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From nocturnal frontal lobe epilepsy to Sleep-Related Hypermotor Epilepsy: A 35-year diagnostic challenge

  • Paolo Tinuper
    Correspondence
    Corresponding author at: IRCCS Institute of Neurological Sciences of Bologna, Bellaria Hospital, Via Altura 3, 40138 Bologna, Italy. Fax: +39 0514966993.
    Affiliations
    IRCCS Institute of Neurological Sciences, Bologna, Italy

    Department of Biomedical and Neuromotor Sciences, University of Bologna, Italy
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  • Francesca Bisulli
    Affiliations
    IRCCS Institute of Neurological Sciences, Bologna, Italy

    Department of Biomedical and Neuromotor Sciences, University of Bologna, Italy
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Open ArchivePublished:December 15, 2016DOI:https://doi.org/10.1016/j.seizure.2016.11.023

      Abstract

      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).

      Keywords

      1. Introduction

      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 [
      • Lugaresi E.
      • Cirignotta F.
      Hypnogenic paroxysmal dystonia: epileptic seizures or a new syndrome?.
      ]. 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) [
      • Lugaresi E.
      • Cirignotta F.
      • Montagna P.
      Nocturnal paroxysmal dystonia.
      ].
      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 [
      • Tharp B.R.
      Orbital frontal seizures. A unique electroencephalographic and clinical syndrome.
      ]. 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 [
      • Tharp B.R.
      Orbital frontal seizures. A unique electroencephalographic and clinical syndrome.
      ]. 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[
      • Wada J.A.
      • Purves S.J.
      Oral and bimanual-bipedal activity as ictal manifestation of frontal lobe epilepsy.
      ,
      • Wada J.A.
      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.
      ]. These reports were followed by other descriptions of bizarre hyperactive seizures originating from the frontal lobe [
      • Williamson P.D.
      • Spencer D.D.
      • Spencer S.S.
      • Novelly R.A.
      • Mattson R.H.
      Complex partial seizures of frontal lobe origin.
      ,
      • Waterman K.
      • Purves S.J.
      • Kosaka B.
      • Strauss E.
      • Wada J.A.
      An epileptic syndrome caused by mesial frontal lobe seizure foci.
      ].
      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 [
      • Tinuper P.
      • Cerullo A.
      • Cirignotta F.
      • Cortelli P.
      • Lugaresi E.
      • Montagna P.
      Nocturnal paroxysmal dystonia with short-lasting attacks: three cases with evidence for an epileptic frontal lobe origin of seizures.
      ] strongly suggested an epileptic origin and the term nocturnal frontal lobe epilepsy (NFLE) was adopted.

      1.2 The clinical spectrum of NFLE

      In the following years a number of groups worked hard to characterize NFLE. Sporadic NFLE is the most common form encountered in clinical practice [
      • 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.
      ]. Epilepsy onset is mostly in the second decade of life with a peak incidence during childhood [
      • Scheffer I.E.
      • Bhatia K.P.
      • Lopes-Cendes I.
      • Fish D.R.
      • Marsden C.D.
      • Andermann F.
      • et al.
      Autosomal dominant frontal epilepsy misdiagnosed as sleep disorder.
      ,
      • Oldani A.
      • Zucconi M.
      • Asselta R.
      • Modugno M.
      • Bonati M.T.
      • Dalprà L.
      • et al.
      Autosomal dominant nocturnal frontal lobe epilepsy. A video-polysomnographic and genetic appraisal of 40 patients and delineation of the epileptic syndrome.
      ,
      • 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.
      ,
      • Nobili L.
      • Francione S.
      • Mai R.
      • Cardinale F.
      • Castana L.
      • Tassi L.
      • et al.
      Nocturnal frontal lobe epilepsy.
      ], although adult onset has also been reported [
      • Scheffer I.E.
      • Bhatia K.P.
      • Lopes-Cendes I.
      • Fish D.R.
      • Marsden C.D.
      • Andermann F.
      • et al.
      Autosomal dominant frontal epilepsy misdiagnosed as sleep disorder.
      ,
      • Oldani A.
      • Zucconi M.
      • Asselta R.
      • Modugno M.
      • Bonati M.T.
      • Dalprà L.
      • et al.
      Autosomal dominant nocturnal frontal lobe epilepsy. A video-polysomnographic and genetic appraisal of 40 patients and delineation of the epileptic syndrome.
      ,
      • 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.
      ]. Seizure frequency at onset is usually high and patients generally experience many attacks per night [
      • 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.
      ,
      • Licchetta L.
      • Bisulli F.
      • Vignatelli V.
      • Zenisi C.
      • Di Vito L.
      • Mostacci B.
      • et al.
      Sleep-related hypermotor epilepsy. Long term outcome in a large cohort.
      ] although episodes may diminish during adulthood [
      • Oldani A.
      • Zucconi M.
      • Asselta R.
      • Modugno M.
      • Bonati M.T.
      • Dalprà L.
      • et al.
      Autosomal dominant nocturnal frontal lobe epilepsy. A video-polysomnographic and genetic appraisal of 40 patients and delineation of the epileptic syndrome.
      ,
      • Scheffer I.E.
      • Bhatia K.P.
      • Lopes-Cendes I.
      • Fish D.R.
      • Marsden C.D.
      • Andermann F.
      • et al.
      Autosomal dominant frontal epilepsy misdiagnosed as sleep disorder.
      ]. Seizures during wakefulness occasionally occur [
      • 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.
      ,
      • Licchetta L.
      • Bisulli F.
      • Vignatelli V.
      • Zenisi C.
      • Di Vito L.
      • Mostacci B.
      • et al.
      Sleep-related hypermotor epilepsy. Long term outcome in a large cohort.
      ]. Frequent parasomnias are reported not only by NFLE patients but also by their healthy relatives [
      • Bisulli F.
      • Vignatelli L.
      • Naldi I.
      • Licchetta L.
      • Provini F.
      • Plazzi G.
      • et al.
      Increased frequency of arousal parasomnias in families with nocturnal frontal lobe epilepsy: a common mechanism.
      ]. Ictal and interictal EEG is unrevealing in a large proportion of cases [
      • 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.
      ,
      • Licchetta L.
      • Bisulli F.
      • Vignatelli V.
      • Zenisi C.
      • Di Vito L.
      • Mostacci B.
      • et al.
      Sleep-related hypermotor epilepsy. Long term outcome in a large cohort.
      ] with the sole exception of patients with drug-resistant epilepsy undergoing prolonged video-EEG recordings for surgical purposes [
      • Nobili L.
      • Francione S.
      • Mai R.
      • et al.
      Surgical treatment of drug-resistant nocturnal frontal lobe epilepsy.
      ]. 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 [
      • Nobili L.
      • Francione S.
      • Mai R.
      • et al.
      Surgical treatment of drug-resistant nocturnal frontal lobe epilepsy.
      ,
      • Licchetta L.
      • Bisulli F.
      • Vignatelli V.
      • Zenisi C.
      • Di Vito L.
      • Mostacci B.
      • et al.
      Sleep-related hypermotor epilepsy. Long term outcome in a large cohort.
      ].
      The clinical spectrum of NFLS comprises distinct paroxysmal sleep-related attacks of variable duration and complexity [
      • Tinuper P.
      • Lugaresi E.
      The concept of paroxysmal nocturnal dystonia.
      ] 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 [
      • Nobili L.
      • Cossu M.
      • Mai R.
      • Tassi L.
      • Cardinale F.
      • Castana L.
      • et al.
      Sleep-related hyperkinetic seizures of temporal lobe origin.
      ,
      • Nobili L.
      • Francione S.
      • Mai R.
      • Cardinale F.
      • Castana L.
      • Tassi L.
      • et al.
      Nocturnal frontal lobe epilepsy.
      ]. Due to the recurrence of these motor events during sleep, NFLE patients may complain of daytime sleepiness [
      • Nobili L.
      • Francione S.
      • Mai R.
      • Cardinale F.
      • Castana L.
      • Tassi L.
      • et al.
      Nocturnal frontal lobe epilepsy.
      ].
      HS have two clinical hallmarks sometimes coexisting in the attacks or in the history of an individual patient [
      • Licchetta L.
      • Bisulli F.
      • Vignatelli V.
      • Zenisi C.
      • Di Vito L.
      • Mostacci B.
      • et al.
      Sleep-related hypermotor epilepsy. Long term outcome in a large cohort.
      ]. 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) [
      • Plazzi G.
      • Tinuper P.
      • Montagna P.
      • Provini F.
      • Lugaresi E.
      Epileptic nocturnal wanderings.
      ] 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 [
      • Montagna P.
      • Sforza E.
      • Tinuper P.
      • Cirignotta F.
      • Lugaresi E.
      Paroxysmal arousals during sleep.
      ]. 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 [
      • Nobili L.
      • Francione S.
      • Mai R.
      • Cardinale F.
      • Castana L.
      • Tassi L.
      • et al.
      Nocturnal frontal lobe epilepsy.
      ] and the nomenclature differs across NFLE study groups worldwide (Table 1) [
      • Oldani A.
      • Zucconi M.
      • Asselta R.
      • Modugno M.
      • Bonati M.T.
      • Dalprà L.
      • et al.
      Autosomal dominant nocturnal frontal lobe epilepsy. A video-polysomnographic and genetic appraisal of 40 patients and delineation of the epileptic syndrome.
      ,
      • 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.
      ,
      • Nobili L.
      • Francione S.
      • Mai R.
      • Cardinale F.
      • Castana L.
      • Tassi L.
      • et al.
      Nocturnal frontal lobe epilepsy.
      ].
      Table 1Classification of NFLE seizures patterns according to duration of the attacks.
      DurationOldani et al.
      • Oldani A.
      • Zucconi M.
      • Asselta R.
      • Modugno M.
      • Bonati M.T.
      • Dalprà L.
      • et al.
      Autosomal dominant nocturnal frontal lobe epilepsy. A video-polysomnographic and genetic appraisal of 40 patients and delineation of the epileptic syndrome.
      Provini et al.
      • 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.
      Nobili et al.
      • Nobili L.
      • Francione S.
      • Mai R.
      • Cardinale F.
      • Castana L.
      • Tassi L.
      • et al.
      Nocturnal frontal lobe epilepsy.
      3–10 sMinimal motor activityPAsShort-lasting stereotyped movements (2–4 s)
      Major motor activity (>5 s)
      10–30 sMinor motor activityPAs (<20 s)PAs (5–10 s)
      Major motor activityNocturnal paroxysmal dystonia (>20 s)Major attacks, (20–30 s)
      30–120 sProlonged motor activity (>60 s)Nocturnal paroxysmal dystonia
      >120 sProlonged motor activityEpilepticnocturnal wanderingIctal deambulatory behaviors
      PAs: paroxysmal arousals; s: seconds.

      1.3 NFLE and genetics

      Following the conclusive demonstration of the epileptic nature of NPD, Scheffer et al. [
      • Scheffer I.E.
      • Bhatia K.P.
      • Lopes-Cendes I.
      • Fish D.R.
      • Marsden C.D.
      • Andermann F.
      • et al.
      Autosomal dominant frontal epilepsy misdiagnosed as sleep disorder.
      ] 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) [
      • Steinlein O.K.
      • Mulley J.C.
      • Propping P.
      • Wallace R.H.
      • Phillips H.A.
      • Sutherland G.R.
      • et al.
      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 [
      • Marini C.
      • Guerrini R.
      The role of the nicotinic acetylcholine receptors in sleep-related epilepsy.
      ,
      • Tinuper P.
      • Cerullo A.
      • Cirignotta F.
      • Cortelli P.
      • Lugaresi E.
      • Montagna P.
      Nocturnal paroxysmal dystonia with short-lasting attacks: three cases with evidence for an epileptic frontal lobe origin of seizures.
      ]. The phenotype produced by mutations of the 3 nAChR subunit genes is generally indistinguishable [
      • Tinuper P.
      • Cerullo A.
      • Cirignotta F.
      • Cortelli P.
      • Lugaresi E.
      • Montagna P.
      Nocturnal paroxysmal dystonia with short-lasting attacks: three cases with evidence for an epileptic frontal lobe origin of seizures.
      ].
      In vitro analyses of nAChR disclosed a gain of function (i.e. an increase in ACh sensitivity) [
      • Marini C.
      • Guerrini R.
      The role of the nicotinic acetylcholine receptors in sleep-related epilepsy.
      ] 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 [
      • Picard F.
      • Bruel D.
      • Servent D.
      • Saba W.
      • Fruchart-Gaillard C.
      • Schöllhorn-Peyronneau M.A.
      • et al.
      Alteration of the in vivo nicotinic receptor density in ADNFLE patients: a PET study.
      ]. 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 [
      • Heron S.E.
      • Smith K.R.
      • Bahlo M.
      • Nobili L.
      • Kahana E.
      • Licchetta L.
      • et al.
      Missense mutations in the sodium-gated potassium channel gene KCNT1 cause severe autosomal dominant nocturnal frontal lobe epilepsy.
      ]. 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) [
      • Dibbens L.M.
      • de Vries B.
      • Donatello S.
      • Heron S.E.
      • Hodgson B.L.
      • Chintawar S.
      • et al.
      Mutations in DEPDC5 cause familial focal epilepsy with variable foci.
      ], encoding for an inhibitor of the rapamycin (mTOR) pathway, a key regulator of cell growth [
      • Bar-Peled L.
      • Chantranupong L.
      • Cherniack A.D.
      • Chen W.W.
      • Ottina K.A.
      • Grabiner B.C.
      • et al.
      A tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1.
      ].
      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 [
      • Tinuper P.
      • Cerullo A.
      • Cirignotta F.
      • Cortelli P.
      • Lugaresi E.
      • Montagna P.
      Nocturnal paroxysmal dystonia with short-lasting attacks: three cases with evidence for an epileptic frontal lobe origin of seizures.
      ]. 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 [
      • Tinuper P.
      • Cerullo A.
      • Cirignotta F.
      • Cortelli P.
      • Lugaresi E.
      • Montagna P.
      Nocturnal paroxysmal dystonia with short-lasting attacks: three cases with evidence for an epileptic frontal lobe origin of seizures.
      ].

      2. NFLE: controversial issues

      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 [
      • Scheffer I.E.
      • Bhatia K.P.
      • Lopes-Cendes I.
      • Fish D.R.
      • Marsden C.D.
      • Andermann F.
      • et al.
      Autosomal dominant frontal epilepsy misdiagnosed as sleep disorder.
      ]. Affected members of the family described by Aridon et al. [
      • Aridon P.
      • Marini C.
      • Di Resta C.
      • Brilli E.
      • De Fusco M.
      • Politi F.
      • et al.
      Increased sensitivity of the neuronal nicotinic receptor alpha 2 subunit causes familial epilepsy with nocturnal wandering and ictal fear.
      ] 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 [
      • Tassinari C.A.
      • Gardella E.
      • Meletti S.
      • Rubboli G.
      The neuroethological interpretation of motor behaviours in “nocturnal-hyperkynetic-frontal-seizures”: emergence of “innate” motor behaviours and role of central pattern generators.
      ]. 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 [
      • Bisulli F.
      • Vignatelli L.
      • Naldi I.
      • Licchetta L.
      • Provini F.
      • Plazzi G.
      • et al.
      Increased frequency of arousal parasomnias in families with nocturnal frontal lobe epilepsy: a common mechanism.
      ].
      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 [
      • Lena C.
      • Popa D.
      • Grailhe R.
      • Escourrou P.
      • Changeux J.P.
      • Adrien J.
      Beta2-containing nicotinic receptors contribute to the organization of sleep and regulate putative micro-arousals in mice.
      ]. 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 [
      • Parrino L.
      • Halasz P.
      • Tassinari C.A.
      • Terzano M.G.
      CAP, epilepsy and motor events during sleep: the unifying role of arousal.
      ,
      • Nobili L.
      Nocturnal frontal lobe epilepsy and non-rapid eye movement sleep parasomnias: differences and similarities.
      ]. Conversely, pronounced NREM fragmentation and instability have been observed in NREM sleep parasomnias [
      • Espa F.
      • Ondze B.
      • Deglise P.
      • Billiard M.
      • Besset A.
      Sleep architecture, slow wave activity, and sleep spindles in adult patients with sleepwalking and sleep terrors.
      ] suggesting an impairment of full arousal from slow wave sleep [
      • Broughton R.
      Pathophysiology of enuresis nocturna, sleep terrors and sleepwalking: current status and the Marseilles contribution.
      ]. 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 [
      • Vignatelli L.
      • Bisulli F.
      • Zaniboni A.
      • Naldi I.
      • Fares J.E.
      • Provini F.
      • et al.
      Interobserver reliability of ICSD-R minimal diagnostic criteria for the parasomnias.
      ], or unavailable, as in NFLE [
      • ASDA
      • American Academy of Sleep Medicine
      ]. A number of historical features may distinguish NFLE from parasomnias [
      • Derry C.P.
      • Duncan J.S.
      • Berkovic S.F.
      Paroxysmal motor disorders of sleep: the clinical spectrum and differentiation from epilepsy.
      ,
      • Tinuper P.
      • Provini F.
      • Bisulli F.
      • Vignatelli L.
      • Plazzi G.
      • Vetrugno R.
      • et al.
      Movement disorders in sleep: guidelines for differentiating epileptic from non-epileptic motor phenomena arising from sleep.
      ] (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) [
      • Derry C.P.
      • Davey M.
      • Johns M.
      • Kron K.
      • Glencross D.
      • Marini C.
      • et al.
      Distinguishing sleep disorders from seizures: diagnosing bumps in the night.
      ] and the Structured Interview for NFLE (SINFLE) [
      • Bisulli F.
      • Vignatelli L.
      • Naldi I.
      • Pittau F.
      • Provini F.
      • Plazzi G.
      • et al.
      Diagnostic accuracy of a structured interview for nocturnal frontal lobe epilepsy (SINFLE): a proposal for developing diagnostic criteria.
      ]. These tools are limited by contradictory diagnostic accuracy [
      • Manni R.
      • Terzaghi M.
      • Repetto A.
      The FLEP scale in diagnosing nocturnal frontal lobe epilepsy, NREM and REM parasomnias: data from a tertiary sleep and epilepsy unit.
      ,
      • Bisulli F.
      • Vignatelli L.
      • Naldi I.
      • Pittau F.
      • Provini F.
      • Plazzi G.
      • et al.
      Diagnostic accuracy of a structured interview for nocturnal frontal lobe epilepsy (SINFLE): a proposal for developing diagnostic criteria.
      ]. 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 [
      • Manni R.
      • Terzaghi M.
      • Repetto A.
      The FLEP scale in diagnosing nocturnal frontal lobe epilepsy, NREM and REM parasomnias: data from a tertiary sleep and epilepsy unit.
      ].
      Fig. 1
      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.

      2.2.2 Video-polysomnography

      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 [
      • Derry C.P.
      • Duncan J.S.
      • Berkovic S.F.
      Paroxysmal motor disorders of sleep: the clinical spectrum and differentiation from epilepsy.
      ,
      • Vignatelli L.
      • Bisulli F.
      • Provini F.
      • Naldi I.
      • Pittau F.
      • Zaniboni A.
      • et al.
      Interobserver reliability of video recording in the diagnosis of nocturnal frontal lobe seizures.
      ,
      • Nobili L.
      Nocturnal frontal lobe epilepsy and non-rapid eye movement sleep parasomnias: differences and similarities.
      ]. 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%) [
      • Manni R.
      • Terzaghi M.
      • Zambrelli E.
      REM sleep behavior disorder and epileptic phenomena: clinical aspects of the comorbidity.
      ]. 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 [
      • Manni R.
      • Terzaghi M.
      • Repetto A.
      The FLEP scale in diagnosing nocturnal frontal lobe epilepsy, NREM and REM parasomnias: data from a tertiary sleep and epilepsy unit.
      ].
      Video-recording may be sufficiently reliable to diagnose NFLE characterized by major motor activity (hypermotor or asymmetric dystonic seizures) [
      • Vignatelli L.
      • Bisulli F.
      • Provini F.
      • Naldi I.
      • Pittau F.
      • Zaniboni A.
      • et al.
      Interobserver reliability of video recording in the diagnosis of nocturnal frontal lobe seizures.
      ]. 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 [
      • Tinuper P.
      • Provini F.
      • Bisulli F.
      • Vignatelli L.
      • Plazzi G.
      • Vetrugno R.
      • et al.
      Movement disorders in sleep: guidelines for differentiating epileptic from non-epileptic motor phenomena arising from sleep.
      ]. 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 [
      • Vignatelli L.
      • Bisulli F.
      • Provini F.
      • Naldi I.
      • Pittau F.
      • Zaniboni A.
      • et al.
      Interobserver reliability of video recording in the diagnosis of nocturnal frontal lobe seizures.
      ]. 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. [
      • Derry C.P.
      • Harvey A.S.
      • Walker M.C.
      • Duncan J.S.
      • Berkovic S.F.
      NREM arousal parasomnias and their distinction from nocturnal frontal lobe epilepsy: a video EEG analysis.
      ] 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 [
      • Derry C.P.
      • Harvey A.S.
      • Walker M.C.
      • Duncan J.S.
      • Berkovic S.F.
      NREM arousal parasomnias and their distinction from nocturnal frontal lobe epilepsy: a video EEG analysis.
      ]. 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 [
      • Derry C.P.
      • Harvey A.S.
      • Walker M.C.
      • Duncan J.S.
      • Berkovic S.F.
      NREM arousal parasomnias and their distinction from nocturnal frontal lobe epilepsy: a video EEG analysis.
      ].
      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 [
      • Vignatelli L.
      • Bisulli F.
      • Provini F.
      • Naldi I.
      • Pittau F.
      • Zaniboni A.
      • et al.
      Interobserver reliability of video recording in the diagnosis of nocturnal frontal lobe seizures.
      ] and non-discriminant value for minor motor events, like PA, or for certain complex fearful behaviors [
      • Nobili L.
      Can homemade video recording become more than a screening tool?.
      ]. 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 [
      • Licchetta L.
      • Bisulli F.
      • Vignatelli V.
      • Zenisi C.
      • Di Vito L.
      • Mostacci B.
      • et al.
      Sleep-related hypermotor epilepsy. Long term outcome in a large cohort.
      ].

      2.3 The extrafrontal origin of NFLE

      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 [
      • Rheims S.
      • Ryvlin P.
      • Scherer C.
      • Minotti L.
      • Hoffmann D.
      • Guenot M.
      • et al.
      Analysis of clinical patterns and underlying epileptogenic zones of hypermotor seizures.
      ]. Patients with hyperkinetic ictal behavior showed the involvement of either mesial-dorso-lateral, orbito-polar, opercular or larger lobar cortical regions [
      • Rheims S.
      • Ryvlin P.
      • Scherer C.
      • Minotti L.
      • Hoffmann D.
      • Guenot M.
      • et al.
      Analysis of clinical patterns and underlying epileptogenic zones of hypermotor seizures.
      ]. 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 [
      • Biraben A.
      • Taussig D.
      • Thomas P.
      • Even C.
      • Vignal J.P.
      • Scarabin J.M.
      • et al.
      Fear as the main feature of epileptic seizures.
      ,
      • Nobili L.
      • Francione S.
      • Cardinale F.
      • Lo Russo G.
      Epileptic nocturnal wanderings with a temporal lobe origin: a stereo-electroencephalographic study.
      ,
      • Bartolomei F.
      • Trebuchon A.
      • Gavaret M.
      • Regis J.
      • Wendling F.
      • Chauvel P.
      Acute alteration of emotional behaviour in epileptic seizures is related to transient desynchrony in emotion-regulation networks.
      ].
      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 [
      • Proserpio P.
      • Cossu M.
      • Francione S.
      • Gozzo F.
      • Lo Russo G.
      • Mai R.
      • et al.
      Epileptic motor behaviors during sleep: anatomo-electro-clinical features.
      ]. 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 [
      • Nobili L.
      • Francione S.
      • Cardinale F.
      • Lo Russo G.
      Epileptic nocturnal wanderings with a temporal lobe origin: a stereo-electroencephalographic study.
      ,
      • Ryvlin P.
      • Minotti L.
      • Demarquay G.
      • Hirsch E.
      • Arzimanoglou A.
      • Hoffman D.
      • et al.
      Nocturnal hypermotor seizures, suggesting frontal lobe epilepsy, can originate in the insula.
      ,
      • Rheims S.
      • Ryvlin P.
      • Scherer C.
      • Minotti L.
      • Hoffmann D.
      • Guenot M.
      • et al.
      Analysis of clinical patterns and underlying epileptogenic zones of hypermotor seizures.
      ,
      • Gibbs S.A.
      • Proserpio P.
      • Terzaghi M.
      • Pigorini A.
      • Sarasso S.
      • Lo Russo G.
      • et al.
      Sleep-related epileptic behaviors and non-REM-related parasomnias: insights from stereo-EEG.
      ]. Hyperkinetic automatisms and complex behaviors appeared when the ictal discharge involved structures such as the cingulate, frontal and parietal regions, irrespective of its origin [
      • Rheims S.
      • Ryvlin P.
      • Scherer C.
      • Minotti L.
      • Hoffmann D.
      • Guenot M.
      • et al.
      Analysis of clinical patterns and underlying epileptogenic zones of hypermotor seizures.
      ]. 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 [
      • Tinuper P.
      • Bisulli F.
      • Cross J.H.
      • Hesdorffer D.
      • Kahane P.
      • Nobili L.
      • Provini F.
      • Scheffer I.E.
      • Tassi L.
      • Vignatelli L.
      • Bassetti C.
      • Cirignotta F.
      • Derry C.
      • Gambardella A.
      • Guerrini R.
      • Halasz P.
      • Licchetta L.
      • Mahowald M.
      • Manni R.
      • Marini C.
      • Mostacci B.
      • Naldi I.
      • Parrino L.
      • Picard F.
      • Pugliatti M.
      • Ryvlin P.
      • Vigevano F.
      • Zucconi M.
      • Berkovic S.
      • Ottman R.
      Definition and diagnostic criteria of sleep-related hypermotor epilepsy.
      ].
      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.

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