CC BY 4.0 · Semin Neurol 2022; 42(03): 259-272
DOI: 10.1055/a-1883-0861
Review Article

New Behavioral Signs of Consciousness in Patients with Severe Brain Injuries

Beril Mat
1   Coma Science Group, GIGA Consciousness, University of Liège, Liège, Belgium
2   Department of Neurology, University of Wisconsin–Madison, Madison, Wisconsin
,
Leandro R.D. Sanz
1   Coma Science Group, GIGA Consciousness, University of Liège, Liège, Belgium
3   Centre du Cerveau2, University Hospital of Liège, Liège, Belgium
,
Anat Arzi
4   Paris Brain Institute, Paris, France
5   Department of Medical Neurobiology and Cognitive Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel
,
Melanie Boly
2   Department of Neurology, University of Wisconsin–Madison, Madison, Wisconsin
6   Department of Psychiatry, University of Wisconsin–Madison, Madison, Wisconsin
,
Steven Laureys
1   Coma Science Group, GIGA Consciousness, University of Liège, Liège, Belgium
3   Centre du Cerveau2, University Hospital of Liège, Liège, Belgium
7   Joint International Research Unit on Consciousness, CERVO Brain Research Centre, CIUSS, Laval University, Québec, Canada
,
Olivia Gosseries
1   Coma Science Group, GIGA Consciousness, University of Liège, Liège, Belgium
3   Centre du Cerveau2, University Hospital of Liège, Liège, Belgium
› Author Affiliations
Funding The study was supported by the University and University Hospital of Liège, the Belgian National Funds for Scientific Research (FRS-FNRS), the European Union's Horizon 2020 Framework Programme for Research and Innovation under the specific grant agreement no. 945539 (Human Brain Project SGA3), the European Space Agency (ESA) and the Belgian Federal Science Policy Office (BELSPO) in the framework of the PRODEX Programme, the BIAL Foundation, the Mind Science Foundation, the fund Generet of the King Baudouin Foundation, the Léon Fredericq Foundation, the Mind-Care foundation, the AstraZeneca Foundation, the Télévie and the Fondation Contre le Cancer, and a Marie Curie Individual Fellowship (840711) awarded to A.A. L.R.D.S. is research fellow, O.G. is research associate, and S.L. is research director at FRS-FNRS.

Abstract

Diagnostic and prognostic assessment of patients with disorders of consciousness (DoC) presents ethical and clinical implications as they may affect the course of medical treatment and the decision to withdraw life-sustaining therapy. There has been increasing research in this field to lower misdiagnosis rates by developing standardized and consensual tools to detect consciousness. In this article, we summarize recent evidence regarding behavioral signs that are not yet included in the current clinical guidelines but could detect consciousness. The new potential behavioral signs of consciousness described here are as follows: resistance to eye opening, spontaneous eye blink rate, auditory localization, habituation of auditory startle reflex, olfactory sniffing, efficacy of swallowing/oral feeding, leg crossing, facial expressions to noxious stimulation, and subtle motor behaviors. All of these signs show promising results in discriminating patients' level of consciousness. Multimodal studies with large sample sizes in different centers are needed to further evaluate whether these behaviors reliably indicate the presence of consciousness. Future translation of these research findings into clinical practice has potential to improve the accuracy of diagnosis and prognostication for patients with DoC.



Publication History

Accepted Manuscript online:
23 June 2022

Article published online:
13 September 2022

© 2022. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

 
  • References

  • 1 Maas AIR, Menon DK, Adelson PD. et al; InTBIR Participants and Investigators. Traumatic brain injury: integrated approaches to improve prevention, clinical care, and research. Lancet Neurol 2017; 16 (12) 987-1048
  • 2 GBD 2016 Traumatic Brain Injury and Spinal Cord Injury Collaborators. Global, regional, and national burden of traumatic brain injury and spinal cord injury, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol 2019; 18 (01) 56-87
  • 3 Elmer J, Torres C, Aufderheide TP. et al; Resuscitation Outcomes Consortium. Association of early withdrawal of life-sustaining therapy for perceived neurological prognosis with mortality after cardiac arrest. Resuscitation 2016; 102: 127-135
  • 4 Turgeon AF, Lauzier F, Simard JF. et al; Canadian Critical Care Trials Group. Mortality associated with withdrawal of life-sustaining therapy for patients with severe traumatic brain injury: a Canadian multicentre cohort study. CMAJ 2011; 183 (14) 1581-1588
  • 5 Peberdy MA, Kaye W, Ornato JP. et al. Cardiopulmonary resuscitation of adults in the hospital: a report of 14720 cardiac arrests from the National Registry of Cardiopulmonary Resuscitation. Resuscitation 2003; 58 (03) 297-308
  • 6 Izzy S, Compton R, Carandang R, Hall W, Muehlschlegel S. Self-fulfilling prophecies through withdrawal of care: do they exist in traumatic brain injury, too?. Neurocrit Care 2013; 19 (03) 347-363
  • 7 Giacino JT, Katz DI, Schiff ND. et al. Practice guideline update recommendations summary: disorders of consciousness: report of the guideline development, dissemination, and implementation subcommittee of the American Academy of Neurology; the American Congress of Rehabilitation Medicine; and the National Institute on Disability, Independent Living, and Rehabilitation Research. Arch Phys Med Rehabil 2018; 99 (09) 1699-1709
  • 8 Teasdale G, Jennett B. Assessment of coma and impaired consciousness: a practical scale. Lancet 1974; 2 (7872): 81-84
  • 9 Laureys S, Celesia GG, Cohadon F. et al; European Task Force on Disorders of Consciousness. Unresponsive wakefulness syndrome: a new name for the vegetative state or apallic syndrome. BMC Med 2010; 8: 68
  • 10 Jennett B, Plum F. Persistent vegetative state after brain damage: a syndrome in search of a name. Lancet 1972; 1 (7753): 734-737
  • 11 Multi-Society Task Force on PVS. Medical aspects of the persistent vegetative state (1). N Engl J Med 1994; 330 (21) 1499-1508
  • 12 Giacino JT, Ashwal S, Childs N. et al. The minimally conscious state: definition and diagnostic criteria. Neurology 2002; 58 (03) 349-353
  • 13 Bruno MA, Vanhaudenhuyse A, Thibaut A, Moonen G, Laureys S. From unresponsive wakefulness to minimally conscious PLUS and functional locked-in syndromes: recent advances in our understanding of disorders of consciousness. J Neurol 2011; 258 (07) 1373-1384
  • 14 Schiff ND. Cognitive motor dissociation following severe brain injuries. JAMA Neurol 2015; 72 (12) 1413-1415
  • 15 Gosseries O, Zasler ND, Laureys S. Recent advances in disorders of consciousness: focus on the diagnosis. Brain Inj 2014; 28 (09) 1141-1150
  • 16 Thibaut A, Panda R, Annen J. et al. Preservation of brain activity in unresponsive patients identifies MCS star. Ann Neurol 2021; 90 (01) 89-100
  • 17 Schnakers C, Giacino JT, Løvstad M. et al. Preserved covert cognition in noncommunicative patients with severe brain injury?. Neurorehabil Neural Repair 2015; 29 (04) 308-317
  • 18 Schnakers C, Vanhaudenhuyse A, Giacino J. et al. Diagnostic accuracy of the vegetative and minimally conscious state: clinical consensus versus standardized neurobehavioral assessment. BMC Neurol 2009; 9 (01) 35
  • 19 Stender J, Gosseries O, Bruno MA. et al. Diagnostic precision of PET imaging and functional MRI in disorders of consciousness: a clinical validation study. Lancet 2014; 384 (9942): 514-522
  • 20 Wang J, Hu X, Hu Z, Sun Z, Laureys S, Di H. The misdiagnosis of prolonged disorders of consciousness by a clinical consensus compared with repeated coma-recovery scale-revised assessment. BMC Neurol 2020; 20 (01) 343
  • 21 Wannez S, Heine L, Thonnard M, Gosseries O, Laureys S, Collaborators CSG. Coma Science Group Collaborators. The repetition of behavioral assessments in diagnosis of disorders of consciousness. Ann Neurol 2017; 81 (06) 883-889
  • 22 Wijdicks EFM, Bamlet WR, Maramattom BV, Manno EM, McClelland RL. Validation of a new coma scale: the FOUR score. Ann Neurol 2005; 58 (04) 585-593
  • 23 Aubinet C, Cassol H, Bodart O. et al. Simplified evaluation of CONsciousness disorders (SECONDs) in individuals with severe brain injury: a validation study. Ann Phys Rehabil Med 2021; 64 (05) 101432
  • 24 Sanz LRD, Aubinet C, Cassol H. et al. SECONDs administration guidelines: a fast tool to assess consciousness in brain-injured patients. J Vis Exp 2021; (168) e61968
  • 25 Giacino JT, Kalmar K, Whyte J. The JFK Coma Recovery Scale-Revised: measurement characteristics and diagnostic utility. Arch Phys Med Rehabil 2004; 85 (12) 2020-2029
  • 26 Seel RT, Sherer M, Whyte J. et al; American Congress of Rehabilitation Medicine, Brain Injury-Interdisciplinary Special Interest Group, Disorders of Consciousness Task Force. Assessment scales for disorders of consciousness: evidence-based recommendations for clinical practice and research. Arch Phys Med Rehabil 2010; 91 (12) 1795-1813
  • 27 Kondziella D, Bender A, Diserens K. et al; EAN Panel on Coma, Disorders of Consciousness. European Academy of Neurology guideline on the diagnosis of coma and other disorders of consciousness. Eur J Neurol 2020; 27 (05) 741-756
  • 28 Martens G, Bodien Y, Sheau K, Christoforou A, Giacino JT. Which behaviours are first to emerge during recovery of consciousness after severe brain injury?. Ann Phys Rehabil Med 2020; 63 (04) 263-269
  • 29 Wannez S, Gosseries O, Azzolini D. et al. Prevalence of coma-recovery scale-revised signs of consciousness in patients in minimally conscious state. Neuropsychol Rehabil 2018; 28 (08) 1350-1359
  • 30 Carrière M, Llorens R, Navarro MD, Olaya J, Ferri J, Noé E. Behavioral signs of recovery from unresponsive wakefulness syndrome to emergence of minimally conscious state after severe brain injury. Ann Phys Rehabil Med 2022; 65 (02) 101534
  • 31 Fisher CM. Reflex blepharospasm. Neurology 1963; 13: 77-78
  • 32 Larumbe R, Vaamonde J, Artieda J, Zubieta JL, Obeso JA. Reflex blepharospasm associated with bilateral basal ganglia lesion. Mov Disord 1993; 8 (02) 198-200
  • 33 Grandas F, López-Manzanares L, Traba A. Transient blepharospasm secondary to unilateral striatal infarction. Mov Disord 2004; 19 (09) 1100-1102
  • 34 Jankovic J, Patel SC. Blepharospasm associated with brainstem lesions. Neurology 1983; 33 (09) 1237-1240
  • 35 van Ommen HJ, Thibaut A, Vanhaudenhuyse A. et al. Resistance to eye opening in patients with disorders of consciousness. J Neurol 2018; 265 (06) 1376-1380
  • 36 Huang Z, Stanford MS, Barratt ES. Blink rate related to impulsiveness and task demands during performance of event-related potential tasks. Pers Individ Dif 1994; 16 (04) 645-648
  • 37 Chen S, Epps J. Using task-induced pupil diameter and blink rate to infer cognitive load. Hum Comput Interact 2014; 29 (04) 390-413
  • 38 Magliacano A, Fiorenza S, Estraneo A, Trojano L. Eye blink rate increases as a function of cognitive load during an auditory oddball paradigm. Neurosci Lett 2020; 736: 135293
  • 39 Magliacano A, Rosenfelder M, Hieber N, Bender A, Estraneo A, Trojano L. Spontaneous eye blinking as a diagnostic marker in prolonged disorders of consciousness. Sci Rep 2021; 11 (01) 22393
  • 40 Annen J, Filippini MM, Bonin E. et al. Diagnostic accuracy of the CRS-R index in patients with disorders of consciousness. Brain Inj 2019; 33 (11) 1409-1412
  • 41 Carrière M, Cassol H, Aubinet C. et al. Auditory localization should be considered as a sign of minimally conscious state based on multimodal findings. Brain Commun 2020; 2 (02) a195
  • 42 Chennu S, Finoia P, Kamau E. et al. Spectral signatures of reorganised brain networks in disorders of consciousness. PLOS Comput Biol 2014; 10 (10) e1003887
  • 43 Chennu S, Annen J, Wannez S. et al. Brain networks predict metabolism, diagnosis and prognosis at the bedside in disorders of consciousness. Brain 2017; 140 (08) 2120-2132
  • 44 Lechinger J, Bothe K, Pichler G. et al. CRS-R score in disorders of consciousness is strongly related to spectral EEG at rest. J Neurol 2013; 260 (09) 2348-2356
  • 45 Hermann B, Salah AB, Perlbarg V. et al. Habituation of auditory startle reflex is a new sign of minimally conscious state. Brain 2020; 143 (07) 2154-2172
  • 46 Sattin D, Bruzzone MG, Ferraro S, Nigri A, Leonardi M, Guido D. Coma Research Center, Fondazione IRCCS Istituto Neurologico “Carlo Besta”, Milan, Italy. Olfactory discrimination in disorders of consciousness: a new sniff protocol. Brain Behav 2019; 9 (08) e01273
  • 47 Nigri A, Ferraro S, Bruzzone MG. et al; CRC - Coma Research Centre Members. Central olfactory processing in patients with disorders of consciousness. Eur J Neurol 2016; 23 (03) 605-612
  • 48 Arzi A, Rozenkrantz L, Gorodisky L. et al. Olfactory sniffing signals consciousness in unresponsive patients with brain injuries. Nature 2020; 581 (7809): 428-433
  • 49 Wang J, Zhang S, Liu W. et al. Olfactory stimulation and the diagnosis of patients with disorders of consciousness: a double-blind, randomized clinical trial. Front Neurosci 2022; 16: 712891
  • 50 Mackay LE, Morgan AS, Bernstein BA. Swallowing disorders in severe brain injury: risk factors affecting return to oral intake. Arch Phys Med Rehabil 1999; 80 (04) 365-371
  • 51 Formisano R, Voogt RD, Buzzi MG. et al. Time interval of oral feeding recovery as a prognostic factor in severe traumatic brain injury. Brain Inj 2004; 18 (01) 103-109
  • 52 Hansen TS, Engberg AW, Larsen K. Functional oral intake and time to reach unrestricted dieting for patients with traumatic brain injury. Arch Phys Med Rehabil 2008; 89 (08) 1556-1562
  • 53 Mélotte E, Maudoux A, Delhalle S. et al. Is oral feeding compatible with an unresponsive wakefulness syndrome?. J Neurol 2018; 265 (04) 954-961
  • 54 Mélotte E, Maudoux A, Delhalle S. et al. Swallowing in individuals with disorders of consciousness: a cohort study. Ann Phys Rehabil Med 2021; 64 (04) 101403
  • 55 Chatelle C, Hauger SL, Martial C. et al. Assessment of nociception and pain in participants in an unresponsive or minimally conscious state after acquired brain injury: the relation between the Coma Recovery Scale-Revised and the Nociception Coma Scale-Revised. Arch Phys Med Rehabil 2018; 99 (09) 1755-1762
  • 56 Gélinas C, Boitor M, Puntillo KA. et al. Behaviors indicative of pain in brain-injured adult patients with different levels of consciousness in the intensive care unit. J Pain Symptom Manage 2019; 57 (04) 761-773
  • 57 Pignat JM, Mauron E, Jöhr J. et al. Outcome prediction of consciousness disorders in the acute stage based on a complementary motor behavioural tool. PLoS One 2016; 11 (06) e0156882
  • 58 Pincherle A, Jöhr J, Chatelle C. et al. Motor behavior unmasks residual cognition in disorders of consciousness. Ann Neurol 2019; 85 (03) 443-447
  • 59 Jöhr J, Halimi F, Pasquier J, Pincherle A, Schiff N, Diserens K. Recovery in cognitive motor dissociation after severe brain injury: a cohort study. PLoS One 2020; 15 (02) e0228474
  • 60 Rémi J, Pfefferkorn T, Owens RL. et al. The crossed leg sign indicates a favorable outcome after severe stroke. Neurology 2011; 77 (15) 1453-1456
  • 61 Mélotte E, Belorgeot M, Herr R. et al. The development and validation of the SWADOC: a study protocol for a multicenter prospective cohort study. Front Neurol 2021; 12: 662634
  • 62 Bruno MA, Vanhaudenhuyse A, Schnakers C. et al. Visual fixation in the vegetative state: an observational case series PET study. BMC Neurol 2010; 10: 35
  • 63 Venturella I, Crivelli D, Fossati M, Fiorillo F, Balconi M. EEG and autonomic responses to nociceptive stimulation in disorders of consciousness. J Clin Neurosci 2019; 60: 101-106
  • 64 Bekinschtein TA, Coleman MR, Niklison III J, Pickard JD, Manes FF. Can electromyography objectively detect voluntary movement in disorders of consciousness?. J Neurol Neurosurg Psychiatry 2008; 79 (07) 826-828
  • 65 Habbal D, Gosseries O, Noirhomme Q. et al. Volitional electromyographic responses in disorders of consciousness. Brain Inj 2014; 28 (09) 1171-1179
  • 66 Bekinschtein TA, Shalom DE, Forcato C. et al. Classical conditioning in the vegetative and minimally conscious state. Nat Neurosci 2009; 12 (10) 1343-1349
  • 67 Lesenfants D, Habbal D, Chatelle C, Schnakers C, Laureys S, Noirhomme Q. Electromyographic decoding of response to command in disorders of consciousness. Neurology 2016; 87 (20) 2099-2107
  • 68 Riganello F, Chatelle C, Schnakers C, Laureys S. Heart rate variability as an indicator of nociceptive pain in disorders of consciousness?. J Pain Symptom Manage 2019; 57 (01) 47-56
  • 69 Riganello F, Larroque SK, Bahri MA. et al. A heartbeat away from consciousness: heart rate variability entropy can discriminate disorders of consciousness and is correlated with resting-state fMRI brain connectivity of the central autonomic network. Front Neurol 2018; 9: 769
  • 70 Raimondo F, Rohaut B, Demertzi A. et al. Brain-heart interactions reveal consciousness in noncommunicating patients. Ann Neurol 2017; 82 (04) 578-591
  • 71 Pérez P, Madsen J, Banellis L. et al. Conscious processing of narrative stimuli synchronizes heart rate between individuals. Cell Rep 2021; 36 (11) 109692
  • 72 Candia-Rivera D, Annen J, Gosseries O. et al. Neural responses to heartbeats detect residual signs of consciousness during resting state in postcomatose patients. J Neurosci 2021; 41 (24) 5251-5262
  • 73 Casali AG, Gosseries O, Rosanova M. et al. A theoretically based index of consciousness independent of sensory processing and behavior. Sci Transl Med 2013; 5 (198) 198ra105
  • 74 Demertzi A, Tagliazucchi E, Dehaene S. et al. Human consciousness is supported by dynamic complex patterns of brain signal coordination. Sci Adv 2019; 5 (02) eaat7603
  • 75 Vassilieva A, Olsen MH, Peinkhofer C, Knudsen GM, Kondziella D. Automated pupillometry to detect command following in neurological patients: a proof-of-concept study. PeerJ 2019; 7: e6929
  • 76 Minami Y, Mishima S, Oda J. Prediction of the level of consciousness using pupillometer measurements in patients with impaired consciousness brought to the emergency and critical care center. Acute Med Surg 2020; 7 (01) e537
  • 77 Tobaldini E, Toschi-Dias E, Trimarchi PD. et al. Cardiac autonomic responses to nociceptive stimuli in patients with chronic disorders of consciousness. Clin Neurophysiol 2018; 129 (05) 1083-1089
  • 78 Leo A, Naro A, Cannavò A. et al. Could autonomic system assessment be helpful in disorders of consciousness diagnosis? A neurophysiological study. Exp Brain Res 2016; 234 (08) 2189-2199
  • 79 Okumura Y, Asano Y, Takenaka S. et al. Brain activation by music in patients in a vegetative or minimally conscious state following diffuse brain injury. Brain Inj 2014; 28 (07) 944-950
  • 80 Carrière M, Larroque SK, Martial C. et al. An echo of consciousness: brain function during preferred music. Brain Connect 2020; 10 (07) 385-395
  • 81 Magliacano A, De Bellis F, Galvao-Carmona A, Estraneo A, Trojano L. Can salient stimuli enhance responses in disorders of consciousness? A systematic review. Curr Neurol Neurosci Rep 2019; 19 (12) 98
  • 82 Magee WL, Ghetti CM, Moyer A. Feasibility of the music therapy assessment tool for awareness in disorders of consciousness (MATADOC) for use with pediatric populations. Front Psychol 2015; 6: 698
  • 83 Salvato G, Berlingeri M, De Maio G. et al. Autonomic responses to emotional linguistic stimuli and amplitude of low-frequency fluctuations predict outcome after severe brain injury. Neuroimage Clin 2020; 28: 102356
  • 84 Lord V, Opacka-Juffry J. Electroencephalography (EEG) measures of neural connectivity in the assessment of brain responses to salient auditory stimuli in patients with disorders of consciousness. Front Psychol 2016; 7: 397
  • 85 Stoll J, Chatelle C, Carter O, Koch C, Laureys S, Einhäuser W. Pupil responses allow communication in locked-in syndrome patients. Curr Biol 2013; 23 (15) R647-R648
  • 86 Trojano L, Moretta P, Loreto V, Santoro L, Estraneo A. Affective saliency modifies visual tracking behavior in disorders of consciousness: a quantitative analysis. J Neurol 2013; 260 (01) 306-308
  • 87 Trojano L, Moretta P, Masotta O, Loreto V, Estraneo A. Visual pursuit of one's own face in disorders of consciousness: a quantitative analysis. Brain Inj 2018; 32 (12) 1549-1555
  • 88 Blume C, Lechinger J, Santhi N. et al. Significance of circadian rhythms in severely brain-injured patients: a clue to consciousness?. Neurology 2017; 88 (20) 1933-1941
  • 89 Wilhelm B, Jordan M, Birbaumer N. Communication in locked-in syndrome: effects of imagery on salivary pH. Neurology 2006; 67 (03) 534-535
  • 90 Frank RA, Dulay MF, Gesteland RC. Assessment of the Sniff Magnitude Test as a clinical test of olfactory function. Physiol Behav 2003; 78 (02) 195-204