Comatose, Vegetative and Minimally Conscious States

D. Alan Shewmon, MD

Professor of Neurology and Pediatrics David Geffen School of Medicine at UCLA Chief, Neurology Department Olive View-UCLA Medical Center Judicial Seminar on Emerging Issues in Neuroscience Stanford University December 8, 2006

from Laureys et al. In Machado & Shewmon (eds): Brain Death and Disorders of Consciousness. Kluwer, 2004

Coma vs. “Brain Death”

• • Coma = sleep-like, unarousable unconsciousness in a live person • • • “Brain death” = ambiguous term death (necrosis) of the

brain

death of the

person

(= “death by neurological criteria”) statutory death in most countries and states, although there is no consensus on the biological and philosophical rationales for that equivalence

Coma vs. “Brain Death”

Coma

• Describes brain function at a moment in time (

per se

implies nothing re reversibility or prognosis) • Loss of those brain functions related to arousal • Midline brainstem or diencephalic lesions

“Brain Death”

• Permanent, irreversible lack of brain function • Loss of

all

brain functions • Destruction (infarction/ necrosis) of entire brain

“Brain Death”

• • (“party line”): BD = a state beyond coma = death itself (critics’ position): BD = a subset of coma = very deep coma (in a live patient) associated with no respiration or cranial nerve reflexes

Coma vs. Vegetative State

Coma

• Sleep-like, unarousable unresponsiveness (apart from reflexes) • Midline brainstem or diencephalic lesions • Does not remain coma indefinitely; evolves to awake ( ± degrees of disability), VS or death

Vegetative State

• Awake-like, arousable unresponsiveness (apart from reflexes) • Cortex and/or thalamic lesions • Remains VS or evolves to MCS or awake ( ± degrees of disability)

VS, MCS History

• • • • • 1940 – Kretschmer: “apallische Syndrom” 1972 – “Vegetative State” coined by Jennett & Plum 1994 – Multi-Society Task Force on VS 1995-2000 – Aspen Neurobehavioral Conference Workgroup develops “Minimally Conscious State” (MCS) 2002 – MCS diagnostic criteria published

Proposed Alternative Terminologies

Vegetative State

• Coma vigil • Post-coma unresponsiveness • Post-coma unawareness

Min. Cons. State

• Severe disability • Minimally responsive state

Vegetative State Terminology

• •

2 Terminological Axes Phenomenological

(diagnostic) axis: VS = state of (presumed) unawareness at a moment in time (

per se

implies nothing re time-course or prognosis) • • •

Temporal

(prognostic) axis:

“Persistent”

VS = VS lasting ≥ 1 month (= “has persisted until now”;

per se

implies nothing re future)

“Permanent”

VS = ≥ 3 months (anoxic etiology); ≥ 12 months (traumatic etiology) (= statistical prediction: very likely to remain unchanged indefinitely into the future) Acronym “PVS” is ambiguous

Three Definitional Domains of Vegetative State

• • •

The ABCs A

natomy: A pallic Syndrome, “neocortical death” (Ingvar)

B

ehavior: eyes-open unresponsiveness (Jennett and Plum)

C

onsciousness: unaware of self & environment (AAN, Pres Comm, AMA, ANA, MSTF)

The ABC of VS (

to be adjusted according to evidence…) A B C

1

st

Adjustment Most VS is not VS

A A B C

Given VS

A

: Hypotheses re B and C

re B: All apallic pts lack adaptive responsiveness.

re C: All apallic pts are necessarily unconscious.

(i.e., at least some cortex is necessary for adaptive responsiveness and consciousness) Two subgroups of VS A – structural – functional

Research on VS

A

Few studies on VS

A

population

• • – – – – Acquired Apallia [Ingvar et al. Ann NY Acad Sci 1978;315:184-208] 8 adults with severe hypoxic-ischemic damage all behaviorally unresponsive (=VS B ) can unconsciousness be inferred? (VS C ?) – – – – Congenital Apallia [Shewmon et al. Dev Med Child Neurol 1999;41:364-74] 3 congenitally decorticate children adaptive interaction with environment (  VS B ) presumably conscious (  VS C )

1.

2.

Possible Reasons for Unresponsiveness in Acquired VS

A

– – – – – Unconsciousness Obstacle(s) to manifesting consciousness (“super-locked-in state”) Spastic quadriplegia & pseudobulbar palsy Apraxia of any residual voluntary movements Global aphasia A k inetic mutism Depression Until #2 has been ruled out as a reason for unresponsiveness, #1 cannot be inferred as

the

reason.

But #2 can never be ruled out. In fact, it is always the case, and could in principle account for the behavioral differences between acquired and congenital apallia.

2

nd

Adjustment Some A are neither B nor C

A B C

Research on VS

C

• – – Intrinsically impossible Pt population is not empirically identifiable VS C can only be an inference from A and B (if such an inference can even be validly made…)

Research on VS

B Defining the Pt Population: Diagnostic Criteria

• • • • • • • • • • Jennett & Plum, 1972 Ingvar et al., 1978 Plum & Posner, 1980 President’s Commission, 1983 AAN Position Statement, 1989 AMA, 1990 IMEWP, 1991 ANA, 1993 MSTF, 1994 AAN Practice Parameter, 1995

Defining the Pt Population: Diagnostic Criteria

• • – No evidence of mental function: no voluntary or purposeful activity – – – – – no learned behavior no language comp or expr, incl signaling by eye movements no adaptive or “meaningful” response to environment “meaningless” spontaneous movements bowel & bladder incontinence – Intact brain-stem & hypothalamic functions spontaneous respiration – sleep-wake cycles; arousal, eye opening, startle to stimuli

Defining the Pt Population: Diagnostic Criteria

• – Affect inconsistently related to any apparent stimulus Brief smiles (AMA, ANA, MSTF) – – Frowning (ANA) Crying, shedding tears (ANA, MSTF)

Defining the Pt Population: Diagnostic Criteria

• • • – No evidence of sustained, reproducible, purposeful, or voluntary responses to visual stimuli (MSTF, AAN) – BUT blink to threat?

No

(AMA, MSTF).

Can

(J&P).

– turn head or dart eyes toward moving object?

No

(J&P, Ingvar).

Can

(AMA, IMEWP, MSTF).

– “inconsistent” visual fixation or tracking (J&P, IMEWP, ANA, MSTF) – No evidence of sustained, reproducible, purposeful, or voluntary responses to auditory stimuli (MSTF, AAN) – BUT can turn head or dart eyes toward noise (AMA, IMEWP, MSTF) – No evidence of sustained, reproducible, purposeful, or voluntary responses to tactile stimuli (MSTF, AAN) – BUT can scratch (J&P)

Defining the Pt Population: Diagnostic Criteria

• – – – – – No evidence of sustained, reproducible, purposeful, or voluntary responses to noxious stimuli (MSTF, AAN) – BUT can have Grunting or groaning (J&P, IMEWP) Grimacing (J&P, Pres Comm, IMEWP, MSTF) “Crying-like behavior” (MSTF) Movement of hands toward stimulus (J&P) Avoidance movements, flexor withdrawal (J&P, Ingvar, AMA, IMEWP, ANA)

Defining the Pt Population: Diagnostic Criteria

• – – – Alimentary stimuli No chewing or swallowing “in a normal manner” (AAN) Chewing, uncoordinated (J&P, Ingvar, ANA, MSTF) Swallowing of liquid or food placed in mouth, uncoordinated (J&P, Ingvar, Pres Comm, IMEWP, ANA, MSTF)

Perils of Misdiagnosis

• • • – Tresch et al.

Arch Intern Med

1991;151:930-2.

18% of pts referred to nursing home as PVS were misdiagnosed.

– Childs et al.

Neurology

1993;43:1465-7.

37% of pts admitted >1 mo post-injury w dx of coma or PVS were misdiagnosed.

– Andrews et al.

BMJ

1996;313:13-6. 43% of pts referred to Royal Hosp for Neurodisability as PVS were misdiagnosed. Reasons: • • • Perceptual disorders (blind – lack of blink to threat, no visual tracking) Positioning & posture interfering w ability to respond Need to adapt response devices to individual pt’s limited motor repertoire

Research on VS

B

Verified Hypotheses re A

struct

• • • Some B are A struct Not all B are A struct (in fact, most aren’t) Neuropathology of VS B – wide variation in location & extent of damage

Research on VS

B

Verified Hypotheses re A

funct

• • VS B can result from a functioning brainstem and the total loss of cerebral cortical functioning. (Some B are A funct .) VS B can result from disconnection between islands of functioning cortex.

Corollary: Not all B are A funct .

Global Cerebral Metabolism

Laureys et al. In Machado & Shewmon (eds): Brain Death and Disorders of Consciousness. Kluwer, 2004

Global Cerebral Metabolism in VS

B

• • 40-65% of normal Similar to deep anesthesia Beuthien-Baumann, DeVolder, Larsen, Levy, Rudolf…

Global Cerebral Metabolism in VS

B

Implications

“Such metabolic hypoactivity has precedent only in deep anesthesia and supports clinical evidence that cerebral cognitive function is lost in the vegetative state, leaving a body that can no longer think or experience pain.” [Levy et al.

Ann Neurol

1987;22(6):673-82] Note: • Not simply “cognitive function,” but “

cerebral

cognitive function.” Why?

• There may be forms of subjective consciousness other than “cognitive function” or “thinking,” e.g., self-awareness, primitive awareness of body & environment, pleasure, pain… • Consciousness- & pain-suppressing effect of general anesthesia is likely due primarily to its depressant effect on

brain stem

rather than on cerebral function (~coma, not VS). Brain stem is functional in VS.

• No logical connection between such data and ability to experience pain.

© 1994-2000 Crump Institute for Molecular Imaging UCLA School of Medicine http://www.crump.ucla.edu/software/lpp/clinpetneuro/metabolicdev.html

courtesy of Stephen Laureys, MD, PhD

VS

B

as a Multi-Modular Disconnection Syndrome

• • • • Activation of primary cortices Non-activation of higher-order association cortices Impaired functional connections between – – distant cortical areas thalami and cortex Recovery of clinical consciousness is paralleled by a restoration of cortico-thalamo-cortical interaction Boly, Davey, Kotchoubey, Laureys, Plum, Schiff…

Research on VS

B

Hypotheses re C

• – – – Hypotheses inferring VS C from VS B are empirically untestable, regardless whether A or not-A.

Pts in VS

B

are unaware of environment.

Pts in VS

B

are unaware of self.

Pts in VS

B

suffering.

are incapable of experiencing pain or

Research on VS

B

Evidence raising questions re C

• • • “Cognitive ERPs” Changes in rCBF to cognitive/emotional stimuli Possibili ty of “super locked-in state”

“Cognitive" Event-Related Potentials

• • • • •

P300 in traumatic coma

Reuter et al.

Arch Psychol

1989;141:155-73

P300 predicts awakening in non-traumatic coma

DeGiorgio et al.

Acta Neurol Scand

1993;87:423-7 Gott et al.

Arch Neurol

1991;48:1267-70 O'Mahony

Lancet

Yingling

Lancet

1990;336:1265-6 1990;336:873

P300 in traumatic PVS

Rappaport et al.

J Neuropsychiatry Clin Neurosci

1991;3(2):180-5

Mismatch negativity in PVS

Glass et al.

Clin EEG

1998;29:19-30 Kaga et al.

Ann Neurol

1996;40:316

Cognitive ERPs in coma and PVS

Kotchoubey et al.

News Physiol Sci

2002;17:38-42

Semantic Processing in VS

B

• • 120 severely brain damaged pts (43 VS, 23 “near VS”, 54 sev. disabil.) N400 ERP generated by semantic error (“The coffee is too hot to fly.”) • • • severe disability – 90% w N400 “near VS” (

NeuroRehabilitation

2004;19:329-34.

Cognitively/Emotionally Induced Changes in rCBF

• •

Photos of familiar faces and meaningless pictures shown to a VS pt



Activation of visual association areas with faces

[Menon et al.

Lancet

1998;352:200]

Cognitively/Emotionally Induced Changes in rCBF

• – – –

Story told by mother of PVS pt (vs. non-word sound)



activation of rostral anterior cingulate right middle temporal cortex right premotor cortex

[de Jong et al.

Clin Neurol Neurosurg

1997;99(3):213-6]

Mental Imagery and Comprehension Revealed by fMRI

• – – Requests for tennis imagery and spatial navigation imagery in VS B pt  specific cortical activation patterns similar to normal controls Supplementary motor area (tennis) Parahippocampal gyrus, posterior parietal lobe, lateral premotor cortex (spatial navigation) Owen et al.

Science

2006;313:1402

Physiology of Pain

• • • • • Traditional emphasis on subcortical structures, especially thalamus – Distinction between crude sensation (sensory system) and unpleasantness (limbic system) Frontal leukotomy, cingulumotomy In intact brain, sensory cortex

participates

in pain processing – probably modulatory role Sensory cortex is not

necessary

for pain perception Limbic cortex is not necessary for crude sensation of noxious stimul i

Noxious Somatosensory Stimulation in VS

B

• activates midbrain, contralateral thalamus, and primary somatosensory cortex in each and every PVS patient, even in the absence of detectable cortical evoked potentials • does

not

activate secondary somatosensory, bilateral insular, posterior parietal, and anterior cingulate cortices • [Laureys et al.

Neuroimage does

2002;17(2):732-41] activate secondary somatosensory, insular, posterior parietal, and cingulate cortices [Kassubek et al.

J Neurol Sci

2003;

212(1-2):

85-91]

VS

B

as a Multi-Modular Disconnection Syndrome

Do disconnection syndromes necessarily reflect a lack of consciousness, or are they fundamentally a type of apraxia?

= an empirically unanswerable question

VS

B

as a “Super Locked-In” Syndrome

What proportion of VS B could be “super locked-in,” with severe cognitive deficits but with primitive awareness of self and environment, including capacity to experience pain?

= an empirically unanswerable question Experience with congenital apallia and noninvasive functional tests in acquired VS not simply assume it is 0.

B suggest we should “Conscious VS B ” could result from locked-in state plus nothing more than receptive aphasia or oculomotor apraxia.

VS

B

as a “Super Locked-In” Syndrome

• • Plasticity of adult brain Could late recoveries from PVS be the clinical tip of a subclinical iceberg of recoveries from VS C to a “super locked-in” state with primitive form of consciousness?

= an empirically unanswerable question Experience with congenital apallia and noninvasive functional tests in acquired VS B suggest it could conceivably happen.

3

rd

Adjustment

All C are B, but not all B are necessarily C A B C

From VS

B

to VS

C Definition vs. Hypotheses vs. Conclusion vs. Fact

• • • C “by definition” – AAN, Pres Comm, AMA, ANA, MSTF – “The persistent vegetative state

is

a form of eyes-open permanent unconsciousness in which the patient has periods of wakefulness and physiological sleep/wake cycles, but at no time is the patient aware of him- or herself or the environment.” [AAN.

Neurology

1989;39:125-6] C as “hypothesis” – “Given the complexity of exactly how physicians determine consciousness or the complete lack thereof, and the medical-philosophical difficulty in proving beyond any doubt that something (e.g., consciousness) doesn’t exist, [Dr. Burke’s] implication is an important reminder to the medical profession that we must be sure of our facts and continue to gather data and experience to prove or disprove our

evolving hypotheses

.” [Cranford.

Neurology

1990;40:385-6] C as “conclusion” – “There are several independent bases for the neurological

conclusion

that persistent vegetative state patients do not experience pain or suffering…” [AAN.

Neurology

1989;39:125-6]

From VS

B

to VS

C Definition vs. Hypotheses vs. Conclusion vs. Fact

• – – C as “fact” “It is a

fundamental fact

of neuroanatomy and neurophysiology that consciousness and the capacity to experience pain and suffering are functions of the neocortex. When a physician can determine on physical examination that there are no neocortical functions present, the patient is completely unconscious and has no capacity to experience pain or suffering [p.237]....

These views on the medical reality of the PVS patient are scientific medical positions – statements of

fact

, not values. [p.241

]” [Cranford & Smith:

Am J Law Med

1987;13:233-48] “Only a neurological organization can make a definite statement on the neurological

facts

, as the Academy does in Part I. Only a neurological society can categorically state, with sufficient expertise and credibility, that persistent vegetative state patients cannot experience (consciously perceive) pain and suffering.

” [Munsat et al.

Neurology

1989;39:123-4]

AAN basis for concluding VS

C

from VS

B

“There are several independent bases for the neurological conclusion that persistent vegetative state patients do not experience pain or suffering.

– – –

First,

direct clinical experience with these patients demonstrates that there is no behavioral indication of any awareness of pain or suffering.

Second,

suffering.

in all persistent vegetative state patients studied to date, postmortem examination reveals overwhelming bilateral damage to the cerebral hemispheres to a degree incompatible with consciousness or the capacity to experience pain or

Third,

recent data utilizing positron emission tomography indicates that the metabolic rate for glucose in the cerebral cortex is greatly reduced in persistent vegetative state patients, to a degree incompatible with consciousness.” [AAN.

Neurology

1989;39:125-6]

© 1994-2000 Crump Institute for Molecular Imaging UCLA School of Medicine http://www.crump.ucla.edu/software/lpp/clinpetneuro/metabolicdev.html

Circular Reasoning

1. We know that VS patients are unconscious, because they lack cortical functioning.

2. We know that cortical functioning is necessary for consciousness, because patients without cortical functioning are in a VS (show no evidence of consciousness).

3. (

Tacit:

Absence of evidence = evidence of absence.)

Alternative Hypothesis

• • • Unity of consciousness based on “centrencephalic system”: reticular formation & thalamus. [Penfield, Jasper] “It is not known which portions of the brain are responsible for cognition and consciousness; what little is known points to substantial interconnections among the brainstem, subcortical structures and the neocortex. Thus, the 'higher brain' may well exist only as a metaphorical concept, not in reality.” (p. 40) [President’s Commission, 1981] • Role of cortex is (1) interface between world/body and conscious self; (2) integration of sensory input and motor output.

Role of cortex in pain perception is primarily modulatory; cortex is not the site of, and is not necessary for, pain perception.

Stimulation out of VS

B

• • • Cervical cord stimulation Deep brain stimulation Pharmacological stimulation

MCS Definition

“The minimally conscious state is a condition of severely altered consciousness in which minimal but definite behavioral evidence of self or environmental awareness is demonstrated.” Giacino JT, et al. The minimally conscious state.

Neurology

2002;58:349-353.

 Minimal consciousness or minimal evidence ?

MCS Diagnostic Criteria

“MCS is distinguished from VS by the presence of behaviors associated with conscious awareness. In MCS, cognitively mediated behavior occurs inconsistently, but is reproducible or sustained long enough to be differentiated from reflexive behavior. The reproducibility of such evidence is affected by the consistency and complexity of the behavioral response. Extended assessment may be required to determine whether a simple response environmental event … or on a coincidental basis.” … that is observed infrequently is occurring in response to a specific Giacino JT, et al. The minimally conscious state.

Neurology

2002;58:349-353.

MCS Diagnostic Criteria

“Recovery from MCS to higher states of consciousness occurs along a continuum in which the upper boundary is necessarily arbitrary… emergence from MCS is characterized by reliable and consistent demonstration of one or both of the following: 1.

2.

Functional interactive communication.

Functional use of two different objects.” Giacino JT, et al. The minimally conscious state.

Neurology

2002;58:349-353.

Minimally Conscious State

“[T]he Aspen Neurobehavioral Consensus Conference could not identify evidence-based guidelines for the diagnosis, prognosis, and management of the MCS and therefore developed consensus-based guidelines.

Proposing disabilities.

” a new clinical state immediately raises questions: the scientific question of whether it is justifiable to carve a new syndrome out of the continuum of diffuse neuronal damage; and the ethical, legal, and political question of the risks and benefits to society of renaming the condition of certain patients with severe neurologic Bernat JL.

Neurology

2002;58:337-338.