Sleep related epilepsy in focal cortical dysplasia type 2: Insights from sleep recordings in presurgical evaluation

Journal Pre-proofs Sleep related epilepsy in focal cortical dysplasia type 2: insights from sleep recordings in presurgical evaluation Christin M. Eltze, Elisabeth Landre, Christine Soufflet, Francine Chassoux PII: DOI: Reference:

S1388-2457(19)31358-6 https://doi.org/10.1016/j.clinph.2019.11.055 CLINPH 2009069

To appear in:

Clinical Neurophysiology

Received Date: Revised Date: Accepted Date:

24 July 2019 9 November 2019 15 November 2019

Please cite this article as: Eltze, C.M., Landre, E., Soufflet, C., Chassoux, F., Sleep related epilepsy in focal cortical dysplasia type 2: insights from sleep recordings in presurgical evaluation, Clinical Neurophysiology (2019), doi: https://doi.org/10.1016/j.clinph.2019.11.055

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Sleep related epilepsy in focal cortical dysplasia type 2: insights from sleep recordings in presurgical evaluation Christin M Eltze1-2MD Res, Elisabeth Landre1 MD, Christine Soufflet3 MD, Francine Chassoux1MD 1

GHU Paris Sainte-Anne, Epilepsy unit, Department of Neurosurgery, Paris, France Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK 3 GHU Paris Sainte-Anne, Neurophysiology Department, Paris, France 2

Objective: To determine the relationship between seizure onset, sleep stage and focal cortical dysplasia type 2 (FCD2) location in sleep related epilepsy (SRE). Methods: We reviewed scalp video-EEG data of 77 patients with SRE among 130 surgically treated patients with histologically confirmed FCD2. Seizure onset was classified as occurring during NREM, REM and after arousal. Results: Sleep recordings were available for 65 patients (37 males, 7-49 years old). FCD2 was located in frontal lobe in 46 (71%) and in extra-frontal regions in 19, including the temporal lobe in 6. MRI was negative/doubtful in 35 cases. Interictal rhythmic/pseudorhythmic spike rate increased from 31% during waking to 65% during sleep. Seizure onset occurred from NREM in 46 cases (71%), mostly from stage 2, and after arousal in 14 (22%). Seizures occurring from NREM/REM sleep were significantly more frequent in frontal (89%) compared to extra-frontal location (42%), whilst arousal preceded seizure onset more often in extra-frontal (58%) compared to frontal location (7%). Conclusions: NREM seizure onset is the most common ictal pattern in SRE due to frontal FCD2 whereas preceding arousal points to extra-frontal regions. Significance: Sleep recordings may help for FCD2 localisation and suggest topography dependent impact on sleep related epileptic networks.

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Sleep related epilepsy in focal cortical dysplasia type 2: insights from sleep recordings in presurgical evaluation Christin M Eltze1-2MD Res, Elisabeth Landre1 MD, Christine Soufflet3 MD, Francine Chassoux1MD 1

GHU Paris Sainte-Anne, Epilepsy unit, Department of Neurosurgery, Paris, France Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK 3 GHU Paris Sainte-Anne, Neurophysiology Department, Paris, France 2

Correspondence Francine Chassoux, Epilepsy Unit Neurosurgery Department, GHU‐Paris Sainte‐Anne 1 rue Cabanis, 75014 Paris, France Tel.: +33 1 45 65 82 26 Fax: +33 1 45 65 74 28

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Abstract Objective: To determine the relationship between seizure onset, sleep stage and focal cortical dysplasia type 2 (FCD2) location in sleep related epilepsy (SRE). Methods: We reviewed scalp video-EEG data of 77 patients with SRE among 130 surgically treated patients with histologically confirmed FCD2. Seizure onset was classified as occurring during NREM, REM and after arousal. Results: Sleep recordings were available for 65 patients (37 males, 7- 49 years old). FCD2 was located in frontal lobe in 46 (71%) and in extra-frontal regions in 19, including the temporal lobe in 6. MRI was negative/doubtful in 35 cases. Interictal rhythmic/pseudorhythmic spike rate increased from 31% during waking to 65% during sleep. Seizure onset occurred from NREM in 46 cases (71%), mostly from stage 2, and after arousal in 14 (22%). Seizures occurring from NREM/REM sleep were significantly more frequent in frontal (89%) compared to extra-frontal location (42%), whilst arousal preceded seizure onset more often in extra-frontal (58%) compared to frontal location (7%). Conclusions: NREM seizure onset is the most common ictal pattern in SRE due to frontal FCD2 whereas preceding arousal points to extra-frontal regions. Significance: Sleep recordings may help for FCD2 localisation and suggest topography dependent impact on sleep related epileptic networks.

Keywords: Sleep Related Epilepsy, Focal Cortical Dysplasia, Epilepsy surgery, sleep EEG.

Highlights   

In pharmaco-resistant sleep related epilepsy associated with focal cortical dysplasia type 2 (FCD2), seizures occur most commonly in NREM sleep stage N2. Seizure onset without prior scalp EEG arousal changes is associated with frontal lobe FCD2 location. Focal rhythmic/pseudorhythmic spike activity, characteristic of FCD2, is recorded in 2/3 of the cases during sleep.

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1 Introduction Focal cortical dysplasia type 2 (FCD2) is amongst the most frequent histopathological diagnoses identified in surgical specimens of children and adults undergoing epilepsy surgery (Blumcke et al., 2017). Seizure onset occurs typically in childhood with a majority presenting in the first decade of life (Fauser et al., 2006). Complete resection of such lesions can result in high chance of seizure free outcome in this patient group (Chassoux et al., 2012; Guerrini et al., 2015; Tassi et al., 2012). FCD2 represents a highly epileptogenic tissue with a characteristic electrographical pattern of continuous or semicontinuous rhythmic spike activity recorded from intracranial EEG. On the scalp EEG, the corresponding typical rhythmic or pseudo-rhythmic spike activity has been reported in up to 50% of patients with confirmed FCD2 during wakefulness, enhancing during sleep (Chassoux et al., 2012; Tassi et al., 2012). Frequent occurrence of sleep-related epilepsy (SRE), defined as seizures occurring exclusively or predominantly during sleep, has been reported more recently (Nobili et al., 2009). Despite the fact that FCD2 is most commonly located in the frontal lobe on the one hand and that frontal lobe epilepsy (FLE) is highly associated with SRE on the other hand, FCD2 has been independently related with SRE (Chassoux et al., 2012; Losurdo et al., 2014; Nobili et al., 2009). However, although up to 50% of patients with FCD2 present with SRE, little attention has been paid to the specific influence of sleep on the epileptic activity and the relationship with the localization of the epileptogenic zone (EZ). It has been shown that in temporal lobe epilepsy (TLE) seizures occur more commonly in waking compared to FLE, and that temporal lobe seizures occurring from sleep are more often preceded by an arousal, whereas frontal lobe seizures occur from NREM sleep (Crespel et al., 2000). These observations suggest that not only the underlying pathology, but also topographical aspects are relevant in SRE. We hypothesized that sleep seizure onset pattern assessed on scalp EEG may differ according to FCD2

location. In this study we examined scalp video-EEG (S-V-EEG) data of sleep recordings, focusing on the relationship between ictal onset and sleep stages (NREM, REM, preceding arousal), and its

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5 potential value for FCD2 localisation. Our goal was to assess the additional information provided by sleep recordings in presurgical evaluation for drug resistant SRE due to FCD2.

2 Patients and Methods 2.1 Selection criteria Of the 130 patients who underwent a corticectomy with subsequent histologically confirmed FCD2 at Sainte-Anne Hospital in Paris between 2000 and 2017, 77 consecutive patients (59%) with SRE were identified. We included in this study 65 patients for whom scalp video EEG data with seizures recorded from sleep were available. Reasons for patient exclusion were (1) insufficient S-V-EEG sleep recordings to capture a seizure (3 patients), (2) seizures recorded during wakefulness only (4 patients); (3) insufficient S-V -EEG data available for review (5 patients).

2.2 Methods Relevant clinical information, such as age of seizure onset, seizure-frequency, results of pre-surgical high-resolution MR images (1.5T in 29 patients or 3T in 36 patients), outcome following epilepsy surgery according to Engel classification (Engel et al., 1993) and histological subtype (Blumcke et al., 2011) were obtained. Stereo EEG (SEEG) was performed in 33 cases but the data were not analysed for this study. S-V-EEG data analysed consisted of digitised EEG recordings with video, available for 52 (80%), non-digitised EEG records (‘paper records’) without video for 7 (11%) and detailed EEG reports for 6 patients (9%). Fifty (78%) patients underwent long-term video EEG monitoring (duration ≥ 24 hours) and 14 (21%) prolonged V-EEG recordings during daytime (one or several consecutive days, duration 1-2 hours). In addition, for one paediatric patient a sleep recording, capturing a seizure during a daytime nap, was obtained during an outpatient visit. Intramuscular injection of Amitriptyline (0.5 mg/kg of body weight) was used for sleep induction during naps in 6 cases. S-V-EEG data were obtained applying IFCN standards for electrode position (10-20 or 10-10 system) (Nuwer et al., 1998). Simultaneous polysomnography recordings were not carried out. Sleep stages were classified in accordance with the EEG criteria of the American Academy of Sleep Medicine guidelines (The AASM

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6 Scoring Manual for Sleep and Associated Events, version 2.3, 2016). An arousal was identified from NREM sleep stages N1, N2, N3 and REM (R) if there was an abrupt shift of EEG frequency from alpha, theta and/or frequencies > 16 Hz (but not spindles) that lasts 3 seconds with at least 10 seconds of stable sleep preceding the change (AASM Scoring Manual, version 2.3, 2016). The distribution of interictal EEG abnormalities and ictal discharges was categorised as focal involving 1 or 2 adjacent electrodes in one lobe, regional (electrodes involving 2 adjacent lobes), hemispheric if all electrodes over one hemisphere were involved, or bilateral if both hemispheres were involved. Presence of rhythmic/pseudo-rhythmic epileptiform discharges, typically described with FCD2 as stereotyped rhythmic sequence of repetitive sharp waves or spikes lasting more than 1 sec (Gambardella et al., 1996), was recorded according to the waking or sleep conditions. Location of FCD2 was based on preoperative MRI findings, histology, post-operative MRI and surgical outcome.

2.3 Statistical analysis: The statistical analysis was carried out using SPSS version 23. Non-Parametric test (Man-Whitney test) was used for in between subject comparison of continuous variables (time lag from onset of ictal discharge to onset of clinical manifestations). Chi-square and Fisher’s exact test were used for categorical data (Location of FCD2 “frontal”, “extra-frontal”, “NREM/REM”, “after arousal”). The study was approved by the local ethics committee and found to conform to generally accepted scientific principles and ethical standards.

3. Results 3.1 Clinical details The clinical information of this patient cohort, localisation of FCD2, distribution of histological subtypes, proportion with lesion positive MRI has been summarised in Table 1. Most of the patients were operated in adulthood despite early onset of epilepsy and high seizure frequency (see table 1 for age of seizure onset and duration of epilepsy). MRI demonstrated typical features of FCD2 in less than half of the cases and was doubtful or negative for the others. However, the rate of positive MRI 6

7 increased from 34% with 1.5T to 55% with 3T MRI. Whilst the majority of FCD2 lesions were resected from frontal lobes (46, 71%), in 19 patients the location was extra-frontal. Surgical outcome was categorised as Engel class I in 55 (85%) of patients after a median follow up of 3 years (range 1-12 years).

3.2 Interictal EEG Interictal EEG abnormalities (slow waves or spikes) were focal or regional in most cases, with a wider distribution during sleep than in waking (Table 1). The pattern of continuous/subcontinuous or runs of rhythmic/pseudorhythmic spikes was identified in 42 patients (65%), for 20 (31%) patients in waking and sleep and 22 others (34%) only during sleep (Figures 1-2).

3.3 Ictal EEG during sleep A total number of 269 seizures were recorded from sleep, including 212 seizures from night-time and 59 from day-time sleep. The median number of sleep seizures recorded per patient was 3 [IQR 6] with data available for at least 2 seizures of 46 (71%) patients. Median seizure duration was 30 seconds (range 10 - 120 seconds). The time lag between onset of ictal discharge and clinical manifestations was determined for each patient with sufficient data (available for 58 patients) and entered in the analysis: median lag time 2 seconds (range 0-30 seconds; IQR 4; no significant difference between frontal and extra-frontal FCD2 location (Mann-Whitney U Test p= 0.561). Seizures were recorded from sleep at night-time for 28 (43%), from day-time naps for 18 (26%) and in both conditions for 19 (30%) patients, including 15 (23%) cases who had additional seizures during waking. The localisation of the ictal discharge at onset was categorised as unilateral focal or regional for 43 (66%), bilateral focal or regional for 13 (20%) and ‘unable to determine’ (due to artefacts) for 9 (14%). The lag time to first seizure was available for 44 of 50 patients undergoing long-term S-V EEG and 12 of 14 serial prolonged S-V EEGs (Amitriptyline was used for sleep induction in 5 patients). The first

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8 seizure was recorded within the first 24 hours or first recording period in 36 (of 44) patients with longterm S-V EEG and 9 (of 12) patients with serial prolonged S-V EEG recordings. In one case, the first seizure was obtained during an outpatient sleep recording. Finally, a sleep seizure was obtained either during the first recording or the first 24 hours in more than 80% of the cases.

3.4 Relationship with sleep stages Overall, seizures occurred only in NREM sleep in 46 (71%) patients (Figure 3). In 2 patients, seizures were also observed from REM. In one case seizures occurred from REM sleep only. Additional seizures after arousal were recorded in 2 other patients. Fourteen (22%) other patients had only seizures preceded by arousal (Figure 4). Of the 50 patients having at last one seizure in NREM, the occurrence in sleep stages was distributed as follows: 45 (90%) from N2, 2 (4%) from N3, 1 (2%) from N1/N2 and 2 (4%) from N2/N3. Relationships between FCD2 location and sleep seizure onset pattern are shown in Table 2.

3.5 Relationship with FCD2 location (Table 2) In frontal location (46 patients), seizure onset predominantly occurred from NREM sleep (38 patients, 83%). Seizures occurring from REM sleep (from NREM and REM in 2 and REM only in 1) corresponded to prefrontal FCD2 location in all cases. The remaining FLE patients had seizures both in NREM and after arousal (2 cases, in precentral location) or after arousal (3 cases, all in prefrontal areas). In extrafrontal location (19 patients), seizure onset was more frequently preceded by arousal (11 cases) than occurring from NREM (8 cases). The relationship between location (frontal versus extra-frontal) and sleep seizure onset pattern (NREM/REM sleep versus preceded by arousal) was statistically significant (Chi-Square test, 2 sided, p< 0.005; see supplementary table S1). Of note, of the 8 patients with extrafrontal FCD2 and NREM seizure onset, 5 had FCD2 located in the post-central areas with an ictal spread to the frontocentral regions and 3 had FCD2 in posterior neocortical areas with early supra-sylvian spread. Conversely, when seizures occurred after arousal, the temporal lobe was involved either initially (during the 10 first seconds of the discharge in 5 patients) or secondarily (>10 seconds in 9 8

9 patients). Temporal secondary spread included 3 FLE patients, all having FCD2 in prefrontal areas (orbitofrontal and anterior cingulate gyrus). In the remaining cases, seizure onset involved the inferior parietal region in 3, the occipital lobe in 2 and the insula in 1. These findings suggest that sleep seizure onset pattern may be related not only to FCD2 location but also to the seizure propagation.

4. Discussion In this large series of patients with SRE due to FCD2, we found over 70% of seizures occurred from NREM sleep, mostly N2, in keeping with previous reported findings (Bazil and Walczak, 1997; Crespel et al., 2000; Minecan et al., 2002; Ng and Pavlova, 2013; Parrino et al., 2012). In contrast, seizure onset from REM sleep was rare, supporting the modulation effect of REM sleep on epileptic activity and seizures. We found a significant relationship between the frontal location of FCD2 and the NREM sleep seizure onset, whilst a preceding arousal pattern was more frequently seen in extra-frontal location, with temporal lobe involvement at onset or during ictal propagation. These findings may be useful for localisation of the epileptogenic zone (EZ) in FCD2, especially in cases with negative MRI. In addition, we emphasize that interictal EEG features characteristic for FCD2 (rhythmic or pseudo-rhythmic spikes) were recorded twice as often during sleep compared to wakefulness. Moreover, seizures were captured during daytime sleep or the first 24 hours of S-V-EEG monitoring in most cases, an observation relevant for planning of presurgical evaluation and more efficient use of long-term S-VEEG monitoring resources. Overall, sleep recordings provide a new insight on the effect of sleep in the context of these highly epileptogenic dysplastic lesions.

4.1 Effect of sleep on epileptic activity in FCD2 SRE account for up to 12% of people with epilepsy, who have predominantly focal epilepsy, usually related to frontal lobe origin (Gibbs et al., 2016). However, SRE was then also identified as significantly correlated with FCD2, independently from the frontal location (Losurdo et al., 2014; Nobili et al., 2009). Enhancement of the characteristic interictal FCD2 pattern during sleep has been first described in reports based on SEEG (Chassoux et al., 2000; Tassi et al., 2002). During wakefulness, intralesional

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10 interictal activity consists of rhythmic continuous/subcontinuous spike- and polyspike- and wave discharges as well as bursts of fast discharges followed by depression of activity. In NREM sleep, this pattern is typically replaced by pseudo-periodic bursts of fast discharges that may spread over the surrounding non-lesional areas and develop into a seizure. Notably, this FCD2 ‘firing pattern’ in NREM sleep was not observed in REM sleep, that shares similar EEG features with wakefulness (Gibbs et al., 2016). The changes of EEG pattern during the sleep-wake cycle reflect the influence of cortical and subcortical networks on the intrinsic activity of FCD2 (Gibbs et al., 2016). Accordingly, reduced inhibitory modulation of the dysplastic neurons during the NREM sleep would increase regional synaptic effectiveness and local synchronization generating bursts of low voltage fast activity and ictal discharges (Frauscher et al., 2016; Gibbs et al., 2016; Menezes Cordeiro et al., 2015). Furthermore, the concept that desynchronization of activities in REM sleep is protective due to suppression of epileptic activity has recently been corroborated by the finding of enhanced suppression of inter ictal discharges and high frequency oscillations (HFOs) in phasic REM sleep (Campana et al., 2017; Frauscher et al., 2016).

4.2 Effect of FCD2 location Focal seizures occurring during sleep are known to predominantly originate from the frontal lobe (Crespel et al., 2000). This fact is supported by the observation of rebound or re-increase of neuronal synchrony during NREM sleep, which has been demonstrated to be largest in the frontal lobe compared with the other lobes (Usami et al., 2015). However, recent studies showed that SRE can also originate in extra-frontal location. On the other hand, FCD2 was the main histological diagnosis in patients operated on for intractable SRE (Losurdo et al., 2014; Nobili et al., 2009; Nobili et al., 2007). Because the main location of FCD2 is in the frontal lobe (Blumcke et al., 2017; Chassoux et al., 2012; Nobili et al., 2007; Tassi et al., 2012), the underlying pathology can introduce a confounding effect on the relationship between the epilepsy localisation and manifestation with seizures from sleep. In our series, the frontal lobe was involved in 71% of the cases, similarly to the previously reported series of SRE due to FCD2 (Jin et al., 2018; Nobili et al., 2009). Despite the clear predominance of frontal lobe 10

11 location, our results confirm that SRE can also be observed in extra-frontal locations in nearly a third of the cases. In addition, we found a high proportion of patients with negative or doubtful MRI (54% in the whole series, 45% with 3T MRI), in keeping with our previous observations (Chassoux et al., 2012). These findings suggest a relationship between the FCD2 size and SRE, as smaller FCDs can be more difficult to detect on visual analysis (Chassoux et al., 2012). This hypothesis has been corroborated by a recent study based on volumetric analysis, showing a significant relationship between small FCD2 and SRE (Jin et al., 2018). A possible explanation is that smaller FCD2 areas might not be able to recruit sufficient non-dysplastic cortex for seizure initiation and propagation during wakefulness due to a low critical mass of neurons and therefore “need sleep to seize”.

4.3 Sleep pattern and seizure onset We observed that NREM seizure onset was significantly more frequently associated with frontal lobe compared to extra-frontal FCD2 location. In contrast, arousal preceding seizure onset was more frequent in extra-frontal location, especially when the temporal lobe was involved as previously reported (Crespel et al., 2000). However, the specificity of this sleep seizure onset pattern with regards to the localisation is debatable. It has been shown that seizure onset could occur either before or after awakening in both TLE and FLE, but the duration between seizure onset and the awakening was shorter in FLE. When behavioural or EEG changes related to awakening were observed before the seizure onset, this occurred especially in temporal lobe epilepsy cases (Yildiz et al., 2012). In this study, awakening was defined as sustained alpha activity in > 50% of epoch, a different definition than the one we used. Another study investigating TLE cases, found that ictal onset was preceded by arousalawakening in two third of the seizures analysed (Gumusyayla et al., 2016). Hence both studies would support the notion that seizure onset occurring after arousal predominantly involves the temporal lobe. Using intracranial depth electrodes combined with scalp electrodes, Malow et al. demonstrated that ictal seizure onset in the hippocampus preceded arousal changes on surface electrodes in most patients with TLE (Malow et al., 2000). Propagation of the focal seizure activity in deeper brain areas 11

12 may involve structures in midbrain and brain steam leading to widespread cortical arousal changes identified with scalp electrodes prior to cortical ictal activity becoming visible. The influence of propagation patterns on seizure semiology and EEG activity has been highlighted in recent studies based on SEEG (Gibbs et al., 2018). In patients with extra-frontal surgical resections (majority of FCD), the lag time from first ictal discharge identified with depth electrodes to clinical seizure onset was longer in extra-frontal compared with frontal lobe location. This observation may explain why in our study some patients with extra-frontal FCD2 and early supra-sylvian spread could present a ‘sleep seizure onset pattern’ similar to the frontal locations, due to rapid propagation of ictal activity via the fronto-parietal system pathways (dorsal superior longitudinal fasciculus) anteriorly to the frontal lobe including premotor areas (Bartolomei et al., 2011; Parlatini et al., 2017). In contrast, extratemporal seizures with preferential spread to the temporal lobe may present a ‘sleep seizure onset pattern’ similar to the temporal locations. Of note, the lag time between ictal EEG onset and clinical seizure manifestations was not helpful to differentiate the frontal and extra-frontal FCD2 location. Based on these different observations, we propose that ‘sleep seizure onset pattern’ is mainly related to the FCD2 location with a strong probability of frontal lobe onset, if the discharge occurs during NREM stage and in extra-frontal areas, if the discharge occurs after arousal. However, early spread of ictal discharges may interfere with these ‘sleep seizure onset patterns’.

4.4 Practical considerations A high seizure burden with ‘daily’ seizure pattern was most common in this surgical cohort with SRE and FCD2. For the majority of patients, seizures were recorded within the first 24 hours, including day time sleep in serial S-V-EEG without night-time recordings, an observation relevant for planning of presurgical evaluation, that could spare time for monitoring resources. Interestingly, seizures could be obtained in 5/6 patients in whom sleep was induced by Amitriptyline during day naps. This can be helpful to increase the information yield of short sleep recordings for pre-surgical evaluation, because the medical team is present to perform assessments during seizures. In addition, we emphasise the

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13 usefulness of sleep recordings for the identification of the characteristic EEG features of FCD2, consisting in rhythmic/pseudorhythmic spiking activity, identified here in a third of patients in wakefulness, but in two thirds in sleep, highlighting this as useful marker for this pathology, especially in MRI negative cases. In spite of the high specificity and positive predictive value of these scalp EEG patterns for FCD, the sensitivity has been reported to be low (Epitashvili et al., 2018). However, changes during sleep were not detailed in this study and the high incidence of this interictal EEG signature during sleep enhances the value of sleep recordings in SRE, as demonstrated in our series.

4.5 Limitations Our study is limited by the retrospective nature of data obtained and absence of formal polysomonography. However, our aim was to base this analysis on the data usually obtained for presurgical evaluation in routine clinical practice. A further limitation was also, that the subgroup of extrafrontal lobe was relatively small compared to frontal lobe cases, but this does reflect the natural topographical distribution of FCD2 lesions.

5. Conclusions In patients with drug resistant SRE undergoing epilepsy surgery with histopathological diagnosis of FCD2, seizures occur most commonly in NREM sleep stage N2. Frontal lobe FCD2 location appears to be associated to seizure onset without preceding arousal changes on S-V-EEG. Although more patients with extra-frontal lobe location presented with arousal change in the S-V-EEG prior seizure onset, this relation is more complex and may not be consistent enough to be used as a reliable marker for topographical location of the FCD2. However, initial or secondary involvement of the temporal lobe may be suggested when arousal occurs before seizure onset. In most patients a short S-V-EEG period over 24-48 hours may be sufficient to capture seizures. These findings highlight the value of sleep recordings in intractable SRE due to FCD2.

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14 Acknowledgements We thank the neurosurgical team and the EEG nurses of Sainte-Anne hospital for patients care. Christin Eltze’s work was supported by a Grant from the Great Ormond Street Hospital Charity, which had no role in the collection, analysis, interpretation of data and in the writing of the manuscript.

Conflict of Interest Statement None of the Authors have potential conflicts of interest to be disclosed.

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Table 1: Clinical, imaging, interictal EEG, histological and surgical data. Characteristics of the population

N=65

Age [years] Range (Median, IQR)

7-49 (18, 13)

Genre: Females/Males

28/37

Age at seizure onset [years] Range (Median, IQR)

0.6-20 (5, 4.7)

Duration of epilepsy [years] Range (Median, IQR)

1-42 (14,11.8)

Seizure Frequency: N (%) Daily Weekly Monthly In clusters

52 (80) 9 (14) 3 (5) 1 (1)

MRI findings: N (%) 1.5T/3T/Total Positive (typical features) Doubtful (subtle features) Negative

29/36/65 10 (34) / 20 (55) / 30 (46) 8 (28) / 6 (17) / 14 (22) 11 (38) / 10 (28) / 21 (32)

Interictal EEG N (%): Waking/Sleep Distribution of abnormalities Unilateral focal Unilateral regional Bilateral focal Bilateral regional No abnormalities Continuous/sub-continuous rhythmic spikes

36 (55) / 7 (11) 24 (37) / 52 (80) 0 (0) / 1 (1) 2 (3) / 5 (8) 3 (5) / 0 (0) 20 (31) / 42 (65)

FCD Localisation: N (%) Frontal Lobe [Pre-frontal / Pre-motor /Pre-central-central] Insula Temporal Lobe Parietal Lobe [Post-central] Occipital Lobe Multilobar [temporo-parieto-occipital]

46 (71) [24 (37) / 9 (14) /13 (20)] 1 (2) 6 (9) 8 (12) [5 (8)] 3 (5) 1 (2)

Histology - FCD type: N (%) 2A / 2B

16 (25) / 49 (75)

Surgical Outcome Follow up [years] Range (Median, IQR) Engel Class: N (%) I II III/IV

1-12 (3,4) 55 (85) 4 (6) 6 (9)

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Table 2: FCD2 location and sleep seizure onset pattern. FCD2 Location

Frontal n (%)

NREM/REM

NREM + after arousal

After arousal

Total

41 (89)*

2 (4)

3 (7)

46

3

24



Pre-frontal

21**

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Pre-motor

9

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Precentral/central

Extra-frontal n (%)

9

11

2

8 (42)

13

11 (58)

19

1

1



Insular



Temporal

2

4

6



Parietal

5

3

8



Occipital

1

2

3



Multilobar (TPO)

1

1

14

65

Total

49

2

TPO=temporo-parieto-occipital; *NREM 38, NREM + REM 2, REM 1; ** including 2 NREM+REM, 1 REM

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Legends Figure 1: Interictal EEG in a patient with a frontal focal cortical dysplasia (FCD) (left SMA): A) during waking, no abnormalities; B) during sleep, runs of low amplitude rhythmic spikes on the left frontocentral areas with left temporal and contralateral propagation. Figure 2: Interictal EEG in a patient with an insular focal cortical dysplasia (FCD) (left superior and anterior part of the insula): A) during waking, high amplitude slow spikes on the left frontotemporal region; B) during sleep, sub-continuous rhythmic spikes, same localisation. Figure 3: Ictal EEG in a patient with a frontal focal cortical dysplasia (FCD) (left paramedian prefrontal area): ictal discharge on the left anterior frontal area (arrow) occurring during sleep (stage 2) with K complex and spindles. Figure 4: Ictal EEG in a patient with a temporal focal cortical dysplasia (FCD) (left temporal pole and anterior part of the superior temporal sulcus): 1) REM stage with ocular movements; 2) waking with eyes opening artefacts and background activity visible on the posterior regions; 3) ictal discharge 20 seconds later, low voltage amplitude activity on the left anterior temporal area (arrow).

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