Spotlight on Sleep:
Dispelling the Sleep Spell: Hypermotor Seizures, Parasomnias, and Leveraging Sleep Medicine in Pediatric Epilepsy Care

Sleep spells in a child present a diagnostic challenge and have a broad differential, including seizures, parasomnia, and physiologic events. Many childhood epilepsy syndromes present with seizures during sleep. Classic examples include self-limited epilepsy with centrotemporal spikes, self-limited epilepsy with autonomic seizures (formerly Panayiotopoulos syndrome), and sleep-related hypermotor epilepsy (SHE).^1–3 Other epilepsy syndromes manifest seizures around sleep–wake transitions (eg, juvenile myoclonic epilepsy, epileptic spasms).^2,3 These childhood epilepsy syndromes often present with a classic, recognizable seizure semiology, but SHE has a broad phenotype that makes it difficult to differentiate from parasomnias.^1–3

This review highlights common diagnostic and therapeutic considerations for sleep-related spells. Using the example of TM, a kindergarten-age child, who presented with stereotyped peculiar, abrupt arousals (see examples in accompanying video available on practicalneurology.com), and eventually was diagnosed with SHE, we highlight diagnostic and therapeutic considerations in the assessment of sleep-related spells.

Parasomnias and Other Sleep Spells

Parasomnias are undesirable physical events or experiences (such as somnambulism or confusional arousals) that occur during sleep. Parasomnias typically occur during stage 3 non–rapid eye movement (NREM) sleep but rarely may occur during rapid eye movement (REM) sleep (eg, REM sleep behavior disorder). Parasomnias affect more than 80% of preschool-age children, and become less common with increasing age.³ Physiologic paroxysmal nocturnal events (eg, sleep myoclonus) and pathologic paroxysmal nocturnal events (eg, nocturnal panic attacks) may be confused with seizures.^2,3 SHE can be difficult to distinguish from a number of well-described nocturnal events, including confusional arousals, somnambulism, sleep terrors, and nocturnal panic attacks.^2,3

TM’s nonstereotyped events outside of sleep included stiffening and shaking leg movements, wandering spells, and spinning in bed. TM appeared to turn consistently to the left in bed, and leg movements appeared to have a dystonic appearance. TM was referred for video electroencephalography (EEG) monitoring.

Sleep-Related Hypermotor Epilepsy

SHE is a rare focal epilepsy involving sleep-related seizures occurring at any age, with typical onset before 20 years.^1,4 SHE was previously called nocturnal frontal lobe epilepsy (NFLE), but the name was changed to reflect that seizures are typically sleep-related, rather than nocturnal, and that seizure onset may be extrafrontal.¹

Clinical Features

SHE is characterized by stereotyped hypermotor seizures with rapid onset and offset, typically lasting less than 2 minutes.¹ “Hypermotor” refers to a variety of complex semiologies, including abrupt arousals, bicycling of legs, body rocking, asymmetric tonic/dystonic posturing, and protracted ambulatory behavior, and it can be associated with affective changes and intense vocalizations.^1,4 Individuals often retain awareness during seizures, and multiple seizures may cluster.¹ Helpful red flag features that can help with the differentiation of SHE from parasomnias include the presence of clustering, high event frequency, stereotyped nature of events, brief duration, and timing of onset.¹ NREM parasomnias have a propensity to be long-lasting events (>2 minutes and often 30 minutes or longer), occurring once a night within the first third of the night, and the individual has no event recall. REM parasomnias tend to occur in the latter third of the night, with preserved event recall. Most REM parasomnias have no discrete motor manifestations (eg, nightmares, hypnopompic hallucinations); pediatric REM sleep behavior disorder is exceedingly rare, but it may be encountered in individuals with narcolepsy. Difficulty with diagnosis prompted the development of the Frontal Lobe Epilepsy and Parasomnias scale, but an age-adjusted pediatric version has not been validated.^4,5 The Table provides a summary of typical features distinguishing SHE from NREM parasomnias in childhood.

Electroencephalography

Continuous video EEG is the highest-yield study for event capture and diagnosis. Scalp EEG testing may be uninformative in SHE because of rare interictal discharges, lack of definitive EEG correlates to clinical events, or significant EEG obscuration from excessive muscle and movement artifacts.^1,4 In TM, EEG testing confirmed hypermotor seizures (Figure 1). For comparison, Figure 2 shows EEG results from another individual experiencing a night terror, demonstrating the lack of rhythmic evolution and persistence of a slow delta-theta frequency sleep background.

Imaging

Because SHE is a focal epilepsy, neuroimaging is recommended to rule out structural brain lesions. Identified causes commonly include acquired injuries and focal cortical dysplasias (FCDs).¹ In a retrospective study of 103 individuals with SHE, 16.5% had FCDs.⁶

Genetics

SHE can be sporadic or the result of a familial autosomal dominant pattern of inheritance. Next-generation sequencing revealed pathogenic variants in 8.7% of individuals (N=103) with SHE.⁶ Among familial cases, pathogenic variants are found in about 19% of individuals.⁶ Known variants include changes in neuronal nicotinic acetylcholine receptor subtypes (eg, CHRNA4, CHRNB2, CHRNA2), KCNT1, and GATOR1 complex components NPRL2, NPRL3, and DEPDC5.^1,6

Whole exome sequencing in TM did not reveal any pathogenic variants.

General Counseling

Up to 30% of individuals with SHE develop refractory epilepsy, in which seizures persist despite the use of 2 appropriately selected and dosed antiseizure medications (ASMs), and only 20% achieve remission by 10 years after onset.^1,4,6 Individuals and families should be counseled on the risk of sudden unexpected death in epilepsy (SUDEP). A retrospective study of 103 individuals diagnosed with NFLE showed a similar incidence of SUDEP as that of the general epilepsy population, although the risk may be higher with insular onset of SHE.^1,4,7 Safety considerations to be discussed include injury prevention during hypermotor seizures and safe sleeping precautions (eg, preventing falls by lowering the bed to the floor). Sleep-related counseling also should address the bidirectional interaction between epilepsy and sleep. Seizures may result in sleep fragmentation, leading to excessive daytime sleepiness (EDS), and sleep fragmentation may exacerbate seizure frequency, contributing to poor quality of life.⁴

Management of Comorbid Sleep Pathology in Epilepsy

Managing sleep pathology in pediatric epilepsy includes addressing comorbidities, such as obstructive sleep apnea (OSA), insomnia, restless legs syndrome, and EDS. In children with sleep-related epilepsies, especially those refractory to ASMs, investigating sleep may introduce new treatment possibilities.

As many as 26.3% of children with epilepsy experience OSA, and individuals with epilepsy appear to have a higher risk for OSA than healthy individuals (odds ratio [OR]: 2.36; 95% CI, 1.33–4.18). Continuous positive airway pressure treatment has been associated with improved seizure control (OR: 5.26; 95% CI, 2.04–13.5).⁸ A retrospective review of 25 participants with pediatric epilepsy and OSA showed that by 3 months after surgical OSA management (with tonsillectomy, adenoidectomy, or both), 10 individuals had seizure cessation, 3 had >50% seizure reduction, and 6 had some reduction in seizures.⁹ The causal link between OSA and epilepsy is hypothetical and likely multifactorial. Medications may reduce upper airway tone or exacerbate hypotonia (benzodiazepines) or contribute to weight gain (valproate), increasing risk of OSA.

Diagnosing restless legs syndrome in children can present challenges. Verbal children may endorse symptoms when asked. More often, families endorse restless sleep patterns or sleep-onset insomnia, and polysomnography may demonstrate excessive periodic limb movements. Evaluation for iron deficiency (ie, ferritin <50 ng/mL) and subsequent treatment can improve sleep substantially. Gabapentin and clonidine treatment also may be considered in the treatment of restless legs syndrome unresponsive to iron repletion.¹⁰

Insomnia in children with epilepsy is multifactorial and often has a strong behavioral component, involving inadequate sleep hygiene and inappropriate sleep-onset associations. Co-sleeping, increased sleep monitoring, and parental hypervigilance around bedtime are common factors associated with this phenotype of insomnia. Treatment strategies include counseling on sleep hygiene, cognitive behavioral therapy, and occasionally pharmacotherapy. No sleep aids have been approved for individuals younger than 18 years by the Food and Drug Administration (FDA), but some medications are used off-label. The most common options include melatonin and alpha-2 adrenergic agonists. Hypnotics are often avoided in children because they may aggravate EDS and be less efficacious than cognitive behavioral therapy.¹¹ Melatonin use can be associated with improvements in sleep continuity, Epworth Sleepiness Scale score, and seizure frequency, although there are reasonable concerns about lack of long-term safety data and inconsistent or inaccurate doses suggested by supplement manufacturers.¹²

TM had notable sleep-onset insomnia since early childhood and attention-deficit/hyperactivity disorder. Clonidine, prescribed to address hyperactivity and sleeplessness symptoms, provided modest symptom benefit. Several ASMs were attempted for TM, but failed: oxcarbazepine, because of hypersensitivity-induced rash; levetiracetam, because of behavioral dysregulation; zonisamide, because of inefficacy; and brivaracetam and clobazam, because of the presence of continued breakthrough seizures. Valproate treatment was initiated and TM was referred for presurgical evaluation.

ASMs and Chronopharmacology

In chronopharmacology, drug effects are considered as functions of biologic time; ASMs, then, are provided at times of greatest seizure susceptibility and best tolerability. Sleep-related epilepsies demonstrate rhythms following circadian and sleep/wake cycles, facilitating anticipatory medication regimens. Minimizing side effects associated with ASMs should be prioritized, such as by providing sedating agents at nighttime and activating agents in the morning to minimize sleep-onset insomnia and EDS. Among 17 children with nocturnal or early-morning seizures whose ASMs were switched to higher evening doses, 11 (5 with NFLE, 1 with self-limited epilepsy with centrotemporal spikes, 5 with structural lesions) had seizure cessation after a mean of 5.3 months.¹³ Four had 75% to 90% reduction in seizures, and 9 required only ASM monotherapy after dose redistribution; none had worsening seizures.¹³

This clinical phenomenon has biologic evidence: phenytoin was most effective in Drosophila seizure models when administered at night because of increased blood-brain barrier permeability dynamics.¹⁴ The data do not clarify the pharmacodynamic idiosyncrasies of more commonly prescribed ASMs in children.

Neuromodulation

Vagus nerve stimulation (VNS) is approved by the FDA for treatment of refractory focal seizures in individuals older than 4 years. The hypothesized mechanisms of action of VNS are manifold and influence both sleep and seizures, presenting opportunities and challenges for sleep-related epilepsies, such as SHE.

There is scant literature examining the use of VNS in sleep-related epilepsies. VNS may independently improve EDS, and responsiveness may facilitate titration of medications and sleep-disruptive side effects.¹⁵ Larger series demonstrate equinumerous ASM use after VNS, but smaller series including children report successful reduction of medications or doses.¹⁶

VNS may contribute to increasing apneas and hypopneas in sleep, mainly in preexisting OSA.¹⁵ In 22 children with refractory epilepsy, VNS implantation was associated with higher incidence and severity of OSA.¹⁷ The problematic VNS/OSA overlap can be mitigated through upper airway surgery (eg, adenotonsillectomy), positive airway pressure therapy, or modification of VNS settings (eg, increasing “off” time or decreasing stimulation current). Newer VNS models include options for differential daytime and nighttime settings to offset these risks. Some institutions perform real-time VNS adjustments with sleep-deprived daytime polysomnography to determine the ideal VNS parameters to resolve sleep-disordered breathing. It is difficult to assess which children may be most at risk for incipient OSA after VNS. Polysomnography before implantation and after achieving goal stimulation settings may be warranted to monitor for OSA.

The influence of deep brain stimulation and responsive neurostimulation on sleep is unclear. Responsive neurostimulation may produce keen chronopharmacology insights by detecting seizure rhythms to permit tailored medication administration plans.

Epilepsy Surgery

In select sleep-related epilepsies, surgical outcomes are similar to those reported for surgeries to address focal lesional epilepsies with daytime seizures. Surgery can ameliorate seizures and improve associated sleep disorders, such as EDS.⁴

Outcomes may be disproportionately better in SHE because of a high incidence of type II FCDs. These FCDs predict favorable outcomes because of typically well-circumscribed and identifiable margins for surgical resection.⁴ In this same study, stereoencephalography evaluation was an unfavorable predictor, likely confounded by its use in challenging nonlesional cases with discordant electro-radio-clinical anatomy.⁴

The literature supports evaluation of epileptiform abnormalities in REM sleep, which may provide localizing value to seizure onset zones, support surgical planning, and result in improved outcomes.¹⁸

TM had been referred for presurgical evaluation. However, the seizures improved markedly with preferential nocturnal dosing of valproate. Seizure control persisted after clobazam discontinuation.

Conclusion

Sleep-related spells present a diagnostic challenge because of overlapping features of sleep-related epilepsies, including SHE, parasomnias, and other sleep-related events. Recognizing red flag symptoms and understanding the applications and limitations of tools such as EEG and polysomnography are essential. Management of sleep-related epilepsies should include chronopharmacology tenets and address comorbid sleep pathology.