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Nocturnal frontal lobe epilepsy (NFLE) is a focal epilepsy with seizures arising mainly during sleep and characterized by complex, often bizarre, motor behavior or sustained dystonic posturing. First described in 1981, it was initially considered a motor disorder of sleep and was named nocturnal paroxysmal dystonia (NPD). The unusual seizure semiology, onset during sleep, and often uninformative scalp EEG and brain MRI make it difficult to distinguish NPD attacks from other non-epileptic nocturnal paroxysmal events, namely parasomnias. The long-debated epileptic origin of the condition was finally demonstrated in 1990 and the term NFLE introduced. Even though many aspects of parasomnias and NFLE have been clarified in the last two decades, the differential diagnosis remains a challenge for clinicians.
To address controversial issues and define the diagnostic criteria for NFLE, a Consensus Conference was held in Bologna, Italy in 2014. Major points of agreement emerged on: (i) the relationship of the seizures with sleep and not with the circadian pattern of seizure occurrence; (ii) the possible extrafrontal origin of hypermotor seizures, without substantial differences in seizure semiology. In the wake of the Consensus, the syndrome was renamed Sleep-Related Hypermotor Epilepsy (SHE).
1.1 From nocturnal paroxysmal dystonia to nocturnal frontal lobe epilepsy
The story of NFLE began in Bologna in 1981 when Lugaresi and Cirignotta described five patients with frequent episodes occurring in clusters during sleep, characterized by bizarre movements and/or dystonic–tonic posturing of the limbs [
]. Both interictal and ictal scalp EEGs in these patients failed to show epileptiform activities, however all cases had a good response to carbamazepine but not to other AEDs. Although an epileptic origin was debated at the time, the lack of EEG abnormalities, the stereotyped dystonic–dyskinetic features of attacks and their recurrence only during sleep led the authors to consider the condition an unusual motor disorder of sleep with an unclear pathophysiology. They labeled the disorder “hypnogenic paroxysmal dystonia”, modified some years later to “nocturnal paroxysmal dystonia” (NPD) [
The epileptic or non-epileptic origin of NPD attacks has been debated since the first descriptions of the disorder. Pre-surgical studies supported the epileptic origin of NPD. Tharp was among the first to describe three children with bizarre motor attacks resembling NPD episodes but recurring during wakefulness and not during sleep [
]. All these children were initially believed to have psychiatric disorders and received inappropriate treatment before Tharp recorded epileptic discharges in the frontal lobe of one child. He suggested that this peculiar type of seizures originated from that area of the brain and could therefore be considered a unique syndrome among the focal epilepsies [
]. About ten years later, Wada confirmed these data in 14 patients undergoing pre-surgical evaluation for drug-resistant epilepsy. He recorded seizures often occurring during sleep, characterized by complex motor behavior with bipedal and bimanual activity, violent rocking axial and pelvic movements, very similar to NPD. Ictal scalp EEG in these cases suggested frontal lobe involvement the night[
Nocturnal recurrence of brief, intensely affective vocal and facial expression with powerful bimanual, bipedal, axial, and pelvic activity with rapid recovery as manifestations of mesial frontal lobe seizure.
The similarity of NPD attacks with frontal seizures recorded in patients undergoing neurosurgical treatment for drug-resistant epilepsy, together with the demonstration of clear-cut epileptiform discharges in ictal and interictal recordings of three patients previously diagnosed as NPD [
Autosomal dominant nocturnal frontal lobe epilepsy. A video-polysomnographic and genetic appraisal of 40 patients and delineation of the epileptic syndrome.
Autosomal dominant nocturnal frontal lobe epilepsy. A video-polysomnographic and genetic appraisal of 40 patients and delineation of the epileptic syndrome.
Autosomal dominant nocturnal frontal lobe epilepsy. A video-polysomnographic and genetic appraisal of 40 patients and delineation of the epileptic syndrome.
]. During NFLE seizures (NFLS), ictal EEG is frequently obscured by artifacts caused by the violent movements, making it hard to identify an epileptic discharge. In addition, epileptic foci in deeper areas of the brain like the orbitofrontal or mesial structures are difficult to detect with scalp EEG. The limited contribution of scalp EEG to localization and lateralization of the seizure onset zone is accompanied by a low incidence of positive neuroradiological findings [
] ranging from very brief motor attacks to hypermotor seizures (HS) sometimes followed by prolonged complex ambulatory behavior. The increasing complexity of ictal motor behaviors, often coexisting in the same patient even during a single night, partly reflects a different duration and propagation of the discharge within the frontal lobe [
]. The most common feature is hyperkinetic with bimanual and bipedal automatisms, sometimes ballistic and violent movements associated with explosive vocalization like screaming, shouted obscenities or laughing. Awareness is frequently preserved but the patient is unable to control the motor behavior. Occasionally patients may jump out of bed and run around in a repetitive manner, a phenomenon was named Epileptic Nocturnal Wandering (ENW) [
] and difficult to distinguish from sleep-walking even for experts in sleep medicine and epileptology. The second feature of HS is an asymmetric tonic–dystonic posturing usually with strong autonomic activation. Also in this case the patient is usually awake and consciousness is not impaired. Both seizure types often end as suddenly as they begin, with little if any post-ictal period and the patient immediately goes back to sleep.
Minor motor events have also been recorded in most patients using video-polysomnography. These episodes, named Paroxysmal Arousals (PAs), are characterized by an abrupt movement of the trunk and upper limbs [
]. Patients seem to wake up but they are unaware of the episode and suddenly go back to sleep. PAs may present with a pseudoperiodic pattern, coinciding with K-complex bursts and/or recalling the typical CAP recurrence, and may be confused with simple motor sleep phenomena like sleep starts or periodic limb movements. The nature of these episodes remains controversial [
Autosomal dominant nocturnal frontal lobe epilepsy. A video-polysomnographic and genetic appraisal of 40 patients and delineation of the epileptic syndrome.
Autosomal dominant nocturnal frontal lobe epilepsy. A video-polysomnographic and genetic appraisal of 40 patients and delineation of the epileptic syndrome.
] described a large Australian family with NFLE inherited in an autosomal dominant manner, naming the condition autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). Also in this family, NFLE had been misdiagnosed as a sleep disorder. The genetic defect was isolated to the gene CHRNA4 coding for the alpha4 subunit of the neuronal nicotinic acetylcholine receptor (nAChR) [
A missense mutation in the neuronal nicotinic acetylcholine receptor alpha 4 subunit is associated with autosomal dominant nocturnal frontal lobe epilepsy.
]. So far more than a hundred families have been described in many countries, and mutations in genes (CHRNA2 and CHRNB2) coding for other subunits (alpha2 and beta2) of the nAChR have been identified [
] by mutant receptors associated with ADNFLE that may underlie the neuronal network dysfunction responsible for epileptic seizures. PET studies in ADNFLE patients suggest a hyperactivation of the cholinergic pathway ascending from the brainstem [
]. As cholinergic neurons modulate sleep and arousal at both thalamic and cortical level, they could be involved in sleep-related disorders, but the pathophysiological mechanism responsible remains unknown.
More recently, additional gene mutations have been discovered in ADNFLE, confirming the genetic heterogeneity of the disorder. Mutations of the sodium-activated potassium channel subunit 1 encoded by KCNT1 have been associated with a severe form of ADNFLE in which some individuals have intellectual disability, regression, and behavioral and psychiatric disorders [
]. Recently some families with ADNFLE have been found to have mutations in DEPDC5, a gene originally implicated in familial focal epilepsy with variable foci (FFEVF) [
The rarity of ADNFLE and the difference in study designs have hampered definition of a genotype–phenotype correlation. No single feature can indicate one particular form and there is no correlation between the functional effects of the mutations and disease severity [
]. All the previously found mutations in known genes have been reported only anecdotally in sporadic cases and in fewer than 30% of ADNFLE families with an incomplete penetrance ranging from 60% to 100%. In summary, ADNFLE and sporadic NFLE share similar clinical and electroencephalographic features irrespective of the genetic origin [
Even though many of NFLE’s core features have been clarified in the last two decades, some critical issues remain controversial.
2.1 The overlap with sleep disorders
The semiological overlap between NFLS and sleep disorders makes the differential diagnosis a challenge even for experts in sleep medicine and epileptology. The behavioral patterns encountered in NREM arousal parasomnias, REM behavior disorders and NFLS may all be similar. Ictal motor sequences in NFLS contain clear-cut “epileptic” features like dystonic posturing and choreic or ballistic movements, but they are usually mixed with more “parasomnic” behaviors like repetitive rocking or rolling, deambulation and even pseudoperiodic patterns. The problem of misdiagnosis also concerns the families with ADNFLE in which parasomnias have been associated with the disorder [
] had seizures with prominent fear and more organized motor behaviors such as nocturnal wanderings instead of the “classical” HS of ADNFLE.
To explain the semiological overlap between NFLS and some parasomnias, Tassinari et al. interpreted these clinical manifestations as the release of inborn fixed motor behaviors critical for survival programmed in cortical and subcortical Central Pattern Generators [
The neuroethological interpretation of motor behaviours in “nocturnal-hyperkynetic-frontal-seizures”: emergence of “innate” motor behaviours and role of central pattern generators.
in: Beaumanoir A. Andermann F. Chauvel P. Mira L. Zifkin B. Frontal lobe seizures and epilepsies in children. John Libbey,
2003: 43-45
]. According to this theory, both epilepsy and sleep can lead to a temporary loss of control of the neocortex with a lack of Central Pattern Generators inhibition.
Another critical issue challenging the differential diagnosis is the possible coexistence of parasomnias and NFLE. A prospective familial aggregation study documented that the lifetime prevalence of arousal parasomnias (sleep-walking, sleep terror and confusional arousal) differed significantly in an NFLE population compared with a control population, being more frequent not only among NFLE probands but also among their healthy relatives. These findings suggest that at least some NFLE cases share a complex genetic component with parasomnias [
Hitherto, genetic analysis has failed to identify a common background, but a model based on the cholinergic system and related pathways could unify the pathogenesis of the two sleep disorders. The physiological involvement of nAChR in the regulation of NREM and REM stability has been demonstrated experimentally, namely in regulating transient events such as micro-arousals [
]. Individuals with NFLE have more micro-arousals, and sleep-related motor attacks tend to arise during unstable sleep, with intense cyclic micro-arousal activity often occurring pseudoperiodically [
]. For these reasons, the high prevalence of arousal disorders in the personal and family histories of patients with sporadic and familial NFLE suggests these parasomnias are intrinsically linked to NFLE and that the pathway controlling physiologic arousal is impaired in both conditions.
2.2 Limits of diagnostic tools
2.2.1 Clinical history and diagnostic criteria
NFLS are difficult to differentiate from non-epileptic sleep-related events on the basis of clinical history alone. NFLE patients may present unusual symptoms like vocalization, complex automatisms and ambulation, whereas scalp EEGs and MRI fail to disclose any abnormal findings. This often leads to misdiagnosis, with the events being labeled as pseudoseizures (i.e. psychogenic non-epileptic seizures) or parasomnias. Misdiagnosis of this type may deprive patients of an accurate prognosis and appropriate treatment. Conversely, some parasomnic behaviors may be violent, mimicking NFLS, and attacks may be frequent at least for a period of life. These patients may receive a misdiagnosis of epilepsy and consequently an inappropriate chronic antiepileptic treatment with a major impact on quality of life and social relations. A reliable description of motor events arising during the night is often difficult to collect because a witness or sleep partner may be lacking or not fully awake. In addition, subjective semiological elements are often absent in all sleep-related motor events. Standard diagnostic criteria are unreliable, as in different parasomnias [
A.S.D. Association The international classification of sleep disorders: diagnostic and coding manual. 2nd ed. American Academy of Sleep Medicine,
Westchester, Ill2005
] (Fig. 1) but have yet to be assessed systematically. Responding to the need to establish the diagnostic accuracy of historical features in distinguishing NFLS from parasomnias, two instruments have been devised: the frontal lobe epilepsy and parasomnias scale (FLEP) [
]. However they could be a useful diagnostic algorithm to help physicians address clinical impressions, suggesting the need for a video or VPSG recording or avoiding these investigations [
Fig. 1Typical features distinguishing nocturnal paroxysmal episodes. On the left NREM parasomnias, in the center REM disorders (e.g. RBD, REM behavior disorders, and nightmares), on the right Sleep Related Hypermotor Epilepsy (SHE), that can appear at any sleep stage. Only the distinctive clinical features of the phenomenon are listed in each field.
Video-EEG or VPSG is the recommended gold standard (i.e. with 100% of sensitivity and 100% of specificity) for the diagnosis of paroxysmal nocturnal events. However, many patients do not have access to video-EEG and VPSG. Video-recording is expensive, entails admission to a hospital sleep laboratory and is only useful for recurrent sleep disorders as it does not always capture the event in single-night recording [
]. In addition, interictal and even ictal scalp EEGs fail to disclose epileptiform abnormalities in a large percentage of NFLE patients, while interictal abnormalities may also occur in parasomnias like RBD (up to 26%) [
]. All these elements reduce the sensitivity of video-recordings for diagnostic purposes and in practice diagnosis tends to be based on the ictal semiology (i.e. ictal symptoms, signs, and behaviors) of video-recorded events rather than EEG correlates [
]. In spite of the difficulty in capturing a paroxysmal event in the sleep laboratory when the episodes are rare, home video-recording (by home videos or mobile phone cameras) may represent a useful diagnostic adjunct [
]. A home-made video is a good option for major episodes but its diagnostic power is reduced by the lack reliable semiological criteria in the case of minor events, like PA [
]. The disagreement in minor events diagnosis probably stems from the lack of interpretation criteria for these brief motor phenomena and reflects the absence of a single terminological definition (Table 1). Even experts have difficulty diagnosing minor PA episodes which can only be confirmed by VPSG recordings of multiple stereotyped and “typical” (abrupt trunk and upper limb movements) activity.
To make the video analysis of nocturnal paroxysmal events more robust, Derry et al. [
] compiled a video-EEG monitoring series investigating the signs of arousal parasomnias and NFLS and providing an evidence base for the accurate diagnosis of these disorders on semiological grounds [
]. They documented that dystonic posturing and hyperkinetic automatisms (such as kicking, rocking or cycling movements) are specific to NFLS. If these major features are not present, a diagnosis of parasomnia is strongly suggested by verbal interaction and failures to arouse fully after the event, whereas other motor patterns, namely complex fearful behaviors like sitting, standing or walking, are not discriminant [
Summing up, the sensitivity of VPSG is below 100% (especially in patients with rare seizures) while its theoretical 100% specificity is flawed by an unsatisfactory interobserver agreement [
]. In other words, VPSG is not the gold standard but an important investigative tool in the diagnostic armamentarium.
2.2.3 Ex juvantibus diagnosis
Response to therapy is not a proper diagnostic tool but it could represent an important element to establish the final diagnosis when video-EEG and VPSG are not available or are uninformative. Unfortunately, even the response to antiepileptic drugs is not discriminant for the diagnosis of NFLE. Although carbamazepine is effective at low doses in most patients, the therapy had no impact on seizure frequency in about a third of them [
Stereo-EEG (SEEG) studies on patients who underwent surgery for drug-resistant NFLE have provided much more information on the possible anatomo-electro-clinical correlations of NFLS. Patients with an asymmetric tonic or dystonic posturing showed a relatively early activation of the supplementary motor area, with the posterior mesial frontal cortex and posterior portion of the frontal cingulated gyrus involved to different degrees [
]. Patients with hyperkinetic ictal behavior showed the involvement of either mesial-dorso-lateral, orbito-polar, opercular or larger lobar cortical regions [
]. The epileptic manifestations characterized by fear associated with more organized motor behaviors, i.e. ENW, are usually associated with activation of anterior cingulate, orbito-polar and temporal regions. This may implicate a network including frontal, and possibly extrafrontal, limbic structures in the genesis of these complex epileptic manifestations [
In the past ten years, stereo-EEG studies on patients operated for drug-resistant NFLE have documented an extrafrontal origin in a significant proportion, up to 30%, of cases [
]. Seizures originating from extrafrontal regions have clinical features very similar to those arising from the frontal area. The epileptogenic zone could be more frequently in the temporal lobe, or in the insular cortex, but also in the parietal and opercular area [
]. Hyperkinetic automatisms and complex behaviors appeared when the ictal discharge involved structures such as the cingulate, frontal and parietal regions, irrespective of its origin [
]. So “frontal lobe” refers to a common final pathway for discharges originating elsewhere rather than to the epileptogenic zone, relevant for surgical purposes. For these reasons the term NFLE could be misleading and has no role in pre-surgical evaluation, and invasive monitoring is frequently required prior to surgery.
3. From NFLE to SHE: the consensus conference
To clarify all these controversial issues and update the diagnosis of the NFLE, a group of international experts in epilepsy, sleep, and epidemiology met at a Consensus Conference (CC) held in Bologna (Italy) in 2014. The CC had two major outcomes: the need to change the nomenclature and the need to recognize the disorder as a distinct epilepsy syndrome with specific diagnostic criteria [
NFLE was renamed Sleep-Related Hypermotor Epilepsy (SHE) based on three critical issues justifying the change. First, the term nocturnal was considered misleading because it implies a chronobiological pattern of seizure occurrence, whereas evidence indicates that occurrence in sleep is the most important characteristic rather than the time of day. Second, the term frontal lobe is not always appropriate because the characteristic seizures may also arise from extrafrontal areas. Third, the term NFLE did not specify the typical clinical semiology involved, which consists primarily of HS.
The CC concluded that at the present state of knowledge, SHE should be considered a single syndrome, without evidence for clear subcategories. In fact, the clinical features of genetic and sporadic forms are similar and genetic and structural etiology are not mutually exclusive.
Finally, the CC provided elements for SHE diagnosis enucleating the following core clinical features (Table 2). Seizures are typically brief, lasting less than two minutes, with a stereotyped motor pattern, abrupt onset and offset. Patients usually have several episodes/night but clustering, even if characteristic, is not obligatory for diagnosis. The primary clinical expression consists of “hypermotor” events. The term “hypermotor” includes seizures with vigorous hyperkinetic features, but also seizures with asymmetric tonic or dystonic posturing. Awareness of the episode does not exclude diagnosis. Seizures are sleep-related but episodes may occasionally occur in wakefulness. Finally, diagnosis is not excluded by extrafrontal origin, intellectual disability or other neuropsychiatric features.
Table 2SHE diagnostic criteria.
Diagnosis is primarily based on clinical history → core clinical features
•
Brief (<2 min) seizures with stereotyped motor pattern within individuals and abrupt onset and offset
–
Clustering is characteristic but not obligatory
•
The most common motor pattern consists of “hypermotor” events
–
“Hypermotor” includes seizures with vigorous hyperkinetic features and seizures with asymmetric tonic or dystonic posturing
–
Awareness of the episode does not exclude diagnosis
•
Seizures occur predominantly during sleep
–
Episodes may occur occasionally in wakefulness
•
Diagnosis not excluded by:
–
Intellectual disability, neuropsychiatric features
–
The absence of clear interictal and ictal EEG correlates
–
Extrafrontal origin
Three levels of certainty
•
Witnessed (possible)
–
Core clinical features provided by eye witness
•
Video-documented (clinical)
–
Recording of at least 1 but preferably 2 stereotyped events (confirmed to be typical by eyewitness),
–
High quality audio–video including the onset and with clear visualization of the entire events, showing the evolution and offset of the attacks
–
Minor motor events or PA excluded, making diagnosis unreliable
•
Video-EEG documented (confirmed)
–
Recording of at least 1 but preferably 2 stereotyped events during a daytime sleep recording after sleep deprivation, or during a full night sleep recording, with at least 19 EEG channels (10–20 International System), ECG, oculogram, and chin EMG
–
Clear-cut ictal epileptic discharge or interictal epileptiform abnormalities
SHE diagnosis is primarily based on the clinical history. The absence of clear interictal and ictal EEG correlates does not exclude the diagnosis. Three different levels of diagnostic certainty have been identified: (1) Witnessed (possible), based on the observation by a witness of the core clinical features, but without other sources of evidence. (2) Video-documented (clinical), which involves a high quality video recording of at least one (but preferably two) stereotyped episode. (3) VEEG-documented (confirmed), which requires the video-polygraphic recording of at least one but preferably two stereotyped events with documented ictal discharge or interictal epileptiform abnormalities.
Conflict of interest statement
The authors declare that they have no conflict of interest.
References
Lugaresi E.
Cirignotta F.
Hypnogenic paroxysmal dystonia: epileptic seizures or a new syndrome?.
Nocturnal recurrence of brief, intensely affective vocal and facial expression with powerful bimanual, bipedal, axial, and pelvic activity with rapid recovery as manifestations of mesial frontal lobe seizure.
Autosomal dominant nocturnal frontal lobe epilepsy. A video-polysomnographic and genetic appraisal of 40 patients and delineation of the epileptic syndrome.
A missense mutation in the neuronal nicotinic acetylcholine receptor alpha 4 subunit is associated with autosomal dominant nocturnal frontal lobe epilepsy.
The neuroethological interpretation of motor behaviours in “nocturnal-hyperkynetic-frontal-seizures”: emergence of “innate” motor behaviours and role of central pattern generators.
in: Beaumanoir A. Andermann F. Chauvel P. Mira L. Zifkin B. Frontal lobe seizures and epilepsies in children. John Libbey,
2003: 43-45
A.S.D. Association The international classification of sleep disorders: diagnostic and coding manual. 2nd ed. American Academy of Sleep Medicine,
Westchester, Ill2005
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