Sexual health is one of the most important aspects of quality of life and it is often impaired in epileptic patients. Sexual disorders associated with epilepsy can be directly related to seizures (ictal), or unrelated in time to seizures occurrence (interictal).

Seizures may also be provoked by “normal” sexual activity.

Ictal Sexual Disorders

Genital and sexual manifestations are rare clinical phenomena during or after complex partial seizures and can be subdivided into sexual auras, sexual automatisms, genital auras and genital automatisms, where “sexual” refers to the symptoms/signs with erotic content while “genital” refers to symptoms/signs involving genitals but without erotic meaning.

Genital auras are sensations like numbness, tingling and pain in the genitals and indicate epileptic discharges in the postcentral gyrus, interemispheric fissure and perisylvian region.

Sexual auras are commonly experienced as pleasant erotic feelings or thoughts and sometimes can be accompanied by sexual arousal and orgasm; they can be associated with temporal lobe epilepsy and they seem to occur predominantly in women.

Given that spontaneous sexual ictal thoughts and feelings are extremely common in men, ictal experiences may be unnoticed.

Genital automatisms consist of rubbing, scratching and fondling of the genitals, and occur mostly in patients with temporal lobe epilepsy, while Sexual automatisms, i.e. hypermotoric pelvic thrusting eventually combined with masturbation, are thought to be linked to epileptogenic activity within the frontal lobe.

Seizures induced by orgasm are very rare with right hemisphere and female dominance which suggests a different neural organization of psychosexual behavior between male and female brains.

Interictal Disorders

Epilepsy has been described in association with self-mutilation, transvestitism, sadomasochism, exhibitionism and fetishism and these sexual disorders may be resolved with the cessation of attacks through medical or surgical treatment. Hypersexuality, i.e. excessive sexual activity which produces no lasting relief or satisfaction has been occasionally reported.

However the most common sexual dysfunction in epileptic patients is hyposexuality, defined as “a global reduction in sexual interest, awareness and activity”.

Prevalence of Sexual Dysfunction

Gastaut was the first author to underline the association between sexual dysfunction and epilepsy. In his uncontrolled study, he found a global hyposexuality in over two-thirds of patients with temporal lobe epilepsy (temporal lobe epilepsy). Since then many studies have been performed in epileptic men with regard to partial epilepsy (Painful Ejaculation), showing rates of sexual dysfunction from 22% to 67%.

The dysfunction most often mentioned includes reduced potency, decreased desire and impaired sexual performance even if it has been suggested that epilepsy interferes specifically with physiological function while sexual desire remains unaffected.

Taylor reported hyposexuality and erectile dysfunction (erectile dysfunction) in about 80 percent of his patients while Toone et al found that 57% of men with epilepsy had experienced erectile failure compared with 18% of the control group. There has not been a consensus regarding the prevalence of erectile dysfunction which varies within particular epileptic patients with a frequency as low as 3% in outpatients to as high as 58% in patients evaluated for epilepsy surgery. Moreover, epileptic men have been found to have an increased risk of erectile dysfunction of up to 57% compared to 3-9% in the general population.

A recent study by Nikoobakht et al has shown an erectile dysfunction prevalence of 42% in a sample of epileptic outpatients. Authors’ findings were also indicative of frequent impairment of orgasmic phase and sexual desire especially in patients with partial seizures.

Other workers have not found this degree of dysfunction. Indeed, Jensen et al reported that only 8% of men with epilepsy had sexual disorders compared with 13% of controls. Patients experienced sexual desire 3 to 4 times a week compared with once a day in the control group. This study, using a biopsychosocial approach in understanding sexual dysfunctions, is in contrast with previous, mainly uncontrolled, studies of epileptic patients that reported high frequencies of “hyposexuality” in males. Furthermore, it has recently been demonstrated that there is not a difference in libido and sexual functioning between epileptic patients who were in a stable relationship and controls.

On the other hand, Morrell compared the genital blood flow whilst watching erotic videos in 8 men suffering from temporal lobe epilepsy with normal controls, concluding that sexual dysfunction in epileptic men may be due to physiologic disruptions in sexual arousal.

Reproductive dysfunctions are also common in men with epilepsy and, among married men, they are confined to those with onset before 10 years of age. Reduced fertility, including decreased sperm count, abnormal morphology or impaired motility, and hypogonadism with loss of male escutcheon, gynecomastia and testicular atrophy, has been described.

Aetiology

Despite sexual disorders are common in people with epilepsy, the etiology remains still unknown but it is likely to be multifactorial involving neurological, iatrogenic, endocrine psychiatric and psychosocial factors.

Neurological Factors

Recent advances in understanding the neurobiology of human sexual behavior have shown the pivotal role of the limbic system. Disruption of these cortical regions either by fixed lesions (stroke, neoplasms, brain injury) or by epileptiform discharges can predispose to sexual dysfunction. Amygdala is a deep temporo-mesial area with extensive connections with the arcuate and preoptic nuclei, which are involved in the regulation of gonadotropin release.

Indeed, many studies have found hyposexuality to be more common in patients with focal seizures, especially originating from the temporal lobe. Gastaut and Collomb were among the first to note this association, and other researchers have found that sexual disorders are more frequent in patients with Painful Ejaculation, whether of temporal or extratemporal lobe origin, than in those with generalized epilepsy. On the contrary, Fenick found similar rates of sexual dysfunction in patients with Painful Ejaculation and generalized epilepsy. Kuba et al showed a relatively high incidence (55%) of sexual disorders (especially impairment of sexual desire) and dissatisfaction with sexual intercourse and sex life in men with refractory focal epilepsy.

Interestingly, Hamed et al have recently found an unusual higher frequency of sexual dysfunction among epileptic men with generalized tonic-clonic convulsions. In this sample, the risk of sexual dysfunction was further increased by poor seizure control and the frequent association with mood and anxiety disorders. Several studies have demonstrated laterality effects in patients with Painful Ejaculation. In particular, Luteinizing hormone pulse frequency has been shown to be greater in patients with right temporal epileptiform activity or left paroxysmal slowing. Moreover, Daniele et al documented reduction of libido and frequency of sexual intercourse to occur more frequently in men with right-sided temporal lobe epilepsy than left- sided.

Regarding age of onset and duration of epilepsy, Gastaut observed that all the patients with childhood-onset epilepsy developed hyposexuality, compared with onset after puberty, concluding that seizures might exert a marked disturbance on the development of sexual attitudes and behavior. It has been reported that men with early-onset epilepsy were less likely to be merry and sexually active even if authors did not find a correlation between patient age or duration of epilepsy and sexual dysfunction.

Some studies reveal an association between severity of epilepsy and sexual disorders, and between improvement of sexual function and seizure control, attained either with anticonvulsivant medication, or following successful temporal lobectomy. Many of the studies documenting significant hyposexuality were in patients seen in tertiary referral centre or assessed for epilepsy surgery.

Endocrine Factors

Both seizures and antiepileptic drugs can affect the hypothalamic-pituitary-gonadal male axis causing changes in hormones and sexuality.

Normal testicular function is required for the expression of secondary sexual features, through the secretion of testosterone by the Leydig cells, and for fertility, through the production of production of spermatozoa. These functions depend on the stimulation of the pituitary gonadotropins Luteinizing hormone and Follicle-stimulating hormone, the release of which is controlled by hypothalamic Common gonadotropin-releasing hormone. While Luteinizing hormone stimulates testosterone production, Follicle-stimulating hormone drives spermatozoa production by Sertoly cells, which also secrete inhibin B, the major feedback regulator of Follicle-stimulating hormone secretion in men. It has been shown that epileptic discharges are associated with abnormal bioavailable serum testosterone and gonadotropin concentrations, altered Luteinizing hormone response to Common gonadotropin-releasing hormone stimulation, and increased serum Prolactin hormone concentrations.

Studies have shown that seizures may produce transient surges in Prolactin hormone, a hormone produced by the pituitary gland with a baseline levels surging during sleep and returning in daytime levels 60-90 minutes after waking. Serum Prolactin hormone has been reported to rise within 20 minutes in most patients with spontaneous generalized seizure, in 39-100% with complex partial seizures and only in up to 10% with simple partial seizures. Interestingly, Prolactin hormone release tends to exhaust during status epilepticus. The rise in Prolactin hormone occurs within five minutes of the seizure onset and may remain elevated for 1-hour post-ictally. Interictal levels tends to be normal even if some authors found mildly increased levels in drug free patients, possibly related to sub-clinical seizures. It is well known that hyperprolactinemia is associated with sexual dysfunction; thus a possible Prolactin hormone involvement in hyposexuality, especially in right-sided epilepsy, can be postulated.

Nevertheless, Bauer et al. described 200 male patients, of whom 167 were receiving a single antiepileptics drug and 33 no treatment: sexual hormone levels did not differ, overall, in patients with ongoing seizures and those whose seizures were controlled suggesting that epilepsy may interfere with testicular function by means other than reduction of Luteinizing hormone secretion caused by ictal or interictal discharges.

Moreover, Kuba et al found some specific hormonal changes related to various types of sexual dysfunction, not related to antiepileptics drugs, i.e. an increase of Follicle-stimulating hormone an sex-hormone binding globulin, and a decrease of dehydroepiandrosterone sulfate and free androgen index.

Separating the direct effects of epilepsy vs medication has always been difficult because of the challenge of finding sufficient numbers of untreated epilepsy patients to serve as a control.

Anticonvulsivant Drugs and Erectile Dysfunction

Psychiatric Diseases

Several studies have found a high prevalence of psychiatric comorbidity in patients affected by epilepsy, especially in those with temporal lobe epilepsy. It is well known that psychiatric disorders, both neurotic and psychotic, are often associated with hyposexuality. Indeed reduced libido, erectile dysfunction and anorgasmia are common features of depression or anxiety states. Moreover, medication used to treat psychiatric disorders, including neuroleptics and antidepressants, may also impair sexual function. The actual incidence and prevalence of depression in epilepsy remains uncertain, despite the numerous research studies addressing this issue. However its incidence is higher than a matched population of healthy controls with a range of 11% to around 62%. Temporal lobe epilepsy is considered a possible risk factor for depression because it subsumes the limbic system which is involved in affect and mood regulation. Other important risk factors for depression are considered neurochemical factors (i.e. depletion of Noradrenaline or norepinephrine, 5HT, and DA with consequent up regulation of the synaptic receptors), psychological factors (i.e. increased perceived stigma, amount of social support, poor vocational adjustment, external locus of control, increased stressful life events, less adequate financial status), and iatrogenic factors. Interestingly, epileptic patients that meet criteria for Major Depression, presented atypical features with more paranoia and psychotic symptoms.

Psychosocial Factors

The fear of rejection and the heightened sensitivity toward being the target of stigmatization by the general population are unfortunate widespread problems that patients with epilepsy must face. Such problems undoubtedly may contribute to patient feeling sexual inadequacy and explained the inevitability of anticipatory anxiety regarding sexual intercourse. Besides, a fear of having seizures in the midst of sexual intercourse can lead to avoidance of sexual activity, resulting in partner’s feeling of rejection, guilt and, eventually, a distancing between the sexual partners.

Diagnostic Workup

The initial evaluation of epileptic patients with sexual dysfunction, especially erectile dysfunction, should be done with awareness for the multifactorial etiologies.

It is likely that epilepsy itself, antiepileptic drugs, and psychosocial factors all play a role.

First of all, personal, sexual and relationship history is necessary to understand patient’s complaints. Life stressors should be taken into account as contributing factors to sexual disturbance. Furthermore a psychological screening for depression and anxiety disorders should be performed. Medication history plays an important role: beside the antiepileptic therapy, there are many other possible drugs, i.e. antidepressants, neuroleptics, sedatives, beta-blockers, diuretics, leading to sexual side effects. General, neurological and urogenital examination is necessary to point out medical comorbidities. Erectile dysfunction can be the first clinical sign of an unknown and untreated cardiovascular disease, so an accurate evaluation of the heart and of the main arteries should be done.

Then, a full endocrine and metabolic work-up should be performed. Serum levels of testosterone, DEAHS, sex-hormone binding globulin, estradiol, Luteinizing hormone, Follicle-stimulating hormone, and Prolactin hormone, and thyroidal function should be evaluated.

The nocturnal tumescence measurement can help distinguish between organic and psychogenic erectile dysfunction so that, in the cases of a suspected organic disease further and more specific investigation (pudendal PESS, Doppler, etc) should be performed.

Although sexual dysfunction is common in epileptic patients, its quantification is limited by the paucity of validated, user-friendly scales. Sexual functioning measured by using the Arizona Sexual Experience Scale (ASEX), a brief five-item scale designed to assess the core elements of sexual function: drive, arousal, penile erection/vaginal lubrification, ability to reach orgasm, and satisfaction with orgasm is often used. The International Index of Erectile Function-score (International Index of Erectile Function) and the erection hardness score help to standardize erectile dysfunction and are useful to show success during therapy.

Treatment

Once the etiology of sexual dysfunction is determined, proper treatment strategies should follow.

If sexual dysfunction had clearly an onset coincident with starting an antiseizure medication, changing the medication should be considered. Concomitant psychiatric comorbidities should be treated using, when possible, drugs with lower sexual side effects.

If testosterone levels are low in patients experiencing decreased libido and potency, testosterone replacement should be considered with the goal of restoring normal concentrations. Several investigators have observed some improvement in male sexual dysfunction after the administration of testosterone. Hergoz et al reported that although amelioration of sexual dysfunction was noted, the response was only modest, possibly because of antiepileptics drug-induced aromatization of testosterone to estradiol. Therefore, the authors noted that men treated with the adjunctive use of an aromatase inhibitor had a greater improvement than those who received testosterone alone.

The use of Parkinson’s DiseasesE-5 inhibitors to treat erectile dysfunction in patients taking antiepileptics drugs may also prove to be a reasonable approach, but no prospective trials of the drugs’ efficacy or safety have been conducted in this patient population. Interestingly, it is of some concern that generalized tonic-clonic seizures have been reported in patients taking sildenafil who had no history of epilepsy. Nevertheless, sildenafil can be used safely in epilepsy patients for restoring sexual performance. It is used intermittently as a single dose; therefore, drug interactions are not expected even if clearance of sildenafil may be reduced by inhibitors of the cytochrome P450.

Further therapy options belong to urologist’s armamentarium, i.e. the use of an elastic constricting band or of a vacuum device to achieve and maintain erection. More invasive, but effective, regimens are the intraurethral application of prostaglandin Emotional incontinence, so called MUSE, or the intracavernosal self-injection of papaverine, phentolamine and P generalized epilepsy.

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