Neuropharmacology & Neurotherapeutics
Fenfluramine
May. 11, 2026
Worddefinition
At vero eos et accusamus et iusto odio dignissimos ducimus qui blanditiis praesentium voluptatum deleniti atque corrupti quos dolores et quas.
Hyperkinetic seizures
- Updated 07.07.2025
- Released 06.10.2014
- Expires For CME 07.07.2028
Hyperkinetic seizures
Introduction
Overview
In this article, the authors present recent data and discussion about the causes, syndromes, diagnosis, and management of hyperkinetic seizures.
Key points
|
• Hyperkinetic seizures are characterized by motor seizures involving predominantly proximal limb or axial muscles in irregular sequential ballistic movements. | |
|
• The origin of hyperkinetic seizures is more commonly localized in the mesial frontal or orbitofrontal regions but originate in other areas, such as the anterior temporal lobe. | |
|
• Seizures often occur during sleep and recur repeatedly, with intervals of a few seconds. | |
|
• Sleep‐related hyperkinetic epilepsy (SHE), previously named nocturnal frontal lobe epilepsy (NFLE), is a focal epilepsy characterized by a wide spectrum of seizures occurring predominantly during sleep, including hyperkinetic seizures. | |
|
• Exclusively or predominantly nocturnal hyperkinetic seizures are the typical manifestations in autosomal dominant sleep-related hypermotor epilepsy (ADSHE), previously named autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), which is associated with mutations in the neuronal nicotinic acetylcholine receptor subunits, and also other gene mutations such as the nitrogen permease regulator-like 3 (NPRL3) gene. |
Historical note and terminology
According to proposed terminology by the International League Against Epilepsy (ILAE), hyperkinetic seizures are characterized by motor seizures involving “predominantly proximal limb or axial muscles producing irregular sequential ballistic movements, such as pedaling, pelvic thrusting, thrashing, rocking movements or by an increase of ongoing movements or inappropriately rapid performance of a movement” (06; 15).
Epileptic seizures with prominent motor components have been described in the literature for over 50 years (16; 05). In 1986, Lugaresi and colleagues proposed the term “nocturnal paroxysmal dystonia” to describe a syndrome of sleep-related motor attacks (31). Lüders and colleagues first introduced the term “hypermotor seizure” in a proposal for a semiologic seizure classification (30). In 2001, the ILAE Task Force on Classification and Terminology proposed the term “hyperkinetic seizure” to describe this type of event (06), and it was chosen for the 2017 classification (15).
Sleep‐related hypermotor epilepsy (SHE), previously named nocturnal frontal lobe epilepsy (NFLE), is a focal epilepsy characterized by a wide spectrum of seizures occurring predominantly during sleep (19; 28). The diagnosis of sleep‐related hypermotor epilepsy (SHE) is based on the clinical history and video-EEG documentation of seizures (50; 28). Sleep‐related hypermotor epilepsy includes hyperkinetic seizures associated with asymmetric‐tonic attacks, dystonic postures, paroxysmal arousals, and epileptic nocturnal wandering (48; 60; 59; 28). Sleep‐related hypermotor epilepsy is recognized in the International League Against Epilepsy (ILAE) Classification as a syndrome with onset at any age (51).
The accurate prevalence of hyperkinetic seizures is not known. In one cohort, this seizure type was reported in 12% of patients (33).
Clinical manifestations
Presentation and course
Hyperkinetic seizures are characterized by bizarre and complex motor patterns. They can be associated with dystonia or affective symptoms, such as fear, and vocalizations are common. Consciousness might or might not be preserved. These attacks often occur in clusters of many seizures per day (30; 13).
Hyperkinetic seizures often occur during sleep, especially during non-rapid eye movement (NREM) sleep phases 1 and 2 (48; 59). A clinical series observed 40% of patients with exclusively nocturnal occurrence of hyperkinetic seizures (33).
Hyperkinetic seizures occurring during sleep can be part of a spectrum of different, but closely related, seizure semiology, which also includes short-lasting (5 to 10 seconds) simple stereotyped motor phenomena that resemble a sudden arousal (paroxysmal arousals) and prolonged episodes that mimic sleepwalking (nocturnal wandering) (48; 59). This spectrum of seizure semiology often coexists in the same patient.
In patients with hyperkinetic seizures occurring during sleep, personal (up to one third) and family history of parasomnias is frequent, including night terrors, sleepwalking, bruxism, and enuresis (48; 59).
Family history of epilepsy is observed in up to 25% of patients with sleep‐related hypermotor epilepsy, and autosomal dominant inheritance characterizing the autosomal dominant sleep-related hypermotor epilepsy (ADSHE), previously termed autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), should be suspected (45; 48; 46; 40). Familial and sporadic sleep‐related hypermotor epilepsy have similar clinical features (60).
Overall, patients with hyperkinetic seizures have normal neurologic and neurophysiological exams (48; 59).
Prognosis and complications
The prognosis of seizure control in patients with hyperkinetic seizures is associated with the underlying etiology of the epilepsy. Overall, 60% to 70% of patients with hyperkinetic seizures will achieve seizure control with antiseizure meditation (48). In NFLE and ADNFLE, the morbidity of the seizures is usually lower than in other types of focal epilepsies due to its occurrence exclusively during sleep. A long-term study of patients with sleep-related hypermotor epilepsy (SHE) showed a cumulative 5-year remission rate of 28.4% after 30 years of follow-up. The study also confirmed that the outcome is primarily related to the underlying etiology (25).
In cases of pharmacoresistant hyperkinetic seizures, the outcome for seizure control is usually good in patients who undergo surgical resection of the epileptogenic zone, with up to two-thirds of patients becoming seizure-free (41). Around 6% of sleep-related hyperkinetic seizures were observed in a population of pharmacoresistant epilepsies (32).
In one study, the estimated incidence of sudden unexplained death in epilepsy (SUDEP) in patients with NFLE was 0.36 per 1000 person-years, similar to other epilepsy populations (35). However, other publications estimate that people with nocturnal seizures may be at highest risk of SUDEP (24; 34).
Clinical vignette
A 38-year-old male patient was referred to a tertiary epilepsy center for the evaluation of pharmacoresistant epilepsy. His seizures started by the age of 11. Seizures were characterized by recurrent attacks during sleep with no warning sensation and sudden arousal with abrupt flexion of the legs, followed by rocking movements of the trunk, ballistic or kicking movements of the legs, and partial extension of the arms. The seizures usually lasted 30 seconds and recurred 10 to 15 times per night, with intervals of 5 to 10 minutes. He had no past medical history and no family history of epilepsy.
His interictal EEG revealed rare low-amplitude epileptiform discharges in the right frontocentral region. However, during the ictal events, his EEGs were unremarkable. His brain MRI revealed a small hypointensity in T1-weighted images in the right medial frontal region, and FDG-PET showed hypometabolism in a concordant area.
This patient demonstrates the most common presentation of hyperkinetic seizures. The attacks are characterized by bizarre motor components that predominantly occur during sleep and recur many times per night. The seizures have a presumed frontal lobe epileptogenic zone as verified by scalp EEG and corroborated by the presence of an epileptogenic structural lesion in a concordant area.
Biological basis
Localization
Hyperkinetic seizures are typically a symptom of frontal lobe epilepsy. They commonly originate in deep structures of the frontal lobes and, therefore, scalp EEGs constantly fail to reveal ictal or interictal abnormalities (48; 01). Intracranial EEG studies have confirmed, however, that hyperkinetic seizures can originate from other brain areas, more commonly the temporal lobe or insula, but also the parietal and occipital lobes (32; 47; 01).
Neuroimaging and intracranial electroencephalography (EEG) studies and postsurgical series point to an epileptogenic zone most often localized in the mesial frontal region (48; 01). Hyperkinetic seizures may also originate from other frontal lobe areas such as the orbitofrontal cortex and frontal pole (33). Irrespective of seizure onset, a combined neuroimaging and neurophysiology study suggests that hyperkinetic seizures are associated with an abnormal network involving mainly the insula, mesial premotor cortex, and middle cingulate cortex is recruited (63; 64).
Kheder and colleagues defined three distinct ictal SPECT hyperperfusion patterns in patients with hyperkinetic seizures: (1) hyperperfusion in the anterior insula orbitofrontal cortex, anterior cingulate, and anterior perisylvian region spreading to basal ganglia and rostral midbrain; (2) hyperperfusion in the anterior cingulate, frontal pole, and orbitofrontal cortex and involving basal ganglia and contralateral cerebellum; and, (3) hyperperfusion in the temporal pole and anterior perisylvian region (23).
One study evaluated patients with hyperkinetic seizures who underwent intracranial EEG evaluation and were seizure-free after a minimum period of 24 months after surgery (50). The authors proposed that two types of hyperkinetic seizures could be distinguished. The first type consisted of marked agitation, body rocking, kicking or boxing, and a facial expression of fear, and the onset was localized on the ventromesial frontal cortex. The second type was characterized by mild agitation, with horizontal movements or rotation of the trunk on the bed, and associated with tonic or dystonic posturing; the onset was localized on the mesial premotor cortex.
Using stereo EEG analysis, Bonini and colleagues identified anatomic organization of different semiologic subgroups of frontal lobe seizures, including hyperkinetic seizures (07). The authors used the term "gestural motor behavior" to describe what they consider as a heterogenous group of complex motor behavior (including stereotypes and hyperkinetic movements). They further subdivided these gestural motor behaviors according to a "natural" or "unnatural" pattern as integrated gestures (for example, reaching, pedaling, kicking) or nonintegrated gestures (anarchic movements), respectively. They observed that the seizure activity of nonintegrated gestural motor behavior involved the premotor and prefrontal regions; integrated gestural motor behavior with distal stereotypies involved anterior lateral and medial prefrontal regions; and seizures with fearful behavior involved the ventromedial prefrontal cortex with or without anterior temporal structures (07).
Another study described three clusters of hyperkinetic seizures and its relationship with the seizure onset zone: (i) asymmetric hyperkinetic seizures associated with marked dystonia in parietal onset seizures, (ii) symmetrical hyperkinetic seizures without dystonia in dorsolateral prefrontal or temporal lobe onset seizures, and (iii) symmetrical hyperkinetic seizures with emotional expression and vocalization in temporal lobe or ventromesial prefrontal onset seizures (13).
In surgical series, a temporal lobe onset origin can be found in up to 28% of patients with drug-resistant hyperkinetic seizures (32). One surgical series reported that 6% of patients with temporal lobe epilepsy had hyperkinetic seizures (55). In these patients with hyperkinetic seizures and temporal lobe epilepsy, the striking motor component, short duration of the event, and prevalence during sleep resembled frontal origin; however, additional characteristics of their attacks were more suggestive of temporal lobe origin, such as a warning sensation or dystonic posture contralateral to the epileptiform discharge (32). Auditory aura was also suggested as a feature associated with extra-frontal origin, more often the left temporal lobe (14). In addition, interictal EEG usually demonstrated clear abnormalities in temporal lobe epilepsy patients, whereas it was often normal in frontal lobe epilepsy. Poor quality of sleep and excessive daytime sleepiness were more often observed in patients with frontal lobe origin. Intracranial EEG studies in patients with hyperkinetic seizures of temporal lobe origin suggested that the hypermotor component starts when the ictal discharge extends and includes the frontal lobe or the cingulate gyrus. Other series have suggested that the temporal pole and its connections with mediobasal prefrontal cortex are the main regions involved in the brain network responsible for the hyperkinetic semiology observed in patients with temporal lobe epilepsy (61).
Hyperkinetic seizures of frontal lobe origin had emotional facial expressions with fear, laughing, or anger; bilateral forceful elbow flexion; bilateral forceful grasping; facial flushing; and bilateral facial contraction more frequently than those with temporal lobe onset, whereas oroalimentary automatisms, seizures during wakefulness, salivation, and bilateral drop of the corners of the mouth were more frequent in temporal lobe onset hyperkinetic seizures (39).
Pathophysiology
There are similar aspects of hyperkinetic seizures that occur during sleep in sleep‐related hypermotor epilepsy and other physiological events of light sleep; a careful evaluation, including semiology, neurophysiology, and imaging, is needed to confirm the diagnosis (16). Similar mechanisms appear to be involved in the organization of the microstructure of sleep and seizures in sleep‐related hypermotor epilepsy (48; 40).
Tassinari and colleagues suggest that the hyperkinetic behaviors in these seizures are the expression of genetically determined motor patterns related to central pattern generators localized in the brainstem, and similar mechanisms are involved in the parasomnias (58). These central pattern generators participate in the innate motor behaviors essential for survival and could be activated by the epileptiform discharges.
Electrical stimulation of the anterior cingulated cortex can elicit complex bilateral movements, and ictal hyperperfusion as well as interictal functional abnormalities of the cingulate gyrus has been demonstrated in patients with hyperkinetic seizures (62; 38).
In patients with sleep‐related hypermotor epilepsy, autosomal dominant inheritance (ADSHE) is observed in up to 25% of patients (48; 56; 04). In patients with ADSHE, a mutation occurs in one of the subunits of the neuronal nicotinic acetylcholine receptor (nAChR) (48; 46; 56; 40). The association of nocturnal seizures, arousal, and abnormal nAChR has led to an investigation of the role of cholinergic systems in the pathophysiology of ADNFLE and hyperkinetic seizures. It has been demonstrated that nAChR is involved in the control of arousals (67). Furthermore, the increased density of nAChR density in the mesencephalon observed in PET studies of patients with ADSHE corroborates the hypothesis of the role of brainstem ascending cholinergic systems in the pathophysiology of this syndrome (46). Therefore, the abnormalities in nAChR in ADSHE could favor the instability of sleep and facilitate seizure origin in these patients.
SHE may also be caused by other gene mutations, including the NPRL3 (nitrogen permease regulator 3-like protein) mutations (10; 68), KCNT1 mutation (20), and PAK3 in frame deletion (18), and may be associated with subtle focal cortical dysplasia in the frontal lobe (65; 05).
A resting state functional MRI study showed that patients with sleep‐related hypermotor epilepsy had a significantly higher functional connectivity in sensorimotor and thalamic regions and suggested that it supports the hypothesis of a hyperexcitability of the motor cortex during thalamic K-complexes in this condition (12). Functional and structural imaging could uncover network abnormalities linked to sleep-related hypermotor epilepsy and may also suggest important noninvasive biomarkers of this condition (34).
Differential diagnosis
Confusing conditions
Because of its bizarre motor components and the predominance of its occurrence during sleep, the most important differential diagnoses of hyperkinetic seizures are sleep disorders and psychogenic nonepileptic seizures.
Hyperkinetic seizures during sleep can easily be mistaken with parasomnias. The absence of clear ictal epileptiform abnormalities in scalp EEG of a significant number of patients with frontal lobe epilepsy and hyperkinetic seizures also contributes to the difficulty in establishing the epileptic nature of the events (48; 37). A high frequency of recurrence of the attacks in the same night and between nights, the stereotyped characteristics of the fits, and the response to antiseizure medications are suggestive of the diagnosis of epileptic events (62).
However, one must have in mind that approximately 30% of patients with hyperkinetic seizures will not respond to antiseizure medications (48; 59). Other features suggestive of an epilepsy diagnosis are the short duration of the episodes (less than 2 minutes), unstructured vocalization, an aura preceding the motor attack, and the history of tonic-clonic seizures during sleep (48; 59).
The intense motor behavior during the attacks can also be a challenge for differentiation from psychogenic nonepileptic seizures or behavioral aberrations in children. The lack of alteration of consciousness, the fact that some actions can resemble normal movements, and the often-normal ictal scalp EEG contributes to the difficulty in diagnosis (66).
Associated and underlying disorders
Sleep-related hypermotor epilepsy (SHE), previously named nocturnal frontal lobe epilepsy (NFLE). NFLE is a syndrome of heterogeneous etiology characterized by the occurrence of hyperkinetic seizures exclusively during sleep (60). It has predominance in males. The age of onset varies, but the majority starts during infancy and adolescence (48). It may have a genetic or structural etiology (05). A consensus conference held in Bologna, Italy in 2014 emphasized the relationship of the seizures with sleep and not with the circadian pattern of seizure occurrence, and hypermotor seizures may originate in areas other than the frontal lobe, without substantial differences in seizure semiology (59).
Autosomal dominant sleep-related hypermotor epilepsy (ADSHE), previously named autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). ADNFLE has autosomal dominant inheritance and is clinically characterized by exclusively nocturnal hyperkinetic seizures of frontal lobe origin (54; 26; 08). Linkage sites were reported in the chromosomes 20q13.1-13.3 (ADNFLE type 1), 15q24 (ADNFLE type 2), and chromosome 1 (44; 45; 11). The mutations are observed in genes encoding α4 (CHRNA4) or β2 (CHRNB2) subunits of the neuronal nicotine acetylcholine receptor (57; 11). Another locus was identified on chromosome 8p21.2-8q12, and a mutation was described in the α2 (CHRNA2) subunit of the neuronal nicotine acetylcholine receptor in an Italian family with ictal fear and nocturnal wanderings (02) and in a family with paroxysmal epileptic arousal (09). Two other loci were found in chromosomes 3p22-p24 and 8q11.2-q21.1, and one gene involved in the corticotropin-releasing hormone is suspected to be associated with the ADSHE phenotype (53). These patients and their relatives also have a high frequency of parasomnias (48).
Other genetic epilepsies. Sleep-related hyperkinetic seizures were demonstrated in patients with a CDKL5 mutation (22). Hyperkinetic seizures were also described in families with drug-resistant epilepsy, frequent status epilepticus, intellectual disabilities, psychiatric comorbidities, and KCNT1 mutation (20). A recessive pattern of NFLE was described in two siblings with a mutation in PRIMA1 gene, which is associated with reduction of acetylcholinesterase and accumulation of acetylcholine at the synapse level in animal models (21).
NPRL3 mutations, which is part of the GATOR1 complex (GAP Activity TOward Rags) have also been described in patients with sleep-related hypermotor epilepsy, with or without evidence of focal cortical dysplasia (10; 68).
Structural/metabolic epilepsies. Hyperkinetic seizures can occur in epilepsies secondary to different types of structural lesions (34). In surgical series of pharmacoresistant sleep-related hyperkinetic seizures, focal cortical dysplasia type II is the most frequent finding (32; 47; 65). Co-occurrence of mild malformation of cortical development (mMCD) and mutation in the sodium-activated potassium channel gene KCNT1 was described in four patients with sleep‐related hypermotor epilepsy (52).
Diagnostic workup
The diagnostic workup of patients with hyperkinetic seizures can be divided into two steps: (1) diagnosis of epilepsy and epileptic syndrome and (2) localization of seizure origin in patients with pharmacoresistant seizures.
The diagnosis of hyperkinetic epileptic seizures can be achieved by a detailed clinical history. However, due to the clinical similarities of these events with sleep disorders and psychogenic nonepileptic seizures, a further workup is usually necessary.
Routine scalp EEG often fails to reveal ictal or interictal discharges in hyperkinetic seizures if the origin is in deep brain structures (48; 59). Interictal scalp EEG, however, can be helpful in demonstrating epileptiform discharges in temporal lobe epilepsy patients with hyperkinetic seizures (32). Ictal events recorded during prolonged video-EEG can be necessary to differentiate epileptic events from parasomnias and psychogenic nonepileptic seizures.
A specific diagnostic criterion based on level of certainty has been developed for sleep‐related hypermotor epilepsy. In this criterion, it can be diagnosed as witnessed (possible), video-documented (clinical), and video-EEG-documented (confirmed) (60).
Although scalp video-EEG can often confirm the epileptic nature of the hyperkinetic attacks, it is sometimes unable to localize the seizure origin due to its origin in deep brain structures or the diffuse electromyography artifacts during the spells (66). Therefore, the accurate localization of seizure origin in patients with pharmacoresistant hyperkinetic seizures aiming the appropriate surgical resection of the epileptogenic zone demands thorough investigation with structural (brain MRI) and functional (ictal SPECT, PET) neuroimaging, or intracranial EEG, or both (41).
Management
There is no evidence of a specific antiseizure medication for the treatment of hyperkinetic seizures, and choice of therapy must follow the same principles as that of other focal seizures (48). Carbamazepine is still considered the first treatment choice for patients with sleep‐related hypermotor epilepsy, and many patients will respond to small doses (03). Studies report seizure control with carbamazepine in approximately 20% of the patients with hyperkinetic seizures and significant reduction of the seizures in about 50% of patients (48; 27). Other antiseizure medications, including topiramate (43), oxcarbazepine (49), and perampanel (27) should be considered in mono or polytherapy in those who do not respond or do not tolerate carbamazepine.
There have been preliminary reports suggesting that nicotine patch can be an effective therapy in ADSHE patients with mutations involving the neuronal nicotinic acetylcholine receptor (nAChR) subunits (CHRNA4, CHRNB2, and CHRNA2) who did not respond to antiseizure medications (29; 17; 42). However, randomized placebo-controlled trials in sleep‐related hypermotor epilepsy patients are lacking.
For patients with pharmacoresistant hyperkinetic seizures, surgical treatment might benefit those with a defined epileptogenic zone in noneloquent areas. To this purpose, a detailed presurgical workup is necessary. In selected patients, seizure freedom can be expected in more than two-thirds of patients submitted to surgical resection of the epileptogenic zone. However, the surgical prognosis is associated with the underlying pathology (41).
Outcomes
The prognosis of seizure control in patients with hyperkinetic seizures is associated with the underlying etiology of the epilepsy. Overall, 60% to 70% of patients with hyperkinetic seizures will achieve seizure control with antiseizure medication treatment (48; 27). In sleep‐related hypermotor epilepsy and ADSHE, the morbidity of the seizures is usually lower than in other types of focal epilepsies due to its occurrence exclusively during sleep. However, seizures in sleep‐related hypermotor epilepsy usually do not remit, and prolonged use of antiseizure medications are needed (48; 59). The identification and treatment of possible associated specific sleep disorders is important for the management and outcome of patients with sleep‐related hypermotor epilepsy (40).
In cases of pharmacoresistant hyperkinetic seizures, the outcome for seizure control is usually good in patients who undergo surgical resection of the epileptogenic zone, with up to two-thirds of patients becoming seizure-free (41). Around 6% of sleep-related hyperkinetic seizures were observed in a population of pharmacoresistant epilepsies (32).
Special considerations
Pregnancy
There is a high risk of seizure worsening during pregnancy in women with sleep-related hypermotor epilepsy (36).
Media
References
- 01
- Alqadi K, Sankaraneni R, Thome U, Kotagal P. Semiology of hypermotor (hyperkinetic) seizures. Epilepsy Behav 2016;54:137-41. PMID 26708064
- 02
- Aridon P, Marini C, Di Resta C, et al. Increased sensitivity of the neuronal nicotinic receptor alpha 2 subunit causes familial epilepsy with nocturnal wandering and ictal fear. Am J Hum Genet 2006;79(2):342-50. PMID 16826524
- 03
- Asioli GM, Rossi S, Bisulli F, Licchetta L, Tinuper P, Provini F. Therapy in sleep-related hypermotor epilepsy (SHE). Curr Treat Options Neurol 2020;22(1):1. PMID 31997091
- 04
- Becchetti A, Grandi LC, Colombo G, Meneghini S, Amadeo A. Nicotinic receptors in sleep-related hypermotor epilepsy: pathophysiology and pharmacology. Brain Sci 2020;10(12):907. PMID 33255633
- 05
- Bisulli F, Berkovic SF, Scheffer IE, et al. Sleep-related hypermotor epilepsy-No longer controversial. Epilepsia 2025;66(7):2182-9. PMID 40085429
- 06
- Blume WT, Lüders HO, Mizrahi E, Tassinari C, van Emde Boas W, Engel J Jr. Glossary of descriptive terminology for ictal semiology: report of the ILAE task force on classification and terminology. Epilepsia 2001;42(9):1212-8. PMID 11580774
- 07
- Bonini F, McGonigal A, Trébuchon A, et al. Frontal lobe seizures: from clinical semiology to localization. Epilepsia 2014;55(2):264-77. PMID 24372328
- 08
- Brodtkorb E, Myren-Svelstad S, Knudsen-Baas KM, Nakken KO, Spigset O. Precision treatment with nicotine in autosomal dominant sleep-related hypermotor epilepsy (ADSHE): An observational study of clinical outcome and serum cotinine levels in 17 patients. Epilepsy Res 2021;178:106792. PMID 34763266
- 09
- Conti V, Aracri P, Chiti L, et al. Nocturnal frontal lobe epilepsy with paroxysmal arousals due to CHRNA2 loss of function. Neurology 2015;84(15):1520-8. PMID 25770198
- 10
- Dainelli A, Iacomino M, Rossato S, et al. Refining the electroclinical spectrum of NPRL3-related epilepsy: A novel multiplex family and literature review. Epilepsia Open 2023;8(4):1314-30. PMID 37491868
- 11
- DeFusco M, Becchetti A, Patrignani A, et al. The nicotinic receptor beta 2 subunit is mutant in nocturnal frontal lobe epilepsy. Nat Genet 2000;26(3):275-6. PMID 11062464
- 12
- Evangelisti S, Testa C, Ferri L, et al. Brain functional connectivity in sleep-related hypermotor epilepsy. Neuroimage Clin 2017;17:873-81. PMID 29527492
- 13
- Fayerstein J, McGonigal A, Pizzo F, et al. Quantitative analysis of hyperkinetic seizures and correlation with seizure onset zone. Epilepsia 2020;61(5):1019-26. PMID 32378738
- 14
- Ferri L, Bisulli F, Nobili L, et al. Auditory aura in nocturnal frontal lobe epilepsy: a red flag to suspect an extra-frontal epileptogenic zone. Sleep medicine 2014;15(11):1417-23. PMID 25224073
- 15
- Fisher RS, Cross HJ, French JA, et al. Operational classification of seizure types by the International League Against Epilepsy: Position Paper of the ILAE Commission for Classification and Terminology. Epilepsia 2017;58(4):522-30. PMID 28276060
- 16
- Fotedar N, Luders HO. Nocturnal paroxysmal dystonia to sleep-related hypermotor epilepsy: A critical review. Epilepsia 2024;65(9):2506-18. PMID 39046177
- 17
- Fox J, Thodeson DM, Dolce AM. Nicotine: a targeted therapy for epilepsy due to nAChR gene variants. J Child Neurol 2021;36(5):371-7. PMID 33284031
- 18
- Gambardella A, Liu YC, Bennett MF, et al. PAK3 pathogenic variant associated with sleep-related hypermotor epilepsy in a family with parental mosaicism. Epilepsia Open 2025;10(2):593-601. PMID 39806575
- 19
- Gibbs SA, Proserpio P, Francione S, et al. Clinical features of sleep-related hypermotor epilepsy in relation to the seizure-onset zone: a review of 135 surgically treated cases. Epilepsia 2019;60(4):707-17. PMID 30866067
- 20
- Heron SE, Smith KR, Bahlo M, et al. Missense mutations in the sodium-gated potassium channel gene KCNT1 cause severe autosomal dominant nocturnal frontal lobe epilepsy. Nat Genet 2012;44(11):1188-90. PMID 23086396
- 21
- Hildebrand MS, Tankard R, Gazina EV, et al. PRIMA1 mutation: a new cause of nocturnal frontal lobe epilepsy. Ann Clin Transl Neurol 2015;2(8):821-30. PMID 26339676
- 22
- Ishida S, Picard F, Rudolf G, et al. Mutations of DEPDC5 cause autosomal dominant focal epilepsies. Nat Genet 2013;45(5):552-5. PMID 23542701
- 23
- Kheder A, Thome U, Aung T, et al. Investigation of networks underlying hyperkinetic seizures utilizing ictal SPECT. Neurology 2020;95(6):e637-42. PMID 32636329
- 24
- Lamberts RJ, Thijs RD, Laffan A, Langan Y, Sander JW. Sudden unexpected death in epilepsy: people with nocturnal seizures may be at highest risk. Epilepsia 2012;53(2):253-7. PMID 22192074
- 25
- Licchetta L, Bisulli F, Vignatelli L, et al. Sleep-related hypermotor epilepsy: long-term outcome in a large cohort. Neurology 2017;88(1):70-7. PMID 27881627
- 26
- Licchetta L, Pippucci T, Baldassari S, et al. Sleep-related hypermotor epilepsy (SHE): Contribution of known genes in 103 patients. Seizure 2020;74:60-4. PMID 31835056
- 27
- Lim SN, Cheng MY, Hsieh HY, Chiang HI, Wu T. Treatment of pharmacoresistant sleep-related hypermotor epilepsy (SHE) with the selective AMPA receptor antagonist perampanel. Sleep Med 2021;81:382-6. PMID 33831666
- 28
- Loddo G, Baldassarri L, Zenesini C, et al. Seizures with paroxysmal arousals in sleep-related hypermotor epilepsy (SHE): dissecting epilepsy from NREM parasomnias. Epilepsia 2020;61(10):2194-2202. PMID 32949468
- 29
- Lossius K, de Saint Martin A, Myren-Svelstad S, et al. Remarkable effect of transdermal nicotine in children with CHRNA4-related autosomal dominant sleep-related hypermotor epilepsy. Epilepsy Behav 2020;105:106944. PMID 32097883
- 30
- Lüders HO, Burgess R, Noachtar S. Expanding the international classification of seizures to provide localization information. Neurology 1993;43(9);1650-5. PMID 8414007
- 31
- Lugaresi E, Cirignotta F, Montagna P. Nocturnal paroxysmal dystonia. J Neurol Neurosurg Psychiatry 1986;49(4):375-80. PMID 2939199
- 32
- Mai R, Sartori I, Francione S, et al. Sleep-related hyperkinetic seizures: always a frontal onset. Neurol Sci 2005;26 Suppl 3:s220-4. PMID 16331400
- 33
- Manford M, Fish DR, Shorvon SD. An analysis of clinical seizure patterns and their localizing value in frontal and temporal lobe epilepsies. Brain 1996;119(Pt 1):17-40. PMID 8624679
- 34
- Misirocchi F, Vaudano AE, Florindo I, et al. Imaging biomarkers of sleep-related hypermotor epilepsy and sudden unexpected death in epilepsy: a review. Seizure 2024;114:70-8. PMID 38088013
- 35
- Mostacci B, Bisulli F, Vignatelli L, et al. Incidence of sudden unexpected death in epilepsy in sleep-related hypermotor epilepsy, formerly named nocturnal frontal lobe epilepsy. Sleep Med 2017;29:98. PMID 27915205
- 36
- Mostacci B, Troisi S, Bisulli F, et al. Seizure worsening in pregnancy in women with sleep-related hypermotor epilepsy (SHE): A historical cohort study. Seizure 2021;91:258-62. PMID 34246880
- 37
- Mutti C, Bernabè G, Barozzi N, et al. Commonalities and differences in NREM parasomnias and sleep-related epilepsy: Is there a continuum between the two conditions? Front Neurol 2020;11:600026. PMID 33362702
- 38
- Naldi I, Bisulli F, Testa C, et al. Proton MR spectroscopy in patients with sleep-related hypermotor epilepsy (SHE): evidence of altered cingulate cortex metabolism. Sleep 2017;40(9). PMID 28934527
- 39
- Nitta N, Usui N, Kondo A, et al. Semiology of hyperkinetic seizures of frontal versus temporal lobe origin. Epileptic Disord 2019; 21(2):154-65. PMID 31010798
- 40
- Nobili L, de Weerd A, Rubboli G, et al. Standard procedures for the diagnostic pathway of sleep-related epilepsies and comorbid sleep disorders: an EAN, ESRS and ILAE-Europe consensus review. Eur J Neurol 2021;28(1):15-32. PMID 32959446
- 41
- Nobili L, Francione S, Mai R, et al. Surgical treatment of drug-resistant nocturnal frontal lobe epilepsy. Brain 2007;130(Pt 2):561-73. PMID 17124189
- 42
- Nguyen SM, Deering L, Nelson GT, McDaniel SS. Nicotine patch improved autosomal dominant sleep-related hypermotor epilepsy. Pediatr Neurol 2021;123:41-2. PMID 34392009
- 43
- Oldani A, Manconi M, Zucconi M, Martinelli C, Ferini-Strambi L. Topiramate treatment for nocturnal frontal lobe epilepsy. Seizure 2006;15(8):649-52. PMID 16973383
- 44
- Phillips HA, Scheffer IE, Berkovic SF, Hollway GE, Sutherland GR, Mulley JC. Localization of a gene for autosomal dominant nocturnal frontal lobe epilepsy to chromosome 20q 13.2. Nat Genet 1995;10(1):117-8. PMID 7647781
- 45
- Phillips HA, Scheffer IE, Crossland KM, et al. Autosomal dominant nocturnal frontal-lobe epilepsy: genetic heterogeneity and evidence for a second locus at 15q24. Am J Hum Genet 1998;63(4):1108-16. PMID 9758605
- 46
- Picard F, Bruel D, Servent D, et al. Alteration of the in vivo nicotinic receptor density in ADNFLE patients: a PET study. Brain 2006;129(Pt 8):2047-60. PMID 16815873
- 47
- Proserpio P, Cossu M, Francione S, et al. Epileptic motor behaviors during sleep: anatomo-electro-clinical features. Sleep Med 2011;12 Suppl 2:S33-8. PMID 22136897
- 48
- Provini F, Plazzi G, Tinuper P, Vandi S, Lugaresi E, Montagna P. Nocturnal frontal lobe epilepsy. A clinical and polygraphic overview of 100 consecutive cases. Brain 1999;122(Pt 6):1017-31. PMID 10356056
- 49
- Raju GP, Sarco DP, Poduri A, Riviello JJ, Bergin AM, Takeoka M. Oxcarbazepine in children with nocturnal frontal-lobe epilepsy. Pediatr Neurol 2007;37(5):345-9. PMID 17950420
- 50
- Rheims S, Ryvlin P, Scherer C, et al. Analysis of clinical patterns and underlying epileptogenic zones of hypermotor seizures. Epilepsia 2008;49(12):2030-40. PMID 18503559
- 51
- Riney K, Bogacz A, Somerville E, et al. International League Against Epilepsy classification and definition of epilepsy syndromes with onset at a variable age: position statement by the ILAE Task Force on Nosology and Definitions. Epilepsia 2022;63(6):1443-74. PMID 35503725
- 52
- Rubboli G, Plazzi G, Picard F, et al. Mild malformations of cortical development in sleep-related hypermotor epilepsy due to KCNT1 mutations. Ann Clin Transl Neurol 2018;6(2):386-91. PMID 30847371
- 53
- Sansoni V, Forcella M, Mozzi A, et al. Functional characterization of a CRH missense mutation identified in an ADNFLE family. PloS One 2013;8(4):e61306. PMID 23593457
- 54
- Scheffer IE, Bhatia KP, Lopes-Cendes I, et al. Autosomal dominant frontal epilepsy misdiagnosed as sleep disorder. Lancet 1994;343(8896):515-7. PMID 7906762
- 55
- Staack AM, Bilic S, Wendling AS, et al. Hyperkinetic seizures in patients with temporal lobe epilepsy: clinical features and outcome after temporal lobe resection. Epilepsia 2011;52(8):1439-46. PMID 21569022
- 56
- Steinlein OK. Genetic heterogeneity in familial nocturnal frontal lobe epilepsy. Prog Brain Res 2014;213:1-15. PMID 25194481
- 57
- Steinlein OK, Mulley JC, Propping P, et al. A missense mutation in the neuronal nicotinic acetylcholine receptor alpha 4 subunit is associated with autosomal dominant nocturnal frontal lobe epilepsy. Nat Genet 1995;11(2):201-3. PMID 7550350
- 58
- Tassinari CA, Rubboli G, Gardella E, et al. Central pattern generators for a common semiology in fronto-limbic seizures and in parasomnias. A neuroethologic approach. Neurol Sci 2005;26 Suppl 3:s225-32. PMID 16331401
- 59
- Tinuper P, Bisulli F. From nocturnal frontal lobe epilepsy to sleep-related hypermotor epilepsy: A 35-year diagnostic challenge. Seizure 2017;44:87-92. PMID 28027860
- 60
- Tinuper P, Bisulli F, Cross JH, et al. Definition and diagnostic criteria of sleep-related hypermotor epilepsy. Neurology 2016;86(19):1834-42. PMID 27164717
- 61
- Vaugier L, Aubert S, McGonigal A, et al. Neural networks underlying hyperkinetic seizures of “temporal lobe” origin. Epilepsy Res 2009;86(2-3):200-8. PMID 19619985
- 62
- Vetrugno R, Mascalchi M, Vella A, et al. Paroxysmal arousal in epilepsy associated with cingulate hyperperfusion. Neurology 2005;64(2):356-8. PMID 15668441
- 63
- Wang X, Hu W, Zhang K, et al. The anatomo-electrical network underlying hypermotor seizures. Front Neurol 2018;9:243. PMID 29695997
- 64
- Wang X, Hu WH, Zhang C, et al. Neural networks underlying hyperkinetic seizures: A quantitative PET and SEEG study. Epilepsy Behav 2021;122:108130. PMID 34153637
- 65
- Weckhuysen S, Marsan E, Lambrecq V, et al. Involvement of GATOR complex genes in familial focal epilepsies and focal cortical dysplasia. Epilepsia 2016;57(6):994-1003. PMID 27173016
- 66
- Weinstock A, Giglio P, Kerr SL, Duffner PK, Cohen ME. Hyperkinetic seizures in children. J Child Neurol 2003;18(8):517-24. PMID 13677576
- 67
- Xu J, Cohen BN, Zhu Y, et al. Altered activity-rest patterns in mice with a human autosomal-dominant nocturnal frontal lobe epilepsy mutation in the β2 nicotinic receptor. Mol Psychiatry 2011;16(10):1048-61. PMID 20603624
- 68
- Zhang H, Deng J, Wang X, et al. Clinical phenotypic and genotypic characterization of NPRL3-related epilepsy. Front Neurol 2023;14:1113747. PMID 36937533
Contributors
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
Author
-
Fernando Cendes MD PhD
Dr. Cendes of the University of Campinas - UNICAMP has no relevant financial relationships to disclose.
See Profile
Editor
-
Jerome Engel Jr MD PhD
Dr. Engel of the David Geffen School of Medicine at the University of California, Los Angeles, has no relevant financial relationships to disclose.
See Profile
Former Authors
- Ana Carolina Coan MD PhD
Patient Profile
- Age range of presentation
-
- 6 to 18 years
This is an article preview.
Start a Free Account
to access the full version.
-
Nearly 3,000 illustrations, including video clips of neurologic disorders.
-
Every article is reviewed by our esteemed Editorial Board for accuracy and currency.
-
Full spectrum of neurology in 1,200 comprehensive articles.
-
Listen to MedLink on the go with Audio versions of each article.
Questions or Comment?
MedLink, LLC
3525 Del Mar Heights Rd, Ste 304
San Diego, CA 92130-2122
Toll Free (U.S. + Canada): 800-452-2400
US Number: +1-619-640-4660
Support: service@medlink.com
Editor: editor@medlink.com
ISSN: 2831-9125
Also in This Category
-
-
Epilepsy & Seizures
Jacksonian seizures
May. 01, 2026
-
Epilepsy & Seizures
Hippocampal and parahippocampal seizures
Apr. 30, 2026
-
Epilepsy & Seizures
Sleep hyperkinetic (hypermotor) epilepsy
Apr. 17, 2026
-
Epilepsy & Seizures
Alcohol withdrawal seizures
Apr. 13, 2026
-
Epilepsy & Seizures
Epilepsy surgery in children
Mar. 11, 2026
-
Epilepsy & Seizures
Functional/dissociative seizures
Mar. 11, 2026
-
Neuropharmacology & Neurotherapeutics
Drug-induced seizures
Mar. 11, 2026