*4.1.1 Primary generalized tonic-clonic seizures*

Gowers first noted that patients with primary generalized tonic-clonic seizures have their seizures in two peaks during sleep: the first - two hours after sleep onset and at the end of the sleep cycle [1]. There are two peaks of sleep-related seizures occurred between 9-11 pm and 3-5 am respectively [10]. Further studies showed that generalized tonic-clonic epilepsy occurs mainly during NREM sleep [15, 16]. Generalized interictal epileptiform activity (IEA) increases in NREM sleep [17]. In arousal epilepsies or epilepsies occurring during awake and sleep states, IEA can occur at any time. Meanwhile, in pure sleep epilepsy, IEA have been described during REM sleep and/or on awakening in 9% of the patients and restricted to NREM sleep in 41% [10].

#### *4.1.2 Juvenile myoclonic epilepsy*

Juvenile myoclonic epilepsy [JME] is a syndrome characterized by the combination of myoclonic, absence, and generalized tonic-clonic seizures that especially occur in the morning in the first one to two hours after awakening, that is a hallmark of this syndrome. Seizures are often triggered by externally provoked arousals in the morning after a sleepless night associated with alcohol consumption. JME is an agerelated, genetic, and generalized epilepsy syndrome that typically begins in early adolescence [10, 18]. Seizures can also occur on awakening from a nap, but rarely at other times during the day [18]. The classic EEG shows generalized spike-wave complexes at 4-6 Hz as well as polypiles. The discharges increase markedly at sleep onset and awakening, but are less frequent in NREM sleep, REM sleep, and wakefulness. The arousal period is apparently a hyper-synchronous state that makes more permissible the conduction of epileptic discharges.

Valproic acid or other newer broad-spectrum antiepileptics [AEDs] such as levetiracetam, lamotrigine, topiramate, zonisamide and perampanel may lead to excellent seizure control in patients who adhere to rigid compliance and avoid seizure precipitant such as sleep deprivation and alcohol binges. Medication requirement typically endures throughout life, with seldom patients being successfully weaned from therapy long-term in later adulthood.

A closely related primary generalized epilepsy syndrome called generalized tonic-clonic seizures upon awakening (GTCOA) has a similar pattern of occurrence of convulsions, but without myoclonic seizures.

#### **4.2 Focal seizures**

#### *4.2.1 Temporal lobe epilepsy*

Sleep related complex partial seizures originating in the temporal lobe are frequent and represent around 33% of all temporal lobe seizures [19]. Nocturnal temporal lobe epilepsy (NTLE) is a subtype of medically refractory temporal lobe epilepsy, usually presenting during adolescence with seizures nearly exclusively

confined to nighttime sleep [18]. In most cases, seizures are characterized by sudden awakening from sleep with a sensory aura, which then progresses to a focal seizure with impaired awareness. The latter is often associated with amnestic automatisms that mimic a NREM parasomnia called confusional arousal. Most patients (around 70%) also have secondary generalized tonic-clonic seizures [18].

Regarding IEA, most studies have found an increase in interictal epileptiform activity during NREM sleep with decrement during REM sleep. The spike frequency was 85% in NREM and 12.5% in REM sleep [20]. Sammaritano found that the extent of the electrical field increased in more than 75% of the spikes in NREM compared with the wake state. Meanwhile, there was a restriction of the electrical field of the epileptiform activity during REM sleep. Desynchronization of EEG pattern during REM sleep reduces the likelihood of spatial and temporal summation of aberrant depolarizations [21]. One third of patients have bilateral IEDs that occur independently on both sides, especially during NREM. However, localization of the primary epileptogenic area is more reliable in REM sleep than in wakefulness, and in wakefulness more than in slow-wave sleep. Therefore, REM sleep provides an opportunity to better localized the epileptic focus. When seizures occur during daytime they are common in the afternoon or are bimodal, and peak in the morning and afternoon [22].
