Disordered Consciousness or Disordered Wakefulness? The Importance of Prolonged Polysomnography for the Diagnosis, Drug Therapy, and Rehabilitation of an Unresponsive Patient With Brain Injury
2017; American Academy of Sleep Medicine; Volume: 13; Issue: 12 Linguagem: Inglês
10.5664/jcsm.6854
ISSN1550-9397
AutoresFrancesca Formica, Marco Pozzi, Paolo Avantaggiato, Erika Molteni, Filippo Arrigoni, Flavio Giordano, Emilio Clementi, Sandra Strazzer,
Tópico(s)Psychosomatic Disorders and Their Treatments
ResumoFree AccessCircadian RhythmsDisordered Consciousness or Disordered Wakefulness? The Importance of Prolonged Polysomnography for the Diagnosis, Drug Therapy, and Rehabilitation of an Unresponsive Patient With Brain Injury Francesca Formica, MD*, Marco Pozzi, PhD*, Paolo Avantaggiato, MD, Erika Molteni, PhD, Filippo Arrigoni, MD, Flavio Giordano, MD, Emilio Clementi, PhD, Sandra Strazzer, MD Francesca Formica, MD* Scientific Institute IRCCS Eugenio Medea, Bosisio Parini, Italy , Marco Pozzi, PhD* Scientific Institute IRCCS Eugenio Medea, Bosisio Parini, Italy , Paolo Avantaggiato, MD Scientific Institute IRCCS Eugenio Medea, Bosisio Parini, Italy , Erika Molteni, PhD Scientific Institute IRCCS Eugenio Medea, Bosisio Parini, Italy , Filippo Arrigoni, MD Scientific Institute IRCCS Eugenio Medea, Bosisio Parini, Italy , Flavio Giordano, MD Neurosurgery Unit, Neuroscience Department, Anna Meyer Pediatric Hospital, University of Florence, Florence, Italy , Emilio Clementi, PhD Address correspondence to: Emilio Clementi, Department of Biomedical and Clinical Sciences, University of Milano, Via GB Grassi 74, 20157 Milano+39-02-50319643+39-02-50319682 E-mail Address: [email protected] Scientific Institute IRCCS Eugenio Medea, Bosisio Parini, Italy Unit of Clinical Pharmacology, CNR Institute of Neuroscience, Department of Biomedical and Clinical Sciences, L. Sacco, "Luigi Sacco" University Hospital, Università di Milano, Milan, Italy , Sandra Strazzer, MD Scientific Institute IRCCS Eugenio Medea, Bosisio Parini, Italy Published Online:December 15, 2017https://doi.org/10.5664/jcsm.6854Cited by:2SectionsAbstractPDF ShareShare onFacebookTwitterLinkedInRedditEmail ToolsAdd to favoritesDownload CitationsTrack Citations AboutABSTRACTDisorders of consciousness may follow brain injury, due to impairments of wakefulness and/or awareness. Polysomnography can identify elements that may be ascribed to impairments of specific neuroanatomical areas. Recognizing which impairments affect each patient is crucial for diagnosis, prognosis, and to select an appropriate therapy. We present a pediatric case of insufficient wakefulness in a patient with severe disability following a pilocytic astrocytoma. Polysomnography was crucial for diagnosis, as it detected a well-structured pattern with daytime sleep initiations in the REM sleep phase. Treatment with modafinil was successful, as confirmed by polysomnography, leading to partial recovery of the patient's consciousness and communication ability. We suggest that polysomnography is a useful diagnostic tool to direct the pharmacotherapy and rehabilitation of states of reduced consciousness.Citation:Formica F, Pozzi M, Avantaggiato P, Molteni E, Arrigoni F, Giordano F, Clementi E, Strazzer S. Disordered consciousness or disordered wakefulness? The importance of prolonged polysomnography for the diagnosis, drug therapy, and rehabilitation of an unresponsive patient with brain injury. J Clin Sleep Med. 2017;13(12):1477–1481.INTRODUCTIONConsciousness can be divided into two main components: arousal (ie, wakefulness or vigilance), and awareness (ie, awareness of the environment and self-awareness).1 Wakefulness refers to a state in which the eyes are open and motor arousal is present, in contrast with sleep. Awareness refers to the ability to process any type of activity. Both wakefulness and awareness are necessary for conscious experiences, and in healthy individuals they are paired. In comatose patients, wakefulness and awareness are both compromised and no sleep-wake cycle is detected. The emergence from coma is defined by a recovery of autonomic functions and the sleep-wake cycle. Disorders of consciousness (DoCs) following brain injury and coma comprise states in which wakefulness and awareness are dissociated, such as unresponsive wakefulness (no awareness) and minimal consciousness (wakefulness with limited awareness). Currently, consciousness is assessed through behavioral evaluations (Glasgow Coma Scale [GCS]; Level of Cognitive Functions Assessment Scale [LOCFAS]; Coma/Near Coma Scale [CNCS]) that may produce unreliable results in the presence of perceptive and motor deficits, or when wakefulness fluctuates, resulting in approximately 35% misdiagnoses.2 Polysomnography (PSG) is becoming increasingly important for the diagnosis of DoCs because it aids in discriminating coma, vegetative state, and minimally conscious state, and in formulating a prognosis.3,4 Current diagnostic difficulties hinder the choice of optimal therapies: indeed, contrasting pharmacological treatments (eg, centrally acting depressants and stimulants) are described as effective in the literature, whereas the mechanisms that may promote awareness recovery remain unknown.5REPORT OF CASEThe current case involves a 15-year-old girl, admitted to our rehabilitation unit 1 month after resection of a right-thalamic pilocytic astrocytoma also occupying the third ventricle (see Figure 1). She had spastic quadriplegia with no antigravity reaction and no voluntary movement; she had extensor posturing of the legs and flexor posturing of the arms; autonomic function and respiration were not impaired and feeding was provided by nasogastric tube. Her wakefulness was fluctuating, with alternating periods of eyes closure (ie, plausible sleep) and of wake, during which she appeared to be unaware. The patient responded to annoying or painful tactile stimulation, most often with nonspecific alterations of physiological parameters, rarely with specific responses involving retraction of the limbs or grimacing. She appeared to perceive sounds only occasionally and partially, when she slowly oriented toward the source of sounds. Her gaze was usually staring; in case of facilitated stimulation (ie, a flashlight in a dark room) she could rarely follow the cue and did so for brief periods of time. However, she displayed slow reactions to visual threats. The patient could not demonstrate understanding of simple requests or commands. This clinical picture was evaluated by behavioral assessment scores (T0): LOCFAS 2, CNCS 3, and Disability Rating Scale (DRS) 23. The LOCFAS scale is composed of 10 levels of cognitive functioning: 1 no response; 2 generalized response; 3 localized response; 4 confused-agitated; 5 confused-inappropriate; 6 confused-appropriate; 7 automatic-appropriate; ≥ 8 purposeful-appropriate. Higher CNCS scale scores correspond to states of more severe coma (0 no coma, 1 near-coma, 2 moderate, 3 marked, 4 extreme coma). Higher DRS scale scores correspond to higher physical disability (range 0–30: ≥ 21 indicates extreme, 7–20 severe, 4–6 moderate, and 1–3 mild disability). At the beginning of rehabilitation, baclofen (2 mg/kg/d) and delorazepam (0.5 mg/d) were prescribed for spasticity. The patient continued to be unaware, with eyes closed in the daytime, despite a favorable hospital setting (minimal nocturnal light and noise, individual rooms) and the presence of a dedicated rehabilitation program (intensive physical, cognitive-behavioral rehabilitation, and speech therapy sessions). Therefore, melatonin was introduced up to 1 mg/d, administered at 9:00 PM with lights off, with no apparent efficacy on the regulation of the sleep-wake cycle. After 3 months, we attempted awakening by fluoxetine 20 mg/d at 8:00 AM, prescribed as an activating drug. A behavioral reassessment after 1 month (T1) scored LOCFAS 3, CNCS 0, and DRS 19, revealing only a modest improvement. The patient was also irritable and akathisic, which warranted drug discontinuation before PSG could be performed. A few days after fluoxetine withdrawal, while the adverse effects disappeared, the patient regressed into a condition of wavering between vigilance and diurnal somnolence (see Table 1 for detailed scores and scale properties). Epilepsy and neurosurgical complications were ruled out by follow-up magnetic resonance imaging (MRI) and electroencephalography. Therefore, 24-hour PSG was performed 1 month after fluoxetine discontinuation (see Figure 2), which identified well-structured neuroelectrical activity during wakefulness and sleep: the wakefulness stage was characterized by dominant, posterior alpha rhythm, reacting to eyes opening, intermingled with theta delta activity, and no epileptiform anomalies were present; sleep stages were also well structured and REM/NREM sleep phases could be scored according with the criteria of the American Academy of Sleep Medicine. From hypnogram analysis (Figure 2), a circadian rhythm sleep disorder (extreme fragmentation of nocturnal sleep, diurnal sleepiness) and sleep-onset rapid eye movement periods (SOREMPs) were evident. In order to improve the patient's wakefulness level, we then introduced modafinil (100 mg bid at 8:00 AM and noon). The following day the patient's diurnal wakefulness and nocturnal sleep were reported by caregivers as improved, and an apparent restoration of circadian rhythm was reported as consistent also by clinicians. Therefore, to substantiate our observation, another 24-hour PSG was performed (see Figure 2). It revealed a partial restoration of circadian rhythms: although diurnal sleep phases still occurred, daytime wakefulness periods were markedly increased and no SOREMPs were detected. Together with wakefulness, the patient also displayed awareness. She demonstrated emotions (tears, smiles) coherent with the environment. She began to feed orally. She subsequently recovered the ability to recognize objects, images, and graphemes but not verbal language. Alternative communication was successful. Her quadriplegia persisted. The final evaluation (T2) scored LOCFAS 3, CNCS 0 (both with more saturated scores) and DRS 14, in a state of consciousness recovery.Figure 1: Magnetic resonance images.Axial postcontrast T1-weighted (A), sagittal T2-weighted (B), and coronal T2-weighted (C,D) images are shown. Residual tumoral mass with intense enhancement can be observed in the right basal ganglia and ventricle (A). The hypothalamus is severely damaged, showing a diffuse gliosis with hyperintense signal on the T2-weighted image (B). Coronal sections (C,D) corresponding to vertical lines in panel B show the extent of hypothalamic damage also involving the suprachiasmatic nucleus (arrows in C) and the dorsomedial and lateral hypothalamus (circle in D).Download FigureTable 1 Details of patient evaluations.Table 1 Details of patient evaluations.Figure 2: Polysomnography and hypnograms.The top panel shows the results of polysomnography before treatment with modafinil. In the first frame is a well-structured stage N2 sleep phase (S2), defined spindles and K-complex. In the second is a well-defined stage R sleep phase (REM) with rapid eye movements and muscle atony. This picture, suggestive of conserved brain functions, drove the decision to attempt awakening the patient from coma. The bottom panel shows extracts from 24-hour hypnograms before and during treatment with modafinil. Frame A—before modafinil—identifies well-structured REM/NREM sleep phases, although with extreme fragmentation of nocturnal sleep and diurnal irruptions of REM and NREM periods. Frame B—during modafinil—reveals partial restoration of circadian rhythms, with a nocturnal sleep still disrupted by several prolonged awakenings. Daytime wakefulness periods were markedly increased; although diurnal sleep phases still occurred the patient was more easily arousable, phase transitions were less abrupt and no REM phases were detected.Download FigureDISCUSSIONAt the emergence from coma due to brain injury, regardless of its etiology, a number of abnormalities and variable degrees of disorganization can be detected in brain activity through PSG. Where consciousness recovery is improbable, PSG would show a monophasic pattern with no electrophysiological differentiation between sleep and wake, even if behavioral elements might suggest an alternating pattern. Starting from this extremely severe scenario, the more complex and organized a pattern gets, the more it suggests a possibility of progression toward consciousness recovery.6 PSG can also identify elements that are useful to evaluate the degree of conservation or impairment of specific neuroanatomical functions: the presence of a symmetric and reactive background electrical activity, the integrity of sleep structure with preserved sleep elements (spindles and k-complex), and pathological elements such as slowings, epileptiform anomalies, and circadian rhythms disorganization. For instance, preservation of a wake pattern can at least suggest the persistence of the reticular activating system, whereas spindles may reflect the functional integrity of the thalamus; slow wave sleep and REM sleep may in turn reflect a residual functioning of the brainstem nuclei; and the circadian organization of sleep patterns may suggest residual hypothalamic functioning.7 In the current case, PSG at T0 revealed good differentiation between wake and sleep, with a reactive background activity and a fully structured sleep according to standard criteria. The most distinctive feature of this patient's PSG was the severe deterioration of circadian rhythms with a polyphasic trend and daytime SOREMPs, and it was crucial for the interpretation and management of this case. From a neurofunctional perspective, the deterioration of circadian rhythms resembled an intrinsic circadian rhythm disorder, which could be determined by an impairment of the suprachiasmatic nucleus, as supported by MRI: the suprachiasmatic nucleus may be confidently included in the damaged areas. Rehabilitation interventions, proper patient housing, and melatonin administration were all ineffective and this lack of response could not suggest by itself damage beyond the suprachiasmatic nucleus. However, the possibility of a multilevel impairment of the hypothalamic control of sleep was suggested by the presence of daytime SOREMPs and supported by MRI. Indeed, we observed a favorable response with a multilevel treatment comprising rehabilitation and melatonin, plus modafinil. Because the patient was never treated with modafinil only, we cannot entirely exclude the contribution of other treatments to the efficacy of modafinil. Nevertheless, modafinil may have been crucial: its effect was also documented through PSG as a restoration of circadian rhythms and abolition of daytime SOREMPs. Last, the appearance of emotional responses and communication definitely demonstrated the recovery of consciousness. Modafinil, which acts also through an orexinergic-mediated regulation of the histaminergic system,8 may indeed be useful to treat DoCs associated with injury to hypothalamic systems, as shown in a similar previous case.9 Considering all behavioral and instrumental data collected, we may speculate that our patient suffered from a failure by hypothalamic circuits to regulate sleep-wake, which resulted in a dissociation between wakefulness and awareness that impaired her consciousness. The 24-hour PSG gave a fundamental diagnostic contribution in this case, where electrooculographic/electromyographic recording was crucial to identify REM phases. PSG is a gold standard for sleep scoring, as compared to continuous electroencephalographic recording that cannot provide comparable information; PSG may also be a fundamental extension of the standard care for disorders of consciousness. PSG can inform the clinician about the temporal organization of the patient's vigilance states, and it can reveal electrophysiological patterns predictive of conserved neurological function, in which unconsciousness may be determined by insufficient wakefulness. More studies using PSG are necessary to quantify the extent to which sleep-wake disorders may undermine consciousness.DISCLOSURE STATEMENTWork for this study was performed at Scientific Institute IRCCS E. Medea – Bosisio Parini (LC), Italy. All authors have contributed significantly to the manuscript and have approved it for submission in its final form. The financial support by Agenzia Italiana del Farmaco (AIFA) and by the Italian Ministry of Health (Ricerca Corrente 2017, to EC and SS) is gratefully acknowledged. The funding public institutions had no role in any part of the work. The authors report no conflicts of interest.REFERENCES1 Zeman AConsciousness. Brain; 2001;124Pt 7:1263-1289, 11408323. CrossrefGoogle Scholar2 Giacino JT, Schnakers C, Rodriguez-Moreno D, Kalmar K, Schiff N, Hirsch JBehavioral assessment in patients with disorders of consciousness: gold standard or fool's gold?Prog Brain Res; 2009;177:33-48, 19818893. CrossrefGoogle Scholar3 Cologan V, Drouot X, Parapatics Set al.Sleep in the unresponsive wakefulness syndrome and minimally conscious state. J Neurotrauma; 2013;305:339-346, 23121471. CrossrefGoogle Scholar4 Avantaggiato P, Molteni E, Formica Fet al.Polysomnographic sleep patterns in children and adolescents in unresponsive wakefulness syndrome. J Head Trauma Rehabil; 2015;305:334-346, 25699626. 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Google Scholar Previous article Next article FiguresReferencesRelatedDetailsCited by Retrospective analysis of sleep patterns in patients with chronic disorders of consciousnessNekrasova J, Kanarskii M, Yankevich D, Shpichko A, Borisov I, Pradhan P and Miroshnichenko M Sleep Medicine: X, 10.1016/j.sleepx.2020.100024, Vol. 2, , (100024), Online publication date: 1-Dec-2020. Fluoxetine Reactions Weekly, 10.1007/s40278-018-41245-5, Vol. 1686, No. 1, (181-181), Online publication date: 1-Jan-2018. Volume 13 • Issue 12 • December 15, 2017ISSN (print): 1550-9389ISSN (online): 1550-9397Frequency: Monthly Metrics History Submitted for publicationMay 26, 2017Submitted in final revised formJuly 29, 2017Accepted for publicationAugust 2, 2017Published onlineDecember 15, 2017 Information© 2017 American Academy of Sleep MedicineKeywordsmelatoninpolysomnographycomamodafinilpediatricACKNOWLEDGMENTSThe authors are thankful to Drs. Oliviero Bruni, Claudia Fedeli, Chiara Milesi, and Liborio Parrino for their clinical collaborations.PDF download
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