Treatment with an antiepileptic drug (AED) may be prolonged. Recognizing long-term adverse effects of AEDs will have a significant effect on the health of the person with epilepsy. This chapter reviews potential long-term effects of AED therapy.

AED treatment can result in numerous cosmetic findings including hirsutism, alopecia, changes in hair structure, gingival hyperplasia, and facial feature changes. Valproate use may increase androgen levels, resulting in hirsutism and alopecia in women, whereas phenytoin, carbamazepine, gabapentin, and phenobarbital treatment are associated with hirsutism independent of hyperandrogenism. The hair growth typically occurs on the face and trunk and can last a year or longer after discontinuation. Valproate therapy can also change the texture of hair, producing a kinky hair structure. Gingival hyperplasia is common in phenytoin-treated persons, necessitating good oral hygiene in persons prescribed this AED. Finally, prolonged phenobarbital and phenytoin treatment may result in subtle facial changes characterized by coarsening of facial features. Recognizing these cosmetic changes is important as discontinuation of the AED can result in reversal of findings over time.

Many AEDs are associated with changes in weight. Changes in body weight, particularly weight gain, may not only pose substantial health risks, but may lead to reduced adherence to AED therapy. Addressing potential weight change before initiating AED therapy and monitoring weight change during therapy is necessary to understand its effect and impact.

Overall, treatment with valproate appears to be consistently associated with weight gain, both in adult as well as adolescent patients.⁵⁵ Weight gain may occur in up to one half of treated patients receiving this medication, and can occur in both men and women. Increases in body weight may be seen relatively early in treatment (within 1 to 2 months), and in one study, did not plateau even after over 6 months of treatment.⁵ Although many patients report an increase in appetite, others do not. While the mechanisms underlying weight gain due to valproate are still uncertain, several mechanisms, including reduced energy expenditure due to impaired fatty acid metabolism as well as hyperinsulinemia and insulin resistance, have been proposed.^17,26 The potential development of insulin resistance may be most concerning, as this not only may lead to excessive weight gain, but also may play a role in the development of polycystic ovary syndrome, which has been associated with valproate therapy.²³

Although the effect appears to be less than valproate-associated weight gain, carbamazepine treatment may also result in weight gain. In a multicenter study comparing carbamazepine and valproate, 32% of patients started on carbamazepine reported weight gain.³⁵ The reported weight gain was less than with valproate, as only 8% exhibited a gain of >5.5 kg. Increased appetite likely mediates the weight gain and other mechanisms may also be a factor.^22,31

Weight gain has been noted in association with gabapentin and pregabalin,⁵⁸ both newer-generation AEDs that are γ-aminobutyric acid (GABA) analogs and are closely related. Weight gain (10% to 15% increases in body weight) may occur in up to one half of patients treated with gabapentin. Increased appetite is commonly reported in patients receiving this agent.⁹ Weight gain associated with pregabalin may be dose related.

In contrast to weight gain seen with several of both older and newer AEDs, weight loss has been reported in patients receiving either felbamate, topiramate (10% to 20% of patients), and, to a lessor extent, zonisamide. In obese patients receiving topiramate, a mean weight loss of approximately 4 kg was seen at 3 months, and 11 kg at 1 year. Reductions in body weight appear to be sustained over time.⁴ The mechanisms involved in weight loss are unclear, but patients receiving felbamate or topiramate commonly report substantial reductions in appetite.

Neither lamotrigine nor levetiracetam have been associated with significant changes in body weight, and may therefore be considered to be weight neutral.¹⁶

Effects on reproductive health can occur in childhood, adolescence, and adulthood in women and men with epilepsy. Reproductive dysfunction may be secondary to epilepsy per se, AED treatment, or a combination of both. In females, common symptoms include hyperandrogenism, menstrual disorders with ovulatory failure, polycystic ovary–appearing ovaries or polycystic ovary syndrome (PCOS), and hyperinsulinemia. In males, effects on sperm quality and motility and small testicular size have been described.

AEDs differentially affect steroid hormone levels, depending on how the individual AED affects the cytochrome P450 enzyme system.⁴¹ Treatment with enzyme-inducing AEDs (carbamazepine, phenytoin, and phenobarbital) in women with epilepsy reduces estrone, free testosterone, and androstenedione when compared to a control population without epilepsy. Also, sex hormone–binding globulin (SHBG) is significantly higher in women with epilepsy, further reducing bioavailable sex steroid hormones. In contrast, valproate, an enzyme-inhibiting AED, increases free testosterone in women with epilepsy. Lamotrigine and gabapentin both have no effect on the cytochrome P450 enzyme system and are not associated with changes in sex steroid hormone concentrations. Studies also suggest an independent effect of epilepsy on reproductive hormones. Women with temporolimbic dysfunction had reduced serum estradiol and dehydroepiandrosterone sulfate (DHEAS) levels in one study.²¹ Interestingly, these findings were more pronounced in women with left temporal lobe epilepsy.

Women with epilepsy are at increased risk for menstrual cycle abnormalities and anovulation, which may occur in association with PCOS or independent of this endocrinopathy. PCOS is a common endocrinopathy in women. The classification and definition of PCOS have changed as our understanding of the syndrome evolves. A recent consensus group proposed that the syndrome be diagnosed when at least two of the following exist: Oligo-ovulation or anovulation; elevated levels of circulating androgens or clinical manifestations of androgen excess; and polycystic ovaries as defined by ultrasonography.¹ Chronic anovulation most often manifests as oligomenorrhea (less than nine menses per year) and may lead to decreased fertility. Clinical manifestations of androgen excess include hirsutism, androgenic alopecia, and acne. Polycystic ovaries are defined by the number of follicles in the ovary (12 or more) measuring 2 to 9 mm in diameter and/or increased ovarian volume.¹ The syndrome is characterized by obesity, elevated androgen levels (free testosterone), and insulin resistance. Associated health risks of PCOS include impaired glucose tolerance, type II diabetes, hypertension, dyslipidemia, coronary disease, obstructive sleep apnea, and endometrial malignancy.¹¹ Other reported menstrual cycle disorders include those with abnormal menstrual cycle intervals, oligomenorrhea, polymenorrhea, increased variability of cycle interval, and menometrorrhagia. Increased menstrual cycle disorders have been reported with both temporal lobe epilepsy and idiopathic generalized epilepsy.^19,42

AEDs, and in particular valproate, may be independently associated with PCOS in women with epilepsy. Hyperandrogenism has been described in reproductive-aged girls and women with epilepsy treated with valproate.^{23,38,44,45,64} The findings are significant when compared to control populations that are age and pubertal status matched. Interestingly, this potential effect of valproate has been described in both women with epilepsy and women with bipolar disease.^29,52,53 Of clinical relevance, after discontinuation of valproate, these reproductive abnormalities reverse.^26,42

Men with epilepsy have reduced fertility, which may be a result of epilepsy and/or AED treatment. Having epilepsy can produce alterations on the hypothalamic-pituitary-gonadal axis as well as effects on sex hormone production and metabolism.^3,39 Testosterone controls both the expression of secondary sex characteristics and production of sperm. Disturbances in testosterone and other male reproductive hormones as well as sperm quality have been described in men with epilepsy.^{3,24,27,54,56} Carbamazepine, oxcarbazepine, and valproate are all associated with sperm abnormalities. Testicular volume may also be reduced.²⁴

Sexual dysfunction, manifested variously as reduced libido, decreased arousal, erectile dysfunction, or anorgasmia, has been reported to occur in 20% to 30% of women and up to 50% of men with epilepsy.^18,39 Both the seizure disorder itself as well as treatment with certain AEDs contribute to this spectrum of adverse effects. Seizures, particularly those arising from the temporal lobe, may alter the release of hypothalamic and pituitary hormones. Epileptic discharges may either stimulate or inhibit the hypothalamus. Treatment with AEDs, particularly the enzyme-inducing drugs including phenytoin, phenobarbital, and carbamazepine, has been associated with decreased sexual function and physiologic arousal in both men and women, as compared to either healthy controls or patients with epilepsy receiving noninducing AEDs.⁴³ Finally, concomitant psychosocial issues, such as social isolation and low self-esteem, as well as anxiety and comorbid depression can also contribute to dysfunction in both men and women.