Residency · Residency · Neurology

Seizures in Special Populations: Pregnancy and the Elderly

Overview

Epilepsy management requires special consideration in two populations where the stakes and complexities are particularly high: pregnancy, where the clinician must balance teratogenicity against the risks of uncontrolled seizures, and the elderly, where new-onset seizures are common, frequently misdiagnosed, and complicated by polypharmacy. The MONEAD study has provided critical prospective data on ASM management during pregnancy, while clinical trials in the elderly have clarified the optimal first-line agents for this vulnerable population.

Epilepsy and Pregnancy

Preconception Counseling

Ideally, counseling begins before conception, though approximately 50% of pregnancies are unplanned. The goals are to optimize seizure control on the safest ASM at the lowest effective dose, preferably as monotherapy. Clinicians must discuss the teratogenicity profile of each ASM with special emphasis on valproate, which is an absolute contraindication when alternatives exist. Folic acid supplementation at 4-5 mg per day (higher than the standard 0.4 mg) should begin at least 1-3 months before conception. Baseline ASM levels should be documented for monitoring during pregnancy.

Teratogenicity Risk

Valproate carries the highest risk, with a 10% major congenital malformation rate that is dose-dependent, neural tube defects in 1-2%, and additionally causes reduced IQ (7-10 points lower) and increased risk of autism and ADHD in offspring, as shown in the NEAD study. Phenobarbital and phenytoin carry moderate risk, with associations to cardiac defects and cleft lip/palate. Topiramate carries a cleft lip/palate risk roughly three times baseline, and received an FDA pregnancy category X labeling change in 2022. Carbamazepine has an NTD risk of approximately 1% with moderate overall risk. Lamotrigine has a low malformation risk of about 2-3%, close to the background rate, and is the most commonly used ASM in pregnancy. Levetiracetam has growing data supporting low risk and is increasingly used alongside lamotrigine. Oxcarbazepine has limited but reassuring data. Monotherapy at the lowest effective dose is always preferred over polytherapy.

MONEAD Study

The Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study is a large prospective multicenter investigation of pregnant women with epilepsy. Key findings include seizure worsening during pregnancy in approximately 15-30% of women, most often attributable to declining ASM levels. Lamotrigine and levetiracetam clearance increases significantly during pregnancy, by up to 50-100% for lamotrigine, requiring proactive dose adjustment. The study confirmed that breastfeeding while on most ASMs is safe and does not cause adverse neurodevelopmental effects in infants. It emphasized the critical importance of monthly ASM level monitoring and dose adjustment throughout pregnancy.

ASM Level Changes During Pregnancy

Lamotrigine clearance increases by 50-100%, primarily due to increased UGT1A4 activity driven by estrogen, with levels declining rapidly in the second and third trimesters. Levetiracetam clearance increases by 40-60% because of enhanced renal elimination from increased GFR. Oxcarbazepine (as its active metabolite MHD) has a moderate clearance increase. Carbamazepine levels remain relatively stable. Valproate protein binding changes with an increased free fraction, so while total levels may decrease, free levels remain more stable. Monitoring should occur monthly, with some experts targeting maintenance of the preconception therapeutic level. After delivery, ASM clearance rapidly normalizes, requiring dose reduction back to preconception levels within 2-3 weeks postpartum to avoid toxicity.

Seizures During Pregnancy

Generalized tonic-clonic seizures pose the greatest risk to both mother and fetus, including maternal injury, placental abruption, fetal hypoxia, and rarely fetal death. Focal seizures with preserved awareness likely carry minimal fetal risk. Status epilepticus during pregnancy is a medical emergency requiring aggressive treatment with the standard protocol, including benzodiazepines and second-line agents, with concurrent fetal monitoring. The risk of uncontrolled seizures generally outweighs the teratogenic risk of ASMs; clinicians should not withdraw or reduce ASMs simply because the patient is pregnant.

Delivery and Postpartum

Vaginal delivery is appropriate for most women with epilepsy, with caesarean section reserved for obstetric indications only. ASMs must be continued through labor and delivery, using IV formulations if the patient cannot take medications orally. Vitamin K 10 mg IM should be administered to the neonate at birth because enzyme-inducing ASMs may reduce neonatal clotting factors. The postpartum period is high-risk for seizures due to sleep deprivation, stress, and rapidly changing ASM levels. If the dose was increased during pregnancy, it should be reduced to preconception levels within 2-3 weeks postpartum.

Breastfeeding

Breastfeeding is encouraged for most women on ASMs, as the benefits outweigh the risks. ASMs with low breast milk transfer include valproate, carbamazepine, and phenytoin, which are highly protein-bound. ASMs with higher transfer but still considered safe include lamotrigine, levetiracetam, and topiramate. Phenobarbital and benzodiazepines may cause neonatal sedation and require infant monitoring. MONEAD and other studies have confirmed no adverse neurodevelopmental outcomes with breastfeeding on standard ASMs.

New-Onset Seizures in the Elderly

Epidemiology

The incidence of epilepsy increases after age 65, making this the age group with the highest incidence of new seizure disorders. The cumulative lifetime risk of epilepsy reaches 3-4% by age 80. Stroke is the most commonly identified cause, accounting for 30-50% of new-onset epilepsy in the elderly. Other causes include neurodegenerative disease (particularly Alzheimer disease), brain tumors, traumatic brain injury, and metabolic derangements.

Diagnostic Challenges

Seizures in the elderly are often focal with impaired awareness, presenting as episodic confusion, staring, or behavioral changes. They are frequently misdiagnosed as dementia, TIA, or delirium. Convulsive seizures are less common as the initial presentation. Postictal confusion may be prolonged for hours to days and can be mistaken for delirium or progressive dementia. Postictal Todd paralysis may mimic an acute stroke. EEG sensitivity is lower in the elderly because interictal discharges are less frequent; prolonged or ambulatory EEG may be necessary for diagnosis.

Distinguishing Seizures from Syncope in the Elderly

Both conditions are common in older adults and can present with falls and loss of consciousness. Syncope is typically provoked by standing, Valsalva, or cardiac triggers; involves brief loss of consciousness (less than 30 seconds); is accompanied by pallor; and features rapid recovery. Myoclonic jerks can occur during syncope (convulsive syncope in up to 10% of episodes), but these are brief and multifocal rather than sustained tonic-clonic activity. Seizures are typically unprovoked or provoked by photic stimulation or sleep deprivation; produce loss of consciousness that may be prolonged; feature cyanosis or facial plethora; involve sustained rhythmic tonic-clonic activity; may cause lateral tongue biting and urinary incontinence; and result in postictal confusion lasting minutes to hours. Overlap features make differentiation difficult, and video-EEG and tilt-table testing may be needed. Cardiac syncope with brief myoclonus remains a major diagnostic pitfall.

ASM Selection in the Elderly

Lamotrigine and levetiracetam are the preferred first-line agents. The STEP-ONE trial and the VA Cooperative Study demonstrated that both are better tolerated than carbamazepine in the elderly while offering favorable pharmacokinetic profiles and fewer drug interactions. Lacosamide is another well-tolerated option, though the PR interval should be monitored given the risk of AV block, especially with concomitant cardiac medications. Older agents should be avoided as first-line choices: phenytoin has nonlinear kinetics, numerous drug interactions, and increases osteoporosis and fall risk; phenobarbital causes sedation, cognitive impairment, and falls; carbamazepine carries risks of hyponatremia, drug interactions, and cardiac conduction abnormalities. The general approach is to start low and go slow, as elderly patients are more sensitive to ASM side effects. Many respond to low doses of a single agent. Polypharmacy interactions with statins, anticoagulants, and cardiovascular medications must always be considered.

Special Considerations

Bone health is important because enzyme-inducing ASMs (phenytoin, carbamazepine, phenobarbital) increase vitamin D metabolism and contribute to osteoporosis; vitamin D and calcium supplementation should be provided and DEXA scanning considered. Sedating ASMs increase fall risk. Cognitive effects should be minimized by avoiding phenobarbital and high-dose topiramate. Levetiracetam behavioral side effects can mimic or worsen dementia-related behavioral symptoms. For post-stroke epilepsy, ASM initiation should be considered after a second unprovoked seizure or after a first seizure with high-risk features such as cortical involvement or hemorrhagic transformation.

<image>A clinical decision diagram for ASM management during pregnancy. The flowchart begins with preconception counseling, branching to: (1) switch to lowest-risk ASM monotherapy (lamotrigine or levetiracetam preferred), (2) establish baseline ASM level, (3) start folic acid 4-5 mg/day. During pregnancy: monthly ASM level monitoring with dose adjustment targets shown for lamotrigine (clearance increases 50-100%) and levetiracetam (clearance increases 40-60%). At delivery: continue ASMs, vitamin K for neonate. Postpartum: reduce ASM dose to preconception level within 2-3 weeks, encourage breastfeeding, sleep hygiene. A sidebar compares teratogenicity rates for common ASMs with a bar chart (valproate highest, lamotrigine/levetiracetam lowest).</image>

<image>A diagnostic comparison table illustrating the differences between seizures, syncope, and convulsive syncope in the elderly. Three columns compare: seizure (unprovoked, sustained rhythmic tonic-clonic activity, cyanosis, lateral tongue bite, prolonged postictal confusion, EEG abnormalities), cardiac syncope (provoked by standing/Valsalva/cardiac arrhythmia, brief LOC, pallor, rapid recovery, normal EEG), and convulsive syncope (brief multifocal myoclonic jerks during syncope, <15 seconds, no postictal confusion). A Venn diagram shows the overlap in clinical features that cause diagnostic confusion. Recommended investigations are listed for each: EEG, ambulatory EEG, and video-EEG for seizures; ECG, Holter, tilt-table for syncope.</image>

Clinical Pearls

Valproate is absolutely contraindicated in women of childbearing potential unless no alternative exists and a pregnancy prevention program is in place; the risk of reduced IQ and neurodevelopmental harm to offspring is unacceptable. Lamotrigine clearance can double during pregnancy, so monthly level monitoring and proactive dose adjustment are essential to prevent breakthrough seizures. Breastfeeding is safe on most ASMs and should be encouraged because the developmental benefits outweigh minimal ASM exposure. ASM doses must be reduced back to preconception levels within 2-3 weeks postpartum to avoid toxicity as clearance normalizes. New-onset seizures in the elderly are frequently misdiagnosed as TIA, dementia, or delirium, requiring a high index of suspicion for focal seizures with impaired awareness. Lamotrigine and levetiracetam are the preferred first-line agents in the elderly due to better tolerability and fewer drug interactions. Convulsive syncope, with brief myoclonic jerks during fainting, is a common mimic of seizures in older adults; clinicians should not diagnose epilepsy without EEG confirmation.

References

• Meador KJ, et al. Fetal antiepileptic drug exposure and cognitive outcomes (NEAD). N Engl J Med. 2009;360(16):1597-1605.
• Pennell PB, et al. Changes in seizure frequency and antiepileptic therapy during pregnancy (MONEAD). JAMA Neurol. 2020;77(10):1-10.
• Rowan AJ, et al. New onset geriatric epilepsy: a randomized study of gabapentin, lamotrigine, and carbamazepine (VA Cooperative Study). Neurology. 2005;64(11):1868-1873.
• Tomson T, et al. Management of epilepsy in pregnancy: a report from the ILAE Task Force on Women and Pregnancy. Epilepsia. 2019;60(8):1536-1550.
• Brodie MJ, et al. Epilepsy in later life. Lancet Neurol. 2009;8(11):1019-1030.

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