Peripartum Management of Vagus Nerve Stimulation and Antiseizure Medications During Two Pregnancies in a Woman With Drug‐Resistant Epilepsy: A Case Report

ABSTRACT

There are limited reports on vagus nerve stimulation (VNS) therapy during pregnancy. We report a case of two pregnancies in a woman with drug‐resistant epilepsy (DRE) managed with VNS. A woman with epilepsy underwent implantation of a VNS device because antiseizure medications (ASMs) and a lobectomy were not sufficient to control seizures. After a spontaneous pregnancy at 29 years old, she could continue epilepsy treatment as before pregnancy by only adjusting the VNS settings. A vaginal delivery was planned, but an emergency cesarean section was performed at 38 weeks' gestation due to chorioamnionitis, complicated by neonatal asphyxia and transient tachypnea of the newborn; both mother and infant recovered fully. Two years later, she conceived her second child spontaneously and continued ASM and VNS treatment as before, delivering by scheduled cesarean section at 37 weeks' gestation; the infant required treatment for transient tachypnea of the newborn but recovered well. This case illustrates that stable seizure control without ASM escalation is achievable during pregnancy in a patient with VNS‐treated DRE whose seizures were well controlled before conception. However, the relative contribution of VNS itself cannot be determined from this experience.

Key Clinical Message

In a woman with drug‐resistant epilepsy treated with VNS and multiple antiseizure medications, seizure frequency remained stable across two pregnancies without dose escalation. This case illustrates individualized peripartum VNS device management, including planned deactivation around cesarean delivery, rather than establishing a therapeutic benefit of VNS during pregnancy.

1. Introduction

Epilepsy is a common disorder in young women and is reported to complicate approximately 0.4%–1.0% of all pregnancies [1]. Pregnant women with epilepsy (WWE) have been reported to be associated with an increased risk of spontaneous abortion, induced labor, cesarean section, hypertensive disorders of pregnancy, and postpartum hemorrhage [2].

Treatment of epilepsy includes both pharmacologic and surgical therapies. Surgical procedures are generally avoided during pregnancy due to their inherent invasiveness. As a result, management of WWE during pregnancy primarily relies on antiseizure medications (ASMs). Seizure frequency tends to increase during pregnancy due to decreased adherence owing to excessive anxiety about teratogenicity, decreased blood drug levels, and a lowered seizure threshold associated with elevated sex hormone levels [3]. Therefore, ASMs are often increased during pregnancy compared to nonpregnancy [4]. Various guidelines, including those established by the Japan Neurological Society for the management of WWE, recommend planned pregnancy, use of the least amount of ASMs that are most appropriate during pregnancy, and folic acid supplementation.

Vagus nerve stimulation (VNS) has recently received attention as an adjunctive treatment for drug‐resistant epilepsy. Although the exact mechanism of VNS is still unknown, it has been recognized as a useful neuromodulation tool that targets the central nervous system through electrical stimulation of peripheral nerves. Specifically, periodic weak electrical stimulation of the vagus nerve acts on the brainstem reticular formation and the nucleus tractus solitarius to suppress abnormal EEG activity. The implantation of the device is approved for use by neurosurgeons with specialized skills, and cases of implantation during pregnancy have been reported [5].

We report a case of two pregnancies in our institution with drug‐resistant epilepsy (DRE) that was managed with VNS therapy.

2. Case Presentation

2.1. Prepregnancy

She was a nulliparous woman (Gravida 2, Para 0) who received a therapeutic termination at age 25 for poorly controlled epilepsy, a preexisting condition.

Bilateral temporal lobe epilepsy was first diagnosed at age 19 with focal‐to‐bilateral tonic–clonic seizures. She started ASM control from the age of 20, and after attempts to control seizures with multiple ASMs proved unsuccessful, surgical treatment was deemed necessary. At the age of 25, she underwent a partial right temporal lobectomy. However, EEG showed that frequent epileptiform discharges remained in the left temporal lobe, and at the age of 26, she underwent surgery to implant a VNS device (AspireHC Model 105) after an induced abortion.

As the patient had a strong desire to conceive, VNS and medication were adjusted in preparation for pregnancy. Before pregnancy, the VNS was set to an off‐time of 5 min, an on‐time of 30 s, a frequency of 30 Hz, a pulse width of 500 μs, and an output current of 1.25 mA, with mood discomfort occurring during VNS stimulation (i.e., during the on‐time) as a side effect. She was also receiving 300 mg carbamazepine (CBZ), 350 mg lacosamide (LCM), 2500 mg levetiracetam (LEV), and folic acid 5 mg/day. Following these adjustments, focal impaired awareness seizures with oral automatisms occurred approximately once weekly, but no focal‐to‐bilateral tonic–clonic seizures were observed for 3 years.

2.2. First Pregnancy

A spontaneous pregnancy was achieved at age 29, and the patient made her first visit to our department at 20 weeks of gestation. Her neurological symptoms remained stable throughout her pregnancy with the above treatment (Figure 1), so a vaginal delivery was planned. We established a strategy to temporarily deactivate the VNS to prevent interference with electrosurgical devices and perform an emergency cesarean section if a status epilepticus occurred, while minimizing the risk of electromagnetic interference during the procedure. The device was not interrogated immediately before deactivation; however, device inactivation was confirmed by interrogation immediately after deactivation was performed.

FIGURE 1.

History of epilepsy treatment during first pregnancy (ASMs and VNS settings). She was first seen in our department at 20 + 5 weeks' gestation and emergency cesarean delivery was performed at 38 + 4 weeks' gestation. During the pregnancy, the VNS settings required only minor adjustments and were interrupted for 72 h before and after the cesarean section.

At 33 + 6 weeks of gestation, the amount of VNS stimulation was reduced to 1.0 mA in consideration of stimulation‐associated mood discomfort experienced during VNS on‐time. Still, no adjustment of ASM was required. She was admitted to the hospital for management of the rupture of the membrane at 38 + 3 weeks' gestation. After admission, the patient expressed a strong desire to focus on the delivery process without distractions. Respecting her wishes, the VNS was discontinued during the daytime by an epilepsy specialist in order to allow her to concentrate fully on the impending childbirth and was kept off throughout the subsequent emergency cesarean section. Nineteen hours after rupture of membranes, she had chills and fever with BT 38.5°C and tachycardia with HR 110 bpm, and laboratory findings revealed an elevated inflammatory response, with a white blood cell count of 17,550/μL and CRP of 1.87 mg/dL. Antimicrobial therapy started, but there was no improvement, and the fetal tachycardia persisted. An emergency cesarean section was performed with a diagnosis of chorioamnionitis. The total VNS‐off time was approximately 72 h, encompassing the period before and after the cesarean section. The female newborn's weight was 2373 g, with an Apgar score of 1/7 at 1 and 5 min after childbirth. No obvious malformations were noted. The infant was admitted to the pediatric department for transient tachypnea of the newborn (TTN) and neonatal asphyxia. Despite the complications of maternal chorioamnionitis and neonatal asphyxia with TTN, both mother and infant recovered without long‐term sequelae and were discharged on the seventh postoperative day. There were no epileptic seizures during the delivery process. VNS resumption was delayed until the second postoperative day at the patient's request, as she had been experiencing VNS‐related hoarseness and throat pain and preferred to wait until her postoperative condition had stabilized before resuming stimulation. VNS was resumed on the second postoperative day with the same settings as before discontinuation. However, because seizure frequency increased to approximately 3 times per week 1 month postpartum, the stimulation increased to 1.50 mA, after which seizure frequency returned to approximately once weekly.

2.3. Second Pregnancy

As shown in Figure 2, 2 years later, she conceived her second child spontaneously. Before the pregnancy, VNS stimulation increased to 1.75 mA and pulse width was reduced from 500 to 250 μs to mitigate hoarseness and throat pain, and regarding ASM, LEV was changed to Perampanel (CBZ 300 mg, LCM 400 mg, and Perampanel 6 mg). She resumed her visits to our department at 12 + 4 weeks' gestation. She had been presenting with focal impaired awareness seizures about once a week before pregnancy, but seizure frequency remained at approximately once weekly throughout pregnancy, unchanged from the prepregnancy baseline, and the same treatment was continued. An elective cesarean section was performed at 37 + 1 weeks' gestation due to a previous cesarean section, and the VNS was stopped on the day of surgery to prevent malfunction. The total VNS‐off time was approximately 84 h. The female newborn's weight was 2823 g, with an Apgar score of 8/8 at 1 and 5 min after childbirth. No obvious malformations were noted. The infant required pediatric admission for TTN but recovered without further complications, and both mother and infant were discharged on the seventh postoperative day. VNS was resumed on the day of discharge with the same settings as before it was discontinued, and the patient continued to have focal impaired awareness seizures at a frequency of approximately once weekly, unchanged from baseline, until 1 month postpartum.

FIGURE 2.

History of epilepsy treatment during second pregnancy (ASMs and VNS settings). She returned to our department at 12 + 4 weeks' gestation and underwent an elective cesarean section at 37 + 1 weeks' gestation. During the pregnancy, no VNS setting was required and was interrupted for 84 h around the time of the cesarean section.

3. Discussion

Epilepsy is one of the most prevalent neurological disorders affecting 65 million people worldwide [1] and is characterized by a high prevalence in women of childbearing age. Epilepsy encompasses a broad spectrum of focal and generalized subtypes, each managed with pharmacotherapy, surgical intervention, or a combination of both, based on seizure type and localization. Several studies have reported that pregnant women with epilepsy are more likely to have seizures during pregnancy than those before pregnancy. In particular, focal epilepsy is more prone to seizures during pregnancy than generalized epilepsy [6]. Seizure management during pregnancy has relied primarily on dose escalation of ASMs and addition of concomitant medications during exacerbations. High‐dose ASMs during pregnancy are associated with the risk of fetal teratogenicity and neonatal abstinence syndrome due to drug exposure via the placenta. Since well‐controlled seizures before pregnancy have been found to be the strongest predictor of whether a woman will have seizures during pregnancy [7], women with epilepsy should ideally achieve optimal seizure control prior to conception [8].

VNS is a device that reduces the frequency and severity of epileptic seizures through intermittent electrical stimulation of the left vagus nerve with a pulse generator implanted in the left anterior thoracic region. The precise antiseizure mechanism of VNS remains incompletely understood, but afferent vagal input is thought to modulate seizure activity through widespread projections to the nucleus tractus solitarius and brainstem reticular formation, with further connections to the thalamus, limbic system, and cortex. In a long‐term follow‐up study of 65 patients treated with VNS for over 10 years, 75.5% showed a reduction in seizure frequency at 8‐ and 10‐year follow‐up [9]. VNS therapy is approved in some countries for DRE as well as for refractory depression and has become one of the most widely used treatments worldwide since its approval in North America in 1988. In Japan, it has been covered by insurance since 2010. More than 100,000 VNS implants have already been performed, and it is reported to be a safe treatment with few complications and side effects, although there are mild side effects (pharyngeal discomfort, cough, hoarseness, and dysphagia) [10], consistent with the hoarseness and throat pain experienced by our patient.

Worldwide, dozens of cases of WWE combined with VNS have been reported, and it is considered safe for both mother and fetus [11]. To our knowledge, no cases of WWE managed with VNS therapy have been reported from Japan. The vagus nerve is a mixed nerve consisting of approximately 80% afferent fibers and 20% efferent (motor) fibers. Anatomical and electrophysiological studies in rats have demonstrated that the vagus nerve provides both afferent and efferent innervation to the uterus [12], raising a theoretical possibility that VNS could influence uterine activity during the peripartum period. However, direct evidence that VNS affects uterine contractility in humans is lacking. Ding et al. examined 44 pregnancies and reported 4.5% miscarriages, which do not correspond to a clear increase compared to the general frequency. They also reported neonatal malformations in 4.8% pregnancies, and the effect on fetal organogenesis seems to be minimal. Additionally, they observed a 4.8% incidence of pregnancy‐induced hypertension, providing insight into the potential maternal complications associated with these pregnancies.

Whether VNS affects teratogenicity and fetal development remains a subject of debate. However, many pregnant women who use VNS are taking multiple ASMs, and it is difficult to assess the effects of VNS on the fetus. Fetal malformation caused by antiseizure medications is a relatively intractable problem in epileptic diseases. Balancing adequate seizure control with minimizing drug exposure to reduce the risk of fetal malformation remains challenging. Multidrug therapy with ASMs is mandatory for DRE and carries both the risk of suboptimal seizure control and the teratogenic risk associated with polypharmacy. In this patient, ASM doses did not require escalation during either pregnancy, consistent with the general principle that prepregnancy seizure stability is the strongest predictor of seizure control during pregnancy [7]. Whether VNS independently contributes to reduced ASM requirements cannot be established from this case, as the relative contributions of VNS, baseline seizure stability, and individual pharmacokinetics cannot be disentangled without systematic ASM level monitoring and controlled comparison.

Regarding ASM management, levetiracetam was switched to perampanel before the second pregnancy because of inadequate seizure control. The second pregnancy was planned, and perampanel was initiated prior to conception. In accordance with guidelines recommending high‐dose folic acid supplementation for women receiving ASM polytherapy, the patient received folic acid 5 mg/day throughout both pregnancies.

The VNS deactivation periods around delivery in this patient (approximately 72 and 84 h for the first and second pregnancies, respectively) were considerably longer than the brief perioperative interruption typically required to avoid electrosurgical interference. These extended periods reflected individualized clinical decisions—respecting the patient's wish to focus on labor without VNS‐related side effects in the first pregnancy, and cautious postoperative reactivation in both—rather than a standardized protocol. The absence of seizures during these intervals in this patient does not establish that such prolonged deactivation is generally safe, and shorter periods of interruption should be considered when clinically feasible to minimize the risk of seizure exacerbation.

This case report has several limitations. First, serum concentrations of ASMs were not systematically monitored during pregnancy; therefore, it is difficult to evaluate the relative contribution of VNS and pharmacotherapy to seizure control. Second, although the neonatal complications observed in both infants were transient and resolved without apparent long‐term sequelae, the long‐term neurodevelopmental outcomes of the offspring have not been assessed. Third, as most WWE receiving VNS therapy are concurrently treated with multiple ASMs, it remains challenging to isolate the independent effects of VNS on pregnancy and fetal outcomes. Fourth, detailed information on perioperative anesthesia management and the use of electrosurgical devices was not systematically documented in this report, although the VNS device model, stimulation parameters, and deactivation and reactivation timing have been described above. Fifth, breastfeeding practices and their potential interaction with VNS therapy were not evaluated. As this report is based on very few cases, our suggestions remain hypothetical. Long‐term follow‐up of maternal and neonatal outcomes is lacking. Further case studies are needed to ensure the safety of VNS therapy during pregnancy for WWE.

In this patient with DRE and well‐controlled seizures before conception, seizure frequency remained stable across two pregnancies without ASM escalation while she continued VNS and ASM therapy. This case highlights the feasibility of individualized peripartum VNS device management including planned deactivation around cesarean delivery rather than establishing a therapeutic benefit of VNS during pregnancy.

Author Contributions

Motoki Ono: writing – original draft. Ryoichi Asaka: validation, supervision, writing – review and editing. Yasuhiro Tanaka: project administration. Chiho Fuseya: project administration. Norihiko Kikuchi: project administration. Tsutomu Miyamoto: writing – review and editing.

Funding

The authors have nothing to report.

Consent

The patient provided written informed consent for case publication under the institutional broad consent framework for medical research and clinical case reporting at Shinshu University Hospital.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

The data supporting the findings of this case report are contained within the article. Additional de‐identified clinical data is available from the corresponding author upon reasonable request, subject to patient confidentiality and institutional guidelines.