Epilepsy with Eyelid Myoclonia Complicated by Polycystic Ovary Syndrome: Valproate Withdrawal, Vagus Nerve Stimulation, and Seizure Reduction

Kyoko TATEBAYASHI; Ichiro TAKUMI; Takashi MATSUMORI; Kimiyuki KAWAGUCHI; Hidetoshi MURATA

doi:10.2176/jns-nmc.2023-0083

Abstract

Epilepsy with eyelid myoclonia is a childhood-onset generalized epilepsy, which is more common in women. Over 90% of the patients continue antiseizure medications, especially valproate, and more than 60% of cases are refractory. The efficacy of vagus nerve stimulation in treating eyelid myoclonia is still unknown. Polycystic ovary syndrome is highly prevalent in women with epilepsy receiving valproate; nevertheless, no reports on the complication of polycystic ovary syndrome in women with epilepsy with eyelid myoclonia were found. In this report, a case of a woman with epilepsy with eyelid myoclonia who developed polycystic ovary syndrome while receiving valproate and underwent vagus nerve stimulation is described. A 26-year-old female patient has been administered valproate since the occurrence of generalized seizures at the age of 12 years and then developed polycystic ovary syndrome. When the dose of valproate was reduced as an adult, her epilepsy became intractable. Information from her mother led to a video electroencephalography re-evaluation, and she was finally diagnosed 15 years after onset. The patient underwent vagus nerve stimulation. In a short-term follow-up, she achieved >50% seizure reduction at low output currents of <1.00 mA. Polycystic ovary syndrome was cured 15 months after valproate withdrawal. There are three key points presented in this case: Vagus nerve stimulation therapy was useful for treating epilepsy with eyelid myoclonia with absence. Women with epilepsy with eyelid myoclonia taking valproate must be aware of the risk of polycystic ovary syndrome and monitor their menstrual cycles. Information from the family, such as home videos, helped with the diagnosis.

Introduction

Epilepsy with eyelid myoclonia with absence (EMA), which is also known as Jeavons syndrome, has been described as eyelid myoclonia with or without absence, eye-closure-induced spike-and-wave activity, and photosensitivity.¹⁾ Jeavons syndrome is reported to occur in 7.3%-12.9% of cases of generalized epilepsy and 2.5%-2.7% of all patients with epilepsy.²^,³⁾ It is a childhood-onset generalized epilepsy, which is more common in women. EMA is associated with multiple seizure types, including absence, generalized tonic-clonic seizure (GTCS), and myoclonic seizure.⁴⁾ Over 90% of the patients must continue antiseizure medication (ASM), especially valproate (VPA).⁴^-⁶⁾ Intractable epilepsy is reported in up to 64.3%-80%.⁴^,⁷⁾ Although VNS has improved EMA outcomes in five out of nine cases in three small-scale studies,⁴^,⁷^,⁸⁾ the efficacy of VNS for EMA is still uncertain. Polycystic ovary syndrome (PCOS) is highly prevalent in women with epilepsy receiving VPA;⁹^,¹⁰⁾ however, to the best of our search, no reports on complications of PCOS in women with EMA were found. In this report, we describe a refractory case of a woman with EMA who developed PCOS while receiving VPA and underwent VNS.

Case Report

A 26-year-old woman, diagnosed with medically refractory focal epilepsy and amenorrhea, was referred to our hospital. She had undergone menarche at the age of 12 years, and subsequently, her periods remained regular, with approximately 30-day cycles. Her development was normal, and she had no mental retardation or neurological deficit. At the age of 12 years, she developed generalized seizures without a history of febrile seizures or a family history of seizure disorder. At that time, VPA was prescribed to control the seizures. Her mother raised a concern about her rapid blinking, upward rotation of the eyeballs, and brief clouding of consciousness. Despite the information from her mother, these symptoms were not considered by the physician, and self-limited focal epilepsy was diagnosed on the basis of outpatient electroencephalography (EEG) outcomes. Carbamazepine was added to the patient's therapy regimen but was discontinued due to the weekly onset of nocturnal impaired awareness. The patient was seizure-free for approximately 5 years while receiving 800 mg of VPA daily. When she was attending university, her life became irregular, and she began to experience seizures again. Thus, topiramate (TPM) was added to her therapy, and the dose was titrated to 250 mg in addition to 800 mg of VPA. This treatment regimen controlled her generalized seizures to the point that they only occurred approximately once a year. A switch from VPA to lamotrigine (LTG) was attempted when the patient was 24 years old. TPM 250 mg was continued, the dose of LTG was increased to 200 mg, and the dose of VPA was reduced to 400 mg. Nevertheless, her epilepsy was not controlled. Due to the ineffectiveness of this regimen, LTG was discontinued, and the dose of TPM was increased to 400 mg (Fig. 1).

Fig. 1

Clinical progress and treatment.

Seizures in the teenage patient were controlled well with 800 mg of VPA daily; however, she experienced seizures annually from the age of 18 years. The patient developed PCOS during VPA administration; thereby, VPA was stopped, and her seizures became refractory. The seizures decreased with VNS therapy; PCOS improved 15 months after VPA was stopped.

VPA: valproate, PCOS: polycystic ovary syndrome, VNS: vagus nerve stimulation

At the age of 26 years, a few months before presenting to our hospital, she became amenorrheic. Her gynecologist diagnosed her with PCOS, and she began taking pills for this issue prior to coming to our hospital.

She had been diagnosed with intractable focal epilepsy at an outside neurosurgery center before referral to our hospital. At the time of referral to our institution, she was experiencing one seizure every few months and was treated with daily VPA and TPM at a dose of 400 mg each. We performed brain magnetic resonance imaging, which revealed no focal abnormalities. Repeat outpatient EEG revealed generalized spike-and-wave complexes during hyperventilation activation. On the basis of these findings, we changed her diagnosis to idiopathic generalized epilepsy, and we made attempts to control the ASM. First, we switched her from VPA to levetiracetam (LEV), and the dose was increased to 1500 mg; however, this worsened her seizures. During long-term video EEG monitoring, bilateral tonic-clonic seizures (BTCS) were detected. At this point, we added 2 mg of perampanel (PER) to the patient's treatment regimen, but again, her condition did not improve. At the next outpatient visit, the patient's mother complained that her daughter's rapid blinking bothered her and presented a home video showing EMA and upward deviation of the eyes. This led us to re-evaluate the EEG recordings. Detecting eyelid myoclonia using full-field images (Video sequence 1) was difficult, but careful observation of the magnified video revealed eyelid myoclonia synchronized with 3-4-Hz spike-/polyspike-and-wave complexes (Video sequence 2). Eyelid myoclonia was induced by slowly closing her eyes in daylight. It continued intermittently for approximately 5 min, followed by BTCS. Based on the findings of long-term video EEG and her mother's complaints, she was finally diagnosed with EMA 15 years after her initial diagnosis of focal epilepsy. Next, we switched from PER to 5 mg of clobazam and reduced the dose of LEV to 1000 mg, but this did not reduce the patient's seizures. Her seizures occurred monthly, sometimes with multiple seizures on the same day. The patient then underwent VNS therapy. Throat discomfort led to a slow increase in stimulation, and after 1 year, the current output was 0.875 mA (Table 1). Low-level stimulation reduced the occurrence of BTCS from monthly to every 4 months. EMA was no longer observed, and brief eyelid myoclonia alone occurred around menstruation.

Table 1

VNS parameters

	Duration after VNS implantation
	2 W	1 M	2 M	5 M	7 M	11 M
W: weeks, M: months, NC: no change, VNS: vagal nerve stimulation
Output current (mA)	0.250	0.375	0.500	0.625	0.750	0.875
Pulse width (μV)	250	250	250	250	250	250
Duty cycle (%)	10	10	10	10	10	10
Responder rate	NC	NC	NC	<50%	>50%	>50%
				reduction	reduction	reduction

During ASM treatment before VNS, her PCOS had been treated with low-dose estrogen-progestin. This was discontinued because of epileptic seizures around menstruation. Fifteen months following VPA discontinuation, her PCOS improved, and her menstrual cycles became regular.

Discussion

In this report, the case of a woman with EMA who developed PCOS while receiving VPA and underwent VNS therapy was described. In this case, three key points were presented: 1) VNS therapy was useful for treating EMA; 2) women with EMA taking VPA must be aware of the risk of PCOS and monitor their menstrual cycles; and 3) information from the family, including home videos, helped with the diagnosis. Without suspecting EMA, detecting eyelid myoclonia was difficult using full-field images of long-term video EEG monitoring.

First, VNS therapy helped treat EMA in this case. Both generalized seizure and EMA were reduced by >50% at low output currents of <1.00 mA after 1 year of VNS. We suggest that VNS therapy could be a treatment option for EMA because it was effective at low levels of stimulation. In cases of epilepsy, higher-level stimulation is more effective,¹¹^,¹²⁾ and the population-level target output current of VNS is 1.61 mA.¹³⁾ Eyelid myoclonia is usually associated with several seizure types:³^,⁴^,⁷^,⁸^,¹⁴⁾ absence seizures (90.6%), GTCS (78.1%), and myoclonic seizures (43.7%).⁸⁾ Several reports suggest that VNS therapy may be effective in treating these seizures. VNS therapy effectively treats approximately 60%-80% of generalized seizures and response rates increase over time.¹⁵^,¹⁶⁾ Atypical absence, generalized tonic-clonic, and myoclonic seizures were significantly reduced via VNS therapy in children with Lennox-Gastaut or Lennox-like syndrome.¹⁷⁾ The efficacy of VNS therapy in patients with medically refractory absence epilepsy was >50%, and the responder rate was 55%.¹⁸⁾ Recently, its use has been extended to epileptic seizure clusters.¹⁹⁾

Second, women with EMA taking VPA should be aware of the risk of PCOS and monitor their menstrual cycles. PCOS is highly prevalent in women with epilepsy on VPA,²⁰⁾ especially if started before the age of 20 years.⁹⁾ EMA occurs around the age of 7 years and requires long-term treatment using ASMs, mainly VPA and LEV.⁴^,⁶⁾ Since the first description of EMA by Jeavons in 1977,¹⁾ case reports and small studies have been published,¹^-⁵^,⁷^,⁸⁾ but the prognostic and clinical features remain partially uncertain.¹^-⁸^,¹⁴⁾ A recent study has reported electroclinical endophenotypes and long-term seizure outcomes in a large cohort of patients with EMA.⁶⁾ We speculate that PCOS, which can occur in adulthood and is not a direct symptom of EMA itself, has received little attention because EMA is a disease of childhood onset. Improvement in PCOS has been reported after VPA discontinuation.¹⁰⁾ VPA should be discontinued if possible; however, in several cases, controlling seizures with medications other than VPA is difficult.²¹⁾ Besides PCOS, VPA has been reported to cause teratogenicity and cognitive decline in children and should be avoided in women if possible.²²^,²³⁾ Other ASMs are preferred for female patients with childhood-onset generalized epilepsy. VNS therapy might be suggested for adult female patients with generalized epilepsy who respond only to VAP.

Third, information from the family, including home videos, helped with the diagnosis. Although EMA was suspected, a careful review of the video EEG revealed that eyelid myoclonia synchronized with spike-/polyspike-and-wave discharges. In one study that involved 70 patients with EMA, 77.1% were misdiagnosed with another epilepsy syndrome, most commonly childhood absence epilepsy and JME.⁷⁾ Another study reported that eyelid myoclonia takes an average of 9.6 years to be diagnosed.⁴⁾ The under-recognition of eyelid myoclonia and various seizure types make diagnosis challenging. Only 18.7% of the patients or their relatives were aware of eyelid myoclonia.⁸⁾ Most of the patients with EMA experienced more than one seizure type: absence, GTCS, myoclonic seizures, and other generalized seizure-like tonic and atonic.³^,⁴^,⁷^,⁸^,¹⁴⁾

To conclude, this report recommends that VNS is an effective option for patients with refractory epilepsy requiring VPA discontinuation. Women with EMA taking VPA must be aware of PCOS and monitor their menstrual cycles. This patient with EMA, who became refractory after discontinuing VPA, achieved >50% seizure reduction with VNS therapy in a short-term follow-up period. Without suspecting EMA, eyelid myoclonia using full-field imaging of video EEG was difficult to detect. Nevertheless, information from the family, such as home videos, aided in the diagnosis.

Supplementary Material

https://doi.org/10.2176/jns-nmc.2023-0083

Acknowledgments

We are grateful to the patient and her family, as well as the medical secretary, for their participation in this study. We also thank Editage for English language editing.

Abbreviations

ASM: antiseizure medication

BTCS: bilateral tonic-clonic seizures

EEG: electroencephalography

EMA: eyelid myoclonia with absence

LEV: levetiracetam

PCOS: polycystic ovary syndrome

PER: perampanel

TPM: topiramate

VNS: vagus nerve stimulation

VPA: valproate

Ethics Approval

The study was approved by the Ethical Committee at St. Marianna University School of Medicine (#4697).

Informed Consent

The patient provided informed consent for the publication of this case report.

Availability of Data and Materials

The data underlying this article cannot be shared publicly for privacy reasons. The data will be shared upon reasonable request from the corresponding author.

Conflicts of Interest Disclosure

The authors have no conflicts of interest to disclose.

References

Corresponding author

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