This reinforces the need to obtain clear diary data with both seizures and menstrual bleeding recorded to assess whether an adolescent girl with epilepsy could benefit from cyclic progesterone administration. The dosages of the oral progesterone lozenges used in this study were 200 mg TID from day 14 through day 25 of each cycle, 100 mg TID for days 26 and 27, 50 mg TID on day 28, and then discontinued. Infrequent side effects of natural progesterone are breast tenderness, fatigue, depressed mood, and vaginal spotting.

When considering treatments, AEDs are the first line of defense, and their use should be maximized before alternative therapies are considered. Adjunctive therapies can be considered according to the treatment algorithm in Figure 43.3. Catamenial epilepsy represents a challenge for epileptologists. It is hoped that with more research into the mechanisms by which hormones effect seizures, better therapies may result.

REPRODUCTIVE FUNCTION IN FEMALES WITH EPILEPSY

It has been reported that fertility is decreased in WWE (31–34). This may be due to alterations in hypothalamic functioning related to epilepsy, which may be influenced by seizures (35,36). However, the specific factors or characteristics that would predict a greater likelihood of infertility are at present unknown due, in large part, to the fact that there have been no published, long-term prospective studies.

FIGURE 43.3 Treatment algorithm for catamenial C1 pattern of seizures.

AEDs, antiepileptic drugs; IM, intramuscularly; PHT, phenytoin.

Note: Most treatments are for focal-onset seizures in women with regular menses. C1 level 3 = three times more seizures on days 25–3 compared to other days of the month.

*If menses start before day 26, start dose tapering on that day according to the same pattern of decreases.

^{^}Treatment strategies used in clinical practice but not supported by data from randomized controlled trials.

^#Increased risk of osteoporosis and slow return to normal fertility.

Source: Reproduced and adapted with permission from Ref. (7). Harden CL, Pennell PB. Neuroendocrine considerations in the treatment of men and women with epilepsy. Lancet Neurol. 2013;12(1):72–83.

Increased rates of polycystic ovary syndrome (PCOS), decreased libido, and decreased fertility have been described in women of reproductive age with epilepsy (37,38). Regions of the limbic cortex, particularly the amygdala, have extensive reciprocal connections with the hypothalamus and can modulate the hypothalamic-pituitary-gonadal axis (Figure 43.1) (7). GnRH is produced primarily in the preoptic area of the hypothalamus and modulates gonadal sex steroid hormonal activity via pulsatile secretion and stimulation of pituitary hormone release. Abnormal release of FSH and luteinizing hormone (LH) has been described in women with epilepsy (7), and animal studies have demonstrated that the GnRH cell population is vulnerable to injury by seizures (39,40). In adult female patients with temporal lobe epilepsy, lateralization of the seizures associates with specific types of reproductive dysfunction. In an investigation of 30 women with complex partial seizures and evidence of reproductive endocrine disorders, left-sided temporal lobe discharges were associated with PCOS, and right-sided discharges with hypogonadotropic hypogonadism (41).

AEDs can also affect reproductive hormones, both endogenous and exogenous hormone levels. In general, AEDs that induce hepatic metabolic enzymes are labeled enzyme-inducing AEDs (EIAEDs) and directly alter reproductive hormone levels. Most of these AEDs also increase production of sex hormone binding globulin (SHBG), thereby reducing biologically active (free) reproductive hormone serum levels (42–44).

Although the mechanism is not completely understood, valproate (VPA) is in general associated with increased testosterone levels, possibly through induction of androgen synthesis in the ovary as well as alteration of hepatic steroid hormone metabolic pathways (7). For women with epilepsy or bipolar disorder, VPA appears to promote hyperandrogenism as well as anovulation and cystic ovaries. Human studies with other AEDs include reports of low total testosterone levels and free androgen indices in women taking carbamazepine or oxcarbazepine (45–47).

Findings from epidemiologic studies vary, with some reporting that women with epilepsy have only one-third of the birth rates of women in the general population. However, some studies report minimal differences (31–34), although social factors and patient choice could not be factored into these studies. The problem of infertility in WWE is therefore complex. There are multiple factors—seizure type, frequency, and the site of ictal onset, as well as AEDs—that may affect an individual patient.

Polycystic Ovarian Syndrome

PCOS is a common hormone disorder that affects 5% to 20% of women, depending on the criteria used. Varying expert-based diagnostic criteria utilize some combination of oligo-ovulation, hyperandrogenism, and the presence of polycystic ovaries (48). The pathophysiology involves abnormal gonadotropin secretion from a reduced hypothalamic feedback response to circulating sex steroids, altered ovarian morphology and functional changes, and disordered insulin action in a variety of target tissues. The enlarged ovaries contain multiple small cysts and a hypervascularized, androgen-secreting stroma leading to the associated signs of androgen excess (hirsutism, alopecia, acne), obesity, and menstrual-cycle disturbance (oligomenorrhea or amenorrhea).

The definition of PCOS has been a source of debate. Minimal diagnostic criteria were defined by a 1990 NIH Consensus Panel: (a) menstrual irregularity, and (b) biochemical or clinical evidence of hyperandrogenism, with (c) exclusion of other diseases that could cause female hyperandrogenism (such as congenital adrenal hyperplasia). These North American minimal criteria did not include the need to identify the polycystic component of the ovaries by ultrasound. The signs and symptoms expressed by women with polycystic ovaries in particular vary substantially. One study reported descriptive findings in a population of 1,741 women who had polycystic ovaries on ultrasound (Table 43.1) (49).

In 2003, the Rotterdam consensus (primarily European and American investigators) expanded the diagnostic criteria to require only two or more of the following features: (a) clinical or biochemical hyperandrogenism; (b) oligo-anovulation; and (c) polycystic ovaries (50). An expert panel from the 2012 NIH Evidence-Based Methodology Workshop on PCOS recommended that clinicians use the more recent Rotterdam criteria for diagnosis (48). Consequently, the 6% to 10% prevalence of PCOS (as defined by 1990 NIH criteria) has doubled under the broader Rotterdam criteria (51). Evidence is strong that women with 1990 NIH-defined PCOS (with hyperandrogenism and oligo-ovulation) are at increased risk of developing reproductive and metabolic abnormalities, including infertility, cardiovascular disease, and type 2 diabetes mellitus (48).

The diagnosis of PCOS in perimenarchal girls remains problematic due to the overlap of stigmata of PCOS with normal pubertal maturation; in fact, there is no adolescent-specific definition for PCOS (52). Carmina et al (53) published criteria to diagnose PCOS in adolescents with the aim of avoiding over-diagnosis of this condition (Table 43.2). These authors recommend that all three of the following findings be present to make a definitive diagnosis: hyperandrogenism, chronic anovulation, and polycystic ovaries. The authors suggest that if only two of the criteria are present the adolescent should be closely followed and re-evaluated for PCOS if the characteristics do not resolve. Additionally, the criteria include the requirement that menstrual irregularities are persistent 2 years post-menarche, and that pelvic ultrasound findings are consistent with increased ovarian volume (>10 cm ³) (53).

TABLE 43.1

Source: From Ref. (49). Balen AH, Gonway GS, Kaltsas G, et al. Polycystic ovary syndrome: the spectrum of the disorder in 1741 patients. Hum Reprod. 1995;10(8):2107–2111. By permission of Oxford University Press.

Herzog et al (54) was one of the first groups to publish on the finding of PCOS in women with epilepsy. He reported that PCOS occurs significantly more often in women with TLE than in the general female population and is associated with predominantly left-sided lateralization of interictal epileptic discharges. These findings suggest that the underlying epilepsy itself likely contributes to the expression of PCOS via effects on hypothalamic control of the menstrual cycle with the tendency toward more anovulatory cycles and oligomenorrhea. Bilo et al also reported a higher incidence of reproductive endocrine disorders including PCOS, but in women with idiopathic generalized epilepsy syndromes (55). Neither group found an association with the type of AED being taken by the women, but other studies do suggest that AED treatment can play a role in the development of PCOS. Using the more strict definition of PCOS (as defined by 1990 NIH criteria), prevalence is reported as approximately 6% to 10% of women of reproductive age in the general population, but 10% to 25% of women with epilepsy (56).

Several studies by Isojärvi et al reported that the higher incidence of PCOS in WWE was specifically associated with VPA use. One of the probable reasons for discrepancies in different studies is the differing definitions for PCOS. A study of 238 WWE in Finland on a variety of AEDs included vaginal ultrasonography and serum sex hormone concentrations (57). Unlike the North American criteria for PCOS, they reported on findings of polycystic ovaries as well as elevated testosterone concentrations as isolated findings. The VPA monotherapy group included findings of polycystic ovaries (43%) and elevated testosterone concentrations without polycystic ovaries (17%). Notably, 80% of this group began VPA treatment before they were 20 years old and had developed polycystic ovaries or hyperandrogenism.

TABLE 43.2

A later study by Isojärvi et al (58) enrolled 16 women who had PCO or hyperandrogenism taking VPA for epilepsy. They were converted to lamotrigine (LTG) monotherapy and followed for 1 year (n = 12 completers). The additional findings of weight gain, hyperinsulinemia, and lipid profiles were monitored. During the first year after drug conversion, the number of polycystic ovaries, BMI, fasting serum insulin, and testosterone concentrations decreased, and the HDL/total cholesterol ratios increased.

Another examination of 148 WWE with factors of epilepsy type and AED use by Löfgren et al (59) reported a higher prevalence of reproductive endocrine disorders in women with idiopathic generalized epilepsy than control subjects, but the specific findings of hyperandrogenism, polycystic ovaries, and PCOS were more prevalent in WWE on VPA than in WWE taking other drugs or control women. The use of VPA and younger age predicted the development of hyperandrogenism.

Morrell et al. (60) studied 447 women prospectively with randomization to initiating 12 months of treatment with either VPA or LTG. More women in the VPA group than the LTG group developed ovulatory dysfunction (54% vs. 38%; P = .010) and more women in the VPA group than in the LTG group developed PCOS (9% vs. 2%; P = .007). Development of hyperandrogenism was more frequent with VPA than LTG among those initiating treatment at an age younger than 26 years (44% vs. 23%; P = .002) but was similar if treatment was started at age 26 years or older (24% vs. 22%).

In conclusion, females with epilepsy are a group at risk for reproductive health disorders regardless of AED use. Questions about reproductive health should be part of the evaluation, both during the initial evaluation and periodically during follow-up visits. History should include menarche, menstrual patterns and regularity, and fertility problems, as well as assessment of hirsutism, acne, and weight and height measurements. When symptoms or signs suggestive of sex steroid hormone disturbances are found, one should consider referral to a reproductive endocrinologist, gynecologist, or endocrinologist familiar with these issues. If female patients have signs of obesity, hyperandrogenism, or menstrual irregularities, then consideration should be given to avoidance of VPA use in women of reproductive age for these risks, in addition to the known increased risk for anatomical and neurodevelopmental teratogenicity (61). Some experts suggest that postpubertal girls who are treated with VPA should not only be frequently monitored for weight gain, but also undergo laboratory investigation on a yearly basis for lipid and glucose metabolism, hyperandrogenism, and ultrasound for polycystic ovaries with more frequent monitoring if they develop menstrual pattern changes (53). If PCOS develops, then the AED regimen should be reconsidered as to whether alternatives could still provide good seizure control given the long-term health consequences and the potential to reverse the VPA-related risks by substituting VPA with another AED (58).

CONTRACEPTION IN FEMALE ADOLESCENTS WITH EPILEPSY

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