Effects of antiepileptic treatment on sleep and seizures in nocturnal frontal lobe epilepsy

Sleep Medicine 14 (2013) 597–604

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Sleep Medicine journal homepage: www.elsevier.com/locate/sleep

Original Article

Effects of antiepileptic treatment on sleep and seizures in nocturnal frontal lobe epilepsy Fernando De Paolis a,⇑, Elena Colizzi a, Giulia Milioli a, Andrea Grassi a, Silvia Riccardi a, Monica Puligheddu b, Mario Giovanni Terzano a, Francesco Marrosu b, Liborio Parrino a a b

Sleep Disorder Center, Department of Neurosciences, Azienda Ospedaliero-Universitaria, Via Gramsci 14, 43126 Parma, Italy Sleep Disorder Center, University of Cagliari, ss554 to Sestu, 09042 Monserrato (Cagliari), Italy

a r t i c l e

i n f o

Article history: Available online 7 June 2013 Keywords: Nocturnal frontal lobe epilepsy (NFLE) Antiepileptic drugs Video-polysomnography Cyclic alternating pattern (CAP) Seizures Minor motor events

a b s t r a c t Objective: To study the effects of antiepileptic treatment on sleep parameters and video-polysomnography (VPSG) seizures in nocturnal frontal lobe epilepsy (NFLE). Methods: Twenty patients with a clinical and VPSG diagnosis of NFLE (baseline polysomnography [PSG]) underwent a clinical follow-up and performed a second VPSG after effective antiepileptic treatment lasting for at least 6 months. Conventional sleep measures, cyclic alternating pattern (CAP) parameters, and objective VPSG seizures were assessed in NFLE patients before and after treatment and were compared with the results of 20 age- and gender-matched control subjects. Results: Antiepileptic treatment determined a partial reduction of objective VPSG seizures of approximately 25% compared to baseline condition. Alterations of most conventional sleep measures recovered normal values, but nonrapid eye movement (NREM) sleep instability remained pathologically enhanced (CAP rate, +26% compared to controls) and was associated with persistence of daytime sleepiness. Conclusions: Residual epileptic events and high levels of unstable NREM sleep can define a sort of objective resistance of both seizures and disturbed arousal system to the therapeutic purpose of the antiepileptic drugs in NFLE. This finding could determine the need for new therapeutic options in this particular form of epilepsy. Ó 2013 Elsevier B.V. All rights reserved.

1. Introduction Nocturnal frontal lobe epilepsy (NFLE) is a particular form of partial epilepsy in which seizures characterized by bizarre motor behaviors or sustained dystonic postures appear almost exclusively during sleep. The clinical spectrum of NFLE comprises distinct paroxysmal sleep-related attacks of variable duration and increased complexity [1–6], ranging from minor motor events (MMEs) [1,6–12] to major attacks (MAs) [1,5,13]. MAs are constituted by: (1) paroxysmal arousals, characterized by brief simple motor phenomena and similar to a sudden arousal recurring several times per night; (2) asymmetric tonic seizures, suggesting the involvement of the frontal mesial area; (3) hyperkinetic seizures, characterized by more complex motor pattern with violent behavior, vocalization, screaming, fearful and repetitive movements of the trunk and limbs; and (4) prolonged episodes such as the epileptic nocturnal wandering, which can mimic sleepwalking episodes [13]. MMEs are brief (2–4 s) stereotyped movements involving the limbs, the axial musculature, or the head [1,6–12]. Although MMEs ⇑ Corresponding author. Tel.: +39 0521 702693; fax: +39 0521 704107. E-mail address: [email protected] (F. De Paolis). 1389-9457/$ - see front matter Ó 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.sleep.2013.02.014

often are not clearly qualified as a kind of seizure in NFLE, a wellestablished association of MMEs to epileptic discharges and fluctuations of arousal activity has been proven in NFLE patients [8,10,12,14]. To the extent that these stereotyped brief motor phenomena are a motor component of an arousal triggered by epileptic discharges, the possibility that MMEs could be considered of epileptic origin appears plausible [10]. Few patients exhibit only one type of seizure; however, different seizures usually are likely to overlap in the same patient, and the briefest episodes are the initial fragment of more prolonged attacks [7]. According to the International Classification of Sleep Disorders [15], nocturnal video-polysomnography (VPSG) is the main investigative tool for a sleep-related epilepsy, in which interictal and ictal epileptic discharges confirm the clinical diagnosis. On the other hand, a normal electroencephalogram (EEG) does not rule out a diagnosis of epilepsy in NFLE (15). Moreover, most of the clinical manifestations of NFLE mimic the motor behavior patterns of arousal-related parasomnias, and differentiating nocturnal frontal seizures from nonepileptic paroxysmal motor phenomena may be arduous [16–22]. The lack of internationally shared interpretation criteria make the diagnosis of NFLE mostly reliant on clinical

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history and VPSG recording of behavioral seizures, suggesting a frontal lobe involvement [16,20]. Clinical manifestations of NFLE are strongly influenced by circadian sleep-wake alternation and by physiologic components of sleep structure. Regardless of their semiology, the majority of NFLE seizures arise during nonrapid eye movement (NREM) sleep and are followed by a sudden transition to a more superficial stage or a frank awakening [1–3]. The epileptic fragmentation of the first part of the night can produce a significant sleep disruption with a consequent increase of wake after sleep onset (WASO) and rapid eye movement (REM) sleep latency but without alterations of slow-wave sleep (SWS), which even increases [23]. Moreover, the temporal development of epileptic events across sleep period seems to be modulated by the homeostatic process of deep NREM sleep [23]. The cyclic alternating pattern (CAP), the marker of unstable NREM sleep [24], plays a primary role in the activation of epileptic events in NFLE patients [23,25]. During CAP, the sleep process swings from periods of activation (phase A), characterized by NREM sleep-phasic events and periods of deactivation (phase B), characterized by paucity or disappearance of phasic events. In contrast, noncyclic alternating pattern (NCAP) consists of a rhythmic and stable EEG background and is the expression of sustained sleep stability. The arrangement of NREM sleep into CAP and NCAP allows identification of three neurophysiologic conditions (phase A, phase B, and NCAP), each exerting a specific modulatory influence on a number of epileptic events occurring in NREM sleep [26–32]. In NFLE patients, CAP is a powerful triggering condition for the occurrence of both ictal and interictal epileptic events that arise in concomitance with phase A. In turn epileptic manifestations act as a subcontinuous sleep disturbance that induces a significant increase of sleep instability [23]. This enhancement of unstable NREM sleep together with the alterations of conventional sleep measures can define distinctive polysomnography (PSG) features in NFLE patients [23] and can be responsible for the poor sleep quality and the excessive daytime sleepiness, which has already been described in these patients [3,9,17,23,33]. In approximately two out of three NFLE patients, carbamazepine (CBZ) [1,4,11] and topiramate (TPM) [34] were reported to reduce nocturnal seizures in frequency and complexity, while the remaining patients, who commonly had a higher seizure frequency, seemed to be drug resistant [2]. Because of the almost exclusive recurrence of seizures during sleep, NFLE patients often are scarcely aware of the presence, complexity, and frequency of attacks. Moreover, a reliable description of epileptic motor events occurring during the night often are difficult to collect from a witness or sleep partner, as observers may be absent, or if present, not fully awake or reliable [16]. Lastly, MMEs often are difficult to be clearly qualified. For these reasons, nocturnal video-EEG features and PSG metrics can provide objective data of the effects of antiepileptic therapy, especially on minor seizures and sleep parameters. In our study, we compare the conventional sleep measures and CAP parameters of 20 healthy subjects with the measures of 20 NFLE controls before and after effective antiepileptic therapy of at least 6 months’ duration. VPSG epileptic seizures of NFLE patients before and after treatment also are analyzed.

2. Methods 2.1. Subjects Among all patients who received a VPSG diagnosis of NFLE according to previous studies [1,6,23,35], 20 consecutive patients (12 men and eight women; mean age, 32 ± 12 y) were selected from the database of the Sleep Disorder Centre of Parma based

on certain criteria: (1) antiepileptic therapy prescribed for at least 6 months, which was effective in the control of seizures as ascertained by seizure diaries based on subjective patient’s report and partner’s report. Only seizure-free patients (disappearance of reported seizures since starting antiepileptic treatment) and responders (reduction of P50% of seizures) were included in the study. Nonresponder patients (NFLE patients showing reduction of <50% of reported seizures or no improvement or worsening of their seizure control, despite taking the maximum tolerated dose) were excluded from the study; (2) an obstructive apnea–hypopnea index <5 per hour and periodic limb movements (PLM) index <15 per hour of sleep in diagnostic VPSG, to exclude an increase of CAP rate and arousals induced by respiratory events or PLM disorder; and (3) the exclusion of coexisting neurologic, medical, or psychiatric disorders known to affect sleep architecture. At time of enrollment, all NFLE patients underwent a clinical evaluation of daytime sleepiness using the Epworth sleepiness scale and a second VPSG study during antiepileptic treatment. All 20 NFLE patients who met the inclusion criteria and had an obstructive apnea–hypopnea index <5 per hour and also had a PLM index <15 per hour during the second VPSG were finally suitable for sleep analysis. Conventional sleep measures and CAP parameters of the selected NFLE subjects were analyzed before (group A) and after (group B) antiepileptic treatment and were compared with the measures of 20 age- and gender-matched healthy control subjects (12 men and eight women; mean age, 33 ± 8 y) who were paid volunteers and free of psychiatric, neurologic, or medical disorders (group C). The absolute number and distribution of VPSG epileptic seizures of NFLE subjects before and after treatment also were compared. Both NFLE subjects and control subjects gave informed consent to perform the study and underwent a nocturnal PSG in a video-monitored sound proof (Leq < 35 dB) laboratory. In the week preceding the PSG recording, all subjects completed a sleep log to determine the personal sleep-wake profile and refrained from alcohol or caffeine consumption and central nervous system drugs other than the prescribed antiepileptic treatment. 2.2. Video-sleep recordings Sleep was recorded from a C3/A2 or a C4/A1 derivation integrated by bihemispheric bipolar montages (Fp1-F3, F3-C3, C3-P3, P3-O1 and Fp2-F4, F4-C4, C4-P4, P4-O2) used to optimize the detection of focal or generalized epileptic abnormalities. A calibration of 50 lV/cm was used for all the EEG channels with a time constant of 0.1 s and a high frequency filter in the 30-Hz range. The total recording time for all recordings was 500 min. Eye movements, electrocardiogram, and chin and tibialis muscles electromyography also were recorded together with oxygen saturation, thoracoabdominal motion, and oronasal flow to exclude sleep apnea syndrome and PLM disorder. Video recording was performed using an infrared camera associated to an audio trace recorder both integrated in EEG acquisition system and synchronized to EEG recording. 2.3. VPSG data analysis 2.3.1. Conventional sleep variables and sleep cycles For conventional sleep measures visual assessment was based on 30-s epochs [36] and was accomplished by a trained scorer blind to the subjects’ conditions. Conventional sleep variables that were measured included, total sleep time, sleep latency, sleep efficiency (SE), WASO, total duration and percentage of all NREM sleep stages (stage 1, stage 2 [S2], stage 3, and stage 4), REM sleep, and REM latency. Stage 3 and stage 4 NREM sleep stages were referred together as SWS.

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PSG recordings of NFLE subjects were subdivided in sleep cycles (SC). Each SC started with the first epoch of NREM sleep and ended with the appearance of the first epoch of S2 after an REM period had been completed. According to established procedures [37], REM period ended when the duration of NREM stages following the last epoch scored as stage REM exceeded 15 min. 2.3.2. CAP parameters Visual scoring of CAP parameters was based on 30–60-s epochs according to the Atlas rules [38] and was accomplished by a trained scorer who was blinded to the subjects’ conditions. A CAP sequence was identified by repetitive clusters of stereotyped EEG features separated by time-equivalent intervals of background activity. Each CAP sequence included at least two consecutive CAP cycles. The CAP cycle consisted of a phase A (composed of transient EEG graphic elements) and a phase B (interval of h/d activity that separates two successive A phases, with an interval 61 min). Each phase of CAP could last from 2 to 60 s. All CAP sequences began with a phase A and ended with a phase B. Based on the reciprocal proportion of high-voltage slow waves (EEG synchrony) and low-amplitude fast rhythms (EEG desynchrony) throughout the entire phase A duration, three subtypes of A phases corresponding to different levels of neurophysiologic activation were distinguished, including subtype A1 (predominance of EEG synchrony), subtype A2 (balanced mixture of EEG synchrony and desynchrony), and subtype A3 (predominance of EEG desynchrony). When the interval between two consecutive A phases exceeded 60 s, the CAP sequence ended and sleep entered into the NCAP mode characterized by stable ongoing EEG rhythms with few randomly distributed arousal-related phasic events [39]. The following CAP variables were measured: (1) the total CAP time (total CAP time in NREM sleep); (2) the CAP rate (the percentage ratio

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of CAP time to NREM sleep time) in total NREM sleep, S2, and SWS; (3) the number and duration of CAP cycles; (4) the duration of phase A and phase B of CAP cycles; (5) number and duration of CAP sequences; and (6) the total number and percentage of each phase A subtype (A1, A2, A3). 2.3.3. VPSG epileptic motor events In NFLE subjects (both basal and treatment conditions), each VPSG motor event, according to clear-cut ictal epileptiform activity and stereotyped motor pattern, was classified as MMEs (Fig. 1), paroxysmal arousal, tonic-dystonic seizure, hyperkinetic seizure, or prolonged motor behavior (i.e., epileptic nocturnal wandering). Paroxysmal arousals, tonic-dystonic seizures, hyperkinetic seizures, and prolonged motor behaviors were classified as MAs. In both groups, the total distribution of MAs and MMEs was analyzed throughout total sleep time, NREM and REM sleep, SC, S2, SWS, CAP and NCAP sleep, as well as phase A and phase B of CAP. To normalize the number of MAs and MMEs to the duration of respective NREM sleep stages, a seizure index for hour of S2 and SWS ([mean number of seizures/min of sleep stage]  60) was calculated for both MAs and MMEs in each SC before and after antiepileptic treatment. 2.4. Statistical analysis The comparison of sleep parameters between NFLE groups (A, B) and controls (C) were assessed by analysis of variance for repeated measures with pairwise contrasts using Bonferroni testing. The analysis of VPSG epileptic events before and after antiepileptic treatment was assessed by the Wilcoxon signed rank test, a nonparametric statistical test for repeated measures in the same sample. Statistical significance was set at p < .05. Both statistical tests were performed using the calculation software, MATLAB.

Fig. 1. A minor motor event in the form of brief movements of the lower limbs associated with bilateral sharp waves on the frontotemporal regions during phase A2 of cyclic alternating pattern (CAP) in a nocturnal frontal lobe epilepsy subject. The following phase A1 of CAP shows only epileptic paroxysms without motor correlates.

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50% of seizure frequency. Daytime sleepiness was not significantly reduced under treatment (mean ESS score before therapy, 13 ± 3; after, 11 ± 3).

3. Results 3.1. Study population The clinical, nuclear magnetic resonance, and routine wake– EEG findings of the 20 NFLE subjects before antiepileptic treatment are summarized in Table 1. In four subjects nocturnal motor events clearly were present since childhood, while the mean duration of paroxysmal motor events during sleep was approximately 7.5 years before the diagnosis in the other subjects. One subject reported a family history of epilepsy, and seven subjects described parasomnias or nocturnal motor events in first-grade relatives. One subject had perinatal hypoxia, two subjects had childhood febrile convulsions, and one subject had mild head injury. Diurnal seizures were never reported. Neurologic examinations were unremarkable in all subjects. 3.2. Clinical and therapeutic assessment Antiepileptic therapy in NFLE subjects included CBZ (mean dose, 514 mg/d), as single therapy in 12 subjects (mean doses ranging from, 400 to 800 mg/d), in association to TPM in one subject (CBZ, 800 mg and TPM, 50 mg/d) or to levetiracetam in three subjects (levetiracetam doses: 250 mg, 500 mg, and 750 mg/d). Two subjects were only treated with TPM (75 mg and 100 mg/d) and two subjects were only treated with levetiracetam (500 mg and 1000 mg/d). All antiepileptic drugs were taken in single daily administration doses at bedtime. After 6 months of antiepileptic therapy, all NFLE subjects treated with CBZ showed blood concentration of the drug within the therapeutic range. According to subjective seizure diaries based on subjects’ and partners’ reports, seven out of 20 subjects were seizure free, while the remaining 13 reported a reduction of at least

3.3. PSG measures Table 2 and Table 3 show the conventional sleep measures and CAP parameters of NFLE subjects before (ranking A) and after treatment (ranking B), compared to control subjects (column C). The statistical significance of comparisons among the three conditions is highlighted in last column. 3.4. Conventional sleep variables Compared to pretreatment conditions, antiepileptic therapy determined a significant increase of SE (+10%) and a reduction of WASO ( 35 min) and REM latency ( 56 min), while REM sleep duration and percentage were only slightly increased. SWS duration (+20 min) and percentage (+3%) also showed a slight increase during treatment (Table 2). Compared to controls the effects of antiepileptic treatment meant the normalization of SE, WASO, and REM latency, while REM sleep duration and percentage remained significantly lower than normal values ( 23 min and 4%, respectively). On the contrary, SWS duration (+30 min) and percentage (+8%) in treated subjects were significantly higher than control values. 3.5. CAP parameters Compared to pretreatment conditions, antiepileptic therapy determined a significant reduction of CAP rate ( 12%), number of CAP cycles ( 130), duration of CAP sequences ( 90 s), and total number of phase A1 of CAP ( 70) (Fig. 2). The reduction of CAP rate

Table 1 Main features of nocturnal frontal lobe epilepsy subjects before treatment. Subject

Sex

Age (y)

Anamnestic nocturnal events

Seizure onset (y)

Seizure frequency

Cerebral NMR

Routine wake–EEG findings

1 2

M M

26 42

PA, ENW PA, MAs

Several times/mo Several times/wk

M W

31 24

PA MMEs, MAs

Normal 2 Small aspecific subcortical white matter lesions in right parietal region Normal Normal

Objective drowsiness Bilateral aspecific temporal slow waves

3 4

7 Since childhood 5 8

5 6 7

M M M

55 48 13

PA, MAs PA PA, MAs, ENW

6 15 6

Normal Normal Normal

8 9

M W

35 27

PA PA

Several times/wk Several times/wk

Mild cerebral chronic vasculopathy Normal

10

W

30

MMEs, PA

17 Since childhood 2

Normal Normal Bilateral frontal high amplitude sharp waves (with left dominance) Normal Normal

Several times/wk

Normal

11

W

25

PA, MAs

Several times/wk

Normal

12 13 14 15 16

W M M W M

55 39 33 32 19

PA, PA, PA, PA, PA,

Since childhood 12 4 13 5 6

Normal Normal Normal Normal Normal

17

W

30

PA, MAs

Several times/wk Several times/wk Several times/wk Several times/wk PA several times/wk, sporadic MAs, ENW Several times/wk

18 19 20

W M M

25 26 16

PA, MAs PA, MAs PA, MAs

Several times/wk Several times/wk Several times/wk

Normal Normal Normal

MAs, ENW MAs MAs MAs MAs, ENW

Since childhood 4 4 6

Several times/wk MMEs several times/d, sporadic MAs Several times/wk Several times/wk Several times/mo

Normal

Normal Normal

Sharp waves on left frontotemporal region Generalized sharp waves, sharp and slow wave with anterior dominance Normal Normal Normal Normal Sporadic sharp waves on right frontal region Aspecific sharp h activity on frontotemporal regions Normal Normal Objective drowsiness

Abbreviations: y, years; NMR, nuclear magnetic resonance; EEG, electroencephalogram; M, man; W, woman; PA, paroxysmal arousal; ENW, episodic nocturnal wanderings; MAs, major attacks; MMEs, minor motor events; mo, month; wk, week; d, day.

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F. De Paolis et al. / Sleep Medicine 14 (2013) 597–604 Table 2 Conventional sleep measures in nocturnal frontal lobe epilepsy subjects and controls.

TST (min) SL (min) WASO (min) SE (%) S1 (min) S1 (%) S2 (min) S2 (%) Light sleep (min) Light sleep (%) SWS (min) SWS (%) NREM (min) REM (min) REM (%) REM L (min)

Basal (A) Mean value (SD)

Treatment (B) Mean value (SD)

Control (C) Mean value (SD)

ANOVA

400.9 (75.1) 23.7 (20.1) 61.1 (46.6) 80.7 (12.4) 22.7 (13.2) 6.1 (4.1) 188.8 (39.8) 48.0 (10.1) 211.4 (39.5) 54.2 (12.0) 115.8 (50.7) 28.0 (9.6) 327.2 (53.1) 73.8 (32.2) 17.8 (5.5) 170.3 (79.4)

438.9 (58.9) 12.6 (10.3) 25.9 (19.7) 91.2 (4.5) 22.4 (18.3) 5.1 (3.8) 190.3 (40.7) 43.2 (6.1) 212.7 (45.5) 48.3 (7.1) 135.7 (28.4) 31.1 (6.2) 348.3 (49.7) 90.6 (25.6) 20.6 (4.8) 114.0 (42.1)

442.0 (35.1) 13 (8.0) 12.2 (11.6) 89.0 (3.6) 13 (8.0) 2.4 (2.0) 211.7 (45.9) 45.4 (8.2) 223.1 (46.8) 47.9 (8.3) 105.0 (28.5) 22.8 (6.4) 328.2 (34.8) 113.8 (19.5) 24.6 (4.2) 98.1 (32.0)

NS NS 0.001 0.001 NS 0.004 NS NS NS NS 0.04 0.004 NS 0.001 0.001 0.001

BONF

A>B=C AC

A = B, B > C A = B, B > C A=BB=C

Abbreviations: SD, standard deviation; ANOVA, analysis of variance; BONF, Bonferroni testing; TST, total sleep time; min, minutes; SL, sleep latency; WASO, wake after sleep onset; SE, sleep efficiency; S1, stage 1; S2, stage 2; SWS, slow-wave sleep; NREM, nonrapid eye movement; REM, rapid eye movement; REM L, rapid eye movement latency; NS, not significant.

Table 3 Cyclic alternating pattern parameters in nocturnal frontal lobe epilepsy subjects and controls.

CAP rate (%) CAP rate S2 (%) CAP rate SWS (%) CAP time (min) CAP sequences (n°) CAP sequence (s) CAP cycles (n) CAP cycles (s) Phase A (s) Phase B (s) Phase A1 (n) Phase A1 (%) Phase A2 (n) Phase A2 (%) Phase A3 (n) Phase A3 (%)

Basal (A) Mean value (SD)

Treatment (B) Mean value (SD)

Control (C) Mean value (SD)

ANOVA

BONF

71.3 (9.4) 73.2 (14.1) 74.8 (16) 231.6 (40.8) 33.2 (10.5) 420.7 (137.6) 557.5 (91.4) 25.1 (3.0) 7.9 (1.4) 17.2 (2.6) 291.8 (82.2) 52.3 (11.7) 132.0 (45.1) 23.6 (6.8) 133.8 (62.8) 24.1 (11.0)

59.2 (11.4) 59.7 (19.2) 65.5 (14.7) 206.3 (54.9) 37.3 (7.5) 331.5 (147.7) 427.8 (106.4) 29.0 (2.2) 8.3 (1.6) 20.7 (2.0) 222.5 (76.1) 52.1 (16.3) 101.4 (45.6) 22.6 (8.1) 117.0 (73.3) 25.3 (11.9)

33.2 (5.5) 35.4 (10.1) 31.3 (8.0) 108.2 (23.6) 39.6 (9.8) 163.6 (36.7) 256.2 (57.8) 25.2 (3.8) 7.5 (1.8) 17.7 (3.2) 155.9 (41.4) 58.1 (9.3) 62.8 (25.6) 23.1 (7.9) 37.5 (20.2) 14.0 (7.2)

0.001 0.001 0.001 0.001 NS 0.001 0.001 0.005 NS 0.005 0.001 NS 0.001 NS 0.001 NS

A>B>C A>B>C A=B>C A=B>C A>B>C A>B>C A=CB>C A=B>C A=B>C

Abbreviations: CAP, cyclic alternating pattern; S2, stage 2; SWS, slow-wave sleep; min, minutes; n, number; s, seconds; SD, standard deviation; ANOVA, analysis of variance; BONF, Bonferroni testing; NS, not significant.

was mainly due to a significant attenuation of sleep instability in S2 rather than in SWS (CAP rate in S2, 13%). CAP time, CAP rate in SWS, and absolute number of phases A2 and A3 of CAP showed insignificant reductions under treatment. Compared to controls, all of these parameters of sleep instability remained significantly higher and farther from normalization. Treated subjects compared with no drug conditions (basal and controls) showed an increase of CAP cycle duration due to a longer phase B. 3.6. VPSG epileptic events A total of 407 epileptic motor events were counted in basal VPSG recordings of our 20 NFLE subjects. The 337 seizures (approximately 83%) were recorded in NREM sleep, while 70 epileptic events (approximately 17%) were recorded in REM sleep. The REM sleep seizures were all attributable to three subjects (No. 3,10, and 20 of Table 1) and were characterized in 91% of cases by MMEs. Approximately 60% of total amount of NREM sleep seizures (201 seizures) arose from S2; further, more than 92% of NREM sleep seizures occurred during a CAP sequence and all were during a phase A of CAP. The 254 epileptic events (75% of total NREM sleep

seizures) were classified as MMEs and they occurred in S2 in 65% of cases. The remaining 83 seizures (25% of total NREM sleep seizures) were classified as MAs and showed a preferential occurrence in SWS (57% of cases). Antiepileptic treatment reduced the total amount of both MA and MME in NREM sleep of approximately 25%, thus leading to a significant decrease of all NREM sleep seizures (from 337 down to 250). Fig. 3 details the reduction of MAs ( 22) and MMEs ( 65) under treatment. Fig. 4 shows the hourly indexes of all VPSG epileptic events (both MAs and MMEs) occurring in S2 and SWS for each SC, before and after antiepileptic treatment. Although only the hourly index of seizures during S2 in the second SC reached a significant reduction under treatment (p < .05), the overall reduction of seizures under treatment appeared to be predominantly due to a greater decrease in the first two SC.

4. Discussion Our study confirms previous PSG data on the relationship between frontal lobe seizures and sleep in NFLE [1,6,11,23] and offers additional parameters to debate the efficacy of antiepileptic

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Fig. 3. Absolute number of nonrapid eye movement sleep seizures (both major attacks and minor motor events) before and after antiepileptic treatment in nocturnal frontal lobe epilepsy subjects.

Fig. 4. Hourly indexes of all video-polysomnography epileptic events (both major attacks and minor motor events) occurring in stage 2 and slow-wave sleep of the first 4 sleep cycles (SC) before and after antiepileptic treatment in nocturnal frontal lobe epilepsy subjects. Note the predominant reduction of seizures under treatment in the first 2 SC.

Fig. 2. Comparison between the time course of phase A of cyclic alternating pattern (CAP) during nonrapid eye movement sleep time (white bars for phase A1, black bars for phases A2 + A3) in a nocturnal frontal lobe epilepsy subject before (up panel) and after (mid panel) antiepileptic therapy as well as in a control subject (bottom). The number of phases (Y axis) for each period of 10 min of sleep (X axis) is plotted for each condition. Note the great amount of all subtypes of phase A and CAP rate (72%) in untreated condition and the partial decrease of CAP rate during treatment (51%) but without achieving normal values (33%) with a preserved normal temporal development of phase A subtypes in all conditions.

treatment in this particular sleep-related disorder. The PSG findings of untreated NFLE subjects confirm that seizures are destabilizing factors for conventional sleep measures [23], as the recurrence of epileptic events especially in the first part of the

night produces a relevant sleep fragmentation with reduction of SE and an increase of WASO and REM latency even without curtailment of SWS. Untreated NFLE subjects also show a global enhancement of NREM sleep instability, as expressed by high values of CAP rate. This increased CAP amount can be the expression of a subcontinuous sleep disturbance due to the recurrence of both major seizures and more subtle arousal activities associated to MMEs. On the other hand, the frequent occurrence of NREM sleep seizures, both major and minor, during a CAP sequence and the triggering role of phase A of CAP confirm that seizures in NFLE are arousal-related phenomena [23,25,40,41]. In our NFLE subjects, effective antiepileptic treatment (established according to clinical subjective parameters) is associated with a normalization of conventional sleep measures (i.e., REM latency, WASO, SE) but only to a partial reduction of both VPSG nocturnal seizures ( 25%), CAP rate ( 12%), and daytime somnolence compared to the pretreatment conditions. In other kinds of focal epilepsies, the effects of long-term CBZ administration on sleep measures are controversial [42]. Significant PSG findings are lacking in temporal lobe seizures [43]; however, an increase of sleep instability and REM latencies or a reduction of REM sleep have been reported in late-onset focal epilepsies [44].

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In our treated NFLE subjects, the attenuation of sleep fragmentation due to major seizures in the first part of the night possibly is the main factor leading to a more physiologic sleep structure during treatment. Due to their normalization after antiepileptic treatment, REM latency, WASO, and SE could be defined as state markers of NFLE. On the contrary, most CAP parameters continue to be pathologically high and far from control values in treated NFLE subjects. This residual high NREM sleep instability could be due to the persistence of epileptic discharges that continue to act as internal triggers of subcontinuous arousal fluctuations during NREM sleep. In turn these triggers exert a gate effect on the occurrence of nocturnal motor events, especially in the form of MMEs (Fig. 1). The association of MME and epileptic discharges with arousal fluctuations has been described in NFLE subjects [8,10,12,14]. In particular, MMEs could be the expression of stereotyped innate motor sequences through arousal facilitation codified by central pattern generators [8,12,45], both in untreated subjects and during antiepileptic treatment. Whatever the cause of the increased NREM sleep instability, the high amount of CAP rate in NFLE subjects appears slightly responsive to antiepileptic agents. Even the abundant and unstable SWS of basal conditions appeared to be unmodified following antiepileptic therapy. In arousal-related parasomnias without treatment, PSG studies also have shown a slight increase of CAP rate and sleep instability in SWS, sometimes with a greater amount of phase A1 of CAP [46,47]. Although our data were independently collected from the antiepileptic drugs used and their dosages, the persistence of a high amount of unstable SWS following treatment in NFLE subjects could disclose a distinctive trait of this condition; this trait needs to be focused on in further studies or through the comparison of the effects of treatment on PSG parameters between NFLE and parasomnia disorders. In our NFLE subjects, the partial efficacy of antiepileptic drugs on seizures’ attenuation seems to be more evident in the first part of the night (Fig. 4), which suggests that the response of seizures to antiepileptic action could be different throughout the whole sleep period.

5. Conclusions The discrepancy between an adequate subjective seizures outcome and PSG findings in treated NFLE subjects can open up the discussion to the identification of clinical and sleep measures, which can define a more objective response to treatment. The subjective effectiveness of antiepileptic treatment in NFLE subjects could be mostly related to the partial reduction of the longer and more complex nocturnal seizures [1,4,34], which are more likely to be perceived. In contrast the persistence of residual objective PSG epileptic phenomena (both MAs and MMEs) and a high level of unstable NREM sleep indicate a partial resistance of both seizures and disturbed arousal system to the therapeutic action of the antiepileptic treatment. So far the principle target of antiepileptic treatment is to eliminate or decrease major epileptic events. However, despite the reduction of nocturnal seizures, the normalization of SE and WASO, and the high values of SWS in our NFLE subjects, daytime sleepiness is still present under drug treatment. The persistence of high values of CAP rate even under therapy could be a partial explanation of diurnal concerns. In this perspective, the goals of therapy in NFLE should include the treatment of structural sleep alterations. This aim can be achieved in two possible ways. First it can be achieved through the attenuation of interictal discharges, which seem to be the triggering factor of increased sleep instability. In this case, the addition of benzodiazepines or other antiepileptic agents able to attenuate cortical excitability could be encouraged.

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Second the aim can be achieved through the increase of the arousal threshold using sleep-promoting agents (i.e., hypnotic drugs or sedative antidepressant such as trazodone), enabling protection of the sleep process against the destabilizing effects of the nocturnal epileptic activity. It is interesting to note that antiepileptic therapy partially acted on sleep instability through the reduction of phase A1 of CAP and the lengthening of the phase B of CAP cycle in our NFLE patients. Further studies are deemed necessary to clarify these issues and to explore new strategies for a more effective and complete therapy for NFLE patients.

Conflict of interest The ICMJE Uniform Disclosure Form for Potential Conflicts of Interest associated with this article can be viewed by clicking on the following link: http://dx.doi.org/10.1016/j.sleep.2013.02.014.

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