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  • www.comascience.org

    Neuro-réanimation: coma & conscience

    Prof Steven Laureys Coma Science Group Centre de Recherches du Cyclotron & Service de Neurologie Université de Liège & Centre Hospitalier Universitaire de Liège

    2ème Master en sciences de la Santé publique, Finalité spécialisée Soins Intensifs et d’Urgences

  • www.comascience.org Demertzi et al, Ann N Y Acad Sci. 2009 (fig 3)

    Coma, consciousness, self, mind & soul

    1858 participants attending scientific meetings on consciousness

    Consciousness | Neural correlates | Diagnosis | Prognosis | Treatment | Ethics | Conclusion

  • www.comascience.org

    Courte histoire du coma

    Anoebis

    cœur Maät

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    Respirateur artificiel (1952)

    The resuscitation greats. Bjørn Ibsen Resuscitation. 2003

    Bjørn Ibsen - Copenhagen

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    Pope Pius XII (1957) Consciousness | History | Death | Coma | Locked-in | Disorders of Consciousness

    •! it remains for the doctor to give a definition of the “moment of death”

    •! no obligation to use extraordinary means to prolong life in critically ill patients

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    Coma dépassé (1959)

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    Première transplantation d’un donneur en mort cérébrale (1963)

    Jean Morelle & Guy Alexandre Neurology, 2005;64;1938-1942

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    Christiaan Barnard (1967)

    Louis Washkansky

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    Définition de la mort cérébrale Comité de Harvard 1968

    Wijdicks, NEJM 2001 Bueri et al Mov Disord. 2000, 15:583-6

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    disorders of consciousness | behavioural evaluation | electrophysiology | neuroimaging | methods, ethics & quality of life | perspectives

    Laureys, Owen and Schiff, Lancet Neurology, 2005

    Conscience & éveil

    NORMAL

    EVEI

    L

    CO

    NSC

    IEN

    CE

    DE

    L’EN

    VIR

    ON

    NEM

    ENT

    COMA ANESTHESIE

    SOMMEIL

    EVEI

    L

    CO

    NSC

    IEN

    CE

    DE

    L’EN

    VIR

    ON

    NEM

    ENT

    ETAT VEGETATIF

    EVEI

    L

    CO

    NSC

    IEN

    CE

    DE

    L’EN

    VIR

    ON

    NEM

    ENT

    ETAT DE CONSCIENCE

    MINIMAL

    EVEI

    L

    CO

    NSC

    IEN

    CE

    DE

    L’EN

    VIR

    ON

    NEM

    ENT

    LOCKED-IN SYNDROME

    EVEI

    L

    CO

    NSC

    IEN

    CE

    DE

    L’EN

    VIR

    ON

    NEM

    ENT

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    L’erreur diagnostique

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    Peur d’être enterré vivant (1896)

    1896, Karnice-Karnicki, chamberlain of the tsar of Russia

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    La mort et les medias (1980)

    Transplants - Are the donors really dead ?

    mort clinique ! mort

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    Erreur de diagnostic et mort cérébrale

    Depuis les années 50, aucun patient en mort cérébrale n’a récupéré sa conscience (test d’apnée!)

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    Locked-in syndrome

    Laureys et al., Progress in Brain Research, 2005

  • www.comascience.org Laureys et al., Progress in Brain Research, 2005

    disorders of consciousness | behavioural evaluation | electrophysiology | neuroimaging | methods, ethics & quality of life | perspectives Locked-in syndrome

    www.alis-asso.fr

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    unconsciousness ! “coma”

    Monti, Laureys & Owen, British Med J, 2010

    1972 1966 1952

    2002

    1994

    Consciousness | Neural correlates | Diagnosis | Prognosis | Treatment | Ethics | Conclusion

  • www.comascience.org

    A new name for « vegetative »

    Laureys et al, BMC Medicine 2011

    “There’s nothing we can do… he’ll always be a vegetable.”

    Consciousness | Neural correlates | Diagnosis | Prognosis | Treatment | Ethics | Conclusion

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    What coma scale to use?

    Wijdicks et al., Ann Neurol 2005

    Consciousness | History | Death | Coma | Locked-in | Disorders of Consciousness

    Teasdale & Jennett, Lancet 1974

    GCS FOUR

    Schnakers et al, Ann Neurol 2006

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    disorders of consciousness | behavioural evaluation | electrophysiology | neuroimaging | methods, ethics & quality of life | perspectives FOUR / GCS

    Wijdicks et al., Ann Neurol (2005) Teasdale G, Jennett B, Lancet (1974)

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    disorders of consciousness | behavioural evaluation | electrophysiology | neuroimaging | methods, ethics & quality of life | perspectives FOUR / GCS / GLS

    Wijdicks et al., (2005) Teasdale G, Jennett B, (1974) Born et al., (1985)

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    disorders of consciousness | behavioural evaluation | electrophysiology | neuroimaging | methods, ethics & quality of life | perspectives

    Eye response

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    disorders of consciousness | behavioural evaluation | electrophysiology | neuroimaging | methods, ethics & quality of life | perspectives

    Motor response

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    disorders of consciousness | behavioural evaluation | electrophysiology | neuroimaging | methods, ethics & quality of life | perspectives

    Brainstem reflexes

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    disorders of consciousness | behavioural evaluation | electrophysiology | neuroimaging | methods, ethics & quality of life | perspectives

    Respiration

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    Diagnostic error

    n=103 post-comatose patients –! 45 clinical consensus diagnosis ‘vegetative state’ –! 18 signs of awareness (Coma Recovery Scale)

    !! 40% potential misdiagnosis

    Schnakers et al, BMC Neurology 2009

    Consciousness | Neural correlates | Diagnosis | Prognosis | Treatment | Ethics | Conclusion

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    Eye tracking : use a mirror!

    Vanhaudenhuyse et al J Neurol Neurosurg Psychiatry 2008

    n=52

    Consciousness | Neural correlates | Diagnosis | Prognosis | Treatment | Ethics | Conclusion

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    Functional MRI PET scan High-density EEG Transcranial magnetic stimulation

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    Sustained visual fixation is a reflex

    Bruno et al, BMC Neurology 2010

    Consciousness | Neural correlates | Diagnosis | Prognosis | Treatment | Ethics | Conclusion

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    disorders of consciousness | behavioural evaluation | electrophysiology | neuroimaging | methods, ethics & quality of life | perspectives

    Automated consciousness classifier

    Phillips et al, NeuroImage, 2010

    “Relevance Vector Machine” on FDG-PET data in DOC

    Consciousness | Neural correlates | Diagnosis | Prognosis | Treatment | Ethics | Conclusion

  • www.comascience.org Owen, Coleman, Boly, Davis, Laureys & Pickard, Science, 2006

    Signs of consciousness on fMRI

    “He’s not in coma… he’s playing tennis!”

    Consciousness | Neural correlates | Diagnosis | Prognosis | Treatment | Ethics | Conclusion

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    disorders of consciousness | behavioural evaluation | electrophysiology | neuroimaging | methods, ethics & quality of life | perspectives

    Monti & Vanhaudenhuyse, Coleman, Boly, Pickard, Tshibanda, Owen, Laureys New England J Med 2010

    Yes-No communication with fMRI Consciousness | Neural correlates | Diagnosis | Prognosis | Treatment | Ethics | Conclusion

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    disorders of consciousness | behavioural evaluation | electrophysiology | neuroimaging | methods, ethics & quality of life | perspectives

    EEG-based Brain Computer Interfaces

    ms -200 50 300 550 800 1050 1300

    -5 -10 -15 -20 -25

    5 10 15 20 25

    Pz (!V)

    Count TARGET (own name)

    Coma or total locked-in syndrome?

    21-y old woman basilar artery thrombosis - day 49

    Other names PASSIVE

    Count TARGET (other name)

    Own name PASSIVE

    Consciousness | Neural correlates | Diagnosis | Prognosis | Treatment | Ethics | Conclusion

    Schnakers et al, Neurology, 2008 Schnakers et al, Neurocase, 2009

    www.decoderproject.eu

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    vegetative state

    ATYPICAL ‘HIGH LEVEL’ CORTICAL ACTIVATION

    Di et al, Neurology, 2007

    ACTIVATION TO THE OWN NAME

    fMRI predictor of outcome? Consciousness | Neural correlates | Diagnosis | Prognosis | Treatment | Ethics | Conclusion

    PUBLISHED DATA (n=48 patients) 6 fMRI (n=17) & 8 PET studies (n=32)

    “low level” or absent activation •! low level activation 84% no recovery

    •! no cortical activation 100% no recovery

    “high level” activation •! 82% recovery (93% specificity 69% sensitivity)

    Di et al, Clinical Medicine, 2008

  • www.comascience.org Bruno et al, Prog Brain Res, 2011 Tshibanda et al, Neuroradiology, 2010

    disorders of consciousness | behavioural evaluation | electrophysiology | neuroimaging | methods, ethics & quality of life | perspectives

    Multimodal imaging Consciousness | Neural correlates | Diagnosis | Prognosis | Treatment | Ethics | Conclusion

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    Traitement "…le cerveau (d’une femme) est un mystère...

    est encore plus dans cet état là"

  • www.comascience.org Schnakers et al, JNNP 2008

    Traitement pharmacologique

  • www.comascience.org Schiff et al., Nature, 2007 Laureys, De Ridder, Schiff et al., European DBS study in EMCS

    disorders of consciousness | behavioural evaluation | electrophysiology | neuroimaging | methods, ethics & quality of life | perspectives Stimuler le cerveau

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    PRONOSTIQUE

  • www.comascience.org Eisenberg NEJM 2001 Laureys et al, Nature Clinical Practice 2008

    Outcome after cardiac arrest EMERGENCE

    MINIMALLY CONSCIOUS STATE

    BRAIN DEATH

    functional communication

    VEGETATIVE STATE

    COMA

    brainstem reflexes

    voluntary movements or command following

    eye opening only reflex movements

    CARDIAC ARREST

    Hemodynamic stabilisation

    20-50% >80%

    77-98%

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    Clinical outcome markers

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    Circumstances surrounding CPR

    •! Time between collapse and CPR > 5 min (FPR 20%; 95% CI 14-25)

    •! Duration CPR > 20 min (FPR 23%; 95% CI 17-29)

    •! Asystole or electro-mechanic dissociation versus ventricular fibrillation or tachycardia

    (FPR 27 %; 95% CI 21-33) •! Cause of the cardiac arrest (cardiac vs noncardiac)

    Rogove et al Crit Care Med 1995;23:18–25 (N=774; class I study)

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    Hyperthermia

    •! each °C > 37° (tympanic thermometry < 48h) -> 2 x more likely to die or remain VS after 6m

    Zeiner et al Arch Intern Med 2001;161:2007–2012 (class II study)

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    Clinical examination

    •! at 72 hours: GCS motor score

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    Electroencephalography

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    Electroencephalography

    1929 Hans Berger

    50 "V

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    Generalized slowing baseline activity

    Cerebral blood flow < 25 ml/100g/min

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    EEG: burst supression

    FPR= 3%, 95% CI: 0.9 à 11

    Wijdicks et al 2006 1 class II 4 class III studies

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    EEG: isoelectrical

    Cerebral blood flow < 15 ml/100g/min

    BRAIN DEATH

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    Evoked potentials

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    Somatosensory evoked potentials

    FPR = 0.7%; 95% CI: 0.1 - 3.7

    Carter Intensive Care Med, 2005 (25 studies) Zanbergen et al, Lancet 1998

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    Visual evoked potentials

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    Auditory brainstem evoked potentials

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    N 1 0 0 s t d N 1 0 0 d e v

    M M N

    1 0 0 m s

    1 µ V -

    +

    d e v i a n t n = 1 4 1 s t a n d a r d n = 7 2 6

    d i f f = d e v - s t d

    Mismatch negativity

    Fischer et al, Crit Care Med, 2006 Naccache et al, Clin Neurophysiol 2005

    presence of MMN -> outcome better than VS

    n=64; 100% specificity

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    Biochemical markers

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    Biochemical markers

    •! NSE : neuron specific enolase < neurons & neuroectodermal cells >33 "g/l at D 1 to 3 (1 class I 4 class III and 1 class IV studies) (FPR = 0%; 95% CI: 0 – 3) •! time-consuming >24h •! hemolysis increases values (NSE < platelets) •! cutoff points for a 0 FPR vary from 20 to 65 "g/l •! NSE is lower in induced hypothermia

    •! S100 protein : calcium-binding astroglial protein (1 class I 4 class III and 1 class IV studies) values measured

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    Pronostic coma anoxique Kirsch et al, Revue Médicale de Liège 63 (2008) 263-268

    DON D’ORGANES

    DON D’ORGANES CŒUR NON-BATTANTS

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    Epidemiology Consecutive admissions CHU ICU (26 beds) over 5 y : n=5908

    631 disorder of consciousness on admission (11%)

    ! 356 vegetative state (56%) 227 non-traumatic (64%) 129 traumatic (36%)

    " 101 died

    " 200 emerged from VS 118 obeyed command & oriented (59%) 68 disoriented or inappropriate words (34%) 14 only localised pain (7%)

    " 55 remained VS at discharge

    Ledoux, Piret, Damas, Moonen & Laureys, in preparation

    VS

    28%

    56% 16%

    died

    trauma

    non- trauma

    emerged

    # 36% recover # 70% recover

    Consciousness | History | Death | Coma | Locked-in | Disorders of Consciousness

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    Chronic disorders of consciousness

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    Outcome

    Ledoux et al, Belgian federal project on VS

    ! "! #! $! %! &! '! (! )! *!

    "!!

    " $ ' "#

    Minimally conscious state (n=84)

    n=35

    %

    ! "! #! $! %! &! '! (! )! *!

    "!!

    " $ ' "# n=49

    %

    ! "! #! $! %! &! '! (! )! *!

    "!!

    " $ ' "# +,+-.+/0+1 ,02 3456 72

    Vegetative state (n=116)

    Trau

    mat

    ic

    n=52

    %

    ! "! #! $! %! &! '! (! )! *!

    "!!

    " $ ' "#

    Non

    -tra

    umat

    ic

    n=64

    %

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    Ethical & social challenges

    Consciousness | Neural correlates | Diagnosis | Prognosis | Treatment | Ethics | Conclusion

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    Cognition & quality of life Cognitive and behavioral changes in 20-50%

    long-term memory, executive function impairment, focal cognitive deficits •! O’Reilly et al Resuscitation 2003;58:73—9 •! Nunes et al Resuscitation 2003 57:287—97. •! Drysdale et al Resuscitation 2000 47:27—32 •! Grubb et al Stroke 2000;31:1509—14 •! Grubb et al BMJ 1996 313:143—6 •! Roine et al J Am Med Assoc 1993 269:237—42

    Posttraumatic stress disorder in 20-25% (more in younger patients) •! Griffiths et al Yearbook of IC & EM 2008: 891-905 •! Gamper et al Crit Care Med 2004 32:378—83 •! O’Reilly et al Br J Clin Psychol 2004 43:83—95 •! Ladwig et al Am J Psychiatry 1999 156:912—9

    Preserved health related quality of life •! Horsted et al Resuscitation. 2007 72:214-8 •! Bunch et al Crit Care Med. 2004 32:963-7 •! van Alem et al Am J Cardiol. 2004 93:131-5 •! Granja et al Resuscitation. 2002 55:37-44 •! Nichol et al Acad Emerg Med 1999 6:95—102

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    Ethical issues

    Demertzi et al, J Neurology 2011

    2,475 medical professionals

    Consciousness | Neural correlates | Diagnosis | Prognosis | Treatment | Ethics | Conclusion

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    Quality of life

    Bruno et al, BMJ Open, 2011

    Consciousness | Neural correlates | Diagnosis | Prognosis | Treatment | Ethics | Conclusion

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    Ethics

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    Ethical conclusions

    •!What is meaningful outcome? •!What is acceptable probability?

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    EVALUER LA DOULEUR

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    disorders of consciousness | behavioural evaluation | electrophysiology | neuroimaging | methods, ethics & quality of life | perspectives Pain without words ?

    Pain is a subjective first-person experience which has to be communicated to be accurately assessed

    Only motor response considered indicative of conscious perception is localization to noxious stimulation

    Laureys & Boly What is it like to be vegetative or minimally conscious? Curr Opin Neurol 20 (2007) 609-13

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    No brain, no pain

    Laureys, 2005

    NORMAL BRAIN DEATH COMA VEGETATIVE STATE

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    Motor response without pain

    Bueri et al Mov Disord. 2000, 15:583-6

    Spinal reflexes 75%

    extension-pronation plantar responses muscle stretch reflexes abdominal reflexes undulating toe flexion sign “Lazarus’ sign

    BRAIN DEATH

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    No cortex, no pain

    Consciousness in congenitally decorticate children: developmental vegetative state as self-fulfilling prophecy

    Shewmon et al Dev Med Child Neurol. 1999

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    Some cortex, some pain?

    Laureys, 2005

    NORMAL BRAIN DEATH COMA VEGETATIVE STATE

  • www.comascience.org Laureys et al., Current Opinion in Neurology, 2005

    disorders of consciousness | behavioural evaluation | electrophysiology | neuroimaging | methods, ethics & quality of life | perspectives

    Pain after coma?

    COGNITIVE CAPACITY

    MO

    TO

    R R

    ES

    PO

    NS

    IVEN

    ES

    S

    coma

    VEGETATIVE/UNRESPONSIVE

    MINIMALLY CONSCIOUS

    severe disability

    arousal = eye opening

    Communication ?

    moderate disability

    good recovery

    live independently

    professional reinsertion

    Awareness ? = response to command or non-reflex movements

    Consciousness | Neural correlates | Diagnosis | Prognosis | Treatment | Ethics | Conclusion

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    disorders of consciousness | behavioural evaluation | electrophysiology | neuroimaging | methods, ethics & quality of life | perspectives Pain in the vegetative state?

    Demertzi et al, Prog Brain Res, 2009

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    disorders of consciousness | behavioural evaluation | electrophysiology | neuroimaging | methods, ethics & quality of life | perspectives

    Laureys et al, Neuroimage, 2002 Laureys, Nature Reviews Neuroscience, 2005

    Brain activation to pain

    Low level disconnected cortical activation

    Noxious electrical stimulation

  • www.comascience.org Boly et al Lancet Neurology, 2008

    disorders of consciousness | behavioural evaluation | electrophysiology | neuroimaging | methods, ethics & quality of life | perspectives Pain in minimally conscious state

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    Assessing pain

    Kappesser and Williams, Pain 2010

    overestimation

    agreement

    underestimation

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    Standardized assessment

    Schnakers et al, Pain 2010

    Standardized stimulation

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    Pain in infants & demented

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    Nociception coma scale

    Checklist of Non-verbal Pain Indicators

    NO

    CIC

    EPTI

    ON

    CO

    MA S

    CALE

    Schnakers et al, Pain 2010

    7

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    Nociception coma scale

    UNCONSCIOUS VEGETATIVE

    MINIMALLY CONSCIOUS

    NO

    CIC

    EPTI

    ON

    CO

    MA S

    CALE

    Schnakers et al, Pain 2010

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    Nociception Coma Scale

    •! New “pain scale” for disorders of consciousness after coma

    •! Assesses motor, verbal (vocal), visual (ocular), and facial responses on scales from 0 (no response) to 3 (total scores 0 – 12) to a quantified standard stimulus

    •! Brief time required (1–5 min) to conduct and rate the examination

    •! More sensitive compared with 4 other “pain” scales

    •! Permits detect, communicate & follow non-communicative patient’s behaviors and their management

    •! Allows monitoring treatment avoiding sedative effects & under-uses of analgesics

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    EXPERIENCES PROCHE DE LA MORT

  • www.comascience.org 86

    NDE (1975)

    Van Lommel 2001 WCEI scale 41 (12%) Parnia 2001 Greyson scale 4 (6%) Schwaninger 2002 Greyson scale 7 (13%) Greyson 2003 Greyson scale 27 (2%) Charland 2011 Greyson scale 17 (10%)

    Sensations, illusions, hallucinations, emotional or mystical feelings classically following life-threatening situations:

    Cardiac arrest, perioperative or post-partum complications, septic or anaphylactic shock, electrocution, coma TBI, CVA, hypoglycaemia

    ? -> Neural correlate of NDE

  • www.comascience.org 87

    Clinical death ! death

    « …defined clinical death (independent of neuro- logical data) as a period of unconsciousness caused by insufficient blood supply to the brain because of inadequate blood circulation, breathing, or both. »

  • www.comascience.org 88

    Brain death = death

    Transplants - Are the donors really dead ?

    Clinically dead ! dead !

  • www.comascience.org 89

    Misdiagnosis of death ?

    Since the 50s, no single patient showing the clinical signs of brain death ever recovered consciousness (apnea test !)

    Laureys, Nature Reviews Neuroscience, 2005

    1896, Karnice-Karnicki, chamberlain of the tsar of Russia

  • www.comascience.org 90

    NDE dimensions

    NDE >7 Greyson Scale Greyson, B. (1985). A typology of near-death experiences. Am J Psychiatry

    (n=17 ; 10% of cardiac arrest)

    Out of Body Experience (Paranormal) 15 Well-Being (Affective) 13 Light (Affective) 9 Sense of a presence (Transcendental) 6 Life Review (Cognitive) 2

    Charland et al, unpublished

  • www.comascience.org 91

    NDE = false memories ? Memory Characteristics Questionnaire (Johnson, M.K., et al., J Exp Psychol Gen, 1988)

    Thonnard et al, submitted

  • www.comascience.org 92

    NDE characteristics ! dreams

    Thonnard et al, submitted

    Memory Characteristics Questionnaire Johnson, M.K., et al., J Exp Psychol Gen, 1988 qualitatively different

    from dreams or drug-induced hallucinations

    ‘For many years, it was the most real thing that ever happened to me. Yes, far more real and vivid than any real-life incident. It was so real, detailed and so vivid and consistent ...; in fact, so totally un-dream- like!’

  • www.comascience.org 93

    NDE characteristics ! dreams

    Thonnard et al, submitted

    Memory Characteristics Questionnaire Johnson, M.K., et al., J Exp Psychol Gen, 1988

  • www.comascience.org 94

    Demertzi et al, Ann N Y Acad Sci. 2009 (fig 3)

    NDE = proof of the soul ?... 1858 participants attending scientific meetings on consciousness

  • www.comascience.org 95

    … no evidence for that hypothesis

    2009 Yearbook - Towards a neuro-scientific explanation of Near-Death Experiences?

  • www.comascience.org 96

    Light optic radiation

    Ammermann et al. 2007 Els et al. 2004

    DWI ADC T2

    T1

    Hieronymus Bosch 1500s

  • www.comascience.org 97

    Flashback mesiotemporal

    Britton and Bootzin 2004

  • www.comascience.org 98

    Presence left temporoparietal

    Arzy, S., et al. (2006) Nature 443:287 Induction of an illusory shadow person.

  • www.comascience.org 99

    OBE right temporoparietal

    Blanke et al Stimulating illusory own-body perceptions. Nature, 2002 (6904)269-70 De Ridder et al Visualizing out-of-body experience in the brain. N Engl J Med, 2007 (357) 1829-1833

  • www.comascience.org 100

    NDE = happening in the brain

    NDE dimension Neural substrate OBE Right temporoparietal junction

    Tunnel & light occipital & optic radiation (tunnel vision & foveal light)

    Life review, memory flashback, enhanced emotions

    Hippocampus/amygdala

    Meeting of spirits Left temporoparietal junction

    Painlessness, wellbeing Anterior cingulate cortex Time distortion Cortico-striatal Mystical & transcendental – oneness, cosmic unity

    Biparietal

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