I. Introduction

Originally published April 17, 2001 on KurzweilAI.net.

The transition between "unconscious" and "conscious" states is not always easily recognized in persons with brain disorders, especially in patients whose neurological course (improvement or deterioration) is evolving slowly. Defining consciousness has historically been an elusive endeavor. Widely accepted definitions of consciousness often include some reference to awareness of self and the environment (Plum and Posner, 1980; James,1890) or the brain's ability to form a unified representation of the world, our bodies and ourselves (Hobson, 1997). These definitions provoke further questions, including what constitutes "awareness" and what level of awareness is sufficient to attribute "conscious awareness." Block (1996) and others have defined hierarchical levels of consciousness and awareness that highlight distinctions between wakefulness ("crude consciousness"), elemental perception without cognitive awareness and decision-making ("phenomenal consciousness") and directed attention with cognitive awareness ("access consciousness")(table 1).

The problem of definition is further compounded by the concepts of conscious and unconscious mental operations that normally occur in persons in fully conscious states. This includes cognitive operations performed at levels apart from explicit conscious awareness. Examples include priming effects on memory retrieval (Schacter,1980; Tulving & Schacter, 1990), procedural learning (Cohen & Squire, 1980) and "covert" recognition in patients with prosopagnosia (Farah et al, 1997). This also raises the question whether such nonconscious mental operations can occur at all or at some level in patients who are not fully consciousness.

A further problem for clinicians is that consciousness can only be inferred from behavior, a task that is challenging in patients who display only infrequent or noncomplex forms of behavior. There is as yet no good biological probe for consciousness, although functional neuroimaging offers some promise to help in the determination of conscious states. Andrews (1996) pointed out a multiplicity of factors that can confound clinical decision-making based on a patients overt responses. These include: a. the physical ability of the patient to respond; b. the desire or will to respond; c. observer-patient rapport; d. the ability to observe accurately; e. the time available for observation and assessment; f. the lack of available and reliable assessment tools. Even if all of these concerns can be optimized there are still ambiguities in deciding whether some individual patients are truly unconscious (in a vegetative state).

The ambiguities of the clinical assessment of the vegetative state have been addressed recently by the Multi-Society Task Force on PVS (1994) subsequently by the American Academy of Neurology practice parameter (1995). These papers stopped at the clinical boundaries of the vegetative state to distinguish it from states of conscious awareness or from clinically related conditions, such as coma, brain death, locked-in syndrome and akinetic mutism. They pointed out that certain ambiguous clinical signs, such as visual tracking and fixation often herald conscious behavior but also occur in those in prolonged vegetative states. Patients who recover to states of consciousness after prolonged unconsciousness were not specifically discussed with respect to diagnostic labels or prognosis. Instead such patients were described in terms of the functional outcome labels used in the Glasgow Outcome Scale (Jennett & Bond, 1975)--i.e. severe disability, moderate disability.

It has been widely recognized that many patients display a clinical condition that does not fit the criteria for vegetative state (VS) or complete unconsciousness, however these patients cannot be considered fully conscious (Andrews, 1996; ACRM, 1995). This clinical state may occur during the transition between unconsciousness and consciousness, or as a fixed, persistent condition in those with profound brain damage. A number of commonly used clinical scales address the transition to these levels (e.g. the Rancho Los Amigos scale [Hagen et al, 1972], Glasgow Coma Scale [Teasdale & Jennett, 1974], Coma-near coma scale [Rappaport et al, 1992], coma recovery scale [Giacino et al, 1991]). Several workgroups have recently grappled with defining this clinical state (American Congress of Rehabilitation Medicine (ACRM) Interdisciplinary Special Interest Group for Head Injury [1995]; International Working Party on the Management of the Vegetative State [Andrews, 1996] and the Aspen Neurobehavioral Conference Workgroup [Giacino et al, 1997]). The ACRM group (ACRM, 1995) proposed the term, minimally responsive state and the International Working Party used inconsistent low awareness state in addition to various gradations of the vegetative state (Andrews, 1996). More recently the Aspen workgroup recommended the term minimally conscious state (Giacino et al., 1997).

All of these groups recognized the need for more precision in the diagnosis of different levels of impaired consciousness. The distinction between vegetative and minimally conscious states is important because prognosis and treatment choices may be different for these two conditions. Decisions regarding withdrawing fluid and nutrition, continuing medical or rehabilitative treatment, or managing pain and suffering might hinge on the differentiation of unconsciousness and minimal consciousness. Further, scientific study of severe alterations of consciousness requires uniform and precise definitions of these clinical states to allow replication and comparisons across studies. Diagnostic accuracy for the vegetative state, distinguishing it from the minimally conscious state and other related conditions has been less than ideal (Childs et al.,1993; Andrews et al,1996).

II. Definition of Minimally Conscious State

The Aspen workgroup defined the minimally conscious state (MCS) as a condition of severely altered consciousness in which the person demonstrates minimal but definite behavioral evidence of self or environmental awareness (Giacino et al, 1997).

As with patients in the vegetative state (VS), patients in MCS have spontaneous eye opening and sleep-wake cycles. Arousal may range from obtundation to full wakefulness but most patients in MCS will have periods of normal arousal. (Table 2 summarizes the clinical features of coma, VS and MCS [Giacino et al, 1997].)

A. Diagnostic criteria distinguishing VS from MCS

Several diagnostic criteria have been proposed (Giacino et al, 1997; Aspen Neurobehavioral Conference Workgroup, submitted). At least one criterion should be present and occur on a reproducible or sustained basis to diagnose MCS:

1. follows simple commands,
2. gestural or verbal "yes/no" responses (regardless of accuracy),
3. intelligible verbalization
4. movements or affective behaviors that occur in contingent relation to relevant environmental stimulus and are not attributable to reflexive activity.

Any of the following behavioral examples provide sufficient evidence for criterion 4, although this list is not meant to be exhaustive:

B. Diagnostic criteria distinguishing MCS from higher levels of consciousness

Criteria for the upper boundary, distinguishing minimal from higher levels of consciousness, are required to complete the definition of MCS. This clinical boundary is somewhat more arbitrary since there is no single clinical dimension that easily delineates full consciousness. This problem points out the difficulty in defining all of these clinical states, trying to apply distinct clinical borders to a process that occurs along a continuum of recovery or deterioration of arousal and cognition. Nevertheless, the Aspen group proposed the following clinical criteria for emergence from the MCS (Giacino et al, 1997). One or both of the following should be present:

1. functional interactive communication (at least, ability to answer basic yes/no questions regarding personal or environmental orientation questions) or,
2. functional use of objects (demonstrating the ability to appropriately use or discriminate among objects)

It should be apparent that the abilities to communicate or use objects may be affected by loss of certain specific capacities such as language and praxis in a person who is otherwise fully conscious. The ability to communicate or manipulate objects may also be constrained by impairments in speech or motor abilities. In such cases, evaluation of communication and object use should be tailored to the person's preserved motor abilities, or enhanced by compensatory strategies or augmentative devices.

C. Other related terms and conditions

There are a number of related neurological conditions and terms that may include patients with MCS or must be distinguished from MCS.

Akinetic Mutism: This refers to a condition, originally described by Cairns (1941), of wakefulness with an absence or paucity of speech and spontaneous movement. There is usually some evidence of conscious behavior in these patients but the drive or intent to speak or move is severely compromised. A number of clinical and pathological variations of this condition have been described. In general, akinetic mutism involves bilateral damage to reticular-cortical or limbic-cortical connections in the central neuraxis, from paramedian reticular areas of the midbrain and diencephalon to basal or medial frontal areas (Plum & Posner, 1980).

Akinetic Mutism should be considered a form of MCS.

Dementia: This term refers to a persistent impairment of intellectual function involving a number of cognitive spheres. It is a general term that may or may not imply a compromise in consciousness. Therefore, patients in MCS may be considered demented but not all patients with dementia may be in a MCS.

Locked-in syndrome: This is a condition of loss of voluntary motor control in the setting of preserved consciousness. The classic syndrome involves damage to corticospinal and corticobulbar pathways in the basis pontis. Other conditions that cause bilateral profound damage to these pathways or diffuse compromise to peripheral nerves (e.g. Guillain-Barre) or neuromuscular junction (e.g. neuromuscular blocking agents) can cause the syndrome.

MCS must be distinguished from locked-in syndrome since locked-in implies fully preserved consciousness. It should be recognized, however, that many patients with MCS have profound loss of motor abilities because of concomitant damage to motor control areas. It may be difficult to demonstrate conscious behavior as it emerges in these patients because of limited motor output capabilities. Therefore, patients in MCS may recover to a relatively locked-in state.

Obtundation and stupor: These terms refer to reductions in alertness and arousal. Patients can be aroused with vigorous stimulation but fall back into unresponsive, sleep-like states without stimulation.

Although patients in MCS may be described as obtunded or stuporous at times, patients in MCS may be fully wakeful.

III. Diagnosis and assessment

A. Pathophysiology and diagnostic studies

The pathologic substrate of MCS has not been specifically studied. The pathologic causes should be the same as those that cause VS because of the relationship of the two conditions. The absence of cognitive activity implies that there is a profound loss of cortical function. The clinical distinction between VS and MCS suggests that the pathophysiological difference is in the amount of cortical dysfunction, so that patients in MCS have resumed some associative cortical activity (see table 3). The principal pathological causes of more prolonged VS are multifocal or diffuse cortical damage (e.g. laminar necrosis), such as occurs after hypoxic-ischemic brain damage (Dougherty et al, 1981), or very severe diffuse axonal injury, as occurs after traumatic brain injury (Adams et al, 1982). Patients with impaired consciousness after severe traumatic brain injury may have combinations of diffuse axonal injury and hypoxic-ischemic injury, or brainstem-diencephalic damage from herniation related to a mass lesion (Multisociety Task Force on PVS, 1994). A much less common cause of VS is relatively selective necrosis of the thalamus after anoxia (Kinney et al, 1994). Degenerative, metabolic and developmental disorders may also cause VS. In addition to those recognized causes of prolonged VS, there are probably other distinct pathologic causes of prolonged MCS. Included are those pathologic profiles that cause akinetic mutism, discussed above. For instance, patients have been described with persistent akinetic mute types of dementia have been described following bilateral damage to the mesencephalon and diencephalon (Katz et al, 1987).

There are no specific findings on neuroimaging or electrodiagnostic studies to distinguish the MCS from VS. In an analysis of MRI findings in patients with prolonged post-traumatic unconsciousness (at least 6 to 8 weeks), patients who did not regain consciousness within 1 year had a significantly higher frequency of lesions in the corpus callosum, corona radiata and dorsolateral brainstem, as well as involvement of more brain regions (Kampfl et al, 1998). Other studies have pointed out that lesions involving the corpus callosum and dorsolateral midbrain occur in the most severe cases of diffuse axonal injury (DAI) (Adams et al, 1989; Blumbergs et al, 1989). These findings suggest that in patients with traumatic brain injury, distinctions between VS and MCS at any time post injury may be reflected in MRI lesion profiles related to the severity of DAI.

The EEG in VS has shown a variety of abnormalities from diffuse delta or theta slowing, to continual alpha activity, to very low voltage activity (Multisociety Task Force on PVS, 1994; Hansotia, 1985). Emergence from the VS has been associated with diminishing theta and delta rhythms and reemergence of reactive alpha activity (Hansotia, 1985).

Functional neuroimaging of patients in VS have demonstrated marked reductions (up to 60%) in studies of cerebral metabolism and blood flow (Levy et al, 1987). There are no specific studies of cerebral metabolism of patients in MCS so the minimum metabolic threshold levels or localization of cortical activity have yet to be determined.

B. Assessment of responses--complexity vs. consistency

Even when the distinctions between VS and MCS as defined here are clarified, the assessment of whether a patient with inconsistent or ambiguous responses fits the criteria for MCS can be difficult. Cognitive awareness or conscious intent may be difficult to interpret when responses are extremely inconsistent or simple. There is an inverse relationship between the dimensions of complexity and consistency when judging whether behavior is evidence of consciousness. When a behavior is more complex, such as a verbalization, fewer instances of the response are sufficient to diagnose consciousness. When a behavior is less complex, such as a finger movement, a greater number of occurrences are necessary to establish a link to stimulus awareness or conscious intention.

C. Methods of evaluation in the diagnosis of MCS

There are no standard evaluation procedures for the neurological examination of patients with minimal consciousness. Most neurologists are familiar with the clinical examination of the patient with impaired consciousness. Nevertheless, frequent errors in diagnosis occur (Childs et al, 1993; Andrews et al, 1996) either because of a misinterpretation in results or examinations that are inadequate to detect minimal, inconsistent responsiveness.

The general goals of the neurological examination of patients with impaired consciousness include assessment of the integrity of brainstem pathways (e.g. pupilary responses, ocular movements, oculovestibular reflexes, breathing patterns) and the presence of higher level cortical functions (e.g. purposeful, voluntary behaviors). It is the latter that determines the distinction of MCS from VS or higher level states. Patients who fit the definition of MCS must have some restoration of cortical functioning and it is the job of the examiner to systematically elicit and distinguish behaviors that are evidence of cortical activity.

A systematic approach to the examination of patients with impaired consciousness includes the following steps:

1. Brainstem integrity and other subcortical evaluation
• Pupillary response, blink reflex to visual threat
• Ocular movements, gaze deviations
• Oculovestibular reflexes (occulocephalic maneuvers, calorics)
• Corneal response
• Gag reflex
• Breathing pattern
• Decerebrate postures
• Other posturing, reflexes and tone
2. Cortical functioning
1. observation of spontaneous activity
2. purposeful, complex movements (involving cortically mediated isolated motor control) vs. posturing (decorticate or decerebrate) or reflex or stereotyped, patterned (subcortically mediated) movements (Note: Pilon and Sullivan (1996) observed differing postural profiles for VS and MCS patients. VS patients demonstrated classic decerebrate, decorticate or hypotonic postures, whereas MCS patients either symmetric, asymmetric or global flexion postures. However, no other pattern of reflex responses discriminated the 2 groups.)
3. spontaneous vocalizations or verbalizations
4. eye movements (signs of fixation or tracking vs. nonspecific roving or no movement)
• responses to stimulation or environment
5. tracking or fixation to stimuli (try salient stimuli such as familiar pictures, faces, money, mirror)
6. verbal stimulation (e.g. patient's name, commands, social greetings):
• Begin with simple commands sampling a variety of areas under different neural control, favoring those areas of potentially preserved movement.
7. eye commands--e.g. 'look up', 'blink twice';
8. limb commands--e.g. 'make a fist', 'show 2 fingers', 'raise your arm';
9. oral commands--e.g. 'open mouth,' 'stick out tongue';
10. axial or whole body commands--e.g. 'turn your head,' 'lean forward').
11. ask patient to 'stop moving' or 'hold still' to distinguish from spontaneous repetitive movements.
12. noxious stimulation
13. look for localization or purposeful defensive maneuvers vs. reflexive or generalized, stereotyped movements or facial expressions.
14. responses in contingent relationship to environment or other stimuli
15. look for intentional reach for or manipulation of objects on or around the patient (e.g. pulling at tubes, clothing, items placed in the hand)
16. look for changes in facial expression contingent on stimuli such as familiar voices, particular conversation, pictures, music, etc.
17. look for attempts at purposeful mobility in bed, chair, and even ambulation
18. gestural behaviors indicating intentive communication (e.g. yes/no signals)

D. Pitfalls in the diagnosis of MCS and examination strategies to enhance detection of consciousness

There are several "pitfalls" in distinguishing MCS from VS. These include:

• attributing purposeful intent for stimulus contingency to reflexive or generalized responses
• inadequate evaluation to detect conscious behavior--e.g. too brief a sampling time, inadequate arousal, insufficient choice of stimuli
• over or underconsideration of family or other's observation of purposeful behavior (recognize that family may be first to observe signs of consciousness and also may tend to overattribute purposefulness to a patient's responses)
• simple, cortically mediated behaviors of uncertain cognitive significance--e.g. tracking, simple isolated limb movements
• confounding factors affecting arousal

The evaluation of patients with impaired consciousness may be confounded by a number of factors. These include effects of centrally acting medications, concurrent illness, distracting environmental stimuli, the patient's state of arousal at the time of evaluation and the frequent occurrence of uninhibited reflex or other stereotypical responses,. The examiner should use strategies to account for some of these confounds and maximize the chance of detecting signs of conscious behavior. Strategies include:

E. Standardized assessment tools and scales

1. Scales for impaired consciousness

Aside from the clinical bedside examination, there are a number of more objective, standardized assessment tools and scales to track patients transitioning between unconsciousness and consciousness. The Glasgow Coma Scale (GCS) (Teasdale and Jennett, 1974) is the most commonly used instrument. The Disability Rating Scale (Rappaport et al, 1982) is frequently used in rehabilitation populations but basically incorporates the same criteria as the GCS for impaired consciousness. The Rancho Los Amigos Levels of Cognitive Functioning (RLA) (Hagen, 1972) is also commonly used in rehabilitation populations, especially for patients with traumatic brain injury (table 4). The first three levels of this 8 level scale describe patients in coma (RLA I--no response), vegetative state (RLA II--generalized responses) and the transition between vegetative and minimally conscious states (RLA III--localized responses). Another similar scale, used to describe stages of recovery after diffuse brain injury, incorporates some of the more familiar neurological nomenclature (table 5) (Katz, 1993, 1997, Katz and Alexander, 1994; Alexander, 1982).

2. Assessment protocols for impaired consciousness

None of the above mentioned scales are sensitive to small changes in responsiveness in unconscious and minimally conscious patients. Several instruments have been developed for this purpose, including the Western Neuro Sensory Stimulation Profile (Ansell et al, 1989), the Coma Recovery Scale (Giacino et al, 1991), the Sensory Stimulation Assessment Measure (Rader & Ellis, 1994) and the Coma/Near Coma Scale (Rappaport et al., 1992). These scales provide a systematic measure of responses using a standardized stimulation protocol. Distinctions between VS and MCS can be made using these scales based on total scores or subscores on individual items demonstrating purposeful responses. Evaluation of these scales on the same group of patients demonstrated fairly high correlations between them (mild floor effect on the Western Neuro Profile) and some prognostic value (O'Dell et al 1996).

3. Quantitative assessment of impaired consciousness

Whyte and colleagues (1995) developed a quantitative method of assessing consciousness in minimally responsive patients. These procedures are an attempt to remove subjective judgement and substitute statistically-based, single subject design trials to assess whether responses are consciously mediated. For instance, patients may be presented either a photograph or white card or both in the left or right visual field in random order. The patients responses are recorded as looking left, right or neither direction in response to stimuli. Statistical evaluation is carried out to determine whether gaze was purposefully directed toward the more salient stimulus greater than chance. This method might also detect a visual field deficit or unilateral neglect in patients with impaired consciousness. Similar quantitative procedures can be carried out for command following and yes/ no responsiveness (DiPasquale & Whyte, 1996).

IV. Prognosis

A. Outcome of MCS

There is very little specific information about the prognosis of the MCS. Rappaport and coworkers (1992) reported improvement in 25% of a small group of patients with impaired consciousness followed over a 4-month period. Only those in MCS (referred to as "near-coma") improved; none in VS improved in the follow-up period.

There is to date only one systematic study comparing outcome of patients in VS versus MCS (Giacino & Kalmar, 1997). In this study 55 patients in VS were compared to 49 patients in MCS when they were first evaluated an average of 9.6 weeks post-injury. Causes of injury were traumatic (n=70) and non-traumatic (n=34) (mostly anoxic brain injury and stroke). Using the Disability Rating Scale as the outcome measure at 1,3,6 and 12 months post-injury they reported the following findings:

• Patients initially in MCS fared better than those initially in VS, the differences becoming progressively more apparent at 3, 6 and 12 months post-injury.
• Patients in MCS after traumatic brain injury had less disability than after non-traumatic injuries. (There were no significant differences in outcome between traumatic and non-traumatic causes among patients initially in VS.)
• The probability of a more favorable outcome (moderate or no disability) by one year was much greater for the MCS group (38%) than the VS group (2%) and only occurred in those patients with traumatic brain injury.
• 43% of the MCS group remained severely disabled or worse (1/10 of the non-traumatic MCS group was vegetative and 2/10 died) at 12 months.
• So-called "borderzone" clinical signs--visual tracking, motor agitation--were much more prevalent among patients in MCS than those in VS. 73% of patients in VS who displayed tracking recovered consciousness, whereas 45% without tracking recovered consciousness.

B. MCS and VS in the natural history of recovery of brain injury

MCS and VS should be viewed as a part of the natural history of diffuse and multifocal brain injury. The majority of patients with diffuse brain injury (traumatic and non-traumatic) pass through a series of stages that are qualitatively similar across a wide range of severity (table 5). The duration of these stages and severity of impairments vary in proportion to injury severity (Katz, 1997; Katz & Alexander, 1994). Most patients with brain injury severe enough to cause unconsciousness, probably progress through stages of unconsciousness, with eyes closed (coma), to unconsciousness with eyes open (vegetative state), to a stage of inconsistent, erratic responsiveness (minimally conscious state). Once consciousness is clearly established, patients enter a stage of impaired attention and anterograde amnesia (e.g. post-traumatic amnesia) (confusional state) followed by a post-confusion phase of recovery.

In patients with very severe damage, recovery may stall at one or another stage (e.g. "permanent" vegetative state or minimally conscious state). Patients with less severe injuries may transition through the early stages quickly and discreet stages may not be clinically apparent. It remains to be established what proportion of patients recovering from unconsciousness at different severities of injury evolve through discernible coma, VS and MCS stages.

Viewed in this way, the transition from unconsciousness to consciousness is a continuum without distinct boundaries. As the transition progresses, and cortical function resumes, the consistency and complexity of behavior increases. The first signs of the transition may be an increase in alertness and spontaneous movement with lower levels of stimulation, such as the arrival of the examiner (Wilson et al., 1996). At the borderzone, behaviors such as tracking, emotional expressions and non-stereotyped motor sequences resume heralding higher level cognitive behaviors (Andrews, 1993; Ansell, 1995; Multisociety Task Force on PVS, 1994; Giacino & Kalmar, 1997). A small number of patients will recover these "borderzone" behaviors without resuming any other cognitive behavior, such as following commands (Andrews, 1993; Giacino & Kalmar, 1997).

V. Treatment implications

Decisions regarding basic medical and rehabilitative care of patients in VS and MCS are largely the same. Some treatment decisions may differ, however, based on 3 factors: 1. Differences in prognosis; 2. Potential for establishing communication; 3. Possibility of pain and suffering.

The more favorable prognosis of MCS over VS and the absence of established guidelines for permanence of MCS would affect decisions with respect to duration of rehabilitative efforts and withdrawal of treatment, including fluid and nutrition. The potential for communication supports greater emphasis on strategies to promote arousal and developing alternative or augmentative systems of communication. The potential for pain and suffering in patients in MCS, in contrast to patients in VS, supports a greater emphasis on comfort measures and on administering or withholding treatment that might cause or avoid discomfort.

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