Cognitive decline and behavioral impairments can lead to reductions in quality of life (QOL) in children with epilepsy. Seizure activities, including frequent seizures and status epilepticus (SE), have been identified as important predictors of QOL. In addition, interictal epileptiform discharges (IEDs) on electroencephalogram (EEG) can lead to behavioral impairments, and thus, may also be an important predictor of QOL. Seizure severity and/or IEDs are, therefore, important QOL-related factors in childhood epilepsy. Brain volumetric studies showed that severe seizures can lead to neuropsychological impairments in association with prefrontal lobe growth disturbances in children with epilepsy. On the other hand, frontal IEDs and secondary bilateral synchrony (SBS) on EEG can be a risk factor for neuropsychological impairments. Behavioral disturbances can be improved in association with a reduction in IEDs in children with frontal IEDs and SBS. Therefore, frontal IEDs and SBS can also lead to neuropsychological impairments in children with epilepsy. These findings suggest that seizure severity and IEDs on EEG may be associated with cognitive decline and behavioral impairments, leading to QOL reduction. Therapeutic management may be desirable to reduce seizures and EEG abnormalities, such as frontal IEDs and SBS, as early as possible to improve QOL in children with epilepsy.

The role of glial cells in the epileptic brain has attracted considerable attention. This is partly because each type of glial cell has unique functions and exhibits unusual features in epileptic pathology. Now that the information held by glial cells can be decoded in different ways, glial cells have become important players in understanding the relationship between epileptic pathology and neural networks. In this workshop, we presented our studies on the mechanisms by which microglia and astrocytes modulate neural networks in epileptic pathology using a kainic acid-induced mouse model of epilepsy.

In particular, we presented the mechanism by which microglia are involved in auditory dysfunction following epileptic seizures. Although auditory dysfunction and increased neuronal activity in the auditory pathway have been reported after epileptic seizures, the cellular mechanisms involved have remained unclear. First, we found that neuronal activity in the auditory pathway, including the primary auditory cortex and medial geniculate body, is increased after epileptic seizures, impairing the ability to discriminate sounds. Second, we found that microglia detach inhibitory synapses projecting to thalamic relay neurons, leading to increased activity in the auditory pathway over an eight-week period after epileptic seizures. Finally, we found that local removal of microglia from the medial geniculate body suppressed relay neuron activity and improved sound discrimination. These results suggest that microglia in the thalamus are involved in auditory dysfunction after epileptic seizures.

In this review, we summarize our recent findings on epilepsy and auditory dysfunction presented at the workshop, as well as the role of synaptic E/I balance alterations and microglia in the epileptic brain.

Significant evolution in the understanding of epileptic encephalopathy has led to the formalization of "developmental and epileptic encephalopathy (DEE)". Hypothalamic hamartoma produce drug-resistant gelastic seizures, with cognitive dysfunction and behavioral abnormalities (GS-HH: gelastic seizures-hypothalamic hamartoma syndrome). GS-HH, formerly considered as "epileptic encephalopathy", is now classified as DEE. This paper aims to advance scientific understanding of DEE by examining the etiology of GS-HH, the mechanisms of epileptogenesis in HH, and cognitive dysfunction before and after surgical intervention. The etiology of HH is primarily associated with abnormal Sonic Hedgehog (Shh) signaling due to somatic mutations during early embryogenesis. The severity of structural brain abnormalities depends on the timing of these mutations, often resulting in developmental encephalopathy for severe cases. The cellular mechanism underlying epileptogenicity in HH is characterized by aberrant expression of Ca2+-permeable AMPA receptors. Stereotactic radiofrequency thermocoagulation (SRT) is an effective surgical method for controlling gelastic seizures by disconnecting the hypothalamic hamartoma from normal brain. Subsequent improvements in cognitive and behavioral function after SRT indicate a pathological basis for epileptic encephalopathy. Cognitive dysfunction in GS-HH, classified as DEE, is also influenced by a variety of social factors and medication side effects. From a neurodevelopmental perspective, early diagnosis and surgical intervention are crucial.

Comorbid neurodevelopmental disorders such as attention-deficit hyperactivity disorder and autism spectrum disorder are known to occur frequently in children with epilepsy. In particular, comorbid conditions are more likely to cause executive dysfunction and maladaptive behaviors. Inattentive symptoms often go unnoticed, and the development of noninvasive, objective biomarkers are required. In this context, electrophysiological evaluation methods such as event-related potentials and functional near-infrared spectroscopy (fNIRS) are being applied clinically. In particular, NoGo potentials, which evaluate behavioral inhibition, have been found to be useful in the evaluation and follow-up of reduced amplitude and prolonged latency in frontal lobe epilepsy, temporal lobe epilepsy, juvenile myoclonic epilepsy, and other forms of epilepsy. In addition, fNIRS can observe brain activation by measuring changes in oxygenated hemoglobin in response to various tasks, and can evaluate various executive functions using behavioral inhibition and verbal fluency tasks. These tests are expected to be clinically applicable as biomarkers of executive function in children with epilepsy in the future.

In the management of epilepsy in women of childbearing age, preparations for potential pregnancy should begin from adolescence.

Regarding antiseizure medications and contraception, some antiseizure medications, including enzyme-inducing drugs, may reduce the effectiveness of oral contraceptives when used in combination. Combining lamotrigine with oral contraceptives can lower lamotrigine blood levels, increasing the risk of seizure frequency.

Supplementing women with epilepsy with folic acid before they become pregnant should be considered.

The teratogenicity of antiseizure medications generally shows dose-dependency, so treatment should aim for the minimum necessary dosage. In general, valproate is considered to have a high teratogenic risk, and fetal exposure to valproate can affect cognitive function after birth. For some antiseizure medications, the maternal physiological changes during pregnancy can lead to decreased blood levels, requiring dosage adjustments.

Breastfeeding by mothers with epilepsy who are taking antiseizure medications is generally possible. Most reports indicate that antiseizure medications transferred through breast milk do not negatively impact the cognitive function of infants.