Sleep-related epilepsy syndromes

INTRODUCTION — Epileptic seizures frequently manifest during the sleep state and are often difficult to distinguish from parasomnias and other nonepileptic events, particularly when seizures occur exclusively during sleep. While most epilepsies have a diurnal component (ie, seizures may occur during both sleep and wake), several epilepsy syndromes have an especially intimate and robust relationship with sleep [1].

This topic reviews the pathophysiology of seizures and epilepsy related to sleep and the clinical features, diagnosis, and treatment of common sleep-related epilepsy syndromes. The clinical features, diagnosis, and treatment of seizures and epilepsy more generally are reviewed elsewhere. (See "Evaluation and management of the first seizure in adults" and "Overview of the management of epilepsy in adults" and "Seizures and epilepsy in children: Clinical and laboratory diagnosis" and "Seizures and epilepsy in children: Classification, etiology, and clinical features" and "Seizures and epilepsy in children: Initial treatment and monitoring".)

The association of sudden unexpected death in epilepsy (SUDEP) with sleep and sleep-related seizures is also reviewed in detail elsewhere. (See "Sudden unexpected death in epilepsy".)

CLASSIFICATION AND EPIDEMIOLOGY — Although the International League Against Epilepsy does not formally classify sleep-related epilepsies, in practice they can be divided into three major categories:

●Pure sleep epilepsies, in which seizures occur exclusively or predominantly during sleep (eg, benign epilepsy of childhood with centrotemporal spikes, sleep-related hypermotor epilepsy) (see 'Self-limited focal epilepsies of childhood' below and 'Sleep-related focal epilepsies' below)

●Sleep-accentuated epilepsies, in which seizures occur during both wakefulness and sleep but epileptiform activity is potentiated during sleep (eg, certain epileptic encephalopathies, including Lennox-Gastaut syndrome and Landau-Kleffner syndrome) (see 'Sleep-accentuated epilepsies' below)

●Arousal epilepsies, in which seizures are most common in the period following awakening from sleep (eg, juvenile myoclonic epilepsy) (see 'Arousal epilepsies' below)

The reported frequency of sleep-related epilepsy as a proportion of all epilepsy varies widely, but most estimates fall between 10 and 15 percent [2,3]. Focal epilepsies are the most frequent manifestation of sleep-related epilepsy, accounting for approximately 80 percent of the pure sleep epilepsies [4].

Among patients following an apparent course of pure sleep epilepsy, the risk of developing subsequent seizures during wakefulness is approximately 6 percent within one year of presentation [2] and 10 to 30 percent overall [5,6], which complicates classification and attempts to estimate prevalence.

SLEEP AND EPILEPTOGENESIS — Sleep and sleep stage have a significant impact on the occurrence and frequency of both seizures and epileptiform discharges that occur in between seizures (interictal epileptiform discharges [IEDs]) [1]. In general, non-rapid eye movement (NREM) sleep facilitates IEDs and seizures, while rapid eye movement (REM) sleep tends to inhibit seizures [7-10]. (See "Electroencephalography (EEG) in the diagnosis of seizures and epilepsy", section on 'Interictal epileptiform discharges'.)

IEDs increase in frequency as sleep depth increases, usually reaching peak frequency during stage N3 of NREM sleep [7,10]. NREM may also lead to altered spike morphology and a more extensive electrographic field of distribution [8,10]. The mechanism by which NREM sleep facilitates IED and seizure expression likely relates to physiological hypersynchrony and thalamocortical oscillatory neural activity during NREM sleep, as reflected on electroencephalography (EEG) by sleep spindles (figure 1). As NREM progresses, responsiveness to external stimuli progressively decreases and the arousal threshold increases, in parallel with increasing delta frequency power (figure 2) [11-14]. (See "Stages and architecture of normal sleep", section on 'NREM sleep'.)

There is additional evidence suggesting that epileptic seizures may "highjack" the normal physiology of strengthening and weakening of synaptic connections and memory consolidation that occurs during N3 sleep, further strengthening the epileptogenic network in refractory focal epilepsies [15]. In a pilot study in patients with focal epilepsy, nocturnal seizures were associated with worse performance on visual memory tasks, indicating that seizures may adversely affect sleep-dependent memory consolidation [16].

In contrast with NREM sleep, REM sleep is relatively inhibitory towards seizure activity [9]. In one literature review, REM sleep was associated with approximately 80 percent fewer focal seizures and 30 percent fewer generalized seizures relative to wakefulness [17]. IEDs during REM sleep tend to be more restricted and localizing, a potentially useful diagnostic localizing feature in patients undergoing preoperative evaluation for epilepsy surgery [8]. (See "Surgical treatment of epilepsy in adults".)

Clinically overt seizures occur most frequently during lighter stages of NREM sleep (N1 and N2), despite peak IED frequency during N3 sleep [18,19]. In patients with refractory focal epilepsy being considered for epilepsy surgery, approximately one-third of recorded seizures arise from the sleep state [18]. In addition, focal temporal lobe seizures during sleep are more likely to spread and become generalized tonic-clonic seizures than those that arise during wakefulness [20]. This may explain why first-time seizures or new-onset epilepsy often presents following a witnessed nocturnal convulsion.

The propensity for seizures during sleep may vary according to brain lobe or region. Patients with extratemporal seizures, especially those of frontal lobe origin, are more likely to have nocturnal seizures than patients with temporal lobe onset seizures [18,21].

Sleep deprivation has long been recognized as a seizure precipitant in some patients with epilepsy, although studies have been inconsistent [1,22,23]. Comorbid sleep disorders may also aggravate seizure burden, and patients with epilepsy are at increased risk for a range of sleep disorders, including sleep-related breathing disorders and insomnia. (See "Comorbidities and complications of epilepsy in adults", section on 'Sleep disorders'.)

SELF-LIMITED FOCAL EPILEPSIES OF CHILDHOOD — Several self-limited epilepsies of early childhood are characterized by seizures and epileptiform activity that occur predominantly or exclusively during sleep [24]:

●Self-limited epilepsy with centrotemporal spikes (SeLECTS) – SeLECTS, previously known as benign rolandic epilepsy or benign (childhood) epilepsy with centrotemporal spikes (BCECTS or BECTS), is one of the more common epilepsy syndromes in childhood and a classic form of pure sleep epilepsy. It is an age-dependent focal epilepsy syndrome of unknown etiology with a peak incidence in children between seven and nine years of age. A genetic basis has been suspected but is not yet well characterized.

Seizures are confined to sleep in the majority of patients. The characteristic focal seizure type involves nocturnal hemifacial clonic twitching accompanied by hypersalivation, evolving to a focal hemi-tonic-clonic seizure. Nocturnal focal seizures may go unnoticed until the development of a secondarily generalized seizure. The clinical features, diagnosis, treatment, and prognosis of SeLECTS are reviewed in more detail separately. (See "Self-limited focal epilepsies of childhood", section on 'Self-limited epilepsy with centrotemporal spikes (SeLECTS)'.)

●Self-limited epilepsy with autonomic seizures (SeLEAS) – This epilepsy syndrome was previously known as early-onset (benign) childhood occipital epilepsy, or Panayiotopoulos syndrome, and is characterized by a unique seizure type that has prominent autonomic features. Most seizures occur from sleep. Visual symptoms, usually a seizure aura, are variably present. (See "Self-limited focal epilepsies of childhood", section on 'Self-limited epilepsy with autonomic seizures (SeLEAS)'.)

SLEEP-RELATED FOCAL EPILEPSIES — Sleep-related (nocturnal) focal epilepsies have traditionally been named according to the localization of seizure onset. The most common of these is sleep-related hypermotor epilepsy (SHE), previously called nocturnal frontal lobe epilepsy (NFLE). Sleep-related temporal, parietal, and occipital lobe epilepsies also exist but are less common and have overlapping clinical features with SHE. Most have an onset in adolescence or early adulthood.

Etiology and genetics — Many sleep-related focal epilepsies are genetic, but structural etiologies as well as sporadic cases with unknown etiology also occur. A family history is often present.

Genetic forms of SHE include autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), a genetically heterogeneous epilepsy syndrome associated with variable disease severity and penetrance. Pathogenic variants in the CHRNA4 gene, which encodes for the alpha 4 subunit of the neuronal nicotinic acetylcholine receptor, were the first to be identified in families with ADNFLE [25,26]. Since then, multiple additional genes have been linked to ADNFLE, most of which are related to the cholinergic system, including CHRNA2, CHRNB2, CRH, KCNT1, and DEPDC5P [27,28]. Both inherited and de novo pathogenic variants have been described, and the known variants account for a minority of cases [29].

Neurodevelopmental lesions appear to be the most frequent structural cause of SHE, in particular type IIb focal cortical dysplasia (FCD) [30]. Regardless of location, type II FCD appears to increase the risk of sleep-related seizures [30,31], and therefore these lesions may also explain some cases of pure sleep epilepsy in which seizures localize outside of the frontal lobe. One study found that the etiology of focal cortical dysplasia was independently associated with sleep-related epilepsy when compared with other pathologies such as hippocampal sclerosis, encephalomalacia, and low-grade tumors [32]. A genetic basis for many of the neurodevelopmental lesions is recognized as well. SHE and magnetic resonance imaging (MRI)-negative type I FCD or periventricular nodular heterotopia were reported in four patients with KCNTI mutations who underwent surgical resection [33]. (See "Focal epilepsy: Causes and clinical features", section on 'Genetic focal epilepsy syndromes'.)

The etiologic basis of sleep-related temporal, parietal, and occipital lobe epilepsies has not been as well characterized, but like SHE, both familial and structural causes may occur. Like SHE, focal cortical dysplasia is the most common lesional pathology identified at the time of epilepsy surgery [34].

Clinical features

Sleep-related hypermotor epilepsy (SHE) — Although previously called nocturnal frontal lobe epilepsy (NFLE), the term SHE has been adopted for the following reasons [35]:

●Seizures are strongly linked to sleep, but less so to the time of day. "Nocturnal" is often an inaccurate label, as this implies a chronobiological pattern of seizure occurrence.

●Seizures may arise primarily in extrafrontal regions such as the temporal lobe (epileptogenic zone) and subsequently activate epileptogenic networks involving frontal brain regions (symptomatic zone).

●"Hypermotor" better characterizes the typical seizure semiology of SHE and distinguishes it from other types of frontal seizures (eg, fencer posturing, akinetic).

The diagnosis of SHE is based primarily on clinical history (table 1) [36]. Core features include:

●Brief (<2 minutes) seizures with stereotyped motor pattern and abrupt onset and offset

●Hypermotor semiology, including vigorous hyperkinetic, and/or asymmetric tonic or dystonic features, with or without impaired awareness

●Occurrence predominantly in sleep, either in nighttime or daytime hours

SHE typically begins in late childhood or adolescence, with a mean age of seizure onset of 14 years (range 1 to 64 years) [37]. Cognitive and psychomotor development are usually normal, although a high prevalence of intellectual disabilities and psychiatric or behavioral problems has been noted in some families [27]. Approximately 25 percent of patients have a positive family history of epilepsy, and up to 40 percent have a personal and/or family history of probable parasomnias. (See "Disorders of arousal from non-rapid eye movement sleep in adults", section on 'Association with sleep-related hypermotor epilepsy'.)

Focal seizures during sleep in patients with SHE have been grouped into three main types, which are of increasing duration and complexity of motor activity [27,38].

●Short (2 to 4 seconds), stereotyped movements involving the limbs, axial musculature, and/or head. Of note, these brief events may or may not correspond with ictal discharges, and some have suggested that they may represent motor release phenomena secondary to arousals rather than seizures per se [39,40].

●Sudden and brief (5 to 10 seconds) arousals from sleep ("paroxysmal arousals"), sometimes accompanied by stereotyped movements, vocalization, frightened expression, or fear. These events mimic confusional arousals, a non-rapid eye movement (NREM) sleep parasomnia. Diagnostic distinction can be difficult, as there may be overlap in parasomnia and epileptic phenomena within families and even within an individual [37,41-43]. (See "Disorders of arousal from non-rapid eye movement sleep in adults", section on 'Association with sleep-related hypermotor epilepsy'.)

●Longer seizures lasting up to two minutes (usually 20 to 30 seconds), characterized by highly stereotyped hyperkinetic ("hypermotor") and/or asymmetric dystonic movements, often with prominent vocalization. Complex movements, such as pedaling, choreoathetoid movements, and ballistic movements of the limbs, can occur. Seizures originating in the supplementary motor area are often characterized by an initial somatosensory aura, "fencer-type" asymmetric tonic posturing of the upper limbs, with or without other motor features.

A retrospective surgical series of 91 cases of frontal SHE and 44 case of non-frontal SHE found that the pattern of symptoms and signs (semiology) could help differentiate anatomic seizure onset zones; elementary motor features were predominant in frontal SHE, while gestural behaviors with high emotional content were frequent in temporal SHE [44].

In some patients, longer events include ambulatory behavior, known as episodic nocturnal wandering, which are sometimes difficult to distinguish clinically from sleepwalking or postictal confusion. In other patients with SHE, prominent dystonic posturing out of sleep was originally thought to represent a sleep-related movement disorder (termed nocturnal paroxysmal dystonia) before the events were shown to be ictal using zygomatic or sphenoidal depth electrodes in a subset of patients [45,46].

Seizures in patients with SHE often occur multiple times per night, almost exclusively during NREM sleep. Although seizure duration and the amount of motor activity may vary across the night, all events tend to begin similarly and remain highly stereotyped and stable within a given individual [37].

With long-term follow-up, nearly half of patients with SHE experience at least one seizure during wakefulness [47]. Such patients are more likely to fail to achieve long-term seizure remission.

Approximately 25 percent of patients with SHE have a family history of epilepsy, including a minority with autosomal dominant NFLE (see 'Etiology and genetics' above), and approximately one-third of patients have a personal or family history of parasomnias such as sleepwalking, sleeptalking, or sleep terrors [37]. (See "Disorders of arousal from non-rapid eye movement sleep in adults", section on 'Association with sleep-related hypermotor epilepsy'.)

Sleep-related temporal lobe epilepsy — Like SHE, sleep-related temporal lobe epilepsy usually presents during adolescence with seizures nearly exclusively confined to nighttime sleep [48]. 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, mimicking a confusional arousal.

Additional features of sleep-related temporal lobe epilepsy include the following:

●During the postictal period of impaired consciousness and persisting amnesia, episodic nocturnal wandering that resembles sleepwalking can occur.

●While hypermotor and/or dystonic motor activity often implicates frontal lobe network activation, seizures originating in the temporal lobe or insula can also manifest similar motor patterns through propagation to extratemporal regions [49-51]. In such cases, aura characteristics may be a clue to temporal lobe localization (eg, epigastric sensation, auditory hallucinations, déjà vu) (table 2).

●Approximately 70 percent of patients also have secondarily generalized tonic-clonic seizures during sleep.

Sleep-related parietal or occipital lobe epilepsy — Sleep-related parietal and sleep-related occipital lobe epilepsies may present throughout the lifespan but tend to begin during adolescence or young adulthood in most cases, with clinical features that are often similar to those of SHE. In one case series of 40 patients with nocturnal focal seizures, 30 percent of cases were not of frontal lobe onset, and many of these were proven to emanate from the parietal or occipital lobes by intracranial stereo-electroencephalography (EEG) recordings [34].

Clinical localization with parietal or occipital lobe epilepsies can be difficult because seizures arise directly from sleep and thereby often lack somatosensory or visual aura symptoms. Seizures can masquerade as frontal lobe seizures, since they may chiefly manifest with hypermotor features, reflecting propagation to the frontal lobe or insula. The chief ictal EEG manifestations may also be frontal, especially on scalp EEG recordings [34,52].

Electroencephalography — Routine outpatient EEG has low diagnostic yield in patients with SHE and other sleep-related focal epilepsies due to low interictal epileptiform discharge (IED) frequency and limited sampling of deep NREM sleep. Routine awake EEG is normal in approximately half of patients with SHE and shows clear-cut focal IEDs in approximately one-third of patients [37].

Prolonged outpatient ambulatory or inpatient video-EEG recordings, or overnight video-EEG polysomnography, are of higher yield in detecting IEDs and capturing seizures in the sleep-related focal epilepsies, although scalp EEG may be insensitive in patients with seizures arising from deep-seated cortex [35]. Even prolonged video-EEG may be uninformative in such cases.

Interpretation of IEDs and other findings on EEG in patients with epilepsy is reviewed in more detail separately. (See "Electroencephalography (EEG) in the diagnosis of seizures and epilepsy", section on 'EEG findings in patients with epilepsy'.)

Diagnostic evaluation — Sleep-related focal epilepsy should be suspected in older children and young adults presenting with stereotyped motor events during sleep, particularly when they occur multiple times per night. Seizures often have unusual yet highly stereotyped clinical characteristics, especially those of SHE, and can be mistaken for parasomnias or psychogenic nonepileptic spells due to their variably impaired awareness with partial or complete preservation of consciousness, bizarre movements, minimal postictal alteration, and absence of clear-cut ictal EEG abnormalities in some cases (see 'Clinical features' above and 'Electroencephalography' above). However, the clinical triad of stereotypy across repeated spells, multiple spells within a single night, and onset directly from the sleep state is highly suggestive of an epileptic disorder. (See 'Differential diagnosis' below.)

As in diurnal epilepsies, the electroclinical diagnosis of SHE and sleep-related epilepsies arising from the temporal, parietal, or occipital lobes is based on clinical features, seizure semiology, and supportive EEG findings. Most cases of SHE and sleep-related temporal lobe epilepsy are nonlesional, and therefore a normal brain MRI does not exclude the diagnosis. In patients with diurnal focal-onset seizures arising from the frontal or temporal lobes, the designation as a sleep-related epilepsy is typically reserved for those with a predominance of seizures during sleep (eg, >90 percent) and otherwise supportive clinical features. (See 'Clinical features' above.)

An awake and asleep EEG should be performed in all patients with suspected seizures during sleep, both to help confirm the diagnosis of epilepsy and to localize seizure onset. The diagnostic yield of interictal EEG in patients with nocturnal epilepsy is limited, however, especially for SHE. Repeat studies, an all-night recording, or polysomnography (PSG) with video and a full EEG montage may be necessary to confidently capture diagnostic abnormalities; even prolonged interictal EEG studies can be normal in patients with SHE, and the absence of IEDs does not exclude the diagnosis. (See 'Electroencephalography' above.)

In patients with refractory seizures being considered for epilepsy surgery, long-term video-EEG monitoring, functional or metabolic imaging, and/or invasive EEG monitoring may be necessary to adequately localize seizures. (See "Surgical treatment of epilepsy in adults", section on 'Seizure localization'.)

Brain MRI is recommended in patients with new-onset sleep-related seizures to evaluate for focal cortical symptomatic pathology such as a tumor, infarct, vascular malformation, or a malformation of cortical development. A high-resolution, epilepsy-protocol MRI is preferred to maximize the sensitivity for detecting subtle neurodevelopmental lesions or other focal abnormalities and is required in the setting of refractory seizures. (See "Neuroimaging in the evaluation of seizures and epilepsy", section on 'Magnetic resonance imaging' and 'Etiology and genetics' above.)

Genetic testing is not routinely indicated for clinical purposes, since the proportion of cases with an identifiable mutation is low, even in the presence of a positive family history, and the clinical utility of results remains limited. (See 'Etiology and genetics' above.)

Differential diagnosis — The nocturnal seizures of SHE and other sleep-related focal epilepsies must be distinguished from other causes of abnormal movements during sleep, including (table 3):

●NREM parasomnias (eg, confusional arousals, sleep terrors, and sleepwalking)

●REM sleep behavior disorder (RBD)

●Periodic limb movements

●Psychogenic nonepileptic spells

●Nocturnal panic attacks

●Other sleep related movements (eg, rhythmic movement disorder, hypnic jerks)

Video PSG with extended EEG and electromyography (EMG) montage enables timely and confident diagnosis when the nature of nocturnal events is unclear on clinical grounds and is strongly suggested when spells are frequent, disruptive to sleep quality and quality of life, or when they are potentially injurious. An approach to distinguishing among the various types of nocturnal events is presented separately. (See "Approach to abnormal movements and behaviors during sleep".)

Distinguishing sleep-related epilepsy from an NREM parasomnia can be particularly challenging in some cases. Seizures and NREM parasomnias often have similar clinical presentations, involving arousal from sleep with confusion, abnormal motor activity, or sleepwalking. Clinical features favoring a diagnosis of sleep-related epilepsy over parasomnia include stereotypy, multiple events per night, prolonged postictal confusion or lateralized weakness or aphasia, lack of corresponding dream mentation, and an abnormal ictal EEG (table 4). Conversely, features favoring a parasomnia include a low frequency of occurrence, prolonged event duration (eg, longer than two minutes), and lack of recall for the events. A video-PSG analysis of 89 patients with SHE or disorders of arousal (DOA) found that DOA episodes occurred mostly during N3 while SHE episodes occurred mostly during N2 [53]. (See "Disorders of arousal from non-rapid eye movement sleep in adults", section on 'Clinical features'.)

The Frontal Lobe Epilepsy and Parasomnias (FLEP) Scale was developed in an effort to distinguish SHE from NREM and REM parasomnias by clinical features alone [54]. A score of zero or less favors a diagnosis of parasomnia, whereas scores of 3 or greater favor SHE. A small validation study found that while the scale had excellent specificity for SHE, sensitivity was only 71 percent; nearly a third of patients (mostly those with RBD) scored in the indeterminant range of 1 to 2, and four patients (6 percent) were misclassified [55]. The scale is therefore best used as an adjunct to the clinical history rather than as a substitute for further testing.

When the cause of recurrent nocturnal events remains uncertain based on clinical history and routine EEG, an overnight ambulatory EEG or video PSG with full montage should be considered. Video PSG with extended EEG in a sleep laboratory may be preferred if spells are nightly or near nightly in frequency, whereas video EEG in an inpatient epilepsy monitoring unit should always be chosen if antiseizure medication discontinuation is necessary, when nocturnal events are more sporadic in frequency, or when there are also daytime spells requiring additional neurophysiologic diagnostic assessment. (See "Polysomnography in the evaluation of parasomnias and epilepsy" and "Video and ambulatory EEG monitoring in the diagnosis of seizures and epilepsy", section on 'Video-EEG monitoring'.)

Management — Patients with sleep-related focal epilepsies such as SHE require prompt treatment with antiseizure medication therapy to avoid potential injury and to prevent secondarily generalized and daytime seizures. Management also includes preventive counseling and referral to a multidisciplinary epilepsy center for patients with medically refractory seizures.

Selection of antiseizure medication therapy — Treatment principles for patients with an established diagnosis of SHE and other sleep-related focal epilepsies are similar to those for diurnal epilepsies, including choosing an antiseizure medication that is appropriate for focal-onset seizures (table 5 and table 6) and using monotherapy initially at the lowest effective dose to avoid adverse effects. Principles of antiseizure medication selection and dosing are reviewed in detail separately; important considerations include patient characteristics such as age, sex, and comorbidities, as well as minimizing potential drug interactions with any concurrent medications. (See "Seizures and epilepsy in children: Initial treatment and monitoring" and "Initial treatment of epilepsy in adults" and "Antiseizure medications: Mechanism of action, pharmacology, and adverse effects".)

Because SHE and other sleep-related focal epilepsies are relatively rare disorders, supporting evidence for specific drugs is sparse and largely anecdotal. In SHE, carbamazepine has been reported as the drug of choice [35,37,56,57]. However, other antiseizure medications with a related mechanism of action (eg, oxcarbazepine, eslicarbazepine, lamotrigine) may be similarly effective. Limited data suggest that lacosamide or perampanel may also be beneficial [58,59]. Most of the literature on carbamazepine predates the availability of second-generation antiseizure medications. (See "Antiseizure medications: Mechanism of action, pharmacology, and adverse effects", section on 'Mechanisms of action'.)

In a case series of 100 patients with SHE, 80 patients were treated with carbamazepine as monotherapy (59 patients) or in polytherapy (21 patients) in daily doses ranging from 200 to 1000 mg [37]. Carbamazepine was associated with improved seizure control in 70 percent of patients, including a complete response in 20 percent, at least 75 percent reduction in seizures and no daytime seizures in 24 percent, and 50 percent reduction in seizure frequency in 24 percent.

Mutation-specific therapies have not yet been identified for those patients with genetic forms of sleep-related epilepsy. There is limited evidence from small case series and case reports that nicotine is associated with benefit in patients who have drug-resistant SHE due to pathogenic variants in CHRNA4 [60-63]. In one trial of six patients with SHE due to KCNT1 mutations, oral quinidine had no effect on seizure frequency and led to a prolonged QT interval even at low doses [28].

Prognosis and indications for referral — Spontaneous remission of SHE and other sleep-related focal epilepsies is rare, and lifelong antiseizure medication therapy is usually required. Up to one-third of patients with SHE have drug-resistant epilepsy, and only 20 to 30 percent have achieved complete seizure freedom for at least five years at last follow-up [37,41-43,47,64]. Principles of drug selection in patients with a poor response to initial therapy are reviewed separately. (See "Seizures and epilepsy in children: Refractory seizures", section on 'Adding a second antiseizure medication' and "Evaluation and management of drug-resistant epilepsy", section on 'Antiseizure medications'.)

As with epilepsy more generally, very few patients who fail two appropriate antiseizure medications for their epilepsy types in adequate doses become seizure-free on other medications. Patients with drug-resistant, sleep-related epilepsy should be referred to multidisciplinary epilepsy center for consideration of additional antiseizure medication options and nonpharmacologic therapies, including epilepsy surgery, neurostimulation, and dietary therapy. In carefully selected patients with sleep-related epilepsies, surgical outcomes are favorable and similar to those reported for focal lesional epilepsy with daytime seizures [65]. (See "Seizures and epilepsy in children: Refractory seizures" and "Evaluation and management of drug-resistant epilepsy" and "Surgical treatment of epilepsy in adults".)

Supportive care and counseling — All patients should receive supportive care and counseling about seizure triggers, seizure precautions, complications of chronic epilepsy, and driving safety.

Importance of adequate sleep — Patients with sleep-related seizures may be particularly sensitive to seizure precipitation by sleep deprivation, and patients should be instructed to adhere to good sleep hygiene and to obtain adequate amounts of sleep on a regular basis. Recommendations for sleep duration in patients with epilepsy are the same as those for the general population, which vary by age group (figure 3) [66]. (See "Insufficient sleep: Evaluation and management".)

Poor sleep quality may also be due to comorbid sleep disorders such obstructive sleep apnea (OSA), restless legs syndrome (RLS), and chronic insomnia. Early identification and treatment of sleep comorbidities can substantially improve seizure frequency in patients with epilepsy, especially for the treatment of comorbid OSA with continuous positive airway pressure (CPAP) [67-69]. (See "Comorbidities and complications of epilepsy in adults", section on 'Sleep disorders'.)

Seizure precautions and risks — All patients with sleep-related seizures and their families and caregivers should be counseled about appropriate seizure precautions, such as moving the mattress to the floor or moving furniture or other objects from near the bed environment to minimize injury potential related to falls from bed. Usual seizure first aid advice should also be provided, including instruction to the family and caregivers for moving the patient to the lateral decubitus position following a seizure to prevent aspiration, timing seizure duration to alert emergency medical services when convulsive seizures exceed three to five minutes, instruction in bystander cardiopulmonary resuscitation (CPR) methods, and provision of benzodiazepines (eg, rectal diazepam, oral lorazepam, or nasal midazolam) for use in the home setting for patients with poorly-controlled or prolonged seizures. (See "Seizures and epilepsy in children: Refractory seizures", section on 'Home rescue therapy (transmucosal antiseizure medications)'.)

Patients with epilepsy are at increased risk for premature mortality due to status epilepticus, sudden unexpected death in epilepsy (SUDEP), injuries, self-harm, and medical comorbidities [70,71]. Most SUDEP deaths are unwitnessed; a disproportionate number occur during sleep and may be related to prone sleep position. (See "Sudden unexpected death in epilepsy", section on 'Other clinical and demographic features'.)

Although nocturnal seizures have been identified as a risk factor for SUDEP in unselected patients, whether patients with SHE and other nocturnal focal epilepsies have an increased risk of SUDEP compared with the general epilepsy population is not clear. One cohort study of 103 patients with SHE estimated a SUDEP risk of 0.36 per 1000 person-years, which is lower than most estimates in the general epilepsy population [72].

The cause of SUDEP remains unclear and is likely multifactorial, involving neurologic and cardiorespiratory mechanisms. Some evidence has suggested that sleep-related seizures have a greater frequency and degree of hypoxemia than waking seizures [73]. (See "Sudden unexpected death in epilepsy", section on 'Pathophysiology'.)

Risk factors, prevention, and counseling about SUDEP and other complications and comorbidities of epilepsy are reviewed in more detail elsewhere. (See "Sudden unexpected death in epilepsy" and "Comorbidities and complications of epilepsy in adults".)

Driving — Patients with exclusively sleep-related seizures may be able to drive in some jurisdictions. Many states and countries specifically exclude nocturnal seizures as a factor limiting driving, provided that the nocturnal pattern is well-established [74]. Local laws governing driving for people with epilepsy should be consulted to determine driving eligibility, and in some cases the treating physician's attestation and clinical opinion regarding sleep confinement of seizures is required to enable licensing. (See "Driving restrictions for patients with seizures and epilepsy".)

SLEEP-ACCENTUATED EPILEPSIES

●Lennox-Gastaut syndrome — Lennox-Gastaut syndrome (LGS) is an epileptic encephalopathy with onset during childhood. It is characterized by multiple seizure types, including atypical absence, myoclonic, generalized tonic-clonic, prominent and frequent nocturnal tonic seizures with nocturnal tonic status epilepticus, and prominent astatic seizures with loss of postural tone and falling. Electroencephalography (EEG) shows characteristic slow (1.5 to 2.5 Hz) spike-wave discharges. Children frequently have cognitive impairment and severe psychomotor disability. (See "Lennox-Gastaut syndrome", section on 'Clinical features'.)

Antiseizure medication therapy is incompletely effective in most cases of LGS, and seizures are often medically refractory. Management is reviewed elsewhere. (See "Lennox-Gastaut syndrome", section on 'Management'.)

●Syndromes with electrical status epilepticus during sleep — Epilepsy associated with continuous or near-continuous spike-and-wave activity during sleep is classified as developmental and epileptic encephalopathy with spike-wave activation in sleep (DEE-SWAS), which encompasses the previously named syndromes of epileptic encephalopathy with continuous spike-and-wave during sleep (CSWS) and Landau-Kleffner syndrome (LKS). These conditions are marked by sleep potentiation of epileptiform activity, particularly in the transition from wakefulness to sleep, leading to an EEG pattern of continuous or near-continuous spikes and waves during non-rapid eye movement (NREM) sleep, and a regression in different aspects of development. They are reviewed separately. (See "Epilepsy syndromes in children", section on 'Developmental and epileptic encephalopathy with spike-wave activation in sleep (DEE-SWAS)'.)

AROUSAL EPILEPSIES — Some epileptic syndromes have a tighter association with arousal from sleep than with the sleep state per se. Genetic generalized epilepsy syndromes such as juvenile myoclonic epilepsy (JME) and generalized tonic-clonic seizures upon awakening often produce myoclonic or generalized tonic-clonic seizures shortly following awakening in the early morning hours.

●Juvenile myoclonic epilepsy – JME is an age-related, genetic, generalized epilepsy syndrome characterized by three major seizure types: myoclonic, generalized tonic-clonic, and absence. Seizures typically begin in early adolescence and occur most frequently in the morning hours, often within an hour of awakening. Electroencephalography (EEG) shows generalized interictal epileptiform discharges, most often either atypical, generalized spike-wave (more rapid than the usual 3 Hz frequency) or fragmentary discharges. The majority of patients respond well to antiseizure medication therapy with valproate or other broad spectrum drugs. Clinical aspects of JME are reviewed in detail elsewhere. (See "Juvenile myoclonic epilepsy".)

●Generalized tonic-clonic seizures upon awakening – Generalized tonic-clonic seizures upon awakening is a syndrome that is closely related to JME, with a similar overall pattern of morning-predominant seizures, but lacking the characteristic myoclonic seizure type seen in JME.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Seizures and epilepsy in adults" and "Society guideline links: Seizures and epilepsy in children" and "Society guideline links: Parasomnias, hypersomnias, and circadian rhythm disorders".)

SUMMARY AND RECOMMENDATIONS

●Classification and epidemiology – Sleep-related epilepsy refers to syndromes in which seizures occur exclusively or predominantly during sleep or in the period shortly after arousal from sleep. Across the lifespan, these syndromes account for approximately 10 to 15 percent of all epilepsy syndromes. (See 'Classification and epidemiology' above.)

●Seizure propensity during sleep – The propensity for seizures during sleep varies by sleep stage and by seizure localization. Non-rapid eye movement (NREM) sleep tends to facilitate epileptiform discharges and seizures, whereas rapid eye movement (REM) sleep is relatively inhibitory. (See 'Sleep and epileptogenesis' above.)

●Self-limited epilepsies and sleep – Self-limited epilepsy with centrotemporal spikes (SeLECTS), previously known as benign (childhood) epilepsy with centrotemporal spikes or benign rolandic epilepsy, is one of the more common epilepsy syndromes in childhood and a classic form of pure sleep epilepsy. SeLECTS and other self-limited focal epilepsy syndromes of childhood are reviewed separately. (See "Self-limited focal epilepsies of childhood".)

●Sleep-related focal epilepsies – These have traditionally been named according to the localization of seizure onset. The most common of these is sleep-related hypermotor epilepsy (SHE), previously called nocturnal frontal lobe epilepsy. Seizures in SHE may arise primarily in extrafrontal regions such as the temporal lobe and subsequently activate epileptogenic networks involving frontal brain regions (table 1). Sleep-related temporal, parietal, and occipital lobe epilepsies also occur but are less common and have overlapping clinical features with SHE. Peak onset is in adolescence. Focal cortical dysplasia is independently associated with sleep-related seizures. (See 'Sleep-related focal epilepsies' above.)

●Evaluation and diagnosis – The clinical features of sleep-related seizures have significant overlap with parasomnias and other nocturnal motor or behavioral events, and video polysomnography (PSG) with extended electroencephalography (EEG) may be required for full characterization of the events and accurate diagnosis. (See 'Diagnostic evaluation' above and 'Differential diagnosis' above.)

●Initial treatment – For patients with newly diagnosed SHE or other sleep-related focal epilepsy, we suggest initial treatment with carbamazepine or a related drug (eg, oxcarbazepine, eslicarbazepine, lamotrigine) (Grade 2C). Supporting evidence for these drugs is largely anecdotal, however, and a number of other antiseizure medications may be equally reasonable choices based on individual considerations of patient age, sex, human leukocyte antigen (HLA) type, and comorbidities. (See 'Selection of antiseizure medication therapy' above.)

●Treatment failure – When patients have had two appropriate antiseizure medications that have failed to produce adequate seizure control, they are considered to have drug-resistant epilepsy and should be referred to a multidisciplinary epilepsy center for consideration of additional medications and nonpharmacologic approaches, including epilepsy surgery. (See "Evaluation and management of drug-resistant epilepsy".)

●Prognosis – Spontaneous remission of SHE and other sleep-related focal epilepsies is rare, and most patients require lifelong antiseizure medication therapy. In addition to antiseizure medication therapy, management includes preventive counseling and education about common seizure precipitants and risks and complications of chronic epilepsy. (See 'Prognosis and indications for referral' above and 'Supportive care and counseling' above.)