Sleep Medicine 12 (2011) S33–S38

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Sleep Medicine

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Original Article

Epileptic motor behaviors during sleep: Anatomo-electro-clinical features

P. Proserpio a,b, M. Cossu a, S. Francione a, F. Gozzo a, G. Lo Russo a, R. Mai a, A. Moscato a, M. Schiariti a,I. Sartori a, L. Tassi a, L. Nobili a,b,⇑a ‘‘C. Munari’’ Centre of Epilepsy Surgery, Niguarda Hospital, Milan, Italyb Centre of Sleep Medicine, Department of Neuroscience, Niguarda Hospital, Milan, Italy

a r t i c l e i n f o

Article history:Received 28 July 2011Received in revised form 11 October 2011Accepted 13 October 2011

1389-9457/$ - see front matter � 2011 Elsevier B.V. Adoi:10.1016/j.sleep.2011.10.018

⇑ Corresponding author at: Centre of Sleep Medicience, Niguarda Hospital, Piazza Ospedale Maggiore0264447323; fax: +39 0264442868.

E-mail address: Lino.nobili@ospedaleniguarda.it (L

a b s t r a c t

Background: Sleep-related complex motor seizures have long been considered pathognomonic features ofNocturnal Frontal Lobe Epilepsy (NFLE). In recent years, these manifestations have also been reported tohave a temporal or insular origin.Method: We describe 40 drug-resistant epileptic patients with complex motor seizures during sleep, sub-mitted to presurgical stereo-EEG (SEEG) evaluation and seizure-free after surgical resection of the epilep-togenic zone.Results: In a significant proportion (30%) of these patients, seizures arose from extra-frontal regions,including mainly the temporal lobe and the insular cortex, but also the parietal and occipital lobes. Inpatients with extra-frontal epilepsy, when complex motor behaviors appeared, SEEG revealed that theictal discharge involved the cingulate and the frontal regions. Finally, at histology, Taylor’s focal corticaldysplasia (TFCD) was the most common finding (90% of patients), independent of the site of seizure onset.Conclusion: As previously reported by other studies, this histologic substrate may be a major determinantof sleep-related seizures in drug-resistant epileptic patients.

� 2011 Elsevier B.V. All rights reserved.

1. Introduction

Complex motor seizures occurring during sleep have long beenconsidered a pathognomonic manifestation of Nocturnal FrontalLobe Epilepsy (NFLE) [1–3]. In NFLE, seizures can be mainly charac-terized by different motor features, including hyperkinetic autom-atisms, such as bimanual/bipedal activity, kicking, thrashing,rocking, axial and pelvic movements, or asymmetric tonic or dys-tonic posturing [2]. About 30% of patients with NFLE are drug-resistant and, in most of them, surgical treatment can provideexcellent results both on seizures and on epilepsy-related sleepdisturbances [2,4]. However, in the last decade, several reportshave demonstrated that nocturnal complex motor seizures mayoriginate outside the frontal lobe. In particular, seizures stronglyresembling those occurring in NFLE may have a temporal [5–8]and insular [9–11] origin. These observations are clinically relevantwhen considering drug-resistant epileptic patients, since the cor-rect localization of the epileptogenic zone (EZ, the cortical regionof onset and of primary organization of the ictal discharge [12]) be-comes mandatory in a surgical perspective. Moreover, establishingthe correct localization of the EZ may be useful to understand thenetworks involved in these kinds of sleep-related epileptic motor

ll rights reserved.

ne, Department of Neurosci-3, Milano, Italy. Tel.: +39

. Nobili).

behaviors. Scalp EEG recordings usually do not establish the exactbrain region involved in such manifestations, while intracerebralrecordings provide more accurate information.

With these premises, we analyzed the clinical, neuroradiologi-cal, and histopathologic features of drug-resistant patients withsleep-related seizures who received surgical treatment. In orderto present reliable data, we selected only patients investigated byintracerebral EEG recordings during the presurgical evaluationand rendered seizure-free after surgical resection of the EZ.

2. Materials and methods

We evaluated all consecutive patients with drug-resistant focalepilepsy operated on at ‘‘C. Munari Epilepsy Surgery Center’’ fromMay 1996 to January 2010. We selected those cases who met allthe following criteria:

presence of sleep-related seizurespresurgical evaluation with stereotactically implanted intrace-rebral electrodes (stereo-EEG, SEEG)post-operative follow-up of at least 2 yearsgood post-operative seizure outcome (seizure free, Engel’s classIa–Id [13])

Patients were considered to be affected by sleep-related sei-zures if more than 90% of ictal events occurred during sleep, basedon questioning of patients and their relatives. This distribution of

Table 1Anamnestic, clinical, neuroradiological features, and localization of the EZ. Abbreviations: f, female; m, male; Hyper. Autom., Hyperkinetic Automatisms; Asym. Ton. Post.,Asymmetric Tonic Posturing; Asym. Dyst. Post., Asymmetric Dystonic Posturing; Mimetic Autom., Mimetic Automatisms; +, positive; -, unrevealing; F, Frontal; I, Insular; P,Parietal; T, Temporal; O, occipital; F3, inferior frontal gyrus; F1, superior frontal gyrus; F2 middle frontal gyrus; T1, first temporal circumvolution; T2 second temporalcircumvolution.

Case Sex Epilepsy onset (years) Seizure frequency/month Objective manifestations MRI EZ Side EZ Lobe EZ site

1 f 4 0,3 Hyper. Autom. + Right F F3 (opercular region)2 m 15 150 Asym. Ton. Post. + Left F F1 (posterior mesial)3 m 5 100 Hyper. Autom. - Left F F1 (anterior mesial)4 m 0 60 Hyper. Autom. - Right F F1 (posterior mesial), cingulate gyrus5 m 6 180 Hyper. Autom. - Right F F1 (fronto-polar)6 f 9 60 Asym. Ton. Post. + Right F F3 (opercular region)7 f 7 150 Mimetic Autom. + Left F F3 (opercular region)8 f 14 60 Hyper. Autom. + Left F F2 (anterior part)9 f 3 7 Hyper. Autom. + Right F frontal cingulate gyrus10 m 7 100 Hyper. Autom. + Left F Anterior F1–F2 sulcus11 m 1 60 Asym. Ton. Post. + Right F F1 (posterior mesial)12 m 7 160 Hyper. Autom. - Right F F1 (anterior mesial)13 m 1 70 Hyper. Autom. - Right F F1 (fronto-polar)14 m 3 90 Asym. Ton. Post. + Left F Posterior F1–F2 sulcus15 f 8 44 Asym. Ton. Post. - Right F F1 (posterior mesial)16 m 17 60 Hyper. Autom. - Right F Anterior F1-F2 sulcus17 f 4 100 Hyper. Autom. + Left F Anterior F1-F2 sulcus18 m 16 300 Asym. Dyst. Post. + Right F F1 (posterior mesial)19 m 0 100 Asym. Ton. Post. + Right F Orbital region20 m 4 100 Hyper. Autom. + Right F Fronto-polar region21 m 6 15 Hyper. Autom. + Left F Gyrus rectus22 m 4 5 Hyper. Autom. - Right F Orbital region23 f 14 120 Hyper. Autom. + Left F Frontal cingulate gyrus24 f 9 300 Asym. Ton. Post. + Left F Anterior F1–F2 sulcus25 f 4 50 Hyper. Autom + Right F Posterior F1–F2 sulcus26 f 5 150 Asym. Ton. Post. + Left F Central cingulate gyrus27 m 7 23 Asym. Ton. Post. + Right F F1 (posterior mesial)28 m 4 5 Hyper. Autom. + Right F Fronto-polar region29 m 3 6 Hyper. Autom. - Right I Insula and operculum30 f 1 90 Asym. Ton. Post. + Left I Insula and operculum31 m 6 60 Hyper. Autom. + Right I Insula and operculum32 f 7 105 Asym. Dyst. Post. + Left P Parietal cingulate gyrus33 m 3 60 Asym. Dyst. Post. + Left P Precuneus34 f 5 4 Asym. Ton. Post. + Left T T1 (anterior part)35 m 24 2 Versive + Right T Temporo-basal region36 m 0 30 Hyper. Autom. + Right T T1 (posterior part)37 m 4 40 Hyper. Autom. + Left T T2 (posterior part)38 f 3 30 Hyper. Autom. + Right T Temporo-basal region39 f 3 168 Hyper. Autom. + Right T Temporo-basal region40 m 13 50 Oral Automatisms + Right O Subcalcarin cortex

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seizures was confirmed by seizure diaries filled over a period for atleast one year, and by subsequent long-term video-EEG recordings.

For each patient we evaluated the main clinical features, theneuroradiological aspects, the site of seizure onset determined bySEEG, and the results of histopathologic examinations. All patientsunderwent scalp video-EEG (VEEG) investigation and magneticresonance imaging (MRI). Complex motor seizures were catego-rized according to the International League Against Epilepsy classi-fication [14] using video-EEG analysis of the seizures. The site ofseizure onset was determined on the basis of the anatomo-electro-clinical correlations. In particular, because video-EEG alone failedto correctly localize the ictal onset zone in these patients, a SEEGinvestigation was performed [15–16] for an adequate definitionof the EZ. An individualized arrangement of electrodes (explora-tion) was employed, according to a predefined localization hypoth-esis based on non-invasive findings. The dysplastic tissue wasclassified according to Tassi et al. [17]. Postoperative outcome onseizures was assessed using the scoring system proposed by Engelet al. [13].

3. Results

Among 942 consecutive patients operated on for drug-resistantepilepsy, 40 cases met the inclusion criteria. There were 24 males

and 16 females, mean age at onset of seizures was 6.4 years (SD5.2; range 0–24). Mean seizure frequency was 81 seizures/month(SD 71; range 0.3–300). All patients were referred for surgical con-sideration after several therapeutic attempts with different antiep-ileptic drugs on monotherapy or polytherapy at maximal tolerateddosages, with no benefit on seizures. Table 1 describes the patients’main anamnestic, clinical, and neuroradiological features, as wellas the site of the EZ according to the results of SEEG investigation.

According to video-EEG analysis of the seizures, in most of ourpatients the objective manifestations could be grouped into threemain complex motor patterns: hyperkinetic automatisms (23/40patients), asymmetric tonic posturing (11/40 patients), and asym-metric dystonic posturing (3/40 patients). The other three patientsshowed different clinical features: case seven showed dyspnoeaand mimetic automatisms, case 35 showed versive seizures withsecondary generalization, and case 40 showed complex oralautomatisms. MRI disclosed an anatomical abnormality in 31patients.

SEEG examinations localized the EZ in the frontal lobe in 28 pa-tients (70%), the insulo-opercular region in three patients, the pari-etal lobe in two patients, the temporal lobe in six patients, and theoccipital lobe in one patient (Fig. 1). In particular, among NFLE pa-tients, hyperkinetic automatisms were observed in 17 cases, while10 patients showed seizures characterized by asymmetric tonic ordystonic posturing. Regarding the latter group, seizure onset was

Fig. 1. Localization of the EZ in the studied population (40 patients). The site of theEZ is superimposed on the Montreal Neurological Institute (MNI) brain template.Colors indicate the main clinical pattern of seizures: yellow, hyperkinetic autom-atisms; red, asymmetric tonic posturing; blue, asymmetric dystonic posturing;violet, other manifestations (see text). L, left; R, right; a, dorsolateral view; b, mesialview; c, transparent images, and axial projection showing the EZ located in theinsular cortex. (For interpretation of the references to colour in this figure legend,the reader is referred to the web version of this article.)

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mainly localized in the posterior portion of the frontal cingulategyrus and in the posterior mesial frontal cortex. When seizurescharacterized by asymmetric tonic or dystonic posturing arose inthe orbital or dorso-lateral frontal regions, complex motor mani-festations appeared only when the ictal discharge spread to theposterior fronto-mesial cortex (Fig. 2).

In NFLE patients with hyperkinetic automatisms, the EZ in-volved different frontal areas, mainly the dorso-lateral and anteriorfrontal regions (fronto-polar and frontal antero-mesial regions).

In patients with extrafrontal sleep-related seizures, hyperki-netic automatisms were observed in 6/12 cases, while four cases

Fig. 2. SEEG recordings in a patient (case 19) with tonic asymmetric seizures. Note thatappears when the epileptic discharge involves the posterior mesial frontal region.

showed asymmetric tonic or dystonic posturing. Independent fromthe site of the EZ, in the majority of these subjects, complex motorbehaviors appeared when the epileptic discharge reached the fron-tal lobe.

Mean age at onset of seizures was 6.5 in NFLE patients and 6.0in those with extra-frontal sleep-related seizures. Seizure fre-quency was 93/month in NFLE patients and 53/month in thosewith extra-frontal sleep-related seizures.

Regarding the electrophysiological features, the interictal SEEGactivity recorded from the EZ independently from its localizationshowed a peculiar pathological electrical pattern consisting ofsub-continuous, pseudorhythmic spikes or polyspikes alternatingwith short bursts of fast discharges interrupted by suppression ofactivity in most patients, a pattern strongly increased in frequencyduring slow wave sleep (Fig. 3).

Details on surgical resection, histology, and postoperative fol-low-up are summarized in Table 2. Mean age at surgery was25 years (SD: 10 range 7–53). At histology, Taylor’s focal corticaldysplasia was the most common finding (90% of patients). Meanduration of postoperative follow-up was 76 months (SD 36; range24–148). Postoperatively, antiepileptic drugs were tapered orwithdrawn in 30 patients, whereas in the remaining 10 cases med-ical treatment was unchanged.

4. Discussion

In order to determine with accuracy the correct localization ofthe EZ and the possible networks underlying sleep-related sei-zures, out of the population of patients with this kind of seizuresevaluated in our centre, only patients submitted to SEEG investiga-tion and seizure-free after surgical treatment were considered. Ourresults show that in the majority (70%) of patients sleep-relatedcomplex motor seizures originate from the frontal lobe; however,the possible extrafrontal origin of these manifestations was con-firmed. As previously reported [5–11], a number of patientsshowed a temporal lobe or an insular nocturnal epilepsy. More-over, two patients had a parietal and one an occipital onset ofthe seizures.

Our data concerning NFLE patients are in accordance with pre-vious reports [4,18–21] showing that, in patients with an asym-metric tonic or dystonic posturing, the EZ is located within theposterior mesial frontal cortex, with a frequent involvement ofthe supplementary motor area and the posterior mesial frontalcortex.

the ictal discharge starts in the orbital region. Asymmetric tonic posturing (arrow)

Fig. 3. SEEG recording of the electrical pattern of TFCD: inter-ictal activity during wakefulness (a) and Non-REM sleep (b); ictal activity (clinical seizure) (c).

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On the other hand, in patients with a hyperkinetic behavior,SEEG revealed the involvement of the dorsolateral frontal cortex,the anterior frontal cingulate gyrus, and the orbito-polar region[4,21]. Although limited to a small sample of subjects, we didnot find a particular correlation between the site of EZ localiza-tion and a specific, hyperkinetic or tonic-dystonic, clinical patternin subjects with an extra-frontal epilepsy. Nobili et al. [6] ob-served that, in patients with nocturnal temporal lobe epilepsy(NTLE), the hyperkinetic manifestation appeared 8–15 s after theelectrical onset, when the discharge spread to extratemporalstructures, particularly the frontal and parietal cortex. Althoughwe did not address this issue in this paper, our data (not reportedhere) confirm that there is a long delay (10–20 s) between theelectrical and the clinical onset in the majority of patients withan extrafrontal nocturnal epilepsy. Moreover, in this group of pa-tients SEEG investigations disclosed that, when complex motorbehaviors appeared, the ictal discharge involved the cingulateand the frontal regions. Therefore, the frontal lobe seems to bethe ‘‘generator’’ of these complex motor seizures even when theEZ is extrafrontal. Alternatively, at least as far as seizures withmore complex behaviors (bipedal activity, kicking, thrashing,rocking) are concerned, one may speculate that the involvementof distinct frontal regions, including the frontal cingulate gyrusand the pre-frontal cortex, disinhibits cortical and subcorticalcentral pattern generators, thus inducing the emergence of innatebehaviors [22].

Concerning the anamnestic features, the mean age of epilepsyonset was similar in patients with frontal and extrafrontal seizureorigin. Seizure frequency was slightly lower in patients with anextrafrontal seizure origin.

Considering the ictal clinical characteristics, seizures arisingfrom different lobes were hardly distinguishable on the basis of

their objective manifestations. However, previous data [6,7] sug-gested that, compared to NFLE, complex motor automatisms inNTLE are more asymmetric, prevailing ipsilaterally to the originof the epileptic discharge, at least in the first part of the seizure.The present work did not analyze the subjective manifestationsof our patients. However, a careful investigation of these symp-toms could be particularly helpful. Indeed, a warning sensation(consisting of fear, especially associated with epigastric discomfortor déjà vu) awakening the patient or occurring after awakeningseems to be more indicative of a temporal onset. On the otherhand, as previously reported [23], we are assembling data showingthat patients with nocturnal insulo-opercular epilepsy often refer asequence of ictal symptoms possibly peculiar of insular seizures,consisting in viscerosensitive (laryngeal and throat sensations,breathing discomfort, unpleasant or rising epigastric sensations)and somatosensory (unpleasant or electrical paresthesiae, diffuseor restricted to a small cutaneous area) manifestations and audi-tory hallucinations.

In the present study, the only patient with occipital lobe sei-zures (case 40) was long considered an NFLE case, and all his neu-roradiological investigations were focused on the anterior brainregions. On more accurate anamnesis, he referred occasional aurascharacterized by left-sided visual hallucinations. A subsequent MRIexamination focused on the occipital region disclosed a focal lesionin the right subcalcarine cortex.

According to these observations, an accurate analysis of all theanamnestic, clinical, electrophysiological, and neuroradiologicaldata is essential in patients with nocturnal drug-resistant epilepsyin order to identify clues suggestive of a specific site of origin.

At histology, 90% of our patients presented a TFCD, which rep-resents the most frequent etiological substrate in drug-resistantsurgically treated patients with both frontal and extrafrontal

Table 2Main features of surgical resection, histology, and postoperative follow-up. Abbreviations: C, Cortical resection; L, lesionectomy; pL, partial Lesionectomy; TFCD, Taylor FocalCortical Dysplasia; CytoArchiFCD, Cyto-architectural Focal Cortical Dysplasia; ArchiFCD Architectural Focal Cortical Dysplasia; DNET, Dysembryoplastic Neuroepithelial Tumor.

Case Age at surgery (years) Surgery Histology Outcome (Engel) Therapy Follow up (months)

1 17 C; L TFCD Ia None 702 26 C; pL TFCD Ia Tapering 1383 15 C TFCD Ia Tapering 674 29 C TFCD Ia Tapering 865 20 C TFCD Ia None 386 13 C TFCD Ib Unmodified 617 34 C; L TFCD Ia None 958 37 C; L TFCD Ia Tapering 249 17 C; pL TFCD Ia None 10510 24 C; L TFCD Ia Tapering 6911 11 C TFCD Ib Unmodified 2812 36 C TFCD Ia Tapering 2413 38 C Archi FCD;TFCD Ia Tapering 2914 11 C; L TFCD Ia Unmodified 7315 35 C TFCD Ic None 14316 24 C TFCD Ia None 13217 23 C; L TFCD Ia None 8218 28 C; L TFCD Ia Tapering 9719 22 C; L TFCD Ia Tapering 9820 40 C; L TFCD Ia Tapering 5921 19 C; L CytoArchi FCD; DNT Ia Tapering 7922 36 C TFCD Ia Tapering 3523 33 C; L TFCD Ia Tapering 3524 15 C; L TFCD Ia Unmodified 2825 10 C; L TFCD Ia Tapering 4926 16 L TFCD Ia Unmodified 4127 28 C; L TFCD Ia Tapering 10828 30 C; L TFCD Ia Tapering 7229 20 C Cripto Ia Tapering 4330 12 C; L TFCD Ia Tapering 2631 23 C CytoArchi FCD Ia Tapering 6332 42 C; L TFCD Id Unmodified 10833 32 C; pL TFCD Ia Unmodified 4934 29 C; L ArchiFCD; DNET Ib Unmodified 13235 36 C; L TFCD Ia Tapering 10836 7 C; L TFCD Ia Tapering 10237 22 C; pL TFCD Ic Unmodified 9738 34 C; L TFCD Ia None 11439 21 C; L TFCD Ia None 14840 53 C; L TFCD Ic Unmodified 83

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sleep-related seizures [4,6,7]. In particular, Nobili et al. [24] founda strong association between nocturnal epilepsy and TFCD in drug-resistant epileptic patients and demonstrated that this corticalmalformation represents an independent risk factor for sleep-related seizures. They hypothesized that this correlation may beascribed to the particular firing pattern of TFCD during Non-REMsleep. In fact, TFCD shows a pattern of continuous spikes or spikesand waves activity during wakefulness, that could reduce the pos-sibility of an ictal fast discharge [25–27]. On the contrary, duringNon-REM sleep the interictal activity is mainly organized in pseu-do-periodically recurrent short bursts of fast discharges that inter-rupt the continuous pattern of spike and waves [28]. These burstsoften spread to surrounding non lesional regions and develop intoa seizure.

In conclusion, our data confirm that a significant proportion(30%) of sleep-related complex motor seizures originate outsidethe frontal lobe. These results are clinically relevant when consid-ering drug-resistant epileptic patients in whom a surgical approachcould be an effective treatment.

Disclosure of financial support and conflicts of interest

The authors have reported no financial support or conflict ofinterest.

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