Journal of Neurology

, Volume 258, Issue 7, pp 1373–1384 | Cite as

From unresponsive wakefulness to minimally conscious PLUS and functional locked-in syndromes: recent advances in our understanding of disorders of consciousness

  • Marie-Aurélie Bruno
  • Audrey Vanhaudenhuyse
  • Aurore Thibaut
  • Gustave Moonen
  • Steven Laureys
Medical Progress in the Journal of Neurology


Functional neuroimaging and electrophysiology studies are changing our understanding of patients with coma and related states. Some severely brain damaged patients may show residual cortical processing in the absence of behavioural signs of consciousness. Given these new findings, the diagnostic errors and their potential effects on treatment as well as concerns regarding the negative associations intrinsic to the term vegetative state, the European Task Force on Disorders of Consciousness has recently proposed the more neutral and descriptive term unresponsive wakefulness syndrome. When vegetative/unresponsive patients show minimal signs of consciousness but are unable to reliably communicate the term minimally responsive or minimally conscious state (MCS) is used. MCS was recently subcategorized based on the complexity of patients’ behaviours: MCS+ describes high-level behavioural responses (i.e., command following, intelligible verbalizations or non-functional communication) and MCS− describes low-level behavioural responses (i.e., visual pursuit, localization of noxious stimulation or contingent behaviour such as appropriate smiling or crying to emotional stimuli). Finally, patients who show non-behavioural evidence of consciousness or communication only measurable via para-clinical testing (i.e., functional MRI, positron emission tomography, EEG or evoked potentials) can be considered to be in a functional locked-in syndrome. An improved assessment of brain function in coma and related states is not only changing nosology and medical care but also offers a better-documented diagnosis and prognosis and helps to further identify the neural correlates of human consciousness.


Coma Vegetative state Minimally conscious state Locked-in syndrome Consciousness Unresponsive wakefulness syndrome 



This study was supported by the Fonds de la Recherche Scientifique (FRS), University and University Hospital of Liège, James S. McDonnell Foundation, Mind Science Foundation, European Commission (Mindbridge, DISCOS, DECODER & COST) and Belgian French-Speaking Community Concerted Research Action. AV is Postdoctoral Fellows at FRS. MAB is Research Fellow at FRS. SL is Senior Research Associate at FRS.

Conflict of interest

The authors declare that they have no competing interests.


  1. 1.
    Demertzi A, Ledoux D, Bruno MA, Vanhaudenhuyse A, Gosseries O, Soddu A, Schnakers C, Moonen G, Laureys S (2011) Attitudes towards end-of-life issues in disorders of consciousness: a European survey. J Neurol 258(6):1058–1065Google Scholar
  2. 2.
    Luchetti M (2010) Eluana Englaro, chronicle of a death foretold: ethical considerations on the recent right-to-die case in Italy. J Med Ethics 36:333–335PubMedCrossRefGoogle Scholar
  3. 3.
    Laureys S (2005) Science and society: death, unconsciousness and the brain. Nat Rev Neurosci 6:899–909PubMedCrossRefGoogle Scholar
  4. 4.
    Laureys S, Pellas F, Van Eeckhout P, Ghorbel S, Schnakers C, Perrin F, Berre J, Faymonville ME, Pantke KH, Damas F, Lamy M, Moonen G, Goldman S (2005) The locked-in syndrome: what is it like to be conscious but paralyzed and voiceless? Prog Brain Res 150:495–511PubMedCrossRefGoogle Scholar
  5. 5.
    Jennett B (2005) Thirty years of the vegetative state: clinical, ethical and legal problems. Prog Brain Res 150:537–543PubMedCrossRefGoogle Scholar
  6. 6.
    The Multi-Society Task Force on PVS (1994) Medical aspects of the persistent vegetative state (1). N Engl J Med 330:1499–1508CrossRefGoogle Scholar
  7. 7.
    Estraneo A, Moretta P, Loreto V, Lanzillo B, Santoro L, Trojano L (2010) Late recovery after traumatic, anoxic, or hemorrhagic long-lasting vegetative state. Neurology 75:239–245PubMedCrossRefGoogle Scholar
  8. 8.
    Solarino B, Bruno F, Frati G, Dell’erba A, Frati P (2011) A national survey of Italian physicians’ attitudes towards end-of-life decisions following the death of Eluana Englaro. Intensive Care Med 37:542–549PubMedCrossRefGoogle Scholar
  9. 9.
    Giacino JT, Ashwal S, Childs N, Cranford R, Jennett B, Katz DI, Kelly JP, Rosenberg JH, Whyte J, Zafonte RD, Zasler ND (2002) The minimally conscious state: definition and diagnostic criteria. Neurology 58:349–353PubMedGoogle Scholar
  10. 10.
    Shewmon DA (2004) A critical analysis of conceptual domains of the vegetative state: sorting fact from fancy. NeuroRehabilitation 19:343–347PubMedGoogle Scholar
  11. 11.
    Laureys S, Celesia GG, Cohadon F, Lavrijsen J, Leon-Carrion J, Sannita WG, Sazbon L, Schmutzhard E, von Wild KR, Zeman A, Dolce G (2010) Unresponsive wakefulness syndrome: a new name for the vegetative state or apallic syndrome. BMC Med 8:68PubMedCrossRefGoogle Scholar
  12. 12.
    Tavalaro J, Tayson R (1997) Look up for yes. Kodansha America, Inc, New YorkGoogle Scholar
  13. 13.
    Borthwick C (1995) The proof of the vegetable: a commentary on medical futility. J Med Ethics 21:205–208PubMedCrossRefGoogle Scholar
  14. 14.
    Velez GJ (2005) Death of John Paul II and the basic human care for the sick and the dying. Ethics Med 21:167–177Google Scholar
  15. 15.
    Racine E, Amaram R, Seidler M, Karczewska M, Illes J (2008) Media coverage of the persistent vegetative state and end-of-life decision-making. Neurology 71:1027–1032PubMedCrossRefGoogle Scholar
  16. 16.
    Owen AM, Schiff ND, Laureys S (2009) A new era of coma and consciousness science. Prog Brain Res 177:399–411PubMedCrossRefGoogle Scholar
  17. 17.
    Laureys S, Boly M (2008) The changing spectrum of coma. Nat Clin Pract Neurol 4:544–546PubMedCrossRefGoogle Scholar
  18. 18.
    Schnakers C, Vanhaudenhuyse A, Giacino J, Ventura M, Boly M, Majerus S, Moonen G, Laureys S (2009) Diagnostic accuracy of the vegetative and minimally conscious state: clinical consensus versus standardized neurobehavioral assessment. BMC Neurol 9:35PubMedCrossRefGoogle Scholar
  19. 19.
    Monti MM, Vanhaudenhuyse A, Coleman MR, Boly M, Pickard JD, Tshibanda L, Owen AM, Laureys S (2010) Willful modulation of brain activity in disorders of consciousness. N Engl J Med 362:579–589PubMedCrossRefGoogle Scholar
  20. 20.
    Rodriguez Moreno D, Schiff ND, Giacino J, Kalmar K, Hirsch J (2010) A network approach to assessing cognition in disorders of consciousness. Neurology 75:1871–1878PubMedCrossRefGoogle Scholar
  21. 21.
    Laureys S, Boly M, Maquet P (2006) Tracking the recovery of consciousness from coma. J Clin Invest 116:1823–1825PubMedCrossRefGoogle Scholar
  22. 22.
    Voss HU, Uluc AM, Dyke JP, Watts R, Kobylarz EJ, McCandliss BD, Heier LA, Beattie BJ, Hamacher KA, Vallabhajosula S, Goldsmith SJ, Ballon D, Giacino JT, Schiff ND (2006) Possible axonal regrowth in late recovery from the minimally conscious state. J Clin Invest 116:2005–2011PubMedCrossRefGoogle Scholar
  23. 23.
    Monti MM, Laureys S, Owen AM (2010) The vegetative state. Bmj 341:292–296CrossRefGoogle Scholar
  24. 24.
    Bruno MA, Gosseries O, Ledoux D, Hustinx R, Laureys S (2011) Assessment of consciousness with electrophysiological and neurological imaging techniques. Curr Opin Crit Care 17:146–151PubMedCrossRefGoogle Scholar
  25. 25.
    Boly M, Faymonville ME, Schnakers C, Peigneux P, Lambermont B, Phillips C, Lancellotti P, Luxen A, Lamy M, Moonen G, Maquet P, Laureys S (2008) Perception of pain in the minimally conscious state with PET activation: an observational study. Lancet Neurol 7:1013–1020PubMedCrossRefGoogle Scholar
  26. 26.
    Vanhaudenhuyse A, Noirhomme Q, Tshibanda LJ, Bruno MA, Boveroux P, Schnakers C, Soddu A, Perlbarg V, Ledoux D, Brichant JF, Moonen G, Maquet P, Greicius MD, Laureys S, Boly M (2010) Default network connectivity reflects the level of consciousness in non-communicative brain-damaged patients. Brain 133:161–171PubMedCrossRefGoogle Scholar
  27. 27.
    Coleman MR, Davis MH, Rodd JM, Robson T, Ali A, Owen AM, Pickard JD (2009) Towards the routine use of brain imaging to aid the clinical diagnosis of disorders of consciousness. Brain 132:2541–2552PubMedCrossRefGoogle Scholar
  28. 28.
    Luaute J, Maucort-Boulch D, Tell L, Quelard F, Sarraf T, Iwaz J, Boisson D, Fischer C (2010) Long-term outcomes of chronic minimally conscious and vegetative states. Neurology 75:246–252PubMedCrossRefGoogle Scholar
  29. 29.
    Dolce G, Quintieri M, Serra S, Lagani V, Pignolo L (2008) Clinical signs and early prognosis in vegetative state: a decisional tree, data-mining study. Brain Inj 22:617–623PubMedCrossRefGoogle Scholar
  30. 30.
    Gosseries O, Bruno MA, Chatelle C, Vanhaudenhuyse A, Schnakers C, Soddu A, Laureys S (2011) Disorders of consciousness: what’s in a name? NeuroRehabilitation 28:3–14PubMedGoogle Scholar
  31. 31.
    Bruno M-A, Schnakers C, Boly M, Hustinx R, Vanhaudenhuyse A, Kirsch M, Bernard C, Moonen G, Laureys S (2009) Subcategorizing the minimally conscious state based on cerebral metabolism PET studies [abstract]. In: 19th Meeting of the European Neurological Society. Milan, ItalyGoogle Scholar
  32. 32.
    Demertzi A, Vanhaudenhuyse A, Bruno MA, Schnakers C, Boly M, Boveroux P, Maquet P, Moonen G, Laureys S (2008) Is there anybody in there? Detecting awareness in disorders of consciousness. Expert Rev Neurother 8:1719–1730PubMedCrossRefGoogle Scholar
  33. 33.
    Laureys S (2005) The neural correlate of (un)awareness: lessons from the vegetative state. Trends Cogn Sci 9:556–559PubMedCrossRefGoogle Scholar
  34. 34.
    Vanhaudenhuyse A, Demertzi A, Schabus M, Noirhomme Q, Bredart S, Boly M, Phillips C, Soddu A, Luxen A, Moonen G, Laureys S (2010) Two distinct neuronal networks mediate the awareness of environment and of self. J Cogn Neurosci 23:570–578PubMedCrossRefGoogle Scholar
  35. 35.
    Majerus S, Bruno MA, Schnakers C, Giacino JT, Laureys S (2009) The problem of aphasia in the assessment of consciousness in brain-damaged patients. Prog Brain Res 177:49–61PubMedCrossRefGoogle Scholar
  36. 36.
    Bruno M-A, Fernández-Espejo D, Lehembre R, Tshibanda L, Vanhaudenhuyse A, Gosseries O, Lommers E, Noirhomme Q, Boly M, Napolitani M, Owen AM, Laureys S, Soddu A (2010) Multi-modal imaging in left hemisphere damaged patients with disorders of consciousness. Prog Brain Res (in press)Google Scholar
  37. 37.
    Bruno M, Schnakers C, Damas F, Pellas F, Lutte I, Bernheim J, Majerus S, Moonen G, Goldman S, Laureys S (2009) Locked-in syndrome in children: report of five cases and review of the literature. Pediatr Neurol 41:237–246PubMedCrossRefGoogle Scholar
  38. 38.
    Smart CM, Giacino JT, Cullen T, Moreno DR, Hirsch J, Schiff ND, Gizzi M (2008) A case of locked-in syndrome complicated by central deafness. Nat Clin Pract Neurol 4:448–453PubMedCrossRefGoogle Scholar
  39. 39.
    Seel RT, Sherer M, Whyte J, Katz DI, Giacino JT, Rosenbaum AM, Hammond FM, Kalmar K, Pape TL, Zafonte R, Biester RC, Kaelin D, Kean J, Zasler N (2010) Assessment scales for disorders of consciousness: evidence-based recommendations for clinical practice and research. Arch Phys Med Rehabil 91:1795–1813PubMedCrossRefGoogle Scholar
  40. 40.
    Jennett B, Bond M (1975) Assessment of outcome after severe brain damage. Lancet 1:480–484PubMedCrossRefGoogle Scholar
  41. 41.
    Rankin J (1957) Cerebral vascular accidents in patients over the age of 60. II. Prognosis. Scott Med J 2:200–215PubMedGoogle Scholar
  42. 42.
    Bruno MA, Ledoux D, Lambermont B, Damas F, Schnakers C, Vanhaudenhuyse A, Gosseries O, Laureys S (2011) Comparison of the full outline of unresponsiveness and Glasgow Liege Scale/Glasgow Coma Scale in an intensive care unit population. Neurocrit Care [Epub ahead of print]Google Scholar
  43. 43.
    Schnakers C, Perrin F, Schabus M, Hustinx R, Majerus S, Moonen G, Boly M, Vanhaudenhuyse A, Bruno MA, Laureys S (2009) Detecting consciousness in a total locked-in syndrome: An active event-related paradigm. Neurocase 15(4):271–277PubMedCrossRefGoogle Scholar
  44. 44.
    Schnakers C, Giacino J, Kalmar K, Piret S, Lopez E, Boly M, Malone R, Laureys S (2006) Does the FOUR score correctly diagnose the vegetative and minimally conscious states? Ann Neurol 60:744–745PubMedCrossRefGoogle Scholar
  45. 45.
    Giacino JT, Kalmar K, Whyte J (2004) The JFK Coma Recovery Scale-Revised: measurement characteristics and diagnostic utility. Arch Phys Med Rehabil 85:2020–2029PubMedCrossRefGoogle Scholar
  46. 46.
    Rader MA, Ellis DW (1994) The Sensory Stimulation Assessment Measure (SSAM): a tool for early evaluation of severely brain-injured patients. Brain Inj 8:309–321PubMedCrossRefGoogle Scholar
  47. 47.
    Shiel A, Horn SA, Wilson BA, Watson MJ, Campbell MJ, McLellan DL (2000) The Wessex Head Injury Matrix (WHIM) main scale: a preliminary report on a scale to assess and monitor patient recovery after severe head injury. Clin Rehabil 14:408–416PubMedCrossRefGoogle Scholar
  48. 48.
    Ansell BJ, Keenan JE (1989) The western neuro sensory stimulation profile: a tool for assessing slow-to-recover head-injured patients. Arch Phys Med Rehabil 70:104–108PubMedGoogle Scholar
  49. 49.
    Gill-Thwaites H (1997) The sensory modality assessment rehabilitation technique—a tool for assessment and treatment of patients with severe brain injury in a vegetative state. Brain Inj 11:723–734PubMedCrossRefGoogle Scholar
  50. 50.
    Pape TL, Senno RG, Guernon A, Kelly JP (2005) A measure of neurobehavioral functioning after coma. Part II: Clinical and scientific implementation. J Rehabil Res Dev 42:19–28PubMedCrossRefGoogle Scholar
  51. 51.
    Rappaport M, Dougherty AM, Kelting DL (1992) Evaluation of coma and vegetative states. Arch Phys Med Rehabil 73:628–634PubMedGoogle Scholar
  52. 52.
    Wijdicks EF, Bamlet WR, Maramattom BV, Manno EM, McClelland RL (2005) Validation of a new coma scale: the FOUR score. Ann Neurol 58:585–593PubMedCrossRefGoogle Scholar
  53. 53.
    Stanczak DE, White JG 3rd, Gouview WD, Moehle KA, Daniel M, Novack T, Long CJ (1984) Assessment of level of consciousness following severe neurological insult. A comparison of the psychometric qualities of the Glasgow Coma Scale and the Comprehensive Level of Consciousness Scale. J Neurosurg 60:955–960PubMedCrossRefGoogle Scholar
  54. 54.
    Benzer A, Mitterschiffthaler G, Marosi M, Luef G, Puhringer F, De La Renotiere K, Lehner H, Schmutzhard E (1991) Prediction of non-survival after trauma: Innsbruck Coma Scale. Lancet 338:977–978PubMedCrossRefGoogle Scholar
  55. 55.
    Born JD, Albert A, Hans P, Bonnal J (1985) Relative prognostic value of best motor response and brain stem reflexes in patients with severe head injury. Neurosurgery 16:595–601PubMedCrossRefGoogle Scholar
  56. 56.
    Borer-Alafi N, Gil M, Sazbon L, Korn C (2002) Loewenstein communication scale for the minimally responsive patient. Brain Inj 16:593–609PubMedCrossRefGoogle Scholar
  57. 57.
    Stalhammar D, Starmark JE, Holmgren E, Eriksson N, Nordstrom CH, Fedders O, Rosander B (1988) Assessment of responsiveness in acute cerebral disorders. A multicentre study on the reaction level scale (RLS 85). Acta Neurochir (Wien) 90:73–80CrossRefGoogle Scholar
  58. 58.
    Laureys S, Owen AM, Schiff ND (2004) Brain function in coma, vegetative state, and related disorders. Lancet Neurol 3:537–546PubMedCrossRefGoogle Scholar
  59. 59.
    Owen AM, Coleman MR, Boly M, Davis MH, Laureys S, Pickard JD (2006) Detecting awareness in the vegetative state. Science 313:1402PubMedCrossRefGoogle Scholar
  60. 60.
    Boly M, Coleman MR, Davis MH, Hampshire A, Bor D, Moonen G, Maquet PA, Pickard JD, Laureys S, Owen AM (2007) When thoughts become action: an fMRI paradigm to study volitional brain activity in non-communicative brain injured patients. Neuroimage 36:979–992PubMedCrossRefGoogle Scholar
  61. 61.
    Bekinschtein TA, Manes FF, Villarreal M, Owen AM, Della Maggiore V (2011) Functional imaging reveals movement preparatory activity in the vegetative state. Front Hum Neurosci 5:5PubMedCrossRefGoogle Scholar
  62. 62.
    Bardin JC, Fins JJ, Katz DI, Hersh J, Heier LA, Tabelow K, Dyke JP, Ballon DJ, Schiff ND, Voss HU (2011) Dissociations between behavioural and functional magnetic resonance imaging-based evaluations of cognitive function after brain injury. Brain 134:769–782PubMedCrossRefGoogle Scholar
  63. 63.
    Schnakers C, Perrin F, Schabus M, Majerus S, Ledoux D, Damas P, Boly M, Vanhaudenhuyse A, Bruno MA, Moonen G, Laureys S (2008) Voluntary brain processing in disorders of consciousness. Neurology 71(20):1614–1620PubMedCrossRefGoogle Scholar
  64. 64.
    Bekinschtein TA, Dehaene S, Rohaut B, Tadel F, Cohen L, Naccache L (2009) Neural signature of the conscious processing of auditory regularities. Proc Natl Acad Sci USA 106:1672–1677PubMedCrossRefGoogle Scholar
  65. 65.
    Bekinschtein TA, Coleman MR, Niklison J 3rd, Pickard JD, Manes FF (2008) Can electromyography objectively detect voluntary movement in disorders of consciousness? J Neurol Neurosurg Psychiatry 79:826–828PubMedCrossRefGoogle Scholar
  66. 66.
    Soddu A, Vanhaudenhuyse A, Bahri MA, Bruno MA, Boly M, Demertzi A, Tshibanda JF, Phillips C, Stanziano M, Ovadia-Caro S, Nir Y, Maquet P, Papa M, Malach R, Laureys S, Noirhomme Q (2011) Identifying the default-mode component in spatial IC analyses of patients with disorders of consciousness. Hum Brain Mapp. doi: 10.1002/hbm.21249
  67. 67.
    Giacino JT, Schnakers C, Rodriguez-Moreno D, Kalmar K, Schiff N, Hirsch J (2009) Behavioral assessment in patients with disorders of consciousness: gold standard or fool’s gold? Prog Brain Res 177:33–48PubMedCrossRefGoogle Scholar
  68. 68.
    Sorger B, Dahmen B, Reithler J, Gosseries O, Maudoux A, Laureys S, Goebel R (2009) Another kind of ‘BOLD Response’: answering multiple-choice questions via online decoded single-trial brain signals. Prog Brain Res 177:275–292PubMedCrossRefGoogle Scholar
  69. 69.
    Laureys S, Boly M (2007) What is it like to be vegetative or minimally conscious? Curr Opin Neurol 20:609–613PubMedCrossRefGoogle Scholar
  70. 70.
    Bruno M-A, Vanhaudenhuyse A, Schnakers C, Boly M, Gosseries O, Demertzi A, Majerus S, Moonen G, Hustinx R, Laureys S (2010) Visual fixation in the vegetative state: an observational case series PET study. BMC Neurol 10:35PubMedCrossRefGoogle Scholar
  71. 71.
    Bruno M-A, Bernheim J, Ledoux D, Pellas F, Demertzi A, Laureys S (2011) A survey on self-assessed wellbeing in a cohort of chronic locked-in syndrome patients: happy majority, miserable minority. BMJ Open, Published Online First 23 February 2011Google Scholar
  72. 72.
    Rousseau MC, Pietra S, Blaya J, Catala A (2011) Quality of life of ALS and LIS patients with and without invasive mechanical ventilation. J Neurol, Published Online First Apr 2 2011Google Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Marie-Aurélie Bruno
    • 1
  • Audrey Vanhaudenhuyse
    • 1
  • Aurore Thibaut
    • 1
  • Gustave Moonen
    • 1
  • Steven Laureys
    • 1
  1. 1.Coma Science Group, Neurology Department and Cyclotron Research CentreUniversity Hospital and University of LiègeLiègeBelgium

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