What is the appropriate management for a transgender female on Hormone Replacement Therapy (HRT) experiencing seizure-like activity?

Management of Seizure-Like Activity in Transgender Women on HRT

Conduct a comprehensive neurological evaluation to differentiate true epileptic seizures from non-epileptic events, while recognizing that gender-affirming hormone therapy (GAHT) does not appear to increase seizure risk and may actually reduce seizure occurrence in some patients. 1

Initial Diagnostic Approach

Confirm Seizure Diagnosis

• Obtain detailed seizure semiology including timing, duration, associated symptoms, and post-ictal state to distinguish epileptic from non-epileptic events 2
• Consider serum prolactin measurement within 10-20 minutes of the event, as temporal lobe seizures characteristically elevate prolactin levels 2
• Important caveat: Baseline hyperprolactinemia may already exist in transgender women on estrogen therapy, potentially complicating interpretation of post-ictal prolactin elevation 2
• Document current medications, as dopamine antagonists and certain antiepileptic drugs can independently elevate prolactin 2

Assess HRT Regimen and Drug Interactions

• Review current GAHT components: estradiol formulation (oral vs. transdermal), dose, and anti-androgen type (typically spironolactone 100-300 mg daily) 3
• Critical interaction: If lamotrigine is being considered or used as an anti-seizure medication, estrogen significantly decreases lamotrigine serum concentrations through glucuronidation induction, potentially leading to breakthrough seizures 4, 5
• Conversely, enzyme-inducing anti-seizure medications (phenytoin, carbamazepine, phenobarbital) may decrease estrogen levels and interfere with feminization goals 4, 6

Evidence-Based Reassurance About GAHT Safety

GAHT Does Not Increase Seizure Risk

• Recent retrospective data from 34 transgender individuals with seizure history showed that seizure occurrence significantly decreased after initiating GAHT (52.9% had seizures before but not after GAHT vs. 17.6% who developed new seizures after GAHT, p=0.025) 1
• Feminizing hormone therapy (estrogen-based) showed no significant impact on seizure occurrence, contradicting older assumptions about estrogen's purely proconvulsant effects 1
• This finding challenges historical concerns: While estrogen can have proconvulsant properties in certain contexts, modern GAHT regimens do not appear to worsen epilepsy control in most patients 1, 7

Nuanced Understanding of Estrogen Effects

• Estrogen's effects on seizures are complex and bidirectional—both proconvulsant and anticonvulsant effects exist depending on dose, duration, administration route, and hormonal context 7
• High-dose exogenous estrogen (such as in assisted reproduction protocols reaching >1000 pg/mL) has been associated with seizure clusters, but typical GAHT doses are substantially lower 5

Management Algorithm

If New-Onset Seizures on Established GAHT

1. Do not automatically discontinue GAHT, as evidence does not support routine cessation and discontinuation may cause significant psychological harm 3, 1
2. Obtain EEG, neuroimaging (MRI brain), and basic metabolic panel to identify structural or metabolic causes 2
3. Check estradiol and testosterone levels to ensure appropriate dosing (target testosterone <50 ng/dL) 3
4. Initiate anti-seizure medication if indicated, avoiding lamotrigine as first-line due to significant estrogen interaction 4, 5
5. Consider levetiracetam, which has no significant hormonal interactions and was used successfully in reported cases 5

If Pre-Existing Epilepsy Before GAHT Initiation

1. Review current anti-seizure medication regimen before starting or continuing GAHT 8, 4
2. If on lamotrigine: anticipate 50% or greater reduction in serum levels when estrogen is added; increase lamotrigine dose proactively with close monitoring 4, 5
3. If on enzyme-inducing anti-seizure medications: counsel patient that feminization may be suboptimal; consider switching to non-enzyme-inducing alternatives (levetiracetam, gabapentin, pregabalin) 4, 6
4. GAHT can generally be initiated safely with appropriate medication adjustments and monitoring 1, 6

Monitoring Protocol

• Check anti-seizure medication levels 1-3 months after GAHT initiation or dose changes, particularly for lamotrigine 4
• Monitor estradiol and testosterone levels every 3-6 months during first year, then annually 3
• Assess seizure frequency and severity at each visit 1
• Screen for comorbidities common in both epilepsy and transgender populations: depression, anxiety, bone mineral density concerns 4

Specific Medication Recommendations

Preferred Anti-Seizure Medications in Transgender Women on GAHT

• Levetiracetam: No hormonal interactions, effective broad-spectrum coverage 5
• Gabapentin or pregabalin: No hormonal interactions, useful for focal epilepsy 4
• Clobazam: Successfully used as adjunctive therapy in cases of estrogen-related seizure exacerbation 5

Medications to Avoid or Use with Extreme Caution

• Lamotrigine: Requires significant dose adjustments (often 50-100% increases) when combined with estrogen; risk of breakthrough seizures if not properly adjusted 4, 5
• Enzyme-inducing agents (phenytoin, carbamazepine, phenobarbital, topiramate at doses >200mg): Will reduce estrogen efficacy and interfere with feminization 4, 6
• Valproate: While no direct hormonal interaction, associated with reproductive endocrine disorders including polycystic ovary syndrome and should be avoided in patients of reproductive age when possible 8

Common Pitfalls to Avoid

• Do not assume estrogen is causing seizures without thorough evaluation—recent evidence suggests GAHT may actually improve seizure control 1
• Do not discontinue GAHT reflexively when seizures occur, as this causes psychological harm and lacks supporting evidence 3, 1
• Do not start lamotrigine without anticipating major dose adjustments in patients on estrogen 4, 5
• Do not overlook baseline prolactin elevation when using post-ictal prolactin for diagnosis in transgender women on chronic estrogen therapy 2
• Do not prescribe enzyme-inducing anti-seizure medications without counseling about reduced feminization efficacy 4, 6

Multidisciplinary Coordination

• Coordinate care between neurology and endocrinology/transgender medicine specialists to optimize both seizure control and gender-affirming care 4, 6
• Ensure accurate documentation of gender identity, sex assigned at birth, and organ inventory in medical records to facilitate appropriate care 9
• Address mental health comorbidities (depression, anxiety, gender dysphoria) that are elevated in transgender populations and may be exacerbated by seizure disorders 4