Ethosuximide is a succinimide-class ASM that has been used clinically since the 1960s. It is primarily indicated for the treatment of absence (petit mal) seizures and is typically administered as monotherapy in patients with uncomplicated absence epilepsy [2,4]. Its principal mechanism of action involves inhibition of low-threshold T-type calcium channels in thalamic neurons, which play a critical role in generating the 3-Hz spike-and-wave discharges characteristic of absence seizures [2,4]. By reducing T-type calcium currents, ethosuximide suppresses abnormal thalamocortical rhythmic activity and stabilizes neuronal excitability. Additional proposed mechanisms include modulation of sodium and potassium currents, as well as alterations in cortical neurotransmitter levels [2].

Although ethosuximide is generally effective and well tolerated, rare but severe psychiatric adverse effects, including hallucinations, psychosis, mania, and suicidal ideation, have been reported [5]. We report the case of an 8-year-old girl who developed visual hallucinations, psychotic symptoms, and suicidal ideation shortly after initiation of ethosuximide therapy and discuss the clinical implications of this adverse reaction.

The patient presented with a 10-month history of daily staring episodes lasting 5 to 10 seconds each. Neurological examination findings were unremarkable. During the initial evaluation, hyperventilation provoked typical absence seizures, which were captured on EEG as 3-Hz generalized spike-and-wave discharges, thereby confirming the diagnosis of CAE (Fig. 1).

Ethosuximide capsules were initially considered as first-line therapy; however, concerns were raised regarding the patient’s ability to swallow them. Although a syrup formulation would have been preferable, only capsules are available in South Korea. Valproic acid was considered as an alternative option; however, it was not selected at that stage because of concerns regarding potential adverse effects in girls. Consequently, lamotrigine was initiated because it is generally well tolerated and effective for absence seizures. Nevertheless, the seizures persisted despite adequate dose escalation. Ethosuximide was subsequently initiated at 250 mg/day (6.25 mg/kg/day) while the lamotrigine dose was gradually tapered. One week later, the ethosuximide dose was increased to 500 mg/day (12.5 mg/kg/day).

Shortly after the dose was increased to 500 mg/day, the patient began experiencing visual hallucinations, including seeing people in the room who were not actually present, as well as distressing intrusive imagery involving chewing feces. She also demonstrated verbal aggression, including blasphemous speech directed toward religious figures. Notably, she developed delusional beliefs, such as perceiving her parents as ‘ghosts in disguise’ and viewing her own face as ‘hideous,’ accompanied by suicidal ideation. Neurological examination and laboratory findings remained unremarkable. Importantly, there was no personal or family history of psychiatric disorders.

Ethosuximide was discontinued immediately. The patient’s hallucinations, psychotic symptoms, and suicidal ideation gradually resolved within 3 days without additional psychiatric medication. Subsequently, valproic acid monotherapy was initiated, and her seizures have since remained well controlled.

Ethosuximide is a well-established first-line treatment for CAE because of its efficacy and generally favorable safety profile [2,4]. However, as demonstrated in the present case, clinicians should remain aware that serious psychiatric adverse effects, including hallucinations, psychosis, and suicidal ideation, may occur in pediatric patients. Three potential explanations were considered for these psychiatric manifestations: a preexisting psychiatric predisposition, forced normalization, or a direct adverse reaction to ethosuximide.

First, the possibility of a comorbid psychiatric disorder or genetic predisposition was considered. Psychosis is known to occur more frequently in individuals with epilepsy, with an estimated prevalence of 7% to 10% among adults with epilepsy compared with approximately 0.4% in the general population [6]. Although the prevalence of psychosis in children with epilepsy has not been clearly established, a recent nationwide population-based survey conducted in the United Kingdom reported psychiatric disorder rates of 56% among children with complicated epilepsy and 26.2% among those with uncomplicated epilepsy, compared with 9.3% among controls [7]. Given the increased prevalence of psychiatric disorders in patients with epilepsy, one possibility was that the patient’s symptoms reflected a psychiatric condition comorbid with epilepsy. However, the clear temporal association between symptom onset and initiation of ethosuximide therapy argues against this interpretation, particularly in light of the absence of prior psychiatric symptoms or a family history of mental illness.

Second, the possibility of forced normalization was evaluated [8]. This phenomenon refers to the paradoxical emergence of psychiatric symptoms following seizure control or normalization of EEG findings. However, this hypothesis did not adequately explain the clinical course observed in the present case. The patient developed psychotic symptoms and suicidal ideation while continuing to experience absence seizures. Therefore, because the symptoms did not emerge in the setting of seizure suppression, forced normalization was considered unlikely.

Third, a direct adverse effect of ethosuximide was considered the most plausible explanation. Although the symptoms developed during the transition from lamotrigine therapy, the absence of psychiatric symptoms during lamotrigine monotherapy suggests that ethosuximide was the primary causative agent. Notably, the patient’s hallucinations, psychotic symptoms, and suicidal ideation resolved rapidly within 3 days after discontinuation of ethosuximide, without the need for additional psychiatric intervention. This strong temporal relationship, characterized by symptom onset following dose escalation and rapid resolution after drug withdrawal, provides compelling evidence supporting a direct causal association.

Ethosuximide is the first-line treatment for CAE and exerts its effects primarily through inhibition of low-threshold T-type calcium channels in thalamic neurons [2,4]. Common adverse effects include gastrointestinal disturbances and drowsiness; however, rare but serious psychiatric adverse effects, such as hallucinations, psychosis, and suicidal ideation, remain clinically important [5]. Although the mechanisms underlying these psychiatric manifestations are not fully understood, they may involve alterations in thalamocortical neurotransmission induced by ethosuximide.

Although ethosuximide is highly effective for the treatment of CAE, clinicians should remain vigilant for rare but severe psychiatric adverse effects. In the present case, the patient’s symptoms were considered a direct adverse drug reaction to ethosuximide. Discontinuation of the medication resulted in complete symptom resolution, and seizure control was subsequently achieved with valproic acid monotherapy. Further studies are needed to clarify the mechanisms underlying these adverse effects and to identify patients who may be at increased risk.

This report was approved by the Institutional Review Board of Sanggye Paik Hospital (IRB No. 2025-11-002).