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CRITICAL REVIEW AND INVITED COMMENTARY

Caring for transgender patients with Emily L. Johnson and Peter W. Kaplan

Epilepsia, 58(10):1667–1672, 2017 doi: 10.1111/epi.13864

SUMMARY Objective: Approximately 25 million individuals older than age 15 identify as transgen- der, representing about 0.3–0.9% of the world’s population. The aim of this paper is to identify and describe important medical and social considerations facing transgender persons with epilepsy. Methods: We performed literature searches on the following terms: transgender AND epilepsy, transgender AND neurology, gender AND epilepsy, gender dysphoria AND neurology. We also performed literature searches for common femi- nizing or masculinizing treatment regimens, and searched for interactions of those treatment regimens with antiepileptic drugs (AEDs) and with seizures. Results: There are multiple bidirectional interactions between AEDs and the com- monly used treatments for aligning external sex characteristics with identified gender. Dr. Emily Johnson is The scope of the transgender population with epilepsy remains to be elucidated. an assistant professor Significance: Transgender patients with epilepsy face significant social and medical of Neurology at the challenges. Interactions between medical gender-affirming treatments and AEDs are Johns Hopkins School common, and management must depend on knowledge of these interactions to pro- of Medicine. vide appropriate treatment. KEY WORDS: Gender identity, Seizures, Antiepileptic drugs, Male-to-female, Female-to-male.

With several recent high-profile lawsuits involving trans- much higher in transgender persons,1 particularly in trans- gender rights, there has been an increase in awareness of gender persons of color. transgender people and the specific challenges faced by this In addition to medical treatment designed to address bio- community. logic sex characteristics, transgender people have unique Transgender people experience a discordance between health care needs including care related to reproductive the gender with which they identify and the biologic sex health (such as egg or sperm storage), and awareness and assigned to them at birth.1 Current estimates indicate that treatment for diseases associated with birth sex (such as cer- approximately 0.3–0.9% of people are transgender, yielding vical or ovarian in a transgender man).1 Rates of HIV a worldwide estimated population of 25 million transgender prevalence are much higher in transgender individuals than individuals ages 15 and older.1,2 in the general population, with prevalence reported to be as Although numbers of transgender people are relatively high as 12–16%.3,4 small, health disparities and many indicators of poor health Epidemiologic studies of neurologic conditions in trans- outcomes are elevated in transgender individuals.2 Rates of gender individuals are rare. One retrospective cohort using discrimination, abuse, and poor social support structures are English national Hospital Episode Statistics and mortality data of transgender people and multiple sclerosis found a Accepted July 11, 2017; Early View publication August 3, 2017. Department of Neurology, Johns Hopkins School of Medicine, strong association with multiple sclerosis in transwomen Baltimore, Maryland, U.S.A. (male-to-female), with an adjusted rate ratio of 6.63 (95% Address correspondence to Emily L. Johnson, Department of Neurol- confidence interval [95% CI] 1.81–17.01, p = 0.0002) com- ogy, Johns Hopkins School of Medicine, 301 Mason Lord Drive, Baltimore, MD 21224, U.S.A. E-mail: [email protected] pared to non-transgendered men, suggesting possible effects of exogenous hormones. There was no increased rate of Wiley Periodicals, Inc. © 2017 International League Against Epilepsy multiple sclerosis in transmen (female-to-male) compared

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Key Points Table 1. Effects of common AEDs on hormone levels

• Transgender persons make up 0.3–0.9% of the world’s Free AED reduced by AED reduced by AED population; no epidemiologic studies exist on the num- 18,19 34 ber of transgender patients with epilepsy Yes Yes ND ND • -inducing AEDs, in particular, may interact Eslicarbazepine Likely Yes35 with the hormones used for gender-affirming treat- Ezogabine/ ND No36 ment No37 No38 • Likely no No39 Depression and HIV are relatively common comor- 2 a bidities in transgender patients No No (reduced by )40 May be increased21 No41 Likely Yes35 5 a to non-transgendered women. Currently, there are no epi- ND No 35 demiologic studies of epilepsy in transgender persons. As Yes18,19 Yes42 there are approximately 50 million people with epilepsy Yes18,19 Yes34 6 Rufinamide ND Yes35 worldwide, if the prevalence of the transgendered popula- b No43 Yes 35 tion holds for persons with epilepsy, there would be approx- 44 45 – May be increased No imately 150,000 450,000 transgendered persons with Possible46 No47 epilepsy worldwide. ND = no data. a Reduces (perampanel at 12 mg). b Epilepsy-Specific Considerations Dose-dependent.

Hormone use “Gender-affirming health care” refers to treatment dedi- Table 2. Commonly prescribed regimens for gender- affirming therapy cated to matching an individual’s external primary or sec- ondary sex characteristics with their identified gender. Male-to-female Female-to-male Some transgender people may transition to their identified Starting in GnRH analog OR GnRH analog OR gender socially only, without seeking medical care. Trans- adolescence Depot Depot gender adolescents may undergo treatment with gonadotro- medroxyprogesterone Oral 17-b- Intramuscular pin-releasing hormone (GnRH) analogs to suppress biologic starting at 5ug/kg/day, testosterone starting at 1,7 puberty. Older transgender individuals may seek feminiz- increasing up to 25 mg/m2 every 2 weeks, ing or masculinizing hormones, or gender-reassignment sur- 2 mg/day7 increasing up 2 gery.1 The interaction of antiepileptic drugs (AEDs) with to 100 mg/m every 2 weeks7 hormonal treatment must be considered when caring for Starting in OR Testosterone (transdermal transgender patients (Table 1). adulthood acetate or parenteral) Oral or transdermal May add: Transwomen (male-to-female [MTF] transgender estrogens Depot b 7 7 persons) such as 17- -estradiol medroxyprogesterone Typical treatment for transwomen comprises GnRH analog–assisted pubertal suppression (if started in adoles- transdermally, and serum levels checked for a target range cence), starting with the onset of early puberty. However, of <200 pg/ml (although synthetic estrogens or conjugated GnRH analogs are expensive and may not be covered by estrogens cannot be monitored)7 (Table 2). insurance; an alternative approach is treatment with a pro- Long-term treatment with deprivation and gestin (such as depot medroxyprogesterone) to suppress estrogen therapy has been linked to increases in visceral fat peripheral androgen and gonadotropin secretion. This treat- and triglycerides, as well as blood pressure and insulin resis- ment is continued during treatment with cross-sex , tance. Thus far, long-term studies (up to 18 years) have not which leads to induced female puberty. Typical treatment is shown an increase in cardiovascular-related deaths, except with oral 17-b-estradiol, starting at 5 ug/kg per day and for transwomen continuing to use ethinyl estradiol rather increasing up to an adult dose of 2 mg/day7 (Table 2). than other preparations of estrogen.8 No increased cancer Adults seeking treatment use an to reduce rates have been observed. testosterone levels prior to sex reassignment surgery, in con- junction with an estrogen. Spironolactone is commonly Hormone interactions with AEDs and effect of hormones on used in the United States for its testosterone-suppressing seizure control properties, and is used commonly in The interactions of AEDs with female sex hormones are Europe. Estrogen may be administered orally or known from studies on contraception9 and hormone

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Transgender Patients with Epilepsy replacement therapy,10 and must be considered when for estrogen-sensitive , because exogenous testos- managing epilepsy in the transgendered patient (Table 1). terone is partially metabolized to estradiol.8 Intracranial Enzyme-inducing AEDs (such as phenytoin, phenobarbi- hypertension has been reported as a rare side effect of testos- tal, and carbamazepine; EI-AEDs) increase the glu- terone therapy.17 curonidation and hepatic of estradiol11 and subsequently lower the effective systemic dose of estrogen Hormone interactions with AEDs and effect of hormones on (Table 1). EI-AEDs can also increase blood levels of sexual seizure control hormone binding globulin (SHBG), lowering the active free EI-AEDs increase the level of SHBG in the blood, fraction of estrogen and progesterone,12 which could lead to thereby decreasing active free testosterone12,18 (Table 1). In a reversal of the feminizing characteristics in transwomen. some patients, this effect has significant clinical repercus- Noninducing agents could be tried as first-line AEDs in sions over time, and may lead to decreased libido and erec- transgender women to avoid this interaction. When induc- tile dysfunction.12,19 Total serum testosterone levels may be ing agents are necessary, the doses of feminizing hormones low19 or may not change, and therefore serum monitoring of may need to be increased, bearing in mind the risk of throm- testosterone levels for testosterone dosing should be per- boembolism (particularly if a patient has other risk factors formed, measuring free levels in transmen who take an EI- such as smoking or age >40).13 AED. Although levetiracetam can affect sperm parameters, Both lamotrigine and estrogen are metabolized via glu- testosterone levels are not lowered and may be curonidation,9 and estrogen-containing compounds increase increased.20,21 the metabolism of lamotrigine (Table 1). Therefore, when a With the cessation of menstruation, transmen who had patient taking lamotrigine starts or increases the dose of an catamenial exacerbations of seizure frequency may experi- estrogen-containing preparation, the lamotrigine level must ence an improvement in seizure control. Testosterone and be monitored and the dose adjusted.11 have primarily effects; however, Estrogen has proconvulsant properties in some patients because testosterone is metabolized to 17-b-estradiol (with with epilepsy, vividly demonstrated in 1959 by Logothetis proconvulsant activity), the effects are more mixed. Other et al.,14 when intravenous infusion of estrogen increased testosterone metabolites—androstanediol and dihy- epileptic spikes and sharp waves in 11 of 16 women with drotestosterone—are anticonvulsant.22 epilepsy. Therefore, when transwomen with epilepsy begin treatment with estrogen, an exacerbation of seizure activity Comorbidities is possible, and the patient may need medication adjust- ment. Although natural progesterone is a neurosteroid15 and Depression and psychiatric comorbidities has anticonvulsant properties (through the progesterone Depression and anxiety are common in transgender indi- metabolite, ),16 the synthetic medroxypro- viduals as well as in patients with epilepsy. Estimates of gesterone most commonly used for gender-affirming treat- depression in transgendered persons range from 31 to 64%, ment is not metabolized to allopregnanolone, and does not significantly higher than in the general population.2 A offer the same protection. national study in Australia found that 56% of transgender individuals have been diagnosed with depression (four Transmen (female-to-male [FTM] transgender persons) times higher than in the general population), and 38% have Typical treatment for transwomen also uses GnRH been diagnosed with anxiety.1 is a large risk for this analog–assisted pubertal suppression (if started in adoles- population, and one U.S. study revealed that 41% of trans- cence), starting with the onset of early puberty. Depot gender respondents had attempted suicide (a rate over 25 medroxyprogesterone is a less expensive alternative times that of the general population).1 approach for transmen also, used to suppress ovulation and Already marginalized, the social stigma associated with progesterone. Male puberty is then induced with intramus- epilepsy in some areas of the world can only be exacerbated cular testosterone, 25 mg/m2 every 2 weeks increasing to by the stigma against transgender persons. No current stud- 100 mg/m2 every 2 weeks7 (Table 2). ies exist on the rates of stigma, depression, and anxiety in Adults seeking treatment may use transdermal or par- the transgender community with epilepsy. enteral testosterone, with target serum testosterone levels in the 320–1,000 ng/dl range. If menstruation does not stop Use of antidepressant medications with testosterone alone, a progestin (i.e., depot medroxypro- The epileptologist must carefully evaluate patients for gesterone) may be used to stop menses and lower estrogen depression and anxiety, and may wish to avoid medications levels7 (Table 2). associated with detrimental mood side effects such as leve- There are no reports of increased cardiovascular mortality tiracetam or perampanel if depression is a comorbidity. or increased cancer incidence in transmen using testos- Most selective serotonin reuptake inhibitors (SSRIs) and terone, although transmen who have not had breast removal serotonin-norepinephrine reuptake inhibitors (SNRIs) are and hysterectomy-oophorectomy should have monitoring safe in persons with epilepsy, but the epileptologist should

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E. L. Johnson and P. W. Kaplan coordinate with a treating psychiatrist and recommend that adjusted.29,30 Levetiracetam and lacosamide have no known antidepressants that lower the seizure threshold (such as significant interactions with ARVs.30 bupropion) be avoided.23 If levetiracetam is otherwise desir- able in a patient with depression or anxiety, supplementa- Social Issues tion with vitamin B6 (pyridoxine) has been observed to lower rates of agitation and anxiety in some patients, and Stigma related to identification as being a transgender may be beneficial.24 person is high and may prevent individuals from accessing EI-AEDs reduce the levels of SSRIs, some SNRIs, bupro- health care or from disclosing their condition to their physi- pion, and trazodone.25 SSRIs inhibit cian.1 One study showed that 70% of transgender respon- (CYP)2D6 in the , which can lead to increased levels of dents had experienced discrimination in the health care some AEDs25; toxic levels of carbamazepine, phenytoin, setting on at least one occasion, and that 73% of transgender and valproate have been reported after initiation of fluox- individuals were reluctant to share their transgender identity etine (which also inhibits CYP1A2 and CYP2C19).25,26 Ser- with their physician due to fear of discrimination.31 If trans- traline inhibits the of lamotrigine, and has gender patients are not comfortable disclosing their identi- rarely been reported to cause toxic levels.25 Citalopram, esc- ties to their physicians, the use of exogenous estrogens or italopram, and SNRIs have minimal effects on AED testosterone may be unknown to the physician and medica- levels.25 The EI-AEDs increase the metabolism of tricyclic tions may not be chosen properly. When accessing medical antidepressants (TCAs), leading to low levels; conversely, records for continuity of care, the physician must also be valproate may inhibit the metabolism of TCAs causing toxi- aware of any former names used by the patient, which can city.27 TCAs may inhibit the metabolism of some hepati- complicate the process of retrieving information if the name cally metabolized AEDs.27 AED levels should be monitored has been changed. in patients starting treatment with antidepressants. Substance abuse rates are elevated in transgendered per- sons, perhaps as a response to depression or stress. Illicit Human immunodeficiency virus (HIV) drug use was reported by 26.7% of MTFs in a meta-analysis The rate of HIV prevalence is reported to be much higher of five studies, and 43.7% reported using .4 Sub- in transgender individuals than in the general population.3 A stance abuse may increase the risk of poorly controlled epi- meta-analysis of 22 studies of HIV prevalence in transgen- lepsy, as both alcohol and drug use may worsen seizures. der women found an average HIV prevalence of 27.7%,4 Patients with epilepsy and alcohol dependence are at an with large racial differences: the highest prevalence was in increased risk of medication noncompliance, increasing the African American transgender women at 56.3%, compared possibility of epilepsy-related death.32 to 16.7% in white and 16.1% in Hispanic transgender Some transgender persons cannot or do not seek tradi- women.4 Fewer studies of HIV prevalence in transgender tional health care for gender-affirming treatment, and a men exist; a meta-analysis of five studies found a much substantial percentage may purchase hormones from non- lower rate, with self-reported prevalence of 0–3%.4 Some medical sources,33 such as websites or untrained provi- studies have found higher rates of HIV in transgender per- ders. These products may not have the level of oversight sons than in other high-risk groups such as partners of and quality control of medical sources of hormones, and patients living with HIV.4 Transgender individuals may patients may be at risk for seizure exacerbation if using experience a delay in obtaining appropriate care and in impure or adulterated products. Besides hormone prepara- achieving viral suppression compared to non-transgender tions, herbs such as chasteberry, fenugreek, wild yam, individuals.28 fennel, and red clover are marketed as “feminizing” alter- natives to hormone therapy, whereas chasteberry, ginseng, Use of antiretroviral (ARV) medications and sassafras are marketed as “masculinizing” alterna- EI-AEDs may lower the levels of protease inhibitors tives. Some of these herbs have inducing or inhibiting (PIs) and nonnucleotide reverse transcriptase inhibitors effects on the CYP , and may interact with (NNRTIs), which are metabolized by the CYP system. AEDs. Other supplements such as “Ovary Concentrate” When possible, phenytoin, phenobarbital, , and are easily obtainable online. Patients taking these unregu- carbamazepine should be avoided in patients on PIs and lated herbs and supplements may be susceptible to break- NNRTIs29; if used, patients should be monitored for ARV through seizures in the event of sudden hormone level treatment failure.30 Valproate, as an enzyme inhibitor, may fluctuations or drug interactions. increase levels of lopinavir/ (PI) and (NNRTI), and thus adjustments of the ARVs in conjunction Discussion with the patient’s other physicians may be necessary.30 The PI combinations atazanavir/ritonavir and lopinavir/ritonavir The commonly used gender-affirming treatments for are known to reduce the concentration of lamotrigine; if transgender persons have the potential for interactions used, lamotrigine levels should be monitored and the dose with AEDs, as do some antidepressants and ARVs.

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Transgender Patients with Epilepsy

Estimates of the transgender population with epilepsy are 10. Reimers A. Hormone replacement therapy with estrogens may reduce based on reported numbers of transgender persons and lamotrigine serum concentrations: a matched case-control study. Epilepsia 2017;58:e6–e9. population-based epilepsy prevalence data, as no epidemi- 11. Reimers A, Brodtkorb E, Sabers A. Interactions between hormonal ologic studies of epilepsy in transgender persons exist. contraception and antiepileptic drugs: clinical and mechanistic consid- – Well-defined population-based studies are needed to esti- erations. Seizure 2015;28:66 70. 12. Isojarvi JIT, Repo M, Pakarinen AJ, et al. Carbamazepine, phenytoin, mate the true burden of epilepsy in the transgender popu- sex hormones, and sexual function in men with epilepsy. Epilepsia lation, to assess the prevalence of depression and HIV in 1995;36:366–370. transgender patients with epilepsy, and to define other 13. Tangpricha V, den Heijer M. Oestrogen and anti-androgen therapy for transgender women. Lancet Diabetes Endocrinol 2017;5:291–300. special needs and concerns of this population. In addition, 14. Logothetis J, Harner R, Morrell F, et al. The role of estrogens in cata- prospective studies of transgender persons with epilepsy menial exacerbation of epilepsy. Neurology 1959;9:352–360. beginning treatment with cross-sex hormones have the 15. Baulieu E-E, Schumacher M. Progesterone as a neuroactive neuros- teroid, with special reference to the effect of progesterone on myelina- potential to provide valuable information about the effects tion. Steroids 2000;65:605–612. of exogenous sex hormones on seizure control and inter- 16. B€ackstrom€ T, Zetterlund B, Blom S, et al. Effects of intravenous pro- actions with AEDs. gesterone infusions on the epileptic discharge frequency in women with partial epilepsy. Acta Neurol Scand 1984;69:240–248. 17. Park S, Cheng CP, Lim LT, et al. Secondary intracranial hypertension from testosterone therapy in a transgender patient. Semin Ophthalmol Conclusion 2014;29:156–158. 18. Barragry JM, Makin HL, Trafford DJ, et al. Effect of Transgender persons face significant social stigma and on plasma testosterone and binding globulin levels. J challenges when accessing health care. The physician treat- Neurol Neurosurg Psychiatry 1978;41:913–914. ing the transgender patient with epilepsy must be aware of 19. Herzog AG, Drislane FW, Schomer DL, et al. Differential effects of antiepileptic drugs on sexual function and hormones in men with epi- the medical regimens used for gender-affirming treatment lepsy. Neurology 2005;65:1016–1020. and the risk of hormonal interaction with AEDs, of the high 20. Ceylan M, Yalcin A, Bayraktutan OF, et al. Effects of levetiracetam risk of depression and suicide in transgender patients due to monotherapy on sperm parameters and sex hormones: data from newly diagnosed patients with epilepsy. 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Epilepsia, 58(10):1667–1672, 2017 doi: 10.1111/epi.13864