D. Alan Shewmon, MD

Professor of Neurology and PediatricsDavid Geffen School of Medicine at UCLA

Chief, Neurology DepartmentOlive View-UCLA Medical Center

Judicial Seminar on Emerging Issues in NeuroscienceStanford UniversityDecember 8, 2006

Comatose, Vegetative and Minimally Conscious States

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• 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

Coma vs. “Brain Death”Coma vs. “Brain Death”

“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• 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)

Coma vs. Vegetative StateComa vs. Vegetative State

• 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

VS, MCS HistoryVS, MCS History

Vegetative State• Coma vigil• Post-coma

unresponsiveness• Post-coma

unawareness

Min. Cons. State• Severe disability• Minimally responsive

state

Proposed Alternative Terminologies

Proposed Alternative Terminologies

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

• Anatomy: Apallic Syndrome, “neocortical death” (Ingvar)

• Behavior: eyes-open unresponsiveness (Jennett and Plum)

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

The ABC of VS (to be adjusted according to evidence…)

A

B C

1st Adjustment Most VS is not VSA

A

B C

Given VSA:

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 VSA – structural– functional

Research on VSA

Few studies on VSA population

• Acquired Apallia– [Ingvar et al. Ann NY Acad Sci 1978;315:184-208]– 8 adults with severe hypoxic-ischemic damage– all behaviorally unresponsive (=VSB)– can unconsciousness be inferred? (VSC?)

• Congenital Apallia – [Shewmon et al. Dev Med Child Neurol 1999;41:364-74]– 3 congenitally decorticate children – adaptive interaction with environment (VSB)– presumably conscious ( VSC)

Possible Reasons for Unresponsiveness in Acquired VSA

1. Unconsciousness2. Obstacle(s) to manifesting consciousness (“super-locked-in

state”)– Spastic quadriplegia & pseudobulbar palsy – Apraxia of any residual voluntary movements– Global aphasia– Akinetic 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.

2nd AdjustmentSome A are neither B nor C

A

B C

Research on VSC

• Intrinsically impossible– Pt population is not empirically identifiable

– VSC can only be an inference from A and B

(if such an inference can even be validly made…)

Research on VSB

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 VSB

Verified Hypotheses re Astruct

• Some B are Astruct

• Not all B are Astruct (in fact, most aren’t)

• Neuropathology of VSB – wide variation in location & extent of damage

Research on VSB

Verified Hypotheses re Afunct

• VSB can result from a functioning brainstem and the total loss of cerebral cortical functioning. (Some B are Afunct.)

• VSB can result from disconnection between islands of functioning cortex.

Corollary: Not all B are Afunct.

Global Cerebral Metabolism

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

Global Cerebral Metabolism in VSB

• 40-65% of normal • Similar to deep anesthesia

Beuthien-Baumann, DeVolder, Larsen, Levy, Rudolf…

Global Cerebral Metabolism in VSB

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

VSB 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 VSB

Hypotheses re C

• Hypotheses inferring VSC from VSB are empirically untestable, regardless whether A or not-A.

– Pts in VSB are unaware of environment.

– Pts in VSB are unaware of self.

– Pts in VSB are incapable of experiencing pain or

suffering.

Research on VSB

Evidence raising questions re C

• “Cognitive ERPs”

• Changes in rCBF to cognitive/emotional stimuli

• Possibility of “super locked-in state”

“Cognitive" Event-Related Potentials

• P300 in traumatic comaReuter et al. Arch Psychol 1989;141:155-73

• P300 predicts awakening in non-traumatic comaDeGiorgio et al. Acta Neurol Scand 1993;87:423-7Gott et al. Arch Neurol 1991;48:1267-70O'Mahony Lancet 1990;336:1265-6Yingling Lancet 1990;336:873

• P300 in traumatic PVSRappaport et al. J Neuropsychiatry Clin Neurosci

1991;3(2):180-5

• Mismatch negativity in PVSGlass et al. Clin EEG 1998;29:19-30Kaga et al. Ann Neurol 1996;40:316

• Cognitive ERPs in coma and PVSKotchoubey et al. News Physiol Sci 2002;17:38-42

Semantic Processing in VSB

• 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” (<MCS) – 77% w N400• VS – 39% w N400

“We can no longer conceptualize the VS as a state in which only vegetative (i.e. autonomous) functions are preserved and cognitive abilities are nil. Some VS patients [and] an even higher percentage of near-VS patients are able to perform semantic processing.”

Schoenle & Witzke. 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 VSB 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 stimuli

Noxious Somatosensory Stimulation in VSB

• 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 2002;17(2):732-41]

• does activate secondary somatosensory, insular, posterior parietal, and cingulate cortices

[Kassubek et al. J Neurol Sci 2003;212(1-2):85-91]

VSB 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

VSB as a “Super Locked-In” Syndrome

What proportion of VSB 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 VSB suggest we should not simply assume it is 0.

“Conscious VSB” could result from locked-in state plus nothing more than receptive aphasia or oculomotor apraxia.

VSB 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 VSC 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 VSB suggest it could conceivably happen.

3rd AdjustmentAll C are B, but not all B are necessarily C

A

C

B

From VSB to VSC

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 VSB to VSC

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 VSC from VSB

“There are several independent bases for the neurologicalconclusion 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, 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 suffering.

– 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 VSB

• 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… that is observed infrequently is occurring in response to a specific environmental event… or on a coincidental basis.”

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. Functional interactive communication.2. 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 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 disabilities.”

Bernat JL. Neurology 2002;58:337-338.