Unresponsive Wakefulness Syndrome and Minimally Conscious State: Towards a Better Understanding of Disorders of Consciousness

The progress of intensive care medicine led to an increased incidence of patients “awakening” from a coma some days to weeks after an acute brain insult (often also after a period of sedation or anesthesia/pharmacological coma). Disorders of consciousness (DOCs) consist of three main pathological states on a continuum ranging from no awareness and arousal to normal arousal with fluctuating awareness. Coma is an acute condition (i.e. lasting no more than some days or weeks) defined by a complete absence of awareness and consciousness.  The  patient  lies  with  eyes  closed  and  is  not  aware  of  himself  or  his environment1. Patients in a coma cannot be awakened even in the presence of intense stimulation. The two main causes of a comatose state are (1) diffuse cortical damage in the two cerebral hemispheres and / or (2) bilateral white matter lesions or lesions of the brainstem reticular formation that is responsible for awakening.

After a few days or weeks of coma, some patients may evolve to a “vegetative state (VS)”. Here, the patient is still not aware of himself and his surroundings but differs from the coma patients by the presence of preserved sleep-wake cycles2 . Most patients in VS recover some degree of consciousness in the months following the accident but some can remain in this condition for years. Although these patients “awaken” from their coma (i.e. open the eyes, start to breath unaided) they remain “unresponsive” (i.e. without response to commands and only showing reflex movements). This condition raises great interest and a lot of debate because of its paradoxical appearance. In Europe, this clinical syndrome was initially termed apallic syndrome3 or coma vigil4, but it was later coined by Plum and Jennett as “persistent vegetative state (PVS)” 5. The term was chosen because patients in this state would show intact  vegetative  functions  of  the  brainstem  (i.e.  sleep-wake  cycles,  thermoregulation, digestion, respiration). In 1994, the MultiSociety Task Force on PVS defined the temporal criteria for irreversibility and introduced the notion of permanent vegetative state. If the patient is still in a VS three months after a non-traumatic injury or one year after a traumatic accident, his/her chances of recovery are close to zero2. Moreover, if there is no sign of recovery of consciousness within three to twelve months after the accident (depending on the etiology), the patient will receive the diagnosis of permanent VS 6, 7. It is to these latter cases that the ethical and legal end-of-life issues, of withholding and withdrawal of life sustaining treatment (that is, artificial hydration and nutrition), are related 8, 9. Unfortunately the abbreviation for Persistent Vegetative State (i.e., PVS) is time and again confounded with the abbreviation for Permanent Vegetative State 7, 10 and, in line with the recommendations of the American Congress of Rehabilitation Medicine11, we prefer to avoid the use of the terms “persistent” and “permanent” in favor of simply specifying the etiology and length of time patients spent in a vegetative/unresponsive condition.

Since the definition of the condition, physicians and healthcare workers have been feeling uncomfortable with the negative connoted term “vegetative” and a lot of efforts have been put together in order to intellectually justify its choice 6. Its origins begin with Willis who first differentiated between voluntary and involuntary motion. He claimed that voluntary motion was supposedly governed by the cerebrum, and involuntary motion, by the cerebellum12. After him, Bichat brought the knowledge of the nervous system to a new era with the assumption that there is a physiological and anatomical separation of life into two different forms: animalic and vegetative. The first one would refer to voluntary behavior and external senses and the second one would refer to the passive survival functions of the body (i.e. nutrition). Therefore, all bodily functions would be provided through two different nervous systems in parallel. According to the Oxford English dictionary “vegetative” describes “an organic body capable of growth and development but devoid sensations and thoughts”.

The more descriptive and neutral name “Unresponsive Wakefulness Syndrome (UWS)” was chosen in 2010 by the European Task Force on Disorders of Consciousness in order to solve the issue of the pejorative connotation intrinsic to PVS13. “Unresponsive” was chosen to illustrate that these patients only show reflex movements without response to commands. “Wakefulness” refers to the presence of eye opening – spontaneous or stimulation induced – never observed in coma. “Syndrome” stresses that we are assessing a series of clinical signs (in line with the Australian National Health & Medical Research Council Information Paper) 14.

Patients who do recover from the UWS/VS, classically evolve to a minimally responsive or minimally conscious state (MCS), characterized by the presence of inconsistent but reproducible oriented behavior (e.g. response to command) proving that the patient has a sense of self and / or sensory awareness15. By definition, MCS patients cannot communicate their thoughts or wishes16. Like the UWS/VS, MCS may be a transient or a chronic condition.

In sum, what mainly distinguishes these altered states of consciousness is their level of vigilance and awareness. Recently, a subcategorization has been proposed for the MCS condition. Since the patients’ behavioural responses can differ in their level of complexity, MCS+ has been chosen to refer to high-level behavioural responses (i.e. command following and intelligible verbalizations or non-functional communication) and MCS- has been chosen for the display of low-level behavioural responses (i.e., visual pursuit, localization of noxious stimulation or contingent behaviour such as appropriate smiling or crying to emotional stimuli)17. Since clinical research on MCS patients is quite recent, there is still no well- established criterion for the diagnosis of permanent MCS. Some patients may remain in this state for several years and gradually evolve to a normal level of consciousness18. Contrary to coma and UWS/VS states, MCS is still not appearing into the Current World Health Organization’s International Classification of Diseases for disorders of consciousness. Therefore, a new code should be proposed to account for this condition.

Table 1


Current World Health Organization's International Classification of Diseases 2011 ICD9CM codes for disorders of consciousness and locked-in syndrome with proposed code and definition for the minimally conscious state.
Diagnosis code Diagnosis Definition
780.0 Alteration of consciousness None
   -780.01 Coma Profound state of unconsciousness associated with depressed cerebral activity from which the individual cannot be aroused; coma generally occurs when there is dysfunction or injury involving both cerebral hemispheres or the brain stem.
   -780.02 Transient alteration of consciousness None
   -780.03 Persistent vegetative state None
   -780.09 Alteration of consciousness other
  • Loss of the ability to maintain awareness of self and environment combined with markedly reduced responsiveness to environmental stimuli.
  • The neurologic status characterized by the occurrence of a loss of the ability to perceive and respond.
  • Obtundation, a dulled or reduced level of alertness or consciousness.
   *-780.12 Minimally conscious state Non-communicative patients with severly altered consciousness showing minimal but definite signs of consciousness by the presence of inconsistent but reproducible oriented behavior.


MCS (-) - Minimal levels of behavioural interaction characterized by the presence of non-reflex movements such as: (i) orientation of noxious stimuli, (ii) pursuit eye movements that occur appropriately in relation to relevant environmental stimuli.
MCS (+) - Presence of (i) command following, (ii) intelligible verbalization or (iii) gestural or verbal yes/no responses.
344.8 Other specified paralytic syndromes  
   -344.81 Locked-in state None
* New proposed code and definition for the minimally conscious state.
Adapted from Gosseries et al. in NeuroRehabilitation (2011)

As well as for escaping the negative connotation of “vegetative” (unintentionally comparing patients to vegetables), the recent proposal of the new term was also motivated by the increasing evidence from functional neuroimaging and electrophysiology demonstrating some residual cognitive processing in a subgroup of patients who clinically failed to show any response to commands. These findings illustrate the issues in quantifying consciousness at the bedside. It has been shown that misdiagnosis of DOC patients can reach to more than 40% especially when it comes to differentiate UWS/VS and MCS conditions19. Assessing consciousness with behavioral scales remain the "gold standard" for the diagnosis in DOC but can be complicated by the patient’s motor impairments like spasticity or his/her constantly fluctuating arousal level. Therefore, repeated assessments with complementary exams using neuroimaging techniques and brain-computer interfaces are required for a more accurate diagnosis. Furthermore, functional neuroimaging techniques can bring substantial informative elements for the prognostic20. It goes without saying that misdiagnosis can lead to high impact consequences for the patient and his/her family.

Figure 1
Clinical criteria for disorders of consciousness.

Clinical criteria for disorders of consciousness.Adapted from Bruno et al. in Current Opinion in Critical Care (2011)

The improvement of neuroimaging techniques has allowed great progress in our understanding of the structure, function and connectivity of the human brain and its relationship to the emergence of conscious awareness21. Studies using Pet Scan have shown that cerebral activation of the precuneus and anterior cingulate cortex regions seems to be a key feature in differentiating between unconscious and conscious patients7. Furthermore, we now know that each altered state of consciousness corresponds to particular patterns of residual cerebral functioning. For example, patients with chronic traumatic frontal lesions in UWS/VS shows more extensive hypometabolism in the median-basal, medial prefrontal, precuneus and the thalamus than patients in MCS22. DOCs are also characterized by distinct cerebral patterns in response to sensory stimulation. Functional disconnections between cortico-cortical and thalamo-cortical networks have been identified in UWS/VS patients23, 24. Indeed,  a  functional  disconnection  of  the  primary  sensory  cortex  from  the  associative cortical networks has been observed for auditory, somatosensory and visual stimuli, suggesting an impaired perception of the environment. Moreover, salient stimuli or pain, generally leading to the activation involving « high level » associative regions, will only activate primary sensory regions without spreading to associative cortices that are essential for a more elaborate interpretation of the stimuli25, 26. This suggests a lack of information integration and hence, an absence of a conscious perception 21. On the other hand, it is important to stress out that patients in UWS/VS do not show a complete absence of cortical connectivity and some patients may still show brain activity that is similar to what it is observed in patients in MCS in response to stimulations27, 28 29. The presence of such higher level activation has been associated with a favorable prognosis26.

Functional magnetic resonance imaging (fMRI) offers the opportunity to study the neural correlates of consciousness either in healthy subjects or in DOC patients. Several methods currently exist with some observing the cortical responses during sensory stimulation, some measure neural activity at rest30, 31 and others use active paradigms in which cognitive tasks of mental imagery are required32. fMRI has also helped to highlight a particular network corresponding to brain activity at rest. Demonstrated for the first time by Gusnard and Raischle in 2001, this network encompasses the posterior cingulate cortex / precuneus, temporo-parietal junctions, the medial prefrontal cortex, the parahippocampal gyri and the thalamus33. The authors proposed the concept of “default mode network (DMN)” after observing deactivation of all these regions when healthy subjects were currently conducting active tasks, as well as activation of this network when the subjects were at rest, awake with their eyes closed. The DMN have a role in conscious processes and it has been shown that the degree of connectivity within this network identified with fMRI appears to be quantitatively related to the level of awareness in DOC patients31. The study of this network might be an aid to clinical diagnosis of UWS/VS and MCS patients. Moreover, functional neuroimaging studies have demonstrated that UWS/VS patients show a particularly affected fronto-parietal network, including the lateral prefrontal and posterior parietal associative cortices (in red, figure 2, critical for external awareness) and median anterior cingulate/mesiofrontal and posterior cingulate/precuneus areas (in blue, figure 2, important for internal awareness)7, 24.

Figure 2
Brain regions associated with internal and external awareness.

Clinical criteria for disorders of consciousness.Adapted from Bruno et al. in Current Opinion in Critical Care (2011)

Unlike  UWS/VS  patients,  functional  imaging  studies  show  a  more  extensive  cortical activation in MCS patients suggesting a much more integrated information processing34. For instance, auditory stimuli with emotional valence in contrast to neutral stimuli (such as the cries of a baby35, or a story narrated by the patient's mother36) induce significantly extended brain in patients in minimally conscious state as neutral stimuli.

EEG tools also permit improvements in the categorization of DOC patients. In a recent study using high density EEG, Boly and colleagues showed that beyond the activation of specific brain regions necessary for a conscious perception (i.e. fronto-parietal network), the interaction between these regions and, more accurately, top-down feedback loops would be more relevant in differentiating UWS/VS from MCS. Thus, UWS patients would differ from MCS patients by the impairment of backward connectivity from frontal to temporal cortices37.  Such  studies provide essential information for  diagnosis and prognosis purposes in correlating the level of brain functional integrity with the level of consciousness.

In all the individuals living with a DOC, it is estimated that up to 40% of them are children38. Like in adults, the most common causes leading to a DOC in children are acute traumatic and non-traumatic (hypoxic-ischemic) injuries to the nervous system2. There is also the same consensus for the prognosis of UWS/VS condition based on the traumatic and non-traumatic etiology (that is, more than one year for traumatic and three months for non-traumatic (anoxic) etiology)2. Children and adolescents in a UWS/VS condition lack awareness of themselves and of their environment. When emerging from this condition, children might show some minimal but reproducible signs of consciousness that are associated with a MCS diagnosis. However, assessing the level of consciousness at bedside in a pediatric population can be especially challenging because of the possible developmental limitations. Consequently, clinicians must be very careful when assessing infants and young children with behavioural scales39. Therefore, neuroimaging techniques like magnetic resonance imaging are especially important to integrate in the clinical routine to overcome the difficulties inherent to pediatric patients’ evaluation40.

In conclusion, the recent proposal of ‘unresponsive wakefulness syndrome’ as an alternative name for patients previously coined ‘vegetative’ or ‘apallic’ was motivated by the need of replacement of the previous negatively connotated term and by the recent advances in the field of neuroimaging showing that some patients who fail to show response to command with bedside behavioural assessments may still show some residual cognitive processing. Moreover, this new term offers the medical community the possibility to adopt a neutral and descriptive name for the clinical syndrome describing patients who fail to show voluntary motor responsiveness in the presence of eyes-open wakefulness. UWS/VS can be chronic or transient with patients evolving to MCS. The rate of misdiagnosis between these two medical entities is still very high therefore the use of behavioral scales in parallel with the increasingly powerful neuroimaging technologies will help refining our understanding and definition of DOC leading to more accurate diagnosis and prognosis. Furthermore, diagnosis of DOCs in children can be quite an uneasy task for clinicians. Further studies with pediatric populations are needed in order to develop reliable assessment tools for the patients’ specific developmental level and to define clinical guidelines regarding the diagnosis and prognostic indicators.


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