2001 Yearbook of Intensive Care and Emergency Medicine. J-L Vincent (Ed.), Springer, Berlin, pp.

386-396

Cerebral Function in Coma, Vegetative State,

Minimally Conscious State, Locked-in Syndrome,
and Brain Death
S. Laureys, J. Berré, and S. Goldman

Introduction
Progress in intensive care has increased the number of patients who survive severe
acute brain injury. The majority of these patients recover from their coma within the
first days after the insult, others will take more time and go through different stages
before fully or partially recovering awareness (e.g., minimally conscious state,
vegetative state) or will permanently lose all brain functions (i.e., brain death). One of
the most challenging problems facing intensivists is understanding the natural history
of severely brain injured patients and their possibility of recovery. Clinical practice
shows how delicate it is to infallibly recognize unambiguous signs of conscious
perception of the environment and of the self in these patients. This complication is
reflected in the frequent misdiagnosing of the locked-in syndrome, minimally
conscious state and vegetative state [1, 2]. First, objective assessment of residual
brain function in severely brain injured patients is difficult because motor responses
may be small or inconsistent. This is even more so because consciousness is not an
all-or-none phenomenon but part of a continuum [3]. Second, there is a theoretical
limitation to the certainty of our clinical diagnosis, since we can only infer the
presence or absence of conscious experience in another person [4]. In the present
paper, we will first try to define consciousness as it can be assessed at the patient’s
bedside. We then review the major clinical entities of altered states of consciousness
encountered in the intensive care unit. Finally, we discuss the functional
neuroanatomy of these conditions as assessed by positron emission tomography
(PET) scanning.

Consciousness, awareness and arousal

There is at present no satisfactory, universally accepted definition of human

consciousness. The word consciousness originates from the Latin conscio, formed
by the coalescence of cum (with) and scio (to know). The Latin root was used to refer
to knowledge shared with another [5]. William James defined consciousness as
awareness of oneself and the environment [6]. The interpretation of this delineation
depends however on the neuroscientific or philosophical approach of the authors. For
clinical purposes, consciousness consists of two basic elements: arousal and
awareness [7].
Arousal refers to the behavioral continuum that occurs between sleep and
wakefulness. This is not an on-off mechanism as it can show rapid fluctuations in
response to external stimulation (intense, unexpected or novel stimuli) called
2001 Yearbook of Intensive Care and Emergency Medicine. J-L Vincent (Ed.), Springer, Berlin, pp. 386-396

orienting reaction or vigilance. At the patient’s bedside, arousal is defined as the

presence of prolonged periods of spontaneous opening of the eyes.
Awareness refers to the collective thoughts and feelings of an individual. Clinically,
however, our operational definition is limited to the appraisal of the potential to
perceive the external world and to voluntary interact with it (also called perceptual
awareness). In practice this is done by careful and repeated examination of the
capacity to formulate reproducible, voluntary, purposeful and sustained behavioral
responses to auditory, tactile, visual, or noxious stimuli.
Self-consciousness (also called self-awareness) can refer to awareness of
stimuli that impinge directly on our person (e.g., being aware of the seat you sit on) or
it can refer to the control of "an idea of oneself " (e.g., recognizing yourself in the
mirror). The latter can be done from the age of 18 months - as by chimpanzees but
not by macaque or rhesus monkeys [8]. "Awareness of awareness" (e.g., the
knowledge of yourself as a person in a social and cultural world) is thought to emerge
around 5 years of age [5].

Clinical definitions

Coma

Coma is characterized by the absence of arousal and thus also of consciousness. It

is a state of unarousable unresponsiveness in which the patient lies with the eyes
closed and has no awareness of self and surroundings. Although there are
gradations in the depth of coma, the patient lacks the arousal cycles of sleep-
wakefulness characteristic of vegetative state (Table 1). The behavioral repertoire of
coma consists entirely of reflex activity and indicates failure of both the reticular
activating system and the cortex [7]. To be clearly distinguished from syncope,
concussion, or other states of transient unconsciousness, coma must persist for at
least an hour. In general, comatose patients who survive begin to awaken and
recover gradually within 2 to 4 weeks or enter a vegetative or minimally conscious
state.

Vegetative State

Patients in a vegetative state are awake but unaware of self and environment [9].
Jennet and Plum cited the Oxford English Dictionary to clarify their choice of the term
"vegetative": to vegetate is to "live a merely physical life devoid of intellectual activity
or social intercourse" and vegetative describes "an organic body capable of growth
and development but devoid of sensation and thought".
“Persistent vegetative state” is arbitrarily coined as a vegetative state present
one month after acute traumatic or nontraumatic brain injury [10] but does not imply
irreversibility. “Permanent vegetative state” denotes irreversibility after three months
following a nontraumatic brain injury and 12 months after traumatic injury. However,
even after these long and arbitrary delays, some patients may exceptionally recover.
2001 Yearbook of Intensive Care and Emergency Medicine. J-L Vincent (Ed.), Springer, Berlin, pp. 386-396
2001 Yearbook of Intensive Care and Emergency Medicine. J-L Vincent (Ed.), Springer, Berlin, pp. 386-396

Patients in a vegetative state usually show reflex or spontaneous eye opening

and breathing. At times they seem to be awake with their eyes open, sometimes
showing spontaneous roving eye movements and occasionally moving trunk or limbs
in meaningless ways; at other times their eyes are shut and they appear to be
asleep. They may be aroused by painful or prominent stimuli opening their eyes if
they are closed, quickening their breathing, increasing heart rate and blood pressure
and occasionally grimacing or moving. Pupillary, corneal, oculocephalic and gag
reflexes are often preserved. They can make a range of spontaneous movements
including chewing, teeth-grinding and swallowing. More distressingly, they can show
rage, cry, grunt, moan, scream or smile reactions spontaneously or to non-verbal
sounds. Their head and eyes sometimes, inconsistently, turn fleetingly towards new
sounds or sights. These abilities are also seen in another group of patients showing
preserved wakefulness without awareness - namely, infants with anencephaly - and
are considered to be of subcortical origin.
The diagnosis of vegetative state should be questioned when there is any
degree of sustained visual pursuit, consistent and reproducible visual fixation, or
response to threatening gestures. When patients undergo a transition from the
vegetative state to a state if awareness, one of the first and most readily observed
clinical signs of this transition is the appearance of sustained visual pursuit. [10]. The
crucial thing one has to ascertain is the formal absence of any sign of conscious
perception or deliberate action. Any evidence of communication, including a
consistent response to command, or any purposeful movement rule out the
diagnosis. This evidence can easily be missed, especially in patients whose senses
and motor capacities are severely impaired and in whom a blink of an eye (e.g.,
locked-in syndrome) or the subtle movement of a finger may provide the only
evidence of awareness. Careful and prolonged observation is indispensable as
fluctuating arousal or motivation can prevent the assessment of minimal yet present
awareness in these patients.
Apallic state or syndrome is an archaic term for a condition that is now
considered equivalent to vegetative state. The term neocortical death has been used
differently by various authors. Some refer to it as a vegetative state with absence or
substantial slowing of electrocortical activity on electroencephalography (EEG), in
addition to the characteristics of vegetative state. Others equate neocortical death
with the ostensible death of all neurons of the cerebral cortex. It is not clear whether
this term denotes a clinical syndrome or its electrical, pathologic, or anatomical
features [10]. The American Neurological Association has suggested to abandon the
terms apallic state or syndrome, neocortical death, coma vigil, alpha coma and
permanent unconsciousness [11].

Minimally Conscious State

"Minimally conscious state" replaces the term "minimally responsive state" which was
first defined by the American Congress of Rehabilitation Medicine in 1995. It is used
to describe patients who are unable to follow instructions reliably or communicate,
but who demonstrate inconsistent but reproducible behavioral evidence of awareness
of the environment or self-awareness [12]. Patients in minimally conscious state can
2001 Yearbook of Intensive Care and Emergency Medicine. J-L Vincent (Ed.), Springer, Berlin, pp. 386-396

show reproducible visual fixation and emotional or motor behavior that are contingent
upon the presence of specific eliciting stimuli such as episodes of crying that are
precipitated by family voices only, command following, object manipulation,
intelligible verbalization and gestural or verbal yes/no responses. Outcome is thought
to be better relative to vegetative state [13].
Akinetic mutism is a rare condition that has been described as a subcategory
of the minimally conscious syndrome [12], while other authors suggest that the term
should be avoided [11]. It was first introduced by Cairns in 1941 to describe a
condition characterized by severe poverty of movement, speech and thought without
associated arousal disorder or descending motor tract impairment [14]. Typical for
akinetic mutism is the complete or near-complete loss of spontaneity and initiation,
such that action, ideation, speech and emotion are uniformly reduced. The absence
of internally guided behavior allows attention to be passively drawn to any
environmental stimulus that the patient is exposed to [13].

Locked-in Syndrome

The term "locked-in" syndrome was introduced by Plum and Posner in 1966 to reflect
the quadriplegia and anarthria brought about by the disruption of corticospinal and
corticobulbar pathways, respectively [7]. In marked contrast with the previously
described conditions, the defining feature of the locked-in syndrome is the relative
preservation of cognition. The locked-in syndrome superficially resembles vegetative
state, minimally conscious state and akinetic mutism in that wakefulness is generally
well preserved but there is little or no evidence of purposeful verbal or motor behavior
[15]. Consciousness, vertical eye movement and eyelid blinking are intact because
the pontine tegmentum is spared and provides a mechanism for recognizable
command following and communication responses. The locked-in syndrome can also
be associated with diseases of peripheral motor nerves or paralysis produced by the
administration of neuromuscular blocking agents. The mortality rate has been
estimated at 60%, with respiratory failure cited as most frequent cause of death [16].

Brain Death

The concept of brain death as defining the death of the individual is largely accepted.
Most countries have published recommendations for the diagnosis of brain death as
a necessary prerequisite for organ donation, but the diagnostic criteria of brain death
differ from country to country [17]. Some rely on the death of the brainstem only [18],
others feel that death of the whole brain including the brain stem is mandatory [17].
However, the clinical criteria for brain death are very uniform and based on the loss
of all brainstem reflexes and the demonstration of apnea in an irreversibly comatose
patient [19]. The various brain death codes mainly differ for using technical
confirmatory tests to corroborate these clinical signs. Most guidelines allow the use of
EEG, which must demonstrate electrocortical silence. Other neurophysiological tests
which are accepted in some countries as a confirmatory test are: cerebral
panangiography or doppler sonography (demonstrating the cessation of brain
perfusion); brain scintigraphy (confirming the loss of isotope uptake into the brain)
2001 Yearbook of Intensive Care and Emergency Medicine. J-L Vincent (Ed.), Springer, Berlin, pp. 386-396

and evoked potentials (demonstrating the successive loss of activity of various

afferent pathways).

Functional neuroanatomy

Coma

Coma can result from diffuse bihemispheric cortical or white matter damage
secondary to neuronal or axonal injury, or from focal brainstem lesions that disrupt
the rostral segment of the reticular activating system. [18F]fluorodeoxyglucose-PET
has shown a 40 to 50 % reduction of overall gray matter metabolism in traumatic or
hypoxic coma [20, unpublished data]. In patients who recovered from a postanoxic
coma, cerebral metabolic rates for glucose (CMRGlu) still showed a 25 % decrease
[21]. However, cerebral metabolism has recently been shown to correlate poorly with
the level of consciousness, as measured by the Glasgow Coma Scale, in mild to
severely head-injured patients studied within the first month following head trauma
[22]. At present, there is no established correlation between CMRGlu depression and
patient outcome.
A global depression of cerebral metabolism is not unique to coma. When
different anesthetics are titrated to the point of unresponsiveness, the resulting
reduction in CMRGlu is similar as that observed in comatose patients [23-25]. The
lowest values of brain metabolism were reported during propofol anesthesia (72 %

Fig. 1. Cerebral metabolism in the different diagnostic groups (for references see text)
2001 Yearbook of Intensive Care and Emergency Medicine. J-L Vincent (Ed.), Springer, Berlin, pp. 386-396

decrease). Another example of transient metabolic depression can be observed

during deep sleep (stage III and IV) [26, 27]. In this daily physiological condition
CMRGlu can drop to nearly 60 % below normal values (Fig. 1).

Vegetative State

In vegetative state, the brainstem is relatively spared whereas the gray or white
matter of both cerebral hemispheres is widely and severely injured. PET has shown a
50 to 60 % reduction in global cerebral metabolism of vegetative patients [20, 21, 28,
29]. In permanent vegetative state (i.e., 12 months after a trauma or 3 months
following a nontraumatic brain injury), CMRGlu values drop to 60 to 70 % below
normal [20]. This progressive loss of metabolic functioning over time is the result of
progressive Wallerian and transsynaptic neuronal degeneration. Characteristic of
vegetative patients is a relative sparing of CMRGlu in the brainstem (encompassing
the pedunculopontine reticular formation), the hypothalamus and the basal forebrain
[30]. The functional preservation of these structures allows for the preserved arousal,
respiration, and other autonomic functions in these patients. The other hallmark of
the vegetative state is a systematic impairment of CMRGlu in the polymodal
associative cortices (bilateral prefrontal regions, Broca’s area, parieto-temporal and
posterior parietal areas and precuneus) [31]. These brain regions are known to be
important in various consciousness-related functions such as attention, memory and
language. It is still controversial whether the observed metabolic impairment in this
large cortical network reflects an irreversible structural neuronal loss [32] or a
functional and potentially reversible damage. However, in the rare and fortunate
vegetative patients who recover awareness of self and environment, PET shows a
functional recovery of metabolism in these same cortical regions [33, 34]. Moreover,
we demonstrated that the resumption of long-range functional connectivity between
these associative cortices and between some of these and the thalami plays an
important part in the restoration of their functional integrity [35]. The cellular
mechanisms which underlie this functional normalization remain putative: axonal
sprouting, neurite outgrowth, cell division (known to occur predominantly in
associative cortices in normal primates [36]) or even apoptosis. This residual cerebral
plasticity during vegetative state has been largely overlooked and deserves further
investigation. The challenge is now to identify the conditions in which and the
mechanisms by which some vegetative patients may recover consciousness.
The study of possible residual cognitive processing in vegetative state has
been limited to anecdotal case reports [37-40]. Our group was the first to assess
auditory processing in a representative group of vegetative patients [41]. So far,
changes in regional cerebral blood flow (rCBF) and functional cerebral connectivity
have been prospectively studied using H215O-PET in 17 patients. Auditory click
stimuli still activated bilateral primary auditory cortices in vegetative patients but
hierarchically higher-order multimodal association cortices failed to activate.
Moreover, we have shown a cascade of functional disconnections along the auditory
cortical pathways, from primary auditory areas to multimodal and limbic areas,
suggesting that the observed residual cortical processing in the vegetative state
2001 Yearbook of Intensive Care and Emergency Medicine. J-L Vincent (Ed.), Springer, Berlin, pp. 386-396

cannot lead to integrative processes thought to be necessary to attain the normal

level of awareness.

Minimally Conscious State

Because criteria for the minimally conscious state were only recently introduced [12],
there are very few neuropathologic or functional imaging data concerning this
condition. Akinetic mutism is classically caused by bilateral lesions in orbito-mesial
frontal cortex, limbic system encompassing septum and anterior cingulate cortex and
paramedian meso-diencephalic reticular formation [42]. The global inertia is thought
to be the result of inadequate cortical activation arising from disrupted reticulo-
cortical and limbic-cortical circuits [7]. In our experience, minimally conscious patients
show a very different pattern of brain metabolism compared to that observed in
vegetative patients. The region that systematically differentiates both groups of
patients is localized in the medial parietal cortex (precuneus) and adjacent posterior
cingulate cortex (unpublished data). Interestingly, this area is one of the most active
brain regions in conscious waking [43] and is one of the least active regions in
unconscious states such as halothane [25] or propofol [44] induced general
anesthesia and slow wave sleep [26]. We have previously postulated that this
multimodal association cortex represents part of the neural network subserving
human awareness [31].

Locked-in syndrome

Classically, structural brain imaging (magnetic resonance imaging) may show

isolated lesions (bilateral infarction, hemorrhage, or tumor) of the ventral portion of
the basis pontis or midbrain. It is important to stress that EEG and evoked potentials
do not reliably distinguish the locked-in syndrome from the vegetative state [10]. PET
scanning has shown significantly higher metabolic levels in brains of patients in the
locked-in state compared to patients in the vegetative state [29]. Moreover, we have
studied two cases of locked-in syndrome where there was no single voxel in the
supratentorial gray matter that showed a significantly lower CMRGlu than that
observed in our healthy control subjects (unpublished data). These findings
emphasize the terrifying situation of an intact awareness of self and environment in
sensitive beings, locked in immobile bodies.

Brain death

Functional imaging using cerebral perfusion tracers and single photon emission
tomography (SPECT) [45] or cerebral metabolism tracers and PET [46, unpublished
data] typically show an “empty skull” picture in brain death patients confirming the
dead of the “whole brain”.

Conclusion

Comatose, vegetative, minimally conscious or locked-in patients represent a problem

in terms of diagnosis, prognosis, treatment and everyday management at the ICU. At
 2001 Yearbook of Intensive Care and Emergency Medicine. J-L Vincent (Ed.), Springer, Berlin, pp. 386-396

the patient’s bedside, the evaluation of possible cognitive function in these patients is
difficult because voluntary movements may be very small, inconsistent and easily
exhausted. Functional neuroimaging cannot replace the clinical assessment of
patients with altered states of consciousness. Nevertheless, it can describe
objectively how deviant from normal is the cerebral activity and its regional
distribution, at rest and under various conditions of stimulation. The quantification of
brain activity differentiates patients who sometimes only differ by a brief and
incomplete blink of an eye. In our opinion, the use of PET on a wider and wider scale
and the future use of functional magnetic resonance imaging (fMRI) will substantially
increase our understanding of severely brain injured patients.

Acknowledgements. This work was supported by grants from the Fonds National de
la Recherche Scientifique de Belgique (FNRS), the Special Funds for Scientific
Research of the University of Liège, the Funds for Scientific Research of the Erasme
University Hospital and by the Queen Elisabeth Medical Foundation. SL is
Postdoctoral Researcher at the FNRS.

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