J Head Trauma Rehabil Vol. 30, No. 5, pp. 334–346 c 2015 Wolters Kluwer Health, Inc. All rights reserved. Copyright
Polysomnographic Sleep Patterns in Children and Adolescents in Unresponsive Wakefulness Syndrome Paolo Avantaggiato, MD; Erika Molteni, PhD; Francesca Formica, MD; Gian Luigi Gigli, MD; Mariarosaria Valente, MD; Simone Lorenzut, MD; Stefano de Biase, MD; Salvatore Arcieri, MD; Federica Locatelli, MD; Sandra Strazzer, MD Objectives: We aimed (i) to search for qualitative sleep patterns for pediatric unresponsive wakefulness syndrome (SPPUWS) in prolonged polysomnographic (PSG) recordings in children and adolescents with subacute severe disorders of consciousness due to an acquired brain damage; (ii) to investigate the clinical relevance of SPPUWS and of possible neurophysiological markers (rapid eye movement sleep and sleep spindles) in PSG recordings of pediatric patients with unresponsive wakefulness syndrome (UWS). Methods: We performed a PSG study in 27 children with UWS due to acquired brain damage in the subacute phase. Patients received a full neurological examination and a clinical assessment with standardized scales. In addition, outcome was assessed after 36 months. Results: We identified 6 PSG patterns (SPPUWS) corresponding to increasing neuroelectrical complexity. The presence of an organized sleep pattern, as well as rapid eye movement sleep and sleep spindles, in the subacute stage appeared highly predictive of a more favorable outcome. Correlation was found between SPPUWS and recovery, as assessed by several clinical and rehabilitation scales. Conclusions: Polysomnography can be used as a prognostic tool, as it can help determine the capability to recover from a pediatric UWS and predict outcome well before the confirmation provided by suitable clinical scales. Key words: brain injury prognosis, electroencephalography, encephalopathy, pediatric brain injury, pediatric brain tumor, persistent vegetative state, polysomnography, unresponsive wakefulness syndrome
E
MERGING FROM COMA, a state of complete unconsciousness, reflects a transition to the unresponsive wakefulness syndrome (UWS). Unresponsive wakefulness syndrome was first introduced by Laureys et al1 in 2010 to overcome the in-use definitions of vegetative state (VS) and apallic state and to specify those comatose patients who begin to show sleep-wake cycles (ie, eye closing/opening and muscles inactivity/activity) while (still) presenting a number of clinical signs of unreAuthor Affiliations: Acquired Brain Injury Unit,Scientific Institute “Eugenio Medea,” Bosisio Parini, Lecco, Italy (Drs Avantaggiato, Molteni, Formica, Arcieri, Locatelli, and Strazzer); Department of Experimental and Clinical Medicine, University of Udine Medical School, Udine, Italy (Drs Gigli and Valente); and Neurology Unit and Center of Sleep Medicine, "Santa Maria della Misericordia" University Hospital, Udine, Italy (Drs Lorenzut and de Biase). This study was supported by the Italian Department of Health (Ricerca Corrente 2008–2009, Bando Ricerca Finalizzata 2008). The authors acknowledge Drs Katia Colombo, Valentina Pastore, and Federica Villa for their flawless assistance in the clinical scale administration. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (www.headtraumarehab.com). The authors declare no conflicts of interest. Corresponding Author: Erika Molteni, PhD, Scientific Institute E. Medea, Acquired Brain Injury Unit, Via Don Luigi Monza 20, Bosisio Parini, Lecco 23842, Italy ([email protected]). DOI: 10.1097/HTR.0000000000000122
sponsiveness. Be it transient or persistent, UWS is characterized by the absence of self-awareness behaviors of the environment.2–4 Diagnosis of UWS nowadays relies on 2 mainstays performed behaviorally: clinical examination and neuropsychological assessments. Both tools have serious limitations,5,6 as they result in approximately 35% of misdiagnoses7 and more often in insufficient prognostic indications for predicting or excluding the progress toward some responsiveness. On the contrary, neurophysiological studies have shown that, in time, patients with UWS develop some electrophysiological differentiation.8–10 This fact has fostered an increasing interest in the sleep patterns of patients with disorders of consciousness (DOC) and has steered research toward the use of polysomnography (PSG). One of the major difficulties encountered in sleep studies of UWS is the absence of specific staging criteria. Indeed, the official electrophysiological scoring system of sleep11 is currently based on the electroencephalographic (EEG) features of healthy individuals, hardly applicable for sleep staging in patients with severe brain damage.10 Alternative criteria, tailored and adapted to adult and pediatric cohorts of patients, have to be applied for pediatric cases.12 Among them, many studies have attempted to use additional data, such as
334 Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Polysomnographic Sleep Patterns in Unresponsive Wakefulness Syndrome electromyographic (EMG) measurement, heart rate, or blood pressure, for the interpretation of sleep and to detect differentiated stages of DOC.13–16 Furthermore, studies investigating the hormonal effects on sleep in brain-injured patients with DOC and testing the effect of substances acting on the sleep-wake cycle, such as melatonin, are still lacking. Prolonged PSG recordings have been plumbed for possible correlations between neuroelectrical activity and functional levels of impairment. Studies suggest that the presence of specific EEG patterns, ascribed to different DOC,13,17,18 could be proposed as specific prognostic indicators for recovery.18–20 Similar to what has been observed in adults,21 a previous study on comatose children supports the finding that the reappearance of sleeprelated waveforms (eg, spindles, K-complexes) during recovery from brain injury is a sign of a good prognosis.13 Other works compared the PSG prognostic value of PSG waveforms with the Level of Cognitive Functional Assessment Scale,19 as well as Glasgow Coma Scale ratings in patients who had sustained an acute brain injury.20 Furthermore, a number of PSG studies specifically focusing on VS9,21–26 were written before the definition of minimally conscious state (MCS) in 2002,27 making it possible that many patients reported as being in a VS might, in fact, have been in a MCS. As a consequence, the present work can be compared stricto sensu with the few works written only in the last decade.17,28–31 Earlier and recent literature, however, agrees in reporting that the presence of spindles and sleep-stage differentiation in EEG tracks is a potential marker of good outcome23,28 and that the presence of rapid eye movement (REM) sleep is predictive of better cognitive recovery (see also the work by Ron et al32 ). A decade after the pioneering effort of Ch´elioutHeraut et al,13 we conducted a retrospective clinical and PSG analysis of 27 children and adolescents with subacute or chronic UWS due to an acquired brain damage. We searched for possible neurophysiological markers of sleep-wake EEG organization that could predict the children’s outcome. Our analysis isolated 6 qualitative sleep characteristics that we termed sleep patterns for pediatric unresponsive wakefulness syndrome (SPPUWS) and which were tested for correlations with the clinical outcome at 36 months after PSG recordings. METHODS Participants Thirty-five brain-injured pediatric patients with UWS participated in the study. The group was made up of in-patients, admitted to our hospital for intensive neurorehabilitation treatment (physical therapy, dysphagia therapy, and sensory stimulation therapy) throughout a period of 4 years. Inclusion criteria were as follows: (a)
335
severe acquired brain lesion; (b) age 18 years or less; and (c) time since injury 1 year or less at the study enrollment. Exclusion criteria were as follows: (a) congenital neurological pathology; (b) need of mechanical ventilation (due to the interfering effect of ventilation on sleep33,34 ); and (c) administration of drugs in composition and dosages capable of significantly altering the EEG frequency content (however, a complete list of sedative drugs and dosages is provided for each patient in Table 1). At enrollment in the study, a multidisciplinary team (neurologist, neuropsychiatrist, neuropsychologist, and dysphagia therapist) evaluated all patients and concluded that they fulfilled the criteria for UWS diagnosis, according to the diagnostic criteria of the Royal College of Physicians2 and of Giacino et al.27 Seven patients were excluded from the study because of recurrent epileptic seizures/activity that would have dominated the EEG activity and would have impeded the correct sleep staging, and one patient was excluded because of recurrent movement artifacts that would have overwhelmed the neurophysiological evidences. A final group of 27 patients (mean age = 8.44 years, SD = 5.33 years; 21 male patients) was selected. Among the final cohort, none of the patients exhibited epileptic activity with duration of more than 15% of the whole PSG track. Epileptic discharges consisted of all cases in short isolated sequences of epileptiform anomalies, deemed not to interfere with sleep architecture. Table 1 reports the demographic and clinical characteristics of the patients. Ethics statement This study was carried out in compliance with the Declaration of Helsinki and was approved by the “I.R.C.C.S. E. Medea—Ass. La Nostra Famiglia” Ethics Committee, located in Bosisio Parini (Lecco, Italy). Patients’ relatives and/or legal guardians provided written informed consent for the participation in the study. Clinical evaluation and measures On admission, the patients’ medical history was collected, including their Glasgow Coma Scale (GCS) score at insult (see Table 1).35,36 At the time of study (T0 ), the Disability Rating Scale (DRS),37,38 which focuses on the functional abilities, and the Level of Cognitive Functioning Assessment Scale (LOCFAS),39 which is specifically used for the punctual evaluation of the cognitive functions, were administered. Patients also underwent clinical magnetic resonance imaging examination (see Supplemental Digital Content Table ST2, available at http://links.lww.com/JHTR/A134). A clinical follow-up (T1 ) was performed after 36 months from the first evaluation (T0 ); the follow-up included patients’ evaluation with the standardized Glasgow Outcome www.headtraumarehab.com
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27
Head trauma Head trauma Head trauma Hypoxic damage Brain tumor Head trauma Head trauma Encephalitis Head trauma Brain tumor Encephalitis Head trauma Head trauma Head trauma Head trauma Encephalitis Head trauma Head trauma Head trauma Hypoxic damage Head trauma Brain tumor Head trauma Hypoxic damage Hypoxic damage Hypoxic damage Hypoxic damage
4 7 4 3 3 3 6 4 6 6 6 5 3 3 5 4 4 6 4 3 4 3 3 3 3 3 5
4 2 4 4 1 1 3 3 3 2 3 4 4 3 3 3 4 3 3 3 3 3 3 2 2 3 2
2/8 2/2 2/6 2/5 2/2 2/2 2/2 2/2 2/3 2/2 2/3 2/7 2/5 2/3 2/6 2/3 2/6 2/3 2/3 2/3 3/3 1/5 3/5 2/2 2/2 2/3 2/2
24/7 24/22 23/9 24/9 24/30 28/24 24/23 24/20 23/20 24/22 24/19 22/8 23/9 24/19 23/7 24/21 22/8 27/17 25/18 25/20 25/20 26/6 26/7 24/22 23/22 23/20 26/24
1 3 1 1 4 2 2 2 1 2 1 2 1 1 1 2 1 1 4 1 2 1 2 2 2 1 3
UWS/exit-MCS UWS/UWS UWS/exit-MCS UWS/exit-MCS UWS/UWS UWS/UWS UWS/MCS UWS/MCS UWS/MCS UWS/UWS UWS/MCS UWS/exit-MCS UWS/exit-MCS UWS/MCS UWS/exit-MCS UWS/MCS UWS/exit-MCS UWS/MCS UWS/MCS UWS/MCS UWS/MCS UWS/exit-MCS UWS/exit-MCS UWS/UWS UWS/UWS UWS/MCS UWS/UWS
6 2 5 5 4 3 3 3 6 2 5 6 6 4 5 6 5 5 5 5 3 5 6 3 4 5 1
No No No No Yes No No No No No Yes No No No No No No Yes No No No No No Yes Yes Yes Yes
Epilepsy
E = 0.6 None E = 0.7 C = 0.44∗ ; F = 1 A=5 E = 1.8; H = 2 E = 2.3; F = 0.8; H = 12 E = 2.8∗ None None A=5 A = 6; D = 0.05∗ ; E = 0.8 None C = 0.1; D = 0.04; E = 2.5 E = 2.2; F = 0.3 E = 0.2; F = 0.9 None C = 0.04; E = 1.7 A = 5; D = 0.04; E = 0.1; F = 1 C = 0.8∗ ; E = 2.3; F = 1.4∗ E = 1.4; G = 0.5 None None E = 1.8; F = 0.2 F=4 B = 0.015; E = 2.3 E = 0.8; F = 0.8
Drugsc
Abbreviations: C/NCS, Coma/Near Coma Scale at follow-up; DRS, Disability Rating Scale at time of EEG and at follow-up; EEG, electroencephalogram; GCS, Glasgow Coma Scale score at insult; GOS, Glasgow Outcome Scale score at follow-up; LOCFAS, Level of Cognitive Functioning Assessment Scale at time of EEG and at follow-up; SPPUWS, sleep patterns for pediatric unresponsive wakefulness syndrome; T0 , time at study; T1 , time at follow-up. a State of consciousness at time of EEG and at follow-up (UWS is unresponsive wakefulness syndrome and vegetative state; MCS is minimally conscious state; exit-MCS is the recovery of consciousness). b Sleep group according to SPPUWS. c Dosage of drugs with sedative effects: A = phenobarbital (mg/kg/d); B = clonazepam (mg/kg/d); C = diazepam (mg/kg/d); D = lorazepam (mg/kg/d); E = baclofen (mg/kg/d); F = niaprazine (mg/kg/d); G = hydroxyzine dichlorhydrate (mg/kg/d); H = tizianidine chlorhydrate (mg/d). The values with “∗ ” indicate dosages exceeding the recommended ranges.
11/ M 14/M 16/M 5/M 2/M 14/M 13/M 4/M 5/M 14/M 5/M 12/F 13/F 13/M 15/F 5/F 4/M 4/M 9/M 3/M 18/M 6/F 14/M 4/F 2/M 2/M 1/M
Case
GCS LOCFAS DRS C/NCS State of score GOS score score score consciousnessa Primary disease (at insult) score (T1 ) (T0 /T1 ) (T0 /T1 ) (T1 ) (T0 /T1 ) SPPUWSb
Demographic and clinical data
Age, y/sex
TABLE 1
336 JOURNAL OF HEAD TRAUMA REHABILITATION/SEPTEMBER–OCTOBER 2015
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Polysomnographic Sleep Patterns in Unresponsive Wakefulness Syndrome Scale (GOS),40,41 which provides the general degree of recovery, the DRS, the LOCFAS, and the Coma/Near Coma Scale (C/NCS),42 which estimates the level of responsiveness damage, depending on responses to the stimulation of the different sensory channels. The C/NCS was applied in compliance with the American Congress of Rehabilitation Medicine Disorders of Consciousness Task Force guidelines.43 High scores on the GCS, LOCFAS, and GOS reflected a less impaired clinical picture. In contrast, the higher the DRS and C/NCS scores, the more marked the difficulties. The staff (Drs Valentina Pastore, Federica Villa, and Katia Colombo) who administered the clinical scales were blinded to the research study rationale. PSG recordings After admission to our rehabilitation center, PSG recordings of all the 27 patients were obtained overnight, uninterruptedly from the afternoon to the morning of the following day. We agreed to record the longest recording possible, with respect to the daily rehabilitation schedules and the patients’ compliance and needs. Mean time since injury was 106 days (SD = 58 days). Mean duration of recordings was 828 minutes (SD = 197 minutes). Patients received no specific sedation for the execution of EEG examination. EEG tracks were acquired with an Embla RemLogic digital system, with 500-Hz sampling rate. In compliance with the minimal requirements provided in the American Academy of Sleep Medicine (AASM) recommendations for montage, 8 Ag/AgCl electrodes were placed on the patients’ head, corresponding to the standard 10/20 system44 in F3, F4, C3, C4, T3, T4, O1, and O2 positions. EEG recording was performed with reference to 2 additional electrodes, placed in A1 and A2 positions, at the mastoids. A set of polygraphic channels was also added: 2 electrodes for electro-oculogram (EOG) in cross-montage, at least 1 bipolar EMG channel for deltoid activity, and 1 bipolar electrocardiographic (ECG) derivation. Digital bandpass filtering was applied to the EEG and EOG channels in the 0.3- to 35-Hz range, to the EMG in the 10- to 200-Hz range, and to the ECG in the 0.3- to 70-Hz range. EEG impedances were kept under 5 k. During the recording, patients’ caregivers were instructed to accurately report any event in a standard form, also called “sleep diary.” Because of the partial absence of the skull, in patient 18, we could not place electrodes over F3 and F4; instead, we were able to place Fpz electrode. Similarly, patients 19, 21, and 23 completely lacked EEG recording from the frontal area, as the placement of frontopolar and frontal electrodes was impossible. For each patient, PSG tracks were visualized and analyzed by Somnologica software (Reykjavik, Iceland).
337
Sleep was partitioned into 30-second epochs for further staging. After visual selection and exclusion of the artifactual periods, including intervals affected by muscular electrical activity, 2 trained and certified neuropsychiatrists (P.A., F.F.) and 2 experienced neurologists (S.L., S. de B.), belonging to 2 different hospitals, scored the tracks independently. They performed a preliminary scoring of the PSG tracks, using the age-appropriate criteria of the AASM.1 In doing so, they isolated the specific PSG periods for which the criteria were clearly not applicable. Unscored periods were discussed by the team in 2 independent scoring sessions, and scoring conflicts were partially resolved. Then, alternative criteria were developed on the basis of previous works (see Supplemental Digital Content Table ST1, available at http://links.lww.com/JHTR/A134).13,28,45 Such criteria helped in the attribution of sleep-wake status and in the identification of possible sleep stages in unscored epochs, during a second double-blind scoring process. However, segments with debatable score (
Polysomnographic Sleep Patterns in Children and Adolescents in Unresponsive Wakefulness Syndrome Paolo Avantaggiato, MD; Erika Molteni, PhD; Francesca Formica, MD; Gian Luigi Gigli, MD; Mariarosaria Valente, MD; Simone Lorenzut, MD; Stefano de Biase, MD; Salvatore Arcieri, MD; Federica Locatelli, MD; Sandra Strazzer, MD Objectives: We aimed (i) to search for qualitative sleep patterns for pediatric unresponsive wakefulness syndrome (SPPUWS) in prolonged polysomnographic (PSG) recordings in children and adolescents with subacute severe disorders of consciousness due to an acquired brain damage; (ii) to investigate the clinical relevance of SPPUWS and of possible neurophysiological markers (rapid eye movement sleep and sleep spindles) in PSG recordings of pediatric patients with unresponsive wakefulness syndrome (UWS). Methods: We performed a PSG study in 27 children with UWS due to acquired brain damage in the subacute phase. Patients received a full neurological examination and a clinical assessment with standardized scales. In addition, outcome was assessed after 36 months. Results: We identified 6 PSG patterns (SPPUWS) corresponding to increasing neuroelectrical complexity. The presence of an organized sleep pattern, as well as rapid eye movement sleep and sleep spindles, in the subacute stage appeared highly predictive of a more favorable outcome. Correlation was found between SPPUWS and recovery, as assessed by several clinical and rehabilitation scales. Conclusions: Polysomnography can be used as a prognostic tool, as it can help determine the capability to recover from a pediatric UWS and predict outcome well before the confirmation provided by suitable clinical scales. Key words: brain injury prognosis, electroencephalography, encephalopathy, pediatric brain injury, pediatric brain tumor, persistent vegetative state, polysomnography, unresponsive wakefulness syndrome
E
MERGING FROM COMA, a state of complete unconsciousness, reflects a transition to the unresponsive wakefulness syndrome (UWS). Unresponsive wakefulness syndrome was first introduced by Laureys et al1 in 2010 to overcome the in-use definitions of vegetative state (VS) and apallic state and to specify those comatose patients who begin to show sleep-wake cycles (ie, eye closing/opening and muscles inactivity/activity) while (still) presenting a number of clinical signs of unreAuthor Affiliations: Acquired Brain Injury Unit,Scientific Institute “Eugenio Medea,” Bosisio Parini, Lecco, Italy (Drs Avantaggiato, Molteni, Formica, Arcieri, Locatelli, and Strazzer); Department of Experimental and Clinical Medicine, University of Udine Medical School, Udine, Italy (Drs Gigli and Valente); and Neurology Unit and Center of Sleep Medicine, "Santa Maria della Misericordia" University Hospital, Udine, Italy (Drs Lorenzut and de Biase). This study was supported by the Italian Department of Health (Ricerca Corrente 2008–2009, Bando Ricerca Finalizzata 2008). The authors acknowledge Drs Katia Colombo, Valentina Pastore, and Federica Villa for their flawless assistance in the clinical scale administration. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (www.headtraumarehab.com). The authors declare no conflicts of interest. Corresponding Author: Erika Molteni, PhD, Scientific Institute E. Medea, Acquired Brain Injury Unit, Via Don Luigi Monza 20, Bosisio Parini, Lecco 23842, Italy ([email protected]). DOI: 10.1097/HTR.0000000000000122
sponsiveness. Be it transient or persistent, UWS is characterized by the absence of self-awareness behaviors of the environment.2–4 Diagnosis of UWS nowadays relies on 2 mainstays performed behaviorally: clinical examination and neuropsychological assessments. Both tools have serious limitations,5,6 as they result in approximately 35% of misdiagnoses7 and more often in insufficient prognostic indications for predicting or excluding the progress toward some responsiveness. On the contrary, neurophysiological studies have shown that, in time, patients with UWS develop some electrophysiological differentiation.8–10 This fact has fostered an increasing interest in the sleep patterns of patients with disorders of consciousness (DOC) and has steered research toward the use of polysomnography (PSG). One of the major difficulties encountered in sleep studies of UWS is the absence of specific staging criteria. Indeed, the official electrophysiological scoring system of sleep11 is currently based on the electroencephalographic (EEG) features of healthy individuals, hardly applicable for sleep staging in patients with severe brain damage.10 Alternative criteria, tailored and adapted to adult and pediatric cohorts of patients, have to be applied for pediatric cases.12 Among them, many studies have attempted to use additional data, such as
334 Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Polysomnographic Sleep Patterns in Unresponsive Wakefulness Syndrome electromyographic (EMG) measurement, heart rate, or blood pressure, for the interpretation of sleep and to detect differentiated stages of DOC.13–16 Furthermore, studies investigating the hormonal effects on sleep in brain-injured patients with DOC and testing the effect of substances acting on the sleep-wake cycle, such as melatonin, are still lacking. Prolonged PSG recordings have been plumbed for possible correlations between neuroelectrical activity and functional levels of impairment. Studies suggest that the presence of specific EEG patterns, ascribed to different DOC,13,17,18 could be proposed as specific prognostic indicators for recovery.18–20 Similar to what has been observed in adults,21 a previous study on comatose children supports the finding that the reappearance of sleeprelated waveforms (eg, spindles, K-complexes) during recovery from brain injury is a sign of a good prognosis.13 Other works compared the PSG prognostic value of PSG waveforms with the Level of Cognitive Functional Assessment Scale,19 as well as Glasgow Coma Scale ratings in patients who had sustained an acute brain injury.20 Furthermore, a number of PSG studies specifically focusing on VS9,21–26 were written before the definition of minimally conscious state (MCS) in 2002,27 making it possible that many patients reported as being in a VS might, in fact, have been in a MCS. As a consequence, the present work can be compared stricto sensu with the few works written only in the last decade.17,28–31 Earlier and recent literature, however, agrees in reporting that the presence of spindles and sleep-stage differentiation in EEG tracks is a potential marker of good outcome23,28 and that the presence of rapid eye movement (REM) sleep is predictive of better cognitive recovery (see also the work by Ron et al32 ). A decade after the pioneering effort of Ch´elioutHeraut et al,13 we conducted a retrospective clinical and PSG analysis of 27 children and adolescents with subacute or chronic UWS due to an acquired brain damage. We searched for possible neurophysiological markers of sleep-wake EEG organization that could predict the children’s outcome. Our analysis isolated 6 qualitative sleep characteristics that we termed sleep patterns for pediatric unresponsive wakefulness syndrome (SPPUWS) and which were tested for correlations with the clinical outcome at 36 months after PSG recordings. METHODS Participants Thirty-five brain-injured pediatric patients with UWS participated in the study. The group was made up of in-patients, admitted to our hospital for intensive neurorehabilitation treatment (physical therapy, dysphagia therapy, and sensory stimulation therapy) throughout a period of 4 years. Inclusion criteria were as follows: (a)
335
severe acquired brain lesion; (b) age 18 years or less; and (c) time since injury 1 year or less at the study enrollment. Exclusion criteria were as follows: (a) congenital neurological pathology; (b) need of mechanical ventilation (due to the interfering effect of ventilation on sleep33,34 ); and (c) administration of drugs in composition and dosages capable of significantly altering the EEG frequency content (however, a complete list of sedative drugs and dosages is provided for each patient in Table 1). At enrollment in the study, a multidisciplinary team (neurologist, neuropsychiatrist, neuropsychologist, and dysphagia therapist) evaluated all patients and concluded that they fulfilled the criteria for UWS diagnosis, according to the diagnostic criteria of the Royal College of Physicians2 and of Giacino et al.27 Seven patients were excluded from the study because of recurrent epileptic seizures/activity that would have dominated the EEG activity and would have impeded the correct sleep staging, and one patient was excluded because of recurrent movement artifacts that would have overwhelmed the neurophysiological evidences. A final group of 27 patients (mean age = 8.44 years, SD = 5.33 years; 21 male patients) was selected. Among the final cohort, none of the patients exhibited epileptic activity with duration of more than 15% of the whole PSG track. Epileptic discharges consisted of all cases in short isolated sequences of epileptiform anomalies, deemed not to interfere with sleep architecture. Table 1 reports the demographic and clinical characteristics of the patients. Ethics statement This study was carried out in compliance with the Declaration of Helsinki and was approved by the “I.R.C.C.S. E. Medea—Ass. La Nostra Famiglia” Ethics Committee, located in Bosisio Parini (Lecco, Italy). Patients’ relatives and/or legal guardians provided written informed consent for the participation in the study. Clinical evaluation and measures On admission, the patients’ medical history was collected, including their Glasgow Coma Scale (GCS) score at insult (see Table 1).35,36 At the time of study (T0 ), the Disability Rating Scale (DRS),37,38 which focuses on the functional abilities, and the Level of Cognitive Functioning Assessment Scale (LOCFAS),39 which is specifically used for the punctual evaluation of the cognitive functions, were administered. Patients also underwent clinical magnetic resonance imaging examination (see Supplemental Digital Content Table ST2, available at http://links.lww.com/JHTR/A134). A clinical follow-up (T1 ) was performed after 36 months from the first evaluation (T0 ); the follow-up included patients’ evaluation with the standardized Glasgow Outcome www.headtraumarehab.com
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27
Head trauma Head trauma Head trauma Hypoxic damage Brain tumor Head trauma Head trauma Encephalitis Head trauma Brain tumor Encephalitis Head trauma Head trauma Head trauma Head trauma Encephalitis Head trauma Head trauma Head trauma Hypoxic damage Head trauma Brain tumor Head trauma Hypoxic damage Hypoxic damage Hypoxic damage Hypoxic damage
4 7 4 3 3 3 6 4 6 6 6 5 3 3 5 4 4 6 4 3 4 3 3 3 3 3 5
4 2 4 4 1 1 3 3 3 2 3 4 4 3 3 3 4 3 3 3 3 3 3 2 2 3 2
2/8 2/2 2/6 2/5 2/2 2/2 2/2 2/2 2/3 2/2 2/3 2/7 2/5 2/3 2/6 2/3 2/6 2/3 2/3 2/3 3/3 1/5 3/5 2/2 2/2 2/3 2/2
24/7 24/22 23/9 24/9 24/30 28/24 24/23 24/20 23/20 24/22 24/19 22/8 23/9 24/19 23/7 24/21 22/8 27/17 25/18 25/20 25/20 26/6 26/7 24/22 23/22 23/20 26/24
1 3 1 1 4 2 2 2 1 2 1 2 1 1 1 2 1 1 4 1 2 1 2 2 2 1 3
UWS/exit-MCS UWS/UWS UWS/exit-MCS UWS/exit-MCS UWS/UWS UWS/UWS UWS/MCS UWS/MCS UWS/MCS UWS/UWS UWS/MCS UWS/exit-MCS UWS/exit-MCS UWS/MCS UWS/exit-MCS UWS/MCS UWS/exit-MCS UWS/MCS UWS/MCS UWS/MCS UWS/MCS UWS/exit-MCS UWS/exit-MCS UWS/UWS UWS/UWS UWS/MCS UWS/UWS
6 2 5 5 4 3 3 3 6 2 5 6 6 4 5 6 5 5 5 5 3 5 6 3 4 5 1
No No No No Yes No No No No No Yes No No No No No No Yes No No No No No Yes Yes Yes Yes
Epilepsy
E = 0.6 None E = 0.7 C = 0.44∗ ; F = 1 A=5 E = 1.8; H = 2 E = 2.3; F = 0.8; H = 12 E = 2.8∗ None None A=5 A = 6; D = 0.05∗ ; E = 0.8 None C = 0.1; D = 0.04; E = 2.5 E = 2.2; F = 0.3 E = 0.2; F = 0.9 None C = 0.04; E = 1.7 A = 5; D = 0.04; E = 0.1; F = 1 C = 0.8∗ ; E = 2.3; F = 1.4∗ E = 1.4; G = 0.5 None None E = 1.8; F = 0.2 F=4 B = 0.015; E = 2.3 E = 0.8; F = 0.8
Drugsc
Abbreviations: C/NCS, Coma/Near Coma Scale at follow-up; DRS, Disability Rating Scale at time of EEG and at follow-up; EEG, electroencephalogram; GCS, Glasgow Coma Scale score at insult; GOS, Glasgow Outcome Scale score at follow-up; LOCFAS, Level of Cognitive Functioning Assessment Scale at time of EEG and at follow-up; SPPUWS, sleep patterns for pediatric unresponsive wakefulness syndrome; T0 , time at study; T1 , time at follow-up. a State of consciousness at time of EEG and at follow-up (UWS is unresponsive wakefulness syndrome and vegetative state; MCS is minimally conscious state; exit-MCS is the recovery of consciousness). b Sleep group according to SPPUWS. c Dosage of drugs with sedative effects: A = phenobarbital (mg/kg/d); B = clonazepam (mg/kg/d); C = diazepam (mg/kg/d); D = lorazepam (mg/kg/d); E = baclofen (mg/kg/d); F = niaprazine (mg/kg/d); G = hydroxyzine dichlorhydrate (mg/kg/d); H = tizianidine chlorhydrate (mg/d). The values with “∗ ” indicate dosages exceeding the recommended ranges.
11/ M 14/M 16/M 5/M 2/M 14/M 13/M 4/M 5/M 14/M 5/M 12/F 13/F 13/M 15/F 5/F 4/M 4/M 9/M 3/M 18/M 6/F 14/M 4/F 2/M 2/M 1/M
Case
GCS LOCFAS DRS C/NCS State of score GOS score score score consciousnessa Primary disease (at insult) score (T1 ) (T0 /T1 ) (T0 /T1 ) (T1 ) (T0 /T1 ) SPPUWSb
Demographic and clinical data
Age, y/sex
TABLE 1
336 JOURNAL OF HEAD TRAUMA REHABILITATION/SEPTEMBER–OCTOBER 2015
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Polysomnographic Sleep Patterns in Unresponsive Wakefulness Syndrome Scale (GOS),40,41 which provides the general degree of recovery, the DRS, the LOCFAS, and the Coma/Near Coma Scale (C/NCS),42 which estimates the level of responsiveness damage, depending on responses to the stimulation of the different sensory channels. The C/NCS was applied in compliance with the American Congress of Rehabilitation Medicine Disorders of Consciousness Task Force guidelines.43 High scores on the GCS, LOCFAS, and GOS reflected a less impaired clinical picture. In contrast, the higher the DRS and C/NCS scores, the more marked the difficulties. The staff (Drs Valentina Pastore, Federica Villa, and Katia Colombo) who administered the clinical scales were blinded to the research study rationale. PSG recordings After admission to our rehabilitation center, PSG recordings of all the 27 patients were obtained overnight, uninterruptedly from the afternoon to the morning of the following day. We agreed to record the longest recording possible, with respect to the daily rehabilitation schedules and the patients’ compliance and needs. Mean time since injury was 106 days (SD = 58 days). Mean duration of recordings was 828 minutes (SD = 197 minutes). Patients received no specific sedation for the execution of EEG examination. EEG tracks were acquired with an Embla RemLogic digital system, with 500-Hz sampling rate. In compliance with the minimal requirements provided in the American Academy of Sleep Medicine (AASM) recommendations for montage, 8 Ag/AgCl electrodes were placed on the patients’ head, corresponding to the standard 10/20 system44 in F3, F4, C3, C4, T3, T4, O1, and O2 positions. EEG recording was performed with reference to 2 additional electrodes, placed in A1 and A2 positions, at the mastoids. A set of polygraphic channels was also added: 2 electrodes for electro-oculogram (EOG) in cross-montage, at least 1 bipolar EMG channel for deltoid activity, and 1 bipolar electrocardiographic (ECG) derivation. Digital bandpass filtering was applied to the EEG and EOG channels in the 0.3- to 35-Hz range, to the EMG in the 10- to 200-Hz range, and to the ECG in the 0.3- to 70-Hz range. EEG impedances were kept under 5 k. During the recording, patients’ caregivers were instructed to accurately report any event in a standard form, also called “sleep diary.” Because of the partial absence of the skull, in patient 18, we could not place electrodes over F3 and F4; instead, we were able to place Fpz electrode. Similarly, patients 19, 21, and 23 completely lacked EEG recording from the frontal area, as the placement of frontopolar and frontal electrodes was impossible. For each patient, PSG tracks were visualized and analyzed by Somnologica software (Reykjavik, Iceland).
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Sleep was partitioned into 30-second epochs for further staging. After visual selection and exclusion of the artifactual periods, including intervals affected by muscular electrical activity, 2 trained and certified neuropsychiatrists (P.A., F.F.) and 2 experienced neurologists (S.L., S. de B.), belonging to 2 different hospitals, scored the tracks independently. They performed a preliminary scoring of the PSG tracks, using the age-appropriate criteria of the AASM.1 In doing so, they isolated the specific PSG periods for which the criteria were clearly not applicable. Unscored periods were discussed by the team in 2 independent scoring sessions, and scoring conflicts were partially resolved. Then, alternative criteria were developed on the basis of previous works (see Supplemental Digital Content Table ST1, available at http://links.lww.com/JHTR/A134).13,28,45 Such criteria helped in the attribution of sleep-wake status and in the identification of possible sleep stages in unscored epochs, during a second double-blind scoring process. However, segments with debatable score (
