MD Ariana Barros

PhD Ginevra Uguccioni

MS Victoire Salkin-Goux

Smaranda Leu-Semenescu

MD Pauline Dodet

MD Isabelle Arnulf
email: isabelle.arnulf@aphp.fr

MD Smaranda Leu- Semenescu

Simple behavioral criteria for the diagnosis of disorders of arousal

Keywords: Disorders of arousal, sleepwalking, sleep terror, diagnosis, video-polysomnography, behaviors, eye opening

INTRODUCTION

Disorders of arousal (DOA, including sleepwalking, sleep terrors and confusional arousals) are characterized by inappropriate, mostly amnestic behaviors occurring during partial arousals from N3 sleep, reflecting various degrees of motor, emotional and autonomic activations. The disorders expose people to risks of trauma, violence and uncontrolled behaviors that may be life threatening. In addition, patients with DOA have more difficulties initiating and maintaining sleep, a lower quality of life, higher levels of anxiety, and more daytime fatigue and sleepiness than healthy controls. [START_REF] Lopez | Functional impairment in adult sleepwalkers: a case-control study[END_REF][START_REF] Carrillo-Solano | Sleepiness in sleepwalking and sleep terrors: a higher sleep pressure?[END_REF][START_REF] Oudiette | Dreamlike mentations during sleepwalking and sleep terrors in adults[END_REF] Disorders of arousal are common in children but may persist (and sometimes appear) in up to 2-4% of adults. [START_REF] Ohayon | Prevalence and comorbidity of nocturnal wandering in the U.S. adult general population[END_REF] The diagnosis is mostly based on interviews of the patients and their family, as indicated in the international classification of sleep disorders. [START_REF] Ito | The International Classification of Sleep Disorders, third edition. American Academy of Sleep Medicine. Includes bibliographies and index[END_REF] In contrast to many other sleep disorders (e.g., sleep apnea syndrome, REM sleep behavior disorder, periodic leg movements disorder, and central hypersomnias), in which sleep and sometimes video monitoring are mandatory to reach the diagnosis, the place of video-polysomnography in the diagnosis process of DOA is debated and not required based on the present criteria. [START_REF] Ito | The International Classification of Sleep Disorders, third edition. American Academy of Sleep Medicine. Includes bibliographies and index[END_REF] Ambulation and complex behaviors during N3 arousals are rare in the sleep laboratory, and some authors suggest that "normal" polysomnographies are sometimes observed in participants with typical symptoms of DOA. However, a sleep study may document simple behaviors typical of confusional arousals, rule out differential diagnoses (REM sleep behavior disorder, epilepsy, sleep-related motor disorders) and identify potential triggers of parasomniac episodes, such as noises, sleep-related breathing disorders or periodic leg movements. In addition, there is an unmet need (for clinical and forensic purposes) to determine the sensitivity and specificity of the signs observed in a sleep study. Some EEG markers (hypersynchronous delta sleep activities and spectral analysis) lack specificity, but recently, an index of arousals plus awakenings (greater than 6.8 per N3 time) has proven sensitive (79%) and specific (82%) for distinguishing patients referred for DOA from healthy participants. [START_REF] Lopez | Diagnostic criteria for disorders of arousal: A video-polysomnographic assessment[END_REF] A slow/mixed arousal index (greater than 2.5 per N3 time) was even more sensitive (94%) and totally specific (100%). However, this analysis requires highly trained sleep scorers and 8 EEG channels.

We aimed to identify easy video-based criteria to distinguish patients with DOA from healthy controls and from patients with other sleep disorders. For this purpose, we analyzed the behaviors during N3 arousals/awakenings in patients with DOA vs. those in controls (healthy controls and patients with insomnia, hypersomnia and sleep apnea syndrome) to find simple, sensitive and specific markers of DOA.

METHODS

Study design and population

This is a retrospective, case-control study. The participants were selected from the patient and control populations of the sleep disorder center at the Pitié-Salpêtrière University Hospital. The patients with DOA were recruited between January 2016 and July 2018 and diagnosed with sleepwalking or sleep terror by one of the sleep physicians using the international criteria. [START_REF] Ito | The International Classification of Sleep Disorders, third edition. American Academy of Sleep Medicine. Includes bibliographies and index[END_REF] They met criteria for disorders of arousal, including (i) recurrent episodes of incomplete awakening from sleep, (ii) inappropriate or absent responsiveness to efforts of others to intervene or redirect the person during the episode, (iii) limited or no associated cognition or dream imagery, (iv) partial or complete amnesia for the episode and (v) no better explanation for the disturbance, such as another sleep disorder, a mental disorder, a medical condition, or medication or substance use. In addition to the above criteria, patients were classified as suffering from sleepwalking if there was (i) a history of ambulation during sleep or (ii) the persistence of sleep or impaired judgment during ambulation. In addition to the above criteria, patients were classified as having sleep terror if there was (i) a history of sudden episodes of terror occurring during sleep, usually initiated by a cry or loud scream with sympathetic and behavioral manifestations of intense fear, and (ii) difficulty in arousing the person, mental confusion when awakened from an episode, complete or partial amnesia from the episode, or dangerous or potentially dangerous behaviors. Because the comparison of behaviors arising during a confusional arousal in N3 and during a sleep-associated (whatever the sleep stage) epileptic seizure has already been studied, [START_REF] Derry | NREM arousal parasomnias and their distinction from nocturnal frontal lobe epilepsy: a video EEG analysis[END_REF] the patients with positive clinical history of epilepsy were excluded in both groups (DOA and control).

The control group comprised healthy participants and participants with sleep disorders but no DOA. The healthy participants had been recruited by word of mouth for another trial (COREV) that included a video and sleep study and had no sleep complaints, especially present parasomnia, as checked by an interview with the physician. The control population with sleep disorders had to be representative of the source population from which the DOA cases were extracted. For this purpose, it consisted of: i) all consecutive participants who were referred to our sleep unit from May 2018 to July 2018; ii) who had no DOA; iii) who had no positive clinical history of epilepsy; iv) who did not take any psychotropic treatment for at least several months; iv) who were matched for age and sex with the DOA patient; and v) who had at least one awakening episode during N3 sleep (in order to be able to observe at least one behavior associated with one N3 interruption). This control group was matched (as a group and not 1 to 1) for age and sex with the DOA group.

The patients with DOA and the healthy controls gave their written consent to participate in the study, which was approved by the ethics committee Ile de France-06 as part of a larger study on hypnosis in sleepwalking (NCT02648568 on clinicaltrial.gov) and on emotions (NCT03074578 on clinicaltrial.gov). Following the French regulation on clinical research, the other part of the group (control patients) received before, during and after their stay the oral and in writing information that their deidentified measures could be later reused by investigators for research purposes (unless they refused this use) and did not oppose to that. The center had received the agreement MR003 (declaration 1999732) from the National Commission for Rights and Freedom related to Informatics (CNIL) since October 2016 for storing and reusing for research purpose deidentified clinical, polysomnographical and video/audio measures performed in clinical routine in the sleep laboratory.

Video-polysomnography

All participants completed at least one night with video-polysomnography at the sleep unit, but the 52 patients with DOA and 16 healthy controls underwent two consecutive night studies. All rooms were equipped with a single infrared camera (synchronized with the audio recording and the polysomnography), placed in front of the bed. Lights were switched off by the patients by 11 PM at the latest and remained off until they were turned on by staff the next morning. The recordings included at least three channels for electroencephalography (EEG; Fp1/C3, C3/A2 and C3/O1; extensive 8electroencephalophic channel montage in patients with DOA), two channels for electrooculography (inferior left epicanthus/A2 and superior right epicanthus/A2) and three channels for surface electromyography (chin [mentalis] muscle, and right and left tibialis anterior muscles) as well as an electrocardiogram, thoracic and abdominal belts to measure the respiratory efforts via inductive plethysmography, a measure of nasooral airflow through nasal pressure and oral thermistors, and a measure of transcutaneous oxygen saturation. The sleep stages, arousals, apnea and hypopnea events, and periodic leg movements were scored by experienced sleep neurologists according to international criteria. 7

Analysis of behaviors

All interruptions of stage N3 sleep were collected. They included classical awakenings (alpha or higher EEG background rhythm lasting longer than 15 s), as well as arousals (lasting 3 to 15 s) with an acceleration of the background EEG frequency, which was mostly in the alpha rhythm but also (especially in patients with DOA) in a theta rhythm or a mixed theta-alpha rhythm. Additionally, we included the "slow-wave arousals" characterized by sudden events with persistent delta waves (0.5-3 Hz) on central derivations associated with increased muscle activity and lasting more than 3 s, most of which had a high amplitude (named hypersynchronous delta activity [START_REF] Guilleminault | Hypersynchronous slow delta, cyclic alternating pattern and sleepwalking[END_REF] ). The behaviors concomitant with these N3 arousals/awakenings were observed on the video/audio, and the following behaviors were scored by two scorers: (1) eye opening, (2) staring or exploring the environment, (3) head raising, (4) trunk raising, (5) sitting, (6) standing up/walking, (7) speaking, (8) screaming, (9) showing any facial expression of fear or surprise, (10) interacting with the environment and ( 11) making usual comfort arousal movements (i.e., rubbing, yawning, repositioning oneself). The additional features collected for each episode included the triggering event (present/absent; the nature of the trigger), the onset (abrupt or slow) and duration of the episode (defined from onset to the end of any motor activity). These categories were chosen according to local experience of their high frequency in DOA and to previous studies of behaviors in patients with DOA vs. epilepsy 9 or controls [START_REF] Loddo | Specific motor patterns of arousal disorders in adults: a video-polysomnographic analysis of 184 episodes[END_REF] . The scorer was not blinded to the DOA/non DOA diagnosis of each participant.

Statistical analysis

Descriptive statistics were used to describe continuous variables, and qualitative measures were presented as frequencies and percentages. The comparisons between patients were performed using Student's t-test (quantitative measures) and chi-squared test or Fisher's exact test (qualitative measures). The levels of agreement between raters were tested in 20 randomly selected, representative cases using Cohen's kappa for nominal (qualitative) variables and an interrater correlation coefficient for quantitative variables. Values of Cohen's kappa and interrater correlations greater than 0.8 indicate excellent agreement (almost perfect agreement). The association between quantitative measures was tested using Pearson correlation coefficient or Spearman correlation coefficient (in cases where the normality assumption was not verified). All tests were two-sided, and a p-value below 0.05 was considered statistically significant. Receiver operating characteristic (ROC) analysis was applied to evaluate the best cut-off value for diagnostic performance of the criteria to provide the best pair of values for sensitivity and specificity. To compare the diagnostic accuracy of the results, the area under the curve (AUC) with a 95% confidence interval (CI) was calculated. Likelihood were enrolled in the study. As expected by matching, age and gender were not different between the DOA and control group (Table 1). In the DOA group, most patients (N = 40, 76.9%) had combined sleepwalking and sleep terrors, 7 (13.5%) had isolated sleepwalking and 5 (9.6%) had isolated sleep terrors. Associated confusional arousal was diagnosed in 12 of these patients (23.1%). Sleep talking was reported by 49 (94.2%) patients. The mean age at DOA onset was 10.8 ± 5.4 years (mean ± SD), and the mean disease duration was 19.9 ± 10.6 y. Twenty-nine (55.8%) patients reported having had violent or dangerous sleep-related behaviors at home. A positive family history of DOA was reported in 69.2% of patients. The total score on the Paris Arousal Disorders Severity Scale 11 was 16.9 ± 5.0, the behavior subscore A was 8.0 ± 3.8, the subscore B (frequency of the behaviors) was 4.2 ± 1.1 and the subscore C (impact of the DOA) was 4.7 ± 1.4. Neurological and psychiatric comorbidities were equally rare in the DOA (0 and 1.9%, respectively) and control (1.9 and 3.8%, respectively) groups.

RESULTS

Clinical and Sleep Characteristics of the Participants

These comorbidities included migraine, anxiety and depression. The EEG tracings during relaxed wakefulness and sleep stages did not disclose any paroxysmal activity in patients with DOA or in controls. Compared with controls, patients with DOA had longer total sleep time, higher sleep efficiency, higher REM sleep percentage, and a lower apnea/hypopnea index, as well as higher stage shifts and awakening indices (Table 1). Patients with DOA had, on average, a higher number and index of N3 interruptions, awakenings, and arousals than controls (Table 1). The between-scorer agreement for the quantification of N3 interruptions was 0.99 (95% CI = 0.966-0.995).

Behavioral Characteristics of N3 Interruptions

The interruptions from N3 sleep were analyzed in 172 night recordings and totaled 1,335 interruptions (953 in DOA patients and 382 in controls). The N3 interruptions lasted longer in the DOA than in the control group (35.8 ± 33 vs. 23.1 ± 21.4 sec, P < 0.0001). As many as 913 (95.8%) N3 interruptions in the DOA group and 365 (95.5%) in the control group were accompanied by behaviors. In 6% of the cases, the behaviors "eye opening" "exploring the environment" and "expression of fear/surprise" could not be defined from the video images, because the patients were sleeping in the prone position. An abrupt onset of motor behavior, defined as a behavior starting at the very moment of the sleep interruption, was observed in 622 (65.3%) interruptions in the DOA group and in none of the control group (P < 0.0001), whereas the motor behavior started several seconds after the N3 interruption in the controls. In all groups, 170 (12.7%) episodes of N3 interruptions were triggered by a precipitating event (with a similar frequency between groups), including ambient noises (65.7%), limb movement or myoclonus (14.5%), nurse intervention (7.6%), deep inspiration/cough (4.7%), snoring (4.1%) and apnea/hypopnea/flow limitation (3.5%). Patients with DOA opened their eyes during 653 (68.9%) episodes of N3 interruption, whereas controls opened their eyes during 59 (15.5%) episodes (Figure 1). The N3 interruptions triggered by internal stimuli (apnea, hypopnea, cough, leg movement/myoclonus) led to less frequent (14/48; 29.2%) eye openings than those triggered by external stimuli (noises, contacts), which led to eye openings in 77/124 interruptions (62.1%, P < 0.0001). The patients with DOA reacted more to external triggers by opening the eyes (64/90, 71.1%) than the controls (13/34, 38.2%, P = 0.0008) did. All types of behaviors described in Figure 1, which accompanied the N3 interruptions, were more frequent in the DOA than in the control group (P < 0.0001 for each difference), including in decreasing order of frequency: head raising, visually exploring the environment, speaking, trunk raising and interacting with the environment. Some behaviors were exclusively observed in the DOA group, including facial expressions of fear or surprise (20.7%), sitting (8.6%), screaming (3.4%) and standing up (0.3%). In contrast, usual, quiet movements (repositioning, yawning, stretching, rubbing nose or some other body part) were more frequent in the control group (N = 355, 92.9% of N3 interruptions) than in the DOA group (N = 790, 81.9%, P < 0.0001). Notably, the rapid arousing motor pattern (eye opening and head and trunk raising) described in Figure 1, when present, preceded the quiet usual movements in the DOA group. According to the Rasch Model, there was a hierarchical structure of behaviors predicting the "propensity" for DOA during the N3 interruptions: eye opening was the "easiest" criteria (lowest propensity), and standing up/walking was the "hardest" (highest propensity), in the same order as the frequency of these behaviors (Supplemental Table ). The factor analysis (INFIT values between 0.7 -1.4) of the behaviors supports their unidimensionality.

Quantification of Behaviors

Although these N3 interruptions were similarly spontaneous or triggered by an event in the two groups, the frequency of the corresponding behaviors was markedly different between groups (Table 2), including a higher number and index of eye opening, visually exploring the environment, head raising, trunk raising, sitting, speaking, screaming, expressing fear/surprise, interacting with the environment and engaging in usual arousal movements in the DOA group. The interrater agreement for identifying the episodes of eye openings was 97.7% (κ = 0.94, 95% CI = 0.84 -0.96). The other κ coefficients for individual behavior classification were close to 0.9 or above for all other components.

The number of eye openings positively correlated with the number of other behaviors, except for the number of screaming and sitting behaviors.

Cut-off Identification

The results of the ROC analysis for markers are shown in Table 3 and Figure 2. The highest AUC (measure of discriminative ability of the test) was obtained for the number of interruptions with eye opening (AUC = 0.93 95% CI, 0.89-0.98), the number of N3 awakenings (0.86 95% CI, 0.78-0.93), and the number of N3 interruptions (AUC = 0.77 95% CI, 0.685-0.864). The best pair of values for sensitivity and specificity was found at a cut-off value of 6 or more N3 interruptions per night (LR+ = 2.27, accuracy = 77.1%) and 6 or more N3 awakenings per night (LR+ = 3.62, accuracy = 77.9%). For the number of episodes with eye opening, the optimal cut-off point was 2 per night (LR+ = 4.08, accuracy = 85.6%). Of the behaviors that were 100% specific to the DOA group during the first night, 35/52 (67.3%) of patients displayed a facial expression of fear/surprise at least once, 17/52 (32.7%) sat in the bed, 10 (19.2%) screamed, and 2/52 (3.8%) stood up and walked.

Cut-off Application and Test Combination

With the application of the identified cut-off values (Table 4), two or more episodes of N3 interruptions with eye opening yielded a sensitivity of 94.2% and specificity of 76.9%. When this number of eye openings was combined with at least six N3 interruptions (whether arousal and/or awakenings), the sensitivity was 75%, and the specificity was 88.5%. When the number of eye openings was associated with at least six N3 awakenings, the sensitivity was 67.3%, but the specificity reached 94.2%. To retest the cut-offs in a second set of data, their accuracy was tested in the second night (52 nights of DOA patients and 16 nights of controls). The cut-off of two N3 interruptions with eye opening yielded a sensitivity of 94.2% and a specificity of 85.7%, which was better than during the first night.

DISCUSSION

In this controlled study, patients with DOA had more frequent and longer arousals and awakenings from N3 than controls had. Notably, the behaviors observed during the 1335 episodes of N3 interruptions differed between groups. In the DOA group, the onset of behaviors was more abrupt (starting at the exact time of N3 interruption), and eye opening, head raising, visually exploring the environment, speaking, trunk raising, and interacting with the environment (in descending order of frequency) were more frequent than in controls, whereas the frequency of quiet behaviors usually associated with comfort did not differ between groups. Using receiver operator curves, a cut-off of two or more N3 interruptions containing eye opening yielded a sensitivity of 94.2% and a specificity of 76.9% for a diagnosis of DOA. A similarly excellent sensitivity (94.2%) and specificity (88.7%) was confirmed in a second set of data. Combined markers (i.e., six or more N3 awakenings in the whole night, combined with two or more eye openings during these interruptions) yielded a higher specificity (94%).

Motor phenomena during sleep have been the topic of intensive studies since the introduction of video-polysomnography. The pattern of behaviors associated with N3 interruptions is routinely observed in sleep laboratories for more than 50 years, but it has been more rarely quantified and compared to that in controls. It has been previously studied in 30 adult sleepwalkers and 10 controls. [START_REF] Loddo | Specific motor patterns of arousal disorders in adults: a video-polysomnographic analysis of 184 episodes[END_REF] The behaviors had an abrupt onset in 55% of the episodes, which is close to the 65.3% found in our series.

Eye opening is the most frequent behavior associated with N3 interruptions in patients with DOA, as it was observed in 84% of 57 episodes in an Australian series, [START_REF] Derry | NREM arousal parasomnias and their distinction from nocturnal frontal lobe epilepsy: a video EEG analysis[END_REF] in 76% of 184 episodes in an Italian series, [START_REF] Loddo | Specific motor patterns of arousal disorders in adults: a video-polysomnographic analysis of 184 episodes[END_REF] and in 68.9% of 953 episodes in our series. Of interest, eye opening also occurred during N3 interruptions in controls (15%) here and in one of the eight head flexion/extension movements in the Italian series, 10 but opening the eyes more than one time per night during N3 interruption was exceptional, to the point of providing a marker with a high sensitivity and specificity for a DOA diagnosis.

Additionally, this marker was reproduced with a higher specificity/sensitivity in a second set of data, was simple to recognize and had excellent interrater agreement.

Because our control group included not only healthy controls but also patients with sleep apnea, hypersomnia and insomnia, this marker could be a useful indicator (due to its excellent sensitivity) for the diagnosis of DOA in a sleep clinic context. However, when nocturnal behaviors were compared between patients with DOA and patients with nocturnal frontal lobe epilepsy in an Australian series, episodes with eye opening did not discriminate the groups, as 97% of frontal seizures was associated with an opening of the eyes. [START_REF] Derry | NREM arousal parasomnias and their distinction from nocturnal frontal lobe epilepsy: a video EEG analysis[END_REF] Therefore, this criterion can be used for discriminating patients with DOA from usual sleep clinic patients and form healthy controls, but not from patients with sleep-related hypermotor epilepsy.

The specificity of this "two episodes of eye openings" marker did not reach 100% in our group and therefore cannot be used for forensic purposes. Patients with DOA more frequently opened the eyes (72%) in reaction to an external stimulus (noise, contact) triggering the N3 interruption than did controls (38%), suggesting that DOA patients are more reactive (at least if one considers eye opening as a motor, orientating and eventually fear behavior) than are controls. This observation of a higher reactivity to external stimuli in patients with DOA was obtained in a clinical setting. Similarly, it has been previously shown that forced arousals provoked by strong auditory stimuli trigger abnormal confusional reactions (clumsy movements, sleep talking) in patients with DOA but not in healthy controls. [START_REF] Pilon | Precipitating factors of somnambulism: impact of sleep deprivation and forced arousals[END_REF] The pattern of behaviors accompanying N3 interruption often extended beyond the simple, immediate opening of the eyes. In patients with DOA (and much more exceptionally in controls), the behavioral pattern was more typical of a general arousal/orientation behavior, which includes the behavior of raising the head and trunk, as well as staring, looking around, speaking and touching things around them. Because these events follow a hierarchical order (i.e., the probability that the eye is open when the head or trunk is raised is high), as shown here by the Rasch model, these behaviors may result from the activation of a central pattern generator of arousal behavior. When present, this abrupt arousing motor pattern strongly contrasts with the quiet movements associated with comfort (stretching, rubbing, repositioning oneself) performed in both groups but appear after the abrupt initial arousal pattern in the DOA group.

A facial expression of fear or surprise was observed in 20% of N3 interruptions, further reinforcing the feeling of an explosive, surprised behavior, which seems specific to patients with DOA, as expressions of fear/surprise were not observed in the control group. A similar pattern of arousal behaviors has been described at the onset of nocturnal frontal lobe seizures, making paroxysmal arousals indistinguishable from confusional arousals. [START_REF] Derry | NREM arousal parasomnias and their distinction from nocturnal frontal lobe epilepsy: a video EEG analysis[END_REF] However, we show here that these arousal behaviors are markedly distinguishable from the usual, quiet behaviors associated with arousals and awakenings from N3 in normal participants and in patients with non parasomniac sleep disorders (without epilepsy).

For forensic purposes, one may look for highly specific rather than highly sensitive cutoffs, to be able to determine with a high level of certainty that a participant has a DOA.

In this case, several behaviors were exclusively observed in patients with DOA here (100% specific) and never observed in patients with other sleep disorders. These behaviors included showing a facial expression of fear/surprise upon N3 interruption (displayed by more than two-thirds of patients with DOA), sitting (one-third of patients), and screaming (19%). As often reported, ambulation is exceptional in the sleep laboratory, as here only 2/52 patients stood up and walked during the first night of recordings.

A recent study proposed the first video-polysomnography-based criteria for the diagnosis of DOA in adults, based on quantification of the N3 interruptions (N3 fragmentation index) and the postarousal EEG pattern (fast and slow/mixed arousal indices). [START_REF] Lopez | Diagnostic criteria for disorders of arousal: A video-polysomnographic assessment[END_REF] In this study, the N3 fragmentation index cut-off value of 6.8/h reached a sensitivity of 79% and a specificity of 82%. In our study, this cut-off of 6.8/h was too high, as it resulted in a lower sensitivity (19.2%), whereas the "best" cut-off of 3.6/h had a sensitivity of 69.2% and specificity of 59.6%. Eventually, a number of 6 or more N3 interruptions (a number rather than an index, which is possibly easier to collect) yielded a high level of accuracy in our series. Sample fluctuations (the sample size of Lopez and colleagues was larger than ours) [START_REF] Lopez | Diagnostic criteria for disorders of arousal: A video-polysomnographic assessment[END_REF] and differences in inclusion criteria (our controls were required to have at least one N3 interruption to describe the associated behaviors, whereas this was not an inclusion criteria in the other sample) may explain these different results. Notably, the duration of N3 interruptions was longer in patients with DOA than in controls, suggesting that the reactivity during N3 interruption is higher not only in terms of the complexity of the behavioral response in these patients but also in the time it takes to resume sleeping.

Our study presents some methodological limitations, such as a reasonable but limited number of participants in each group. However, more than 1300 episodes of N3 interruption were carefully examined on video, which constitutes one of the largest behavioral studies in this field. The eyes are not visible when the participants sleep in the front position, which sometimes (here in 6% of N3 interruptions) limits the ability to use the two eye opening marker. In these instances, the surrogate markers can be the number of awakenings from N3. Patients with nocturnal epilepsy were not included in this study. They are known to open the eyes when starting a seizure at night. However, seizures mainly take place in N1 and N2 stages, and rarely in N3, [START_REF] Guilleminault | Hypersynchronous slow delta, cyclic alternating pattern and sleepwalking[END_REF] which may help to distinguish DOA from seizures more easily than behavioral criteria. Eventually, the scorer was not blinded to the diagnosis of DOA in participants when analyzing the videoclips.

In conclusion, we found that a simple, video-polysomnography-based marker of behavior reaction during N3 interruption (i.e., eye opening at least two times in the same night) was sensitive, specific and reproducible in the discrimination of patients with DOA from sleep laboratory controls (more than half of the control group were patients with sleep disorders), but not from sleep-related hypermotor epilepsy. This cutoff value allowed the correct classification of 85.6% of patients. Other simple markers

  ratios (LRs) for positive test results and accuracy (number of correct results divided by the total number of tests) were provided as a measure of diagnostic accuracy. The best possible threshold was defined as the highest Youden index [(specificity + sensibility) -1]. Diagnostic criteria based on cut-offs identified by the ROC analysis were evaluated for each test individually and for each test combined with the number of N3 interruptions/awakenings (considered positive for a participant who was positive on each test). The association between test results and the presence of the disease was evaluated by Pearson's test. The Rasch model was conducted with behavioral features of N3 interruptions to examine the model fit statistics, namely, the informationweighted goodness-of-fit statistics (INFIT), and the ordering of the behavior categories. All analyses were performed using IBM SPSS Statistics for Macintosh (Version 23.0. Armonk, NY).

  Fifty-two patients with DOA and 52 controls (23 healthy participants, 10 patients with sleep apnea syndrome [range of apnea/hypopnea index, 15.2-90.1/hour], 11 patients with idiopathic hypersomnia and 8 patients with insomnia, as randomly determined)

( 6

 6 ABBREVIATIONS LIST: AUC: area under the curve; CI: confidence interval; DOA:

FIGURE CAPTIONS Figure 1 -

 CAPTIONS1 FIGURE CAPTIONS

Figure 2 -

 2 Figure 2 -Receiver Operating Characteristics Analyses for Various Markers During N3

Table 1 -Sleep measures in patients with disorders of arousal vs. controls (healthy participants and participants with sleep disorders but no DOA)

 1

	DOA	Controls	p-value

Table 3 -Optimal Cut-Off Points of N3 Interruptions for a Diagnosis of Disorders of Arousal, Evaluated with Receiver Operating Characteristics Curves.

 3

	Test Cut-off	Cut-off	Sensitivity	Specificity	Youden	Cut-off point for 95%	Cut-off point for 95%
		point	(%)	(%)	index	sensitivity	specificity
	No. of N3 interruptions	≥ 6	75.0	67.3	0.423	2.5	11.5
	N3 interruption index	 3.6	69.2	59.6	0.288	1.8	6.2
	No. of N3 awakenings	≥ 6	67.3	92.3	0.596	2.5	6.5
	No. of eye-opening N3 interruptions	 2	94.2	76.9	0.711	0.5	4.5

DISCLOSURE STATEMENT:

This was not an industry-supported study. The HYPNOSOM study was financed by a grant from the Paris Hospital (grant P130603, promotor: APHP) to IA.


Marc Pineton De Chambrun

MD, MSc Dirk W Donker

MD, PhD Alain Combes
email: alain.combes@aphp.fr.

Alain Pr

Combes

What's new in cardiogenic shock?

Keywords: cardiogenic shock, acute myocardial infarction, extracorporeal membrane oxygenation, intra-aortic balloon conterpulsation, temporary circulatory support

come

Cardiogenic shock (CS) is defined as primary cardiac dysfunction leading to critical organ hypoperfusion and hypoxemia. Diagnostic criteria include persistent hypotension and signs of compromised end-organ perfusion such as cold extremities, oliguria, or altered mental status despite correction of underlying hypovolemia [START_REF] Mebazaa | Management of cardiogenic shock complicating myocardial infarction[END_REF]. Acute myocardial infarction (AMI) is the most frequent cause of CS, representing up to 70% of cases and occurring in 5-10% of patients with AMI. Despite major therapeutic advances, mortality of CS in the setting of AMI remained unacceptably high (40-50%) in recent years [START_REF] Thiele | Management of cardiogenic shock complicating myocardial infarction: an update 2019[END_REF]. Since the proportion of patients admitted to intensive care units with CS has increased in recent years, intensivists should benefit from the latest information on the care of this high risk population [START_REF] Puymirat | Cardiogenic shock in intensive care units: evolution of prevalence, patient profile, management and outcomes, 1997-2012[END_REF].

A new classification for cardiogenic shock

Patients with CS represent a heterogeneous population with varying prognosis based on etiology, severity of illness and comorbidities. The Society for Cardiovascular Angiography and Intervention (SCAI) recently proposed a new CS classification featuring 5 stages (A-E) of increasing severity based on clinical, biological and hemodynamic signs of CS (Figure 1) [START_REF] Baran | SCAI clinical expert consensus statement on the classification of cardiogenic shock: This document was endorsed by the American College of Cardiology (ACC), the American Heart Association (AHA), the Society of Critical Care Medicine (SCCM), and the Society of Thoracic Surgeons (STS) in April 2019[END_REF]. The purpose of this initiative was to provide a simple tool for bedside evaluation, prognostication and treatment optimization of patients with CS. It also intended to homogenize definitions of CS to appropriately differentiate patient subsets in clinical trials and registries. SCAI CS scores calculated at cardiac intensive care unit admission provided a robust risk prognosis stratification in a Mayo Clinic cohort of 10,000 patients, with the proportion of patients in stages A-E being 46.0%, 30.0%, 15.7%, 7.3% and 1.0% and an associated hospital mortality of 3.0%, 7.1%, 12.4%, 40.4% and 67% (p<0.001), respectively [START_REF] Jentzer | Cardiogenic Shock Classification to Predict Mortality in the Cardiac Intensive Care Unit[END_REF].

Culprit-lesion-only or multivessel percutaneous coronary intervention (PCI)?

The CULPRIT-SHOCK trial randomized 706 patients to either culprit-lesion-only PCI or immediate multivessel PCI in CS complicating AMI. The composite primary endpoint (death or renal-replacement therapy within 30-days after randomization) occurred more frequently in the multivessel group (55.4% vs. 45.9%, p=0.001) and was mostly driven by an increased mortality (43.3% vs. 51.5%; p= 0.03) [START_REF] Thiele | PCI Strategies in Patients with Acute Myocardial Infarction and Cardiogenic Shock[END_REF]. After 1 year, the rates of repeat revascularization (32.3% vs. 9.4%) and rehospitalisation for heart failure (5.2% vs. 1.2%) were however higher in the culprit-lesion-only group [START_REF] Thiele | One-Year Outcomes after PCI Strategies in Cardiogenic Shock[END_REF]. The latest European Society of Cardiology (ESC) guidelines now recommend against immediate routine multivessel PCI in this setting, while later staged revascularization of other lesions may be performed [START_REF] Neumann | ESC/EACTS Guidelines on myocardial revascularization[END_REF].

Norepinephrine or epinephrine?

In current practice, norepinephrine and epinephrine remain the most commonly used vasopressors in CS. A prospective multicenter study that compared the efficacy and safety of epinephrine and norepinephrine in CS complicating AMI was terminated early as the incidence of refractory CS (main safety endpoint) occurred more frequently with epinephrine (37% vs. 7%, p=0.008). The primary efficacy outcome (cardiac index evolution from baseline to 72h) was however not different between groups (p=0.4) [START_REF] Levy | Epinephrine Versus Norepinephrine for Cardiogenic Shock After Acute Myocardial Infarction[END_REF]. In a meta-analysis including 16 studies and 2583 patients with CS, epinephrine use was associate with an increased risk of adjusted short-term mortality compared to other drugs (OR [95%CI] = 4.4 [3.4-6.4]). This result was confirmed in a subset of 338 propensity-matched patients (OR [95%CI] = 4.3 [3.0-6.0]) [START_REF] Léopold | Epinephrine and short-term survival in cardiogenic shock: an individual data meta-analysis of 2583 patients[END_REF]. Altogether, these data suggest that norepinephrine but not epinephrine should be considered as the first line vasopressor in patients with CS [START_REF] Mebazaa | Management of cardiogenic shock complicating myocardial infarction[END_REF].

Non-pharmalogical interventions

After promising experimental results, a randomized controlled study that evaluated mild hypothermia (33°C) in 40 AMI patients with CS failed to demonstrate an improvement in the cardiac power index after 24h. Mortality at day 30 post-randomization was also not different between groups (60% vs. 50%, p=0.55) [START_REF] Fuernau | Mild Hypothermia in Cardiogenic Shock Complicating Myocardial Infarction[END_REF].

A standardized "shock team" based protocol that included timely diagnosis, mandatory invasive hemodynamic monitoring, and early and appropriate use of circulatory support devices for the management of CS was associated with a significant increase in 30-day survival from 47% in 2016 (before), to 57.9% (2017) and 76.6% (2018) (p<0.01). A simple 3-category risk score including demographic, laboratory, and hemodynamic data was derived from this cohort and may help to guide clinical decision-making in this setting [START_REF] Tehrani | Standardized Team-Based Care for Cardiogenic Shock[END_REF].

Temporary circulatory support (TCS)

The IABP-SHOCK II trial which randomized 600 AMI patients with CS failed to demonstrate any benefit of intra-aortic balloon conterpulsation (IABP) in terms of 30-day, 1-year and 6-years mortality or in any other secondary outcomes [START_REF] Thiele | Intraaortic Balloon Pump in Cardiogenic Shock Complicating Acute Myocardial Infarction: Long-Term 6-Year Outcome of the Randomized IABP-SHOCK II Trial[END_REF]. These results led to a class IIIB recommendation against its routine use in the latest ESC guidelines [START_REF] Neumann | ESC/EACTS Guidelines on myocardial revascularization[END_REF].

Other percutaneous short-term TCS device include the Impella® (ABIOMED Inc., Danvers, MA, USA), the TandemHeart® (LivaNova, London, UK) and venoarterial extracorporeal membrane oxygenation (VA-ECMO) which provides both circulatory support and gas exchange. However, guidelines from the ESC (Class IIb, Level of Evidence C) recommended that TCS implantation should only be considered in selected CS patients [START_REF] Neumann | ESC/EACTS Guidelines on myocardial revascularization[END_REF].

Indeed, a meta-analysis including 4 trials randomizing 148 patients to either TandemHeart TM or Impella® (n=77) vs. IABP (n=71) showed no difference in 30-day mortality [START_REF] Thiele | Percutaneous short-term active mechanical support devices in cardiogenic shock: a systematic review and collaborative meta-analysis of randomized trials[END_REF]. More recently, two retrospective cohort studies failed to demonstrate a benefit with the Impella®. In a study of 237 AMI patients who received the Impella® propensity-matched with 237 patients from the IABP-SHOCK II trial, there was no significant difference in 30-day all-cause mortality (49% vs 46%, P=0.64) [START_REF] Schrage | Impella Support for Acute Myocardial Infarction Complicated by Cardiogenic Shock[END_REF]. In a large-scale registry study including 48,306 patients of whom 50% had CS, undergoing PCI with TCS support at 432 hospitals in the USA, the use of Impella® was even associated with increased mortality (adjusted OR [95%CI] = 1.17 [1.10-1.24] p<0.001) [START_REF] Amin | The Evolving Landscape of Impella® Use in the United States Among Patients Undergoing Percutaneous Coronary Intervention with Mechanical Circulatory Support[END_REF]. The rates of serious adverse events, including bleeding, infections and stroke, were more frequent in patients supported by the Impella® [START_REF] Schrage | Impella Support for Acute Myocardial Infarction Complicated by Cardiogenic Shock[END_REF][START_REF] Amin | The Evolving Landscape of Impella® Use in the United States Among Patients Undergoing Percutaneous Coronary Intervention with Mechanical Circulatory Support[END_REF]. A larger randomized trial comparing the Impella CP® against conventional treatment in 360 AMI CS patients is ongoing (NCT01633502).

While VA-ECMO is currently one of the most commonly applied TCS modalities in CS, high-grade scientific evidence supporting its use is urgently awaited [START_REF] Combes | The ICM research agenda on extracorporeal life support[END_REF] (Supplemental Table 1). A position paper by an international group of ECMO experts advocated for a multidisciplinary team of experts to guide institutional use of ECMO and the specific care of the patients receiving it. Well-defined patient selection and careful attention to complications were identified as key factors in optimizing outcomes [START_REF] Abrams | Position paper for the organization of ECMO programs for cardiac failure in adults[END_REF]. Percutaneous ECMO cannulation should also be preferred over surgical insertion since a retrospective cohort of 266 propensity-score matched patients showed fewer local infections, similar rates of ischemic or sensory-motor complications and improved 30-day survival with the less invasive approach (63.8% vs. 56.3%, p=0.034) [START_REF] Danial | Percutaneous versus surgical femoro-femoral venoarterial ECMO: a propensity score matched study[END_REF]. The role of VA-ECMO in AMI patients with CS may be clarified by three large, adequately powered randomized controlled trials (NCT03813134, NCT03637205, NCT04184635) which are currently underway.

The new classification of CS may allow improved recognition and care of CS patients. While the initial strategy of revascularization has been clarified in patients with AMI and multivessel disease, TCS devices have yet failed to demonstrate improved survival. More randomized clinical trials are pressingly needed to establish optimal medical, pharmacological and TCS strategies in this setting.

Optimized ICU care of these CS patients who frequently develop multiple organ failure may also improve their outcomes. Adapted from [START_REF] Puymirat | Cardiogenic shock in intensive care units: evolution of prevalence, patient profile, management and outcomes, 1997-2012[END_REF]

FIGURE TITLE AND LEGEND

Figure 1 title:Figure 1

 11 Figure 1 title: The Society for Cardiovascular Angiography and Intervention (SCAI) cardiogenic shock

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Marinela Shehaj
email: marinela.shehaj@hds.utc.fr

Dritan Nace
email: dritan.nace@hds.utc.fr

Michal Pióro
email: m.pioro@tele.pw.edu.pl

Issues in robust network dimensioning -the case of FSO networks

Keywords: FSO, robust optimization, multi-commodity flows

Introduction

The considerations of our work are devoted to the problem of networks link dimensioning. The main application area we investigate are networks that apply Free Space Optics (FSO) which is a broadband wireless optical transmission technology. The communication links are provided by means of a laser beam sent from the transmitter to the receiver placed in the line of sight. A major disadvantage of FSO Links (with respect to fiber links) is their sensitivity to weather conditions such as fog, rain and snow, causing substantial loss of the transmission power over the optical channel due mostly to absorption and scattering. Thus, although the FSO technology allows for the fast and low-cost deployment of broadband networks, its operation will be affected by this sensitivity, manifested by substantial losses in links' transmission capacity with respect to the nominal capacity. Therefore, a proper approach to FSO network dimensioning should take such losses into account so that the level of carried traffic is satisfactory under all observed weather conditions.

Objectives and context

The work presented is part of the project activities of the Laboratory of Excellence (LABEX) at the Université de Technologie de Compiègne (UTC) in France, on the Control of Technological Systems of Systems (MS2T). It is in continuation of the work presented in [START_REF] Pióro | Optimizing Flow Thinning Protection in Multicommodity Networks with Variable Link Capacity[END_REF][START_REF] Nace | An optimization model for robust FSO network dimensioning[END_REF][START_REF] Shehaj | Dimensioning of hybris FSO/fiber networks[END_REF] and is essentially devoted to wireless networks, like FSO networks that are subject to failures involving partial loss of links capacity. FSO networks exhibit several important advantages, but this technology remains vulnerable to weather conditions, causing substantial loss of transmission power over optical channel. All this motivates the network optimization problem we study : how to dimension the network links at the lowest cost, and at the same time assure the traffic demand satisfaction at an acceptable level for all observed /predicted weather conditions.

Modeling and solving the problem

To construct our approach we start with building a reference failure set using a set of meteorological records for a given period of time ( for example a period of one year), against which the network must be protected. Typically, the given weather condition affects a subset of the network links. Each affected link loses a portion (percentage) of its nominal capacity (i.e., the bit-rate realized when weather is fine). Such a loss is called the failure (degradation) ratio that we can assume as a value between 0 (no capacity loss) and 1 (100% of capacity lost).

The values of the failure ratio are 0.25, 0.50 and 1.00. In consequence, each particular weather condition that can be observed define a failure state that can be called a multiple partial link failure state. For the sake of simplicity we assume that the link connecting two given areas is affected by the worse of the weather condition in the two areas. The observed conditions are translated into the multiple partial link failure states corresponding to all hourly periods in the considered one-year time horizon, which gives 365*24=8760 "hourly" states in total.

Next, the mathematical formulation of the robust network dimensioning problem uses the above failure set. In contrast to related investigations on resilient networks, we deal with the problem involving a very large number of failure states, described by the so called uncertainty set ( an instance of the budgeted uncertainty set), but this makes the problem intractable because of the size of the failure set. All this calls for a more sophisticated approach which uses a cut-generation algorithm. This algorithm is composed of a master problem and a slave problem where we test feasibility of the link dimensioning with respect to the reference failure set defined as the set of failures to all hourly periods in an one-year time horizon. This failure set, being large, makes the problem difficult. Furthermore, the weather conditions are changing over years, which give to the problem the uncertainty dimension. To deal with this we propose to approximate the reference failure set with a so-called K-set, which covers all possible failures involving at most K links. This K-set stands for uncertainty polytope of failures in our case and can be defined as the subset of possible combinations of K (or less) links that can be affected simultaneously with the same failure ratio β(e) ( for example β(e) = 0.25 for all link e ).

We have also studied alternative uncertainty sets involving geographic areas around a group of node instead of K-links sets defined previously or other sets involving nodes and links and/or different levels of failure. All this gives more flexibility and in some cases reduces the link dimensioning cost while increasing the overall traffic satisfaction ratio. We have tested our model under several types of uncertainty sets and for both pure FSO and hybrid FSO/fiber networks. It is shown that the cut-generation algorithm works quite well for all considered failure sets and instances.