Neurologic Care for Transgender and Gender-Diverse People

Abstract

Purpose of Review

To summarize the literature on neurologic care for transgender and gender-diverse (TGD) people and provide implications for clinical practice.

Recent Findings

There are limited data on the frequency and management of neurologic conditions among TGD people. TGD people have a higher prevalence of various neurologic conditions compared with cisgender or general population cohorts, including migraine, subjective cognitive decline, sleep disturbances, functional disorders, and cerebrovascular disease. Gender-affirming hormone therapy interacts with commonly prescribed neurologic medications and increases stroke risk among transfeminine people. Sex hormones and sex chromosomes may play a role in neurodegeneration and disability progression in neuroimmunologic diseases. Clitoral reduction surgeries on intersex children can cause neurologic disability and sexual dysfunction in adulthood. Socioeconomic disparities among TGD people contribute to health care barriers.

Summary

Neurologists should consider the unique experiences and health care needs of TGD people in their clinical practice and research protocols.

Introduction

The Transgender and Gender-Diverse Community

The transgender and gender-diverse (TGD) community encompasses diverse identities and experiences outside of heteronormative, cisnormative, and/or binary standards of gender identity and expression. A 2020 study conducted in the United States found that one in 20 young adults (ages 18–29 years) identified as TGD,^e1 and the rate of self-identification within the TGD community is increasing.^e2 TGD people are underrepresented in neurologic clinical care and research^1-3; however, neurologists should expect to see more TGD people in their practices.

Systemic stressors, including social stigmatization, have led to socioeconomic disadvantage and reduced access to health care among TGD communities.^e3-e4 Gender minority stressors intersect with other forms of oppression and social disparities—including racial bias, disability, incarceration, homelessness, and food insecurity—to create social determinants of health for the TGD community.⁴ Health care discrimination and other gender minority stressors have been proposed as a framework to study neurologic conditions including stroke and migraine disability.^5,6 Figure 1 presents a more detailed description of gender minority stress and resilience, as well as the effect of social stressors on clinical outcomes.

Figure 1. Overview of the Gender Minority Stress and Resilience Theory.

The purpose of this narrative review was to improve understanding of the neurologic needs of TGD patients using current evidence and expert opinion. This article summarizes the existing literature and its clinical implications regarding the neurologic care of TGD people.

Overview of Gender-Affirming Health Care

Figure 2 presents the historical classification of diagnoses regarding gender and sexuality. Gender dysphoria is a controversial DSM-5-TR diagnosis describing a societally induced distress in relation to incongruence between assigned sex and gender identity that is experienced by many, but not all, TGD people.⁷ Gender incongruence is an ICD-11 diagnosis that is not a mental disorder.^e5

Figure 2. Historical Medical Classification of Gender and Sexuality.

DSM = Diagnostic and Statistical Manual of Mental Disorders; ICD = International Classification of Diseases.

Not all TGD people need or want medical or surgical transition, including gender-affirming hormone therapy (GAHT); however, the psychological benefits of GAHT have been established for those who desire it.⁸ Feminizing GAHT may include estrogens, progesterone, and antiandrogens while masculinizing GAHT includes testosterone. Gonadotropin-releasing hormone (GnRH) agonists reversibly delay puberty in TGD adolescents.⁷ These hormonal medications routinely are used by cisgender people for different indications. For example, GnRH agonists have been used for precocious puberty in the general population since 1981 and are already established as safe and effective.^e6

Affirming social environments and knowledge about TGD people and their medical needs in clinical and research settings are critical to their physical and psychological health.^e7,e8 Affirmation of a patient's gender in health care settings establishes therapeutic rapport and trust with the provider, promoting patient engagement with the treatment process.^e9 Conversely, nonaffirming health care environments and provider knowledge gaps of gender-affirming practices can create barriers to care.^e10 Uninsurance and negative interactions with health providers are highest for those transgender people from Black and American Indian communities, respectively.⁴ The social stigma of TGD identity may be compounded for those living with HIV, necessitating integrated and gender-affirmative clinical care and research systems to improve the health of this patient population.^e11

Search Methods

We defined author expertise as clinical and/or research experience with TGD people and involvement in community health care advocacy. Author selection weighted the recruitment of diversity of race, ethnicity, nationality, sex, sexual orientation, and gender identity to emphasize participation from the affected communities. Authors were assigned to topics based on their clinical neurologic specialization.

We performed a literature search using terms from recent scoping reviews on the neurologic care of TGD people (search terms are listed in eAppendix 1).^1,9 The search period was from inception to October 15, 2023. We excluded non–peer-reviewed articles and those in non-English languages. Based on relevance and quality of study methodology, 3 neurologists (GZ, ZPL, and the assigned specialist) adjudicated the selection of articles and included topics by majority consensus. Clinical implications were developed through full consensus achieved during 4 rounds of online discussion by the entire author panel. Prevention of HIV and management of antiretroviral therapy are covered elsewhere^7,10,11 and considered outside the scope of this narrative review. Online references are provided in eReferences. eAppendix 2 provides additional references not cited in this work, listed by neurologic condition.

Literature Review Results

Headache

Frequency of Condition

The true prevalence of headache among TGD people is unknown because existing data are limited. However, recent studies suggest a higher prevalence of migraine in TGD individuals, particularly among those with disability.¹² A single center case-control study found that of TGD youth, those who were receiving GAHT were more likely to report headache compared with those not on GAHT.¹³ In this study, 7.3% (9/123) of transfeminine patients on estrogen had headache compared with 1.3% (2/150) of those not on estrogen and 12.3% (28/227) of transmasculine patients on testosterone had headache compared with 4.9% (13/263) of those not on testosterone. A cross-sectional study using self-report questionnaires found that in their sample of 88 transgender men, 36.4% had migraine and 40.9% had tension-type headache.¹⁴ A 2004 study from the Netherlands found that transgender women on estrogen have a prevalence of migraine similar to cisgender women (26% vs 25%, respectively) and of those, 54% had aura.¹⁵ Based on these data, it is likely that headache, specifically migraine, is common in the TGD population.

One major study from 2022 suggests that TGD people may experience more disabling headaches compared with cisgender people (OR 1.76, 95% CI 1.34–2.32).⁶ A survey of TGD participants in The Population Research in Identity and Disparities for Equality Study and looked at prevalence of migrainous headache as well as history of traumatic experiences or experiences of discrimination. Researchers found that participants with a history of trauma and/or discrimination reported more significant disability from migraine-like headaches compared with those without such history. In this study, the higher the number of experiences of trauma and/or discrimination the individual experienced, the higher the disability from migrainous headache (adjusted OR 1.11, 95% CI 1.05–1.18). This supports the findings from a 2017 administrative claims study, which found that transgender individuals receiving Medicare disability benefits were 3 times more likely to have a ICD-9 diagnosis of migraine compared with their cisgender counterparts (14.8% vs 4.4%).¹² The gender minority stress and resilience theory has been proposed as a framework to explain higher migraine frequency and disability among TGD people¹⁶; however, more research is needed.

Impact of GAHT

Increased migraine frequency has been observed with high-dose estrogens.^10,17 A retrospective study of 73 TGD people reported a subgroup of transfeminine participants in whom 23.4% developed worsening of chronic pain, including headache, after at least one year of GAHT. Conversely, 23.1% of transmasculine participants experienced improvement.¹⁷ The relationship between GAHT and migraine is likely more complicated than studies suggest, because of the potential influence of other factors such as health-related behaviors known to affect headache frequency.

Transfeminine people on GAHT may have higher risk of secondary headaches from prolactinomas and meningiomas, the latter of which can express estrogen receptors.¹⁸ The United States Food and Drug Administration gave a 2022 safety label warning for GnRH about the risk of idiopathic intracranial hypertension (IIH) after 6 patients (1 TGD patient and 5 precocious puberty patients) developed IIH while taking GnRH agonists.^e12 A study involving 410 TGD people on GnRH agonists over 10 years demonstrated that no individuals were diagnosed with IIH during the study period,^e12 but more research is needed.

Cerebrovascular Disease

TGD people have increased rates of cerebrovascular disease and cardiovascular risk factors, likely because of a combination of gender minority social stressors, disproportionate frequency of atypical stroke mechanisms, and adverse effects of some GAHT formulations.⁵ A large cohort study of 3,325 transfeminine participants receiving GAHT found that the average incidence rates for ischemic stroke were higher among those with 6 or more years of hormone therapy (9.4 cases per 1,000 person-years, 95% CI 5.2–17.0) as compared with those with less than 6 years (2.2, 95% CI 1.4–3.3).¹⁹ Compared with 10:1 matched cisgender women and men in this study, respectively, the adjusted hazard ratios for ischemic stroke in transfeminine participants were 4.2 (95% CI 1.9–9.2) and 3.9 (95% CI 1.8–8.6).

Frequency of Cerebrovascular Risk Factors

Much of the literature on cerebrovascular diseases among the TGD community has focused on cardiovascular risk factors, several of which are more prevalent in TGD people when compared with cisgender people and the general population.²⁰ TGD communities may experience increased rates of diabetes and insulin resistance, but further study is required.^5,12 Compared with cisgender people, those who identify as TGD may have increased tobacco and alcohol use, lower diet quality, and lower physical activity levels⁵; however, these data are discrepant because of variance in sampling techniques and methodology between studies.

Adverse health decisions often represent coping mechanisms to mitigate gender minority stress and the consequences of other social determinants of health, including poverty. For example, a cross-sectional sample of 162 transgender women in Chicago and Atlanta found a 42.9% prevalence of tobacco smoking.^e13 In this study, homelessness (odds ratio [OR 3.8]; 95% CI 2.0–7.3), intimate partner violence (OR 2.1; 95% CI 1.1–4.3), and sex work (OR 2.2; 95% CI 1.1–4.6) were all associated with tobacco use in regression analyses. A cross-sectional online survey of 168 transgender adults and 17,164 cisgender adults living in the United States showed that the past 30-day use of tobacco was higher among the transgender participants (39.7% vs 25.1%; p ≤ 0.003).^e14 Historically, commercial tobacco advertising has targeted marginalized communities, including transgender youth.^e15

TGD people may have higher rates of atypical stroke mechanisms. A single-center series of 8 transfeminine people admitted for stroke found disproportionate amounts of nontraditional stroke risk factors, including stimulant use and hepatitis C (n = 5, 62.5% for both).²¹ A second study from the same center identified 5 TGD adults admitted with stroke using electronic health record queries and administrative claims to identify gender identity and cerebrovascular events, respectively.²² TGD participants were not separated from cisgender, sexual minority people in analyses comparing stroke characteristics with matched cisgender, heterosexual controls. In this study, sexual and gender minority people were more likely to present with nontraditional stroke risk factors including HIV (30.8% vs 0%; p < 0.01), syphilis (19.2% vs 0%; p < 0.01), and hepatitis C (15.4% vs 5.1%; p < 0.01), although they were more likely to be tested for these risk factors.

GAHT moderates the relationship between gender identity and some cardiovascular risk factors. GAHT may elevate blood pressure, but results are inconsistent, and this may depend on other factors such as GAHT duration and age.²³ Transmasculine people receiving testosterone supplementation may be at risk of lower serum high-density lipoprotein levels while transfeminine people on estrogen supplementation may develop increased serum triglyceride levels. A 2017 meta-analysis of 29 articles assessed the effects of GAHT on cardiovascular risk factors.²⁴ Of the included studies, 28 (96.6%) were cohort studies, and a total of 4,731 transgender participants with at least 3 months of follow-up were included in the analysis. A broad range of GAHT formulations were found between studies, including those now considered obsolete based on current standards of care. Among transfeminine people on GAHT, serum triglyceride levels were higher at ≥ 24 months of follow-up (31.9 mg/dL; 95% CI 3.9–59.9) compared with baseline values. Transmasculine people experienced lower high-density lipoprotein levels at all studied follow-up time points, but the results were most pronounced at ≥ 24 months (−8.5 mg/dL; 95% CI −13.0 to −3.9).

Frequency of Cerebrovascular Disease

The literature consistently reports an increased risk of cardiovascular events, including stroke, among transfeminine people on estrogen supplementation. Testosterone usage among transmasculine populations has not been demonstrated to increase the risk of stroke, although data evaluating this association are limited. In a 2018 retrospective cohort study of 4,960 TGD people, investigators matched 10:1 cisgender participants to TGD participants using electronic medical record–linked data in the Kaiser Permanente system.²⁵ Among the transfeminine cohort (n = 2,842), there were 17 stroke events (0.6%) over a mean follow-up of approximately 4 years. Relative to cisgender controls, this study found a higher incidence of ischemic stroke among the transfeminine participants on estrogen supplementation. The risk difference for ischemic stroke at >6 years of follow-up was 36.2 (95% CI 18.1–72.4) cases per 1000 person-years. Adjusted hazard ratios among transfeminine participants treated with estrogen vs reference cisgender men and women were 9.9 (95% CI 3.0–33.1) and 4.1 (95% CI 1.5–11.4), respectively. Similar analyses of transmasculine participants did not find significant differences between transgender and cisgender cohorts. A 2021 meta-analysis, which included 14 studies and a total of 109 transfeminine participants, demonstrated a 2% estimated frequency of cerebrovascular events using random effects.²⁶ In this meta-analysis, ischemic stroke was the most common observed subtype and only one study reported the average maximum daily dosage of administered estradiol therapy.

All-cause mortality and mortality from cardiovascular disease are likely increased for TGD people, particularly those identifying as transfeminine on GAHT²⁷; however, it is less clear whether TGD people are at higher risk of fatal stroke. Studies of mortality from cerebrovascular disease are limited to retrospective cohort studies mostly originating from European countries. A clinical sample of 966 transfeminine participants on GAHT from the Netherlands with a median follow-up of 18.5 years reported standardized mortality rates of 1.5 for total mortality (95% CI 1.5–1.6), 1.6 for ischemic heart disease (95% CI 1.4–1.9), and 2.1 for fatal stroke (95% CI 0.9–1.6).²⁷ Similar associations between gender and mortality were not found among transmasculine participants. A 2019 systematic review found the current level of evidence to be too low to draw conclusions on the risk of mortality related to cerebrovascular disease among transgender populations.^e16

There are limited data on stroke risk in transgender youth or adolescents. Patients younger than 18 are included in meta-analyses assessing stroke risk in transgender participants^24,26; however, these studies analyzed adult and pediatric participants together. Although rates of venous thromboembolism is higher among transfeminine people on GAHT,²⁵ the risk of cerebral venous sinus thrombosis and embolism related to a patent foramen ovale are unexplored.

Epilepsy

Frequency of Condition

A retrospective cohort study suggests a higher prevalence of epilepsy among transgender (10.5%) vs cisgender (3.3%) Medicare beneficiaries.¹² No studies are available on the etiology, natural course of epilepsy, and surgical or neuromodulation outcomes among TGD people. TGD people with epilepsy may be more vulnerable to medical and psychological comorbidities, like mood disorders and reduced bone mineral density.^11,28 Owing to barriers to health care access experienced by TGD people,^e3 there may be an increased risk of treatment nonadherence in this population. A study of 450 people with epilepsy from the general population found that lack of health information (adjusted OR = 2.20, 95% CI 1.41–3.43), poor social support (adjusted OR = 1.9, 95%, CI 1.0–3.5), and perceived stigma (adjusted OR = 2.3, 95% CI 1.5–3.6) were associated with antiepileptic drug nonadherence.²⁹ Low adherence to antiseizure treatment can increase the risk of morbidity and mortality.

Impact of GAHT

Data regarding TGD people with epilepsy are lacking and mainly describe the interactions of GAHT with antiseizure medications,^11,28 which are important to consider when treating this population.

Sleep

Frequency of Condition

Compared with cisgender individuals, TGD people have higher prevalence of poor sleep quality and shorter sleep duration.^30-32 These disparities begin in youth^32-34 and may be explained by gender minority stress, discrimination, and mental health disparities.^32,34,35 In a 2022 study of over 1 million youth aged 12–25 years (2,603 identified as TGD) in the Optum Clinformatics Data Mart Database, adjusted analyses showed higher odds of insomnia (OR 5.4, 95% CI 4.7–6.2), sleep apnea (OR 3.0, 95% CI 2.3–4.0), and other sleep disorders (OR 3.1, 95% CI 2.5–3.9) compared with cisgender youth.³³ There were decreased odds of any sleep disorder in TGD youth on gender-affirming therapy compared with TGD youth not on gender-affirming therapy (OR 0.5, 95% 0.4–0.7). A study of 583 transgender adults in South Korea, recruited through an online platform, found that participants who experienced gender-related discrimination in the previous 12 months were 1.48 times more likely to report disordered sleep compared with those who had not experienced discrimination (95% CI 1.19–1.83).³⁵ When stratified by family support, however, the association between discrimination and disordered sleep only remained significant in those with unsupportive family or in those whose family was unaware of their identity. A qualitative study of 40 TGD adults living in New York City similarly found prevalent sleep issues, with 60% of participants describing sleep problems, including trouble falling asleep, trouble staying asleep, and short sleep duration.³² In addition, TGD people may be at higher risk of sleep apnea (OR 3.0, 95% CI 2.3–4.0),³³ although the mechanisms driving this disparity are not well understood.

Impact of GAHT

There were 2 case studies evaluating the effect of GAHT on sleep: one that suggested feminizing GAHT may increase stage 1 sleep in 7 transgender women and another of 3 transgender people that suggested that GAHT may affect obstructive sleep apnea.¹ A survey of 81 TGD people cared for at a single center found that 20% of respondents taking estrogens and 9.3% of respondents taking testosterone reported symptoms consistent with restless leg syndrome, although this study did not include a comparison group.³⁶ Owing to interactions with GAHT, there may be an increased risk of toxicity with use of benzodiazepine class medications.^e17 Trazodone may increase QTc prolongation in those treated with leuprolide, a GnRH analog, for prostate cancer; however, this association is less clear in TGD adolescents.^e18

Behavioral Neurology and Neuropsychiatry

Frequency of Conditions

TGD older adults seem to be at a higher risk of developing cognitive impairment as compared with the cisgender population. This difference seems to be driven by multiple factors, including multiple “modifiable” dementia risk factors that occur at a higher prevalence among TGD individuals older than 50 years. A 2022 study of 1,784 TGD adults within the OneFlorida Clinical Research Consortium found that the following risk factors of Alzheimer disease and related dementias were higher in TGD individuals than in cisgender controls: ever smoked (26.6% vs 17.9%, p < 0.001), alcohol use disorder (6.8% vs 3.4%, p < 0.001), depression (17.9% vs 6.4%, p < 0.001), using diabetic drugs (10.8% vs 7.1%, p < 0.001), hypertension (18.3% vs 12.7%, p < 0.001), using antihypertensive medications (15.5% vs 9.8%, p < 0.001), obesity (9.5% vs 6.8%, p < 0.001), and sleep disorders (6.8% vs 3.1%, p < 0.001).³⁷

In addition to these medical factors, TGD older adults, particularly those with dementia, experience unique minority stressors because of the intersection of aging, disability, and gender identity. These stress factors include social isolation and discrimination in health care settings.^38,e19 A cross-sectional study, using the data collected from the Rainbows of Aging online national survey between August and November 2018, used multivariate logistic regression to test the association of subjective cognitive decline (SCD), discrimination in medical settings, and TGD identity.³⁸ This analysis evaluated individuals aged 50 years or older who identified as TGD regardless of sexual orientation (n = 115) in comparison with cisgender, sexual minority participants (n = 592). Nearly 16% of TGD older adults reported SCD, and TGD older adults reported experiencing discrimination in medical settings 2 times more than cisgender, sexual minority individuals. SCD was 5–8 times more likely for those who experienced significant discrimination in medical settings. These findings mirror a study of the Behavioral Risk Factor Surveillance System data between 2014 and 2020.³⁹ This study found that SCD was highest in the minoritized ethnoracial transgender (21.6%) and gender-nonconforming (21.1%) populations. The adjusted odds of minoritized ethnoracial transgender individuals reporting SCD were 2.5 (95% CI 1.6–4.0) when compared with White cisgender individuals and 1.9 (95% CI 1.2–3.1) when compared with minoritized ethnoracial cisgender individuals. The factors that affect SCD remain complex and not fully elucidated. Data evaluating the relationship between TGD identity and objective cognitive impairment show mixed results, highlighting the need for longitudinal studies.⁴⁰

Although more data are needed, there is preliminary evidence that TGD older adults have a less robust support system and many rely more frequently on their chosen family rather than their biological family.⁴¹ A recent review article in Clinics in Geriatric Medicine suggests best practice recommendations for sexual and gender minority patients residing in nursing homes.⁴² These included creating an inclusive culture, setting protected time for staff training, and avoiding using assumptions when updating health care proxy and advanced care-planning forms.

Studies are limited by methodology but suggest a higher prevalence of functional disorders (including functional neurologic disorder and fibromyalgia) among TGD people, as compared with the general population or cisgender cohorts. A recent scoping review of the literature regarding functional neurologic disorder and functional somatic syndromes among sexual and gender minority people identified 10 population studies (38.5%) and 16 qualitative studies (61.5%), including 13 case reports and series.⁹ TGD people were included in 7 of 16 qualitative studies (43.8%) and 6 of 10 population studies (60.0%). A cross-sectional study of 154 patients diagnosed with FND in a specialty clinic found an overrepresentation of TGD patients in their sample (5/154, 3%) compared with Australian census data (<1%).⁴³

Cases of gender-nonconforming behaviors are reported in people with neurodegenerative parkinsonism with the use of levodopa, dopamine agonists, and selegiline. A 2015 systematic review using a historical misconception of gender nonconformity as a paraphilia reported 6 cases of “transvestism” in patients with Parkinson disease,^e20 including a case of crossdressing in a man with Parkinson disease treated with selegiline.^e21 However, no studies exist on the frequency of underlying gender nonconformity in this clinical population. Dopamine-blocking agents used to treat hyperkinetic disorders may increase prolactin levels, leading to breast growth and lactation, as well as sexual dysfunction.^e22 Aripiprazole, a partial dopamine agonist, has been found to have less risk of hyperprolactinemia.^e22

Impact of GAHT

It is unclear whether GAHT affects the frequency or severity of functional neurologic disorder or functional somatic syndromes among TGD people. In a case series of 4 TGD adolescents in Texas, the prognosis seemed favorable for those formally diagnosed with functional neurologic disorder by their treating neurologist.⁴⁴ In this series, 3 of 4 patients received some form of GAHT and all had at least one supportive parent. A retrospective cohort study of patients at a transgender health clinic in Israel found that 17 of their 115 patients (14.8%) were diagnosed with fibromyalgia compared with a 2.5% prevalence in a national telephone survey of rheumatology outpatients.⁴⁵ These 2 patient samples used different criteria for a diagnosis of fibromyalgia. In those receiving GAHT, transmasculine participants had a higher prevalence of fibromyalgia compared with transfeminine participants (14/72, 19.4% vs 3/43, 6.9%; p = 0.04). Based on the Widespread Pain Index and Symptom Severity Score, transmasculine participants had no significant change in their fibromyalgia symptoms at baseline and after at least one year of GAHT.

Neuroimmunology

Frequency of Condition

Multiple sclerosis (MS) has a cisgender female-to-male incidence of 2–3:1. Differences in immune system function and autoimmunity due to sexual dimorphism are under investigation.^e23,e24

Impact of Sex Chromosomes and GAHT

Emerging research suggests that sex hormones and sex chromosomes may play a role in neurodegeneration and disability progression in MS.^e25,e26 Estriol and estradiol treatments in cisgender women indicate potential neuroprotective effects of hormonal supplementation.^46-49 Declining estrogen levels during aging and menopause in cisgender women may increase the risk of neurodegeneration and MS progression.⁵⁰ Whether estrogen supplementation can ameliorate this risk is under investigation. The influence of estradiol supplementation on MS susceptibility and disability progression in transgender women has not been studied. Estrogen supplementation in transgender women may offer neuroprotective benefits; however, this may be opposed by the loss of testosterone and the presence of XY sex chromosomes, which may increase the risk of neurodegeneration.⁵¹ Low testosterone levels may increase the risk of disability progression and neurodegeneration in MS.⁵² Among cisgender men with MS, testosterone supplementation to the high normal range reduced gray matter atrophy.⁵³ How testosterone therapy in transgender men influences MS disease susceptibility and clinical course is unknown. XX chromosome T cells induce worse disease course in MS mouse models,⁵⁴ and X chromosome genes that escape X inactivation have a role in regulating autoimmunity.⁵⁵ Transgender men may have both proinflammatory effects from XX chromosomes and neuroprotective effects from testosterone supplementation.

The impact of GAHT in TGD people with MS has not been rigorously investigated. A retrospective study from the United Kingdom suggested that transgender women may be at increased risk of being diagnosed with MS after a diagnosis of gender identity disorder was documented (adjusted rate ratio 6.63, 95% CI 1.81–17.01).⁵⁶ This study was methodologically limited by the reliance on hospitalization coding data to determine onset of MS and TGD identity and did not assess whether TGD individuals were taking exogenous hormones before the diagnosis of MS.

Other Neurologic Conditions

Neuromuscular Disorders

Research on neuromuscular diseases among TGD people is scarce.¹ Subcutaneous “filler” injections for feminization are often performed without medical supervision because of structural barriers. As a result, filler injections may have frequent complications, including self-reported numbness found in 20% of individuals in a secondary analysis of a cross-sectional survey of 631 transgender women.⁵⁷ This study did not address which nerves are most frequently injured by filler injections, and there was no description of how neuropathy was diagnosed. The remainder of the literature on neuromuscular conditions among TGD people is limited to case studies,^1,e27 including one report of tourniquet injury to the median nerve at the donor site in a transmasculine person undergoing single-stage radial forearm free flap phalloplasty.^e28

Neurologic Conditions Among Intersex People

There are multiple neurologic considerations for TGD individuals with variations in sex characteristics. A 2020 study assessing gender identity in 179 individuals with an intersex-related condition found that 63% identified as intersex, 16% identified as transgender men or women, and over 25% identified as nonbinary.^e29 Owing to differences in sampling techniques, the prevalence of transgender identification among intersex people may vary between studies. In this cohort, common intersex-related conditions were varied and included congenital adrenal hyperplasia (CAH), a diagnosis which we will use to exemplify the relevance of intersex identity to neurology. Treatment with prenatal dexamethasone and pediatric hydrocortisone use in CAH have been associated with cognitive pathology independent of testosterone.⁵⁸ Conversely, untreated “salt-wasting” CAH can present with adrenal crisis, seizures, cerebral edema, and other encephalopathies due to hypoxia, hypovolemia and hypoglycemia.^e30 CAH is the most common reason for clitoral reductions in childhood. Adult outcome studies of nerve-sparing surgical protocols have found evidence of neurologic disability and significant sexual dysfunction indicative of postoperative small-fiber damage.⁵⁹ Data are scarce regarding the neurologic care of intersex people,¹ indicating the need for neurologists to increase health care research and advocacy for the intersex community.

Clinical Implications

Table 1 provides a summary of the clinical implications of neurologic practice with TGD people based on expert opinion. A multidisciplinary collaborative approach between the neurologist, patient, behavioral health, and primary care providers is vital to caring for TGD people with neurologic disorders. Disease prevention and risk factor modification are essential in neurologic care, particularly when managing cerebrovascular diseases⁵ and HIV,⁶⁰ for which TGD people are at higher risk. Neurologists can screen for adverse coping mechanisms to gender minority stressors and their subsequent consequences, such as substance use and sleep disorders.

Table 1.

Summary of Clinical Implications of Gender Identity on Neurologic Care Based on Expert Opinion

Headache	• Screening for secondary headaches may be warranted for those on GAHT • Nonpharmacological or peripherally administered alternative treatment options are available for those experiencing medication interactions or adverse events due to GAHT • Respectively, androgen-lowering agents and low-dose transdermal formulations can lower dosages and side effects of estrogen supplementation
Cerebrovascular disease	• Neurologic care can be coordinated with GAHT prescribers and primary care providers to best reduce cardiovascular risk factors • Low-dose transdermal estrogen formulations should be considered in transfeminine people with stroke or who are at risk of stroke • Atypical stroke mechanisms should be considered, as clinically suggested
Epilepsy	• Enzyme-inducing and other antiseizure medications interact with GAHT  ○ Antiseizure medication levels should be monitored closely among those on GAHT, particularly when initiating or adjusting the dosage
Sleep	• Routine screening for sleep disorders and referrals should be considered for TGD patients with neurologic conditions  ○ As indicated, screening for contributing substance misuse and behavioral health comorbidities should be considered • Seep aids should be considered, which have limited interactions with GAHT
Neuromuscular disease	• Medication interactions with GAHT should be considered when treating neuropathic pain
Behavioral neurology and neuropsychiatry	• Gender-affirming environments are important for older TGD adults, particularly those who are cognitively impaired or from racially diverse communities • Gender-affirming health care may help recovery in some TGD patients living with functional disorders • As appropriate, neurologic patients with gender-related distress should be referred to gender-affirming psychotherapists
Neuroimmunology	• More research is required to understand the complex relationship of sex chromosomes, sex hormones, and GAHT in TGD patients with neuroimmunologic diseases • Certain medications (IL-6 inhibitors) and corticosteroids interact with GAHT, and their use may warrant collaboration with a GAHT provider

Abbreviations: CRGP = calcitonin gene-related peptide; GAHT = gender-affirming hormone therapy; MS = multiple sclerosis; SNRI = serotonin and norepinephrine reuptake inhibitors; TGD = transgender and gender-diverse.

The clinical significance of GAHT interactions with medications used to treat neurologic conditions varies (Table 2). Awareness of potential medication interactions or complications can help to avoid them when alternative treatments are available. Neurologic medications may require careful monitoring of potential adverse effects or medication serum levels and subsequent dosage adjustments by the treating neurologist and GAHT prescriber when interactions or complications occur.^11,28 Expert opinion proposes that an adverse event associated with GAHT does not automatically warrant discontinuation.⁷ Decisions to terminate GAHT should be made with the patient, weighing the psychological and physiologic benefits and risks as part of informed consent (Figure 3). Formulation adjustments such as low-dose transdermal estrogen may decrease the risk of adverse effects of estrogen in those at risk of cerebrovascular diseases.^5,7,10 Androgen-lowering agents can allow for therapeutic effects with lower doses of estrogen when estrogen causes neurologic adverse events.

Table 2.

Medication Interactions Between Gender-Affirming Hormone Therapies and Neurologic Medications

	Gender-affirming medication therapies					References
	Testosterone	Estradiol	Progesterone	Spironolactone	Leuprolide
Headache
NSAIDs (e.g., ibuprofen, ketorolac, and naproxen)	—	—	—	May reduce diuretic and antihypertensive effects	—	e32
Tricyclic antidepressants (e.g., amitriptyline, nortriptyline, and doxepin)	—	—	—	—	May prolong QTc intervala	e33
Zolmitriptan	—	May increase zolmitriptan levels	May increase zolmitriptan levels	—	—	10,e34
Cerebrovascular
Angiotensin-converting enzyme (ACE) inhibitors	—	—	—	May increase risk of hyperkalemia	—	e35
Angiotensin II receptor blockers (ARB)	—	—	—	May increase risk of hyperkalemia	—	e35
Warfarin	May increase anticoagulant effects of warfarin	—	—	—	—	e36
Epilepsy
Barbiturate (phenobarbital, primidone)	May decrease testosterone levels	May decrease estradiol levels	May decrease progesterone levels	—	—	11,28
Carbamazepine	May decrease testosterone levels	May decrease estradiol levels	May decrease progesterone levels	May increase carbamazepine levels	—	10,11,28
Cenobamate	—	May decrease estradiol levels	May decrease progesterone levels	—	—	e37
Eslicarbazepine	—	May decrease estradiol levels	May decrease progesterone levels	—	—	11
Lamotrigine	—	May decrease lamotrigine levels	—	—	—	11
Oxcarbazepine	May decrease testosterone levels	May decrease estradiol levels	May decrease progesterone levels	—	—	10,11,28
Perampanel	—	May decrease estradiol levels at 12 mg/d, and effect on progesterone > estrogen	May decrease progesterone levels at 12 mg/d, and effect on progesterone > estrogen	—	—	11,28
Phenytoin	May decrease testosterone levels	May decrease estradiol levels	May decrease progesterone levels	—	—	11,28
Topiramate	—	May decrease estradiol levels particularly at > 200 mg/d	—	—	—	10,11,28
Valproic acid and derivatives	May increase testosterone levels	May decrease valproate levels	—	—	—	10,11
Sleep
Benzodiazepines (e.g., alprazolam and triazolam)	—	—	—	May increase benzodiazepine levels	—	e17,e32
Trazodone	—	—	—	—	May prolong QTc intervala	e18
Dementia
Donepezil	—	—	—	—	May prolong QTc interval	e38-e40
Movement disorders
Carbidopa/levodopa	—	—	—	May enhance hypotensive effects	—	e41
Dopamine agonists (e.g., apomorphine, pramipexole, and rotigotine)	—	—	—	May enhance hypotensive effects	May prolong QTc interval (apomorphine only)a	e41,e42
Ropinirole	—	May increase ropinirole levels	—	May enhance hypotensive effects	—	e41,e43
Safinamide	May increase hypertensive effects	—	—	—	—	e44,e45
Selegiline	—	May increase selegiline levels	—	May enhance hypotensive effects	—	e41,e46
Immunologics
Corticosteroids	—	May increase corticosteroid levels	—	—	—	e47
IL-6 inhibitors (e.g., satralizumab and tocilizumab)	—	May decrease estradiol levels	—	—	—	e48
Intravenous immunoglobulin	—	May increase risk of blood clots	—	—	—	e49

Abbreviations: NSAIDs = nonsteroidal anti-inflammatory drugs; IL-6 = interleukin 6.

^aMay not be present in gender-diverse youth.^e18

Figure 3. Recommended Approach to Manage Adverse Effects or Medication Interactions With Gender-Affirming Hormone Therapy.

GAHT = Gender-affirming hormone therapy.

Disclosure of gender nonconformity or a TGD identity should be handled calmingly, sensitively, and with a patient-centered approach. If present, patient and family distress should be addressed by a qualified, gender-affirming psychotherapist, counselor, or social worker. Promoting resilience factors, like family support³⁴ and access to gender-affirming care,⁴⁴ may mitigate the relationship of minority stressors with adverse neurologic outcomes. When gender-nonconforming behaviors occur with the use of dopaminergic medications,^e20 these agents may be replaced, particularly when patients find such behaviors distressing, or continued if they allow for authentic self-expression. A resource for finding affirming psychotherapists is the World Professional Association of Transgender Health provider directory.^e31 Owing to these neurologic considerations, as well as the other known psychological benefits of gender-affirming health care, neurologists are positioned to be important allies toward increasing access to affirming health care environments for their TGD patients.

The current literature on neurologic conditions among TGD people are limited by various methodological concerns, including (1) the lack of prospective data and randomized trials, (2) the use of diagnostic codes for gender identity disorder or transsexualism to identify TGD research participants, (3) noninclusion of racially diverse research participants, comprising those from indigenous communities such as Two-Spirit or Hijra, (4) nonuse of validated measures of gender minority stress and resilience, and (5) nonstandardized approaches to comparing dosage and formulations of GAHT in clinical research.

Conclusions

TGD people may experience unique minority stressors and may receive GAHT which can affect neurologic and psychological health, social outcomes, and intersect with neurologic therapies. Cultural and medical humility when treating and studying the TGD community, accompanied by affirming environments and health care teams, are critical to the neurologic and psychological health of TGD people. More multidisciplinary and community-engaged research, education, and advocacy are needed to address the unique needs and experiences of TGD people and their neurologic health care.

TAKE-HOME POINTS

• → Research on neurologic conditions and their management in transgender and gender-diverse patients is limited.

• → Systemic stressors have led to biopsychosocial disparities and health care barriers among transgender and gender-diverse community members, including the avoidance of services for the prevention and treatment of human immunodeficiency virus.

• → Gender minority stress may contribute to the increased prevalence of various neurologic conditions experienced by transgender and gender-diverse people, including stroke, migraine, sleep disorders, subjective cognitive decline, functional disorders, and somatic syndromes.

• → Gender-affirming hormone therapies may interact with certain medications used to treat neurologic disorders, which could change medication levels or cause neurologic side effects, such as changes in the frequency of migraines, seizures, or stroke.

Appendix. Authors

Name	Location	Contribution
Gwen Zeigler, DO	Department of Neurology, Albany Medical College, NY	Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; study concept or design; analysis or interpretation of data
Cole A. Harrington, MD, PhD	Department of Neurology, The Ohio State University College of Medicine, Columbus	Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; analysis or interpretation of data
Nicole Rosendale, MD	Department of Neurology and Weill Institute for Neurosciences, University of California, San Francisco	Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; study concept or design; analysis or interpretation of data
Christos Ganos, MD	Movement Disorder Clinic, Edmond J. Safra Program in Parkinson's Disease, Division of Neurology, University of Toronto, Toronto Western Hospital, Ontario, Canada	Drafting/revision of the manuscript for content, including medical writing for content; study concept or design; analysis or interpretation of data
Valeria Roldan, MD	Facultad de Medicina Alberto Hurtado, Universidad Peruana Cayetano Heredia, Lima, Peru	Drafting/revision of the manuscript for content, including medical writing for content
Anna Pace, MD	Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY	Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; analysis or interpretation of data
Sasha Alick-Lindstrom, MD	Department of Neurology, University of Texas Southwestern Medical Center, Dallas	Drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data
Casey Orozco-Poore, MD	Department of Pediatric Neurology, University of California Los Angeles	Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; analysis or interpretation of data
Wissam Deeb, MD	Department of Neurology, UMass Memorial Medical Center and UMass Medical School, Worcester	Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; analysis or interpretation of data
Margaret L. Hansen, PharmD	The Ohio State University Wexner Medical Center, Columbus	Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; analysis or interpretation of data
Z Paige L'Erario, MD, MSW	Greenburgh Pride, Westchester, NY	Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; study concept or design; analysis or interpretation of data

Study Funding

The authors report no targeted funding.

Disclosure

G. Zeigler has been reimbursed for travel-related expenses for speaking at the American College of Osteopathic Neurologists and Psychiatrists Mid-Year Meeting. She had honoraria donated for speaking at the American Academy of Neurology Annual Meeting. C.A. Harrington: No financial disclosures. N. Rosendale receives research funding from the American Academy of Neurology and NIH StrokeNet Fellowship. She receives royalties from McGraw Hill for authorship of a chapter in Current Medical Diagnosis and Treatment 2022 and 2023. She is associate editor of DEI for Continuum. C. Ganos receives research support from the VolkswagenStiftung (Freigeist AZ 94268). He also receives honoraria for educational activities from the Movement Disorder Society. V. Roldan: No financial disclosures. A. Pace received compensation from Abbvie for a one-time speaking engagement on including sexual and gender minority individuals in clinical research. S. Alick-Lindstrom: No financial disclosures. C. Orozco-Poore: No financial disclosures. W. Deeb: Fellowship educational grant for movement disorders from Medtronic. He receives royalties from Rose publishing for co-authorship of Living with Parkinson's Disease. M.L. Hansen: No financial disclosures. Z P. L'Erario has served as expert witness for plaintiff for Weiss Law, PC and receives consultancy payments regarding transgender neurologic health care from medical colleges and universities within the United States. They are on the editorial board of Neurology: Clinical Practice. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/cp.