Vegetative state

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Figure 1: Illustration of the two major components of consciousness: the level of consciousness (i.e., arousal or wakefulness) and the content of consciousness (i.e., awareness).(Adapted from Laureys, 2005)

Consciousness has two dimensions (Zeman, 2001): arousal or wakefulness (i.e., level of consciousness) and awareness (i.e., content of consciousness). Figure 1. In normal physiological states (green); level and content are positively correlated (with the exception of the oneiric activity during REM-sleep). Patients in pathological or pharmacological coma (i.e., general anesthesia) are unconscious because they cannot be awakened (red). The vegetative state (VS, blue) is a unique dissociated state of consciousness.

Progress in medicine has increased the number of patients who survive severe acute brain damage. Although the majority of these patients recover from coma within the first days after the insult, some permanently lose all brain functions (brain death), while others evolve to a state of ‘wakeful unawareness’ (vegetative state). Those who recover, typically progress through different stages before fully or partially (minimally conscious state) recovering consciousness. Exceptionally, patients may awaken from their coma fully aware but unable to move or speak – their only way to communicate is via small eye movements (locked-in syndrome) Figure 2.

An accurate and reliable evaluation of the level and content of consciousness in severely brain-damaged patients is of paramount importance for their appropriate management. The clinical evaluation of consciousness in non-communicative patients remains erroneous in 40% of case (Andrews et al., 1996; Childs and Mercer, 1996; Schnakers et al., 2007). Bedside evaluation of residual brain function in severely brain-damaged patients is difficult because motor responses may be very limited or inconsistent. In addition, consciousness is not an all-or-none phenomenon and its clinical assessment relies on inferences made from observed responses to external stimuli at the time of the examination (i.e. assessing command following). The Glasgow Coma Scale (GCS - Teasdale et al., 1983) is the most used clinical evaluation scale in coma. The GCS has three components: eye, verbal and motor response to external stimuli. The best or highest responses are recorded. In chronic disorders of consciousness, other standardized clinical testing by means of validated scales such as the Coma Recovery Scale (CRS-R - Giacino et al. , 2004) or the Sensory Modality Assessment and Rehabilitation Technique (SMART - Gill-Thwaites and Munday, 2004) are recommended.

Figure 2: Chart of the different conditions that may follow acute brain injury. Coma does not last for more than a couple of days or weeks. For patients evolving to a vegetative state, the term “permanent vegetative state” has been used 3 months after non-traumatic insult or 1 year after traumatic brain injury. Vegetative patient who do recover classically evolve to a minimally conscious state. In rare cases, a person may develop locked-in syndrome, a nearly complete paralysis of the body’s voluntary motor responses – only eye movements permit communication. (Taken from Laureys, 2007)

Contents

Brain death

Brain death means human death determined by neurological criteria. The diagnosis of brain death is based on the loss of all brainstem reflexes and the demonstration of continuing cessation of respiration – i.e. apnea testing - in a persistently comatose patient. There should be an evident cause of coma and confounding factors, such as hypothermia, drugs, electrolyte, and endocrine disturbances, should be excluded (Laureys, 2005). A repeat evaluation in six hours is advised, but this time period is considered arbitrary (The Quality Standards Subcommittee of the American Academy of Neurology, 1995). Electroencephalography (EEG), angiography, doppler sonography or scintigraphy are required as confirmatory neurophysiological tests when specific components of the clinical testing cannot be reliably evaluated. Confirmatory testing are recommended by a number of national societies to confirm the clinical diagnosis of brain death (Wijdicks, 2002). Brain death is classically caused by a massive brain lesion, such as trauma, intracranial hemorrhage or anoxia.

The EEG in brain death shows absent electrocortical activity with a sensitivity and specificity of around 90%. Functional neuroimaging typically show the absence of neuronal function in the whole brain in patients (i.e. the ‘empty skull sign’) (for a review, see Laureys et al., 2004) Figure 3.

Figure 3: Differences in brain metabolism measured in brain death and the vegetative state, compared with healthy subjects. Patients in brain death show an ‘empty-skull sign’, clearly different from what is seen in vegetative patients, in whom brain metabolism is massively and globally decreased (to 40-50% of normal values) but not absent. (Taken from Laureys, 2005)

Defining death and organ donation are inextricably linked. Patients have to be declared dead before the removal of life-sustaining organs for transplantation. It is considered unethical to kill patients for their organs no matter how ill they are or how much good for others can be accomplished by doing so. To avoid conflict, transplant-surgeons are excluded from performing brain death examinations. Classically, organs are taken in patients who are declared brain death. In addition, the protocol for "donation after cardiac death" (or "donation after circulatory death," or "DCD." - University of Pittsburgh Medical Center policy and procedure manual, 1993) also permits to harvest organs in hopelessly comatose, but not brain dead, patients being maintained on positive-pressure ventilators in ICUs. They are allowed to die after their life-sustaining therapy (positive-pressure ventilation) is withdrawn in accordance with their wishes. Once their heart stops beating for a period of 2-10 minutes (that varies by protocol), they are declared dead and only then are their vital organs procured. As in brain dead organ donors, the organ procurement is performed only after the donor is declared dead. Here, confirmatory testing needs to document that the comatose patients has no chances of recovery (Bernat et al., 2006).

Diagnostic criteria for brain death (American Academy of Neurology guidelines, 1995)
Demonstration of coma
Evidence for the cause of coma
Absence of confounding factors (hypothermia, drugs, electrolyte, and endocrine disturbances)
Absence of brainstem reflexes
Absent motor responses
Apnea
A repeat evaluation in 6h
Confirmatory laboratory (when specific components of the clinical testing cannot be reliably evaluated)

Coma

Coma is a state of unarousable unresponsiveness in which the patient lies with the eye closed and has no awareness of self and surroundings (Posner et al., 2007). These patients will never open their eyes even when intensively stimulated. To be clearly distinguished from syncope, concussion, or other states of transient unconsciousness, coma must persist for at least one hour. In general, comatose patients who survive begin to awaken and recover within 2 to 4 weeks. This recovery may sometimes go no further than the vegetative state or the minimally conscious state. There are two main causes for coma: (1) bihemispheric diffuse cortical or white matter damage or (2) brainstem lesions bilaterally affecting the subcortical reticular arousing systems.

Many factors such as etiology, the patient’s general medical condition, age, clinical signs and complimentary examinations influence the management and prognosis of coma. After 3 days of observation, absence of pupillary or corneal reflexes, stereotyped or absent motor response to noxious stimulation, iso-electrical or burst suppression pattern EEG, bilateral absent cortical responses on somatosensory evoked potentials, and (for anoxic coma) biochemical markers such as high levels of serum neuron-specific enolase are known to herald bad outcome. Prognosis in traumatic coma survivors is known to be better than in anoxic cases (Laureys et al., 2008, Posner et al., 2007).

The EEG in patients who are in coma is characterized by an important general slowing. In addition, functional neuroimaging showed a global decrease of 50-70% in cerebral metabolism in coma patients, similar to values observed in general anesthesia Figure 4 (for a review, see Laureys et al., 2004).


Diagnostic criteria for coma (Posner et al., 2007)
Absence of eye opening even with intense stimulation
No evidence of awareness of self and their environment
Duration: at least one hour
Figure 4: Brain function in conscious wakefulness; in brain death; physiological and pharmacological (general anesthesia) modulation of arousal reflecting massive global decreases in cortical metabolism (in REM sleep metabolic activity is paradoxically prominent); and in wakefulness without awareness (i.e., the vegetative state). The recovery from the vegetative state may occur without substantial increase in overall cortical metabolism, emphasizing that some areas in the brain are more important than others for the emergence of awareness. (Adapted from Laureys et al., 2004)

Vegetative state

After some days to weeks comatose patients will eventually open their eyes. When this return of “wakefulness without awareness of self and environment” is accompanied by reflexive motor activity only, devoid of any voluntary interaction with the environment, the condition is called a vegetative state (The Multi-Society Task Force on PVS, 1994). The vegetative state may be a transition to further recovery, or not. It can be diagnosed soon after a brain injury and can be partially or totally reversible or it may progress to a permanent vegetative state or death. Many people in vegetative state regain consciousness in the first month after brain injury. However, after a month, the patient is said to be in a persistent vegetative state and the probability of recovery diminishes as more time passes. If patients show no sign of awareness one year after a traumatic brain injury or three months after brain damage from lack of oxygen, the chances of recovery are considered close to zero, and the patient is considered in a permanent vegetative state (The Multi-Society Task Force on PVS, 1994). However, rare cases of patients who recover after this interval have been reported (Childs and Mercer, 1996). It is very important to stress the difference between persistent and permanent vegetative state which are, unfortunately, too often abbreviated identically as PVS, causing unnecessary confusion (Laureys et al. , 2000). It is now recommended to omit “persistent” and to describe a patient as having been vegetative for a certain time. When there is no recovery after a specified period (depending on etiology three to twelve months) the state can be declared permanent and withholding and withdrawal of treatment can be discussed (Jennett, 2005; Laureys et al., 2004).

We have at present no validated diagnostic nor prognostic markers for patients in a vegetative state. The chances of recovery depend on patient’s age, etiology (worse for anoxic causes), and time spent in the vegetative state. Recent data indicate that damage to the corpus callosum and brainstem indicate bad outcome in traumatic vegetative state (Carpentier et al., 2006; Kampfl et al., 1998).

Importantly, we have to stress that vegetative state is not brain death. Contrary to brain death, the vegetative state can be partially or completely reversible. Unlike vegetative patients who have their eyes spontaneously open, patients in brain death never show eye opening. Moreover, contrary to brain death, vegetative patients can breathe spontaneously without assistance and have preserved brainstem reflexes and hypothalamic functioning. Additionally, positron emission tomography (PET) studies have showed clear differences between brain metabolism of vegetative and brain death patients Figure 3. The so-called ‘empty-skull sign’ classically observed in brain death confirms the absence of neuronal function in the whole brain (Laureys et al., 2004). Such functional ‘decapitation’ is never observed in patients in a vegetative state.

Electroencephalography shows an important general slowing of the electrical brain activity of patients in vegetative state. Somatosensory evoked potentials may show preserved primary somatosensory cortical potentials and brainstem auditory evoked potentials often show preserved brainstem potentials in vegetative patients. Endogenous evoked potentials measuring for example the brain’s response to complex auditory stimuli such as the patient’s own name (as compared to other names) permits to record a so-called P300 response. Recent data show that the P300 is not a reliable marker of awareness but rather signs automatic processing, as it could be recorded in well-documented vegetative state patients who never recovered (Perrin et al., 2006).

Vegetative patients show substantially reduced (40–50% of normal values) but not absent overall cortical metabolism. In some vegetative patients who subsequently recovered, global metabolic rates for glucose metabolism did not show substantial changes Figure 4. In addition, PET studies on pain perception have showed that healthy control subjects and patients in vegetative state didn’t demonstrate the same brain activity when they received a painful stimulation Figure 6. In patients in a vegetative state, the activity of primary somatosensory cortex was isolated and disconnected from the rest of the brain, in particular from the frontoparietal network believed to be critical for conscious perception (Laureys et al., 2002) Figure 5.

Figure 5: The common hallmark of the vegetative state is a metabolic dysfunctioning of a widespread cortical network encompassing medial and lateral prefrontal and parietal multi-modal associative areas. (Taken from Laureys, 2007)
Diagnostic criteria for the vegetative state (US Multi-Society Task Force on Persistent Vegetative State guidelines, 1994)
No evidence of awareness of self or environment and an inability to interact with others
No evidence of sustained, reproducible, purposeful, or voluntary behavioral responses to visual, auditory, tactile, or noxious stimuli
No evidence of language comprehension or expression
Presence of sleep-wake cycles
Sufficiently preserved hypothalamic and brainstem autonomic functions to permit survival with medical and nursing care
Bowel and bladder incontinence
Variably preserved cranial-nerve and spinal reflexes
Figure 6: Healthy control subjects and patients in a vegetative state do not demonstrate the same brain activity when receiving a painful stimulation. In patients in a vegetative state, the activity of primary somatosensory cortex is isolated and disconnected from the rest of the brain. (Taken from Laureys et al., 2002)

Minimally conscious state

The criteria for the minimally conscious state were recently proposed in 2002 (Giacino et al.). The minimally conscious state describes patients who are unable to communicate their thoughts and feelings, but who demonstrate inconsistent but reproducible behavioral evidence of awareness of self or environment. Patients in a minimally conscious state have to show at least one of the following behaviors: oriented response to noxious stimuli, sustained visual pursuit, command following, intelligible verbalization or emotional or motor behaviors that are contingent upon the presence of specific eliciting stimuli such as episodes of crying that are precipitated by family voices only. Like the vegetative state, the minimally conscious state may be chronic and sometimes permanent. At present, no time intervals for “permanent minimally conscious state” have been agreed upon. Some patients who have remained in the minimally conscious state for years were shown to slow recover to meaningful lives (Voss et al., 2006). The emergence from the minimally conscious state is defined by the ability to use functional interactive communication or functional use of objects (Giacino et al., 2002) Figure 7.

Figure 7: Different clinical entities encountered on the gradual recovery from coma, illustrated as a function of cognitive and motor capacities. Restoration of spontaneous or elicited eye-opening, in the absence of voluntary motor activity, marks the transition from coma to vegetative state (VS). The passage from the VS to the minimally conscious state (MCS) is marked by reproducible evidence of “voluntary behavior” on command following. Emergence from MCS is signaled by the return of functional communication or object use. (Taken from Laureys et al., 2005)

Given that the criteria for the minimally conscious state have only recently been introduced, there are few clinical studies of patients in this condition. Similar as for the vegetative state, traumatic etiology has a better prognosis than non-traumatic (anoxic) minimally conscious state. Preliminary data show that overall outcome is better than for the vegetative state (Giacino et al., 2002).

The electroencephalogram shows a general slowing of the electrical brain activity in patients in a minimally conscious state. Neuroimaging has shows that minimally conscious patients differ from vegetative patients in their metabolic activity in the precuneus and posterior cingulate cortex (Laureys et al., 2004). In addition, in patients in a minimally conscious state, auditory stimuli trigger higher-order cortical activity normally not observed in the vegetative state (Boly et al., 2005). In the same line, auditory stimuli with emotional valence (such as infant cries or the patient’s own name (Laureys et al., 2004) or a narrative told by the patients mother (Schiff et al., 2005)) induce a much more widespread activation in patients in minimally conscious state than meaningless stimuli do Figure 8. This indicates that content does matter ‘when talking to a patient in minimally conscious state’.

Figure 8: Brain activations during presentation of noise, infant cries, and the patient’s own name. Stimuli with emotional valence (baby’s cries and names) induce a much more widespread activation than does meaningless noise.(Taken from Laureys et al., 2004)

A recent fMRI study reported a youg women considered as being in a vegetative state while she showed indistinguishable brain activity from these observed in healthy people when we asked her to imaging playing tennis and visiting her house (Owen et al. , 2006) Figure 9. Despite the clinical diagnosis that the patient was in a vegetative state, she understood the tasks and repeatedly performed them and hence must have been conscious. A few months after the study, the patient evolved towards a minimally conscious state. The results of this study should not be misinterpreted as evidence that all patients in a vegetative state may actually be conscious. We have not observed any similar signs of awareness in functional scans of more than 60 other patients in a vegetative state studied at the University of Liège (Belgium). The most likely explanation of these results is that the patient was already beginning the transition to the minimally conscious state at the time of the experiment. A study conducted by Di et al. (2007) also indicated that the activation of higher-level brain regions during functional MRI seems to predict recovery to the minimally conscious state. In addition, MRI studies permit to visualize the extent of brain damage, and new advances in MRI scanning, such as diffusion tensor imaging and spectroscopy, can also offering prognostic information (Galanaud et al. , 2007). This technique can also shed light on mechanisms of recovery from the minimally conscious state. For example, an MRI diffusion tensor imaging study identified axonal regrowth in the brain of a patient who emerged from a minimally conscious state after 19 years of silence (Voss et al., 2006).

Diagnostic criteria for minimally conscious state (Aspen Neurobehavioral Conference Workgroup, 2002)
Clearly discernible evidence of awareness of self or environment, on a reproducible or sustained basis, by at least one of the following behaviors:
Purposeful behavior (including movements or affective behavior that occur in contingent relation to relevant environment stimuli and are not due to reflexive activity) such as:

-Pursuit eye movement or sustained fixation occurring in direct response to moving or salient stimuli

-Smiling or crying in response to verbal or visual emotional (but not neutral) stimuli

-Reaching for objects demonstrating a relationship between object location and direction of reach

-Touching or holding objects in a manner that accommodates the size and shape of the object

-Vocalizations or gestures occurring in direct response to the linguistic content of questions

Command following
Gestural or verbal yes/no response (regardless of accuracy)
Intelligible verbalization
Emergence from MCS is signaled by the return of functional communication or object use
Figure 9: Owen et al. (2006) reported a women clinically considered in a vegetative state showed indistinguishable brain activity from these observed in healthy subject when asked to imaging playing tennis or visiting her house. A few months after the study, the patient recovered consciousness. (Taken from Owen et al., 2006)

Locked-in syndrome

The locked-in syndrome describes patients who are awake and conscious but have no means of producing speech, limb, or facial movements. Brainstem lesions are its most common cause. People with such lesions often remain comatose for some days or weeks, needing artificial respiration and then gradually wake up, albeit remaining paralyzed and voiceless, superficially resembling patients in a vegetative state. Locked-in patients can be divided into three categories (Bauer et al., 1979): (a) classical locked-in syndrome is characterized by quadriplegia and anarthria with eye coded communication; (b) incomplete locked-in syndrome permits remnants of voluntary responsiveness other than eye movement; and (c) total locked-in syndrome consists of complete immobility including all eye movements, combined with preserved consciousness. Once a locked-in syndrome patient becomes medically stable, and given appropriate medical care, life expectancy now is several decades. Even if the chances of good motor recovery are very limited, existing eye-controlled computer-based communication technology currently allows these patient to control their environment, use a word processor coupled to a speech synthesizer and access the world wide net. Neuropsychological testing batteries adapted and validated for eye-response communication, have shown preserved intellectual capacities in locked-in syndrome patients (Schnakers et al., 2008).

Recent surveys show that chronic locked-in syndrome patients self-report meaningful quality of life and the demand for euthanasia, albeit existing, is infrequent (Bruno et al., 2008; Laureys et al., 2008).

According to some studies, the EEG does not consistently distinguishes the locked-in syndrome from the vegetative state (Gutling et al. , 1996). PET scanning has shown preserved metabolic cerebral functioning in a locked-in syndrome when compared to those in a vegetative state or minimally conscious state Figure 10.

Diagnostic criteria for locked-in syndrome (American Congress of Rehabilitation Medicine, 1995)
Presence of sustained eye opening (bilateral ptosis should be ruled out as a complicating factor)
Aphonia or hypophonia
Quadriplegia or quadriparesis
Primary mode of communication that uses vertical or lateral eye movement or blinking of the upper eyelid to signal yes/no responses
Preserved awareness of the environment
Figure 10: Resting cerebral metabolism in healthy individuals and patients in a vegetative state, locked-in syndrome, and minimally conscious state. In healthy conscious individuals and locked-in patients the medial posterior cortex (encompassing the precuneus and adjacent posterior cingulate cortex) is the most metabolically active region of the brain; in patients in vegetative state, this same area is the most dysfunctional. The precuneus and posterior cingulate cortex of patients in a minimally conscious state shows an intermediate metabolism, higher than in a vegetative state, but lower than in healthy subjects.(Taken from Laureys et al., 2004)

Treatment

Some studies have reported cases of patients with chronic disorders of consciousness who exhibited unexpected behavioral amelioration after administration of amantadine (Whyte et al., 2005; Zafonte et al., 1998). Amantadine, a mainly dopaminergic agent, was shown to increase metabolic activity in chronic minimally conscious patients (Schnakers et al., 2008). Placebo controlled randomized trials are needed before making assertive conclusions about the effectiveness of the drug in disorders of consciousness patients. Similarly, some studies reported that administration of zolpidem, a non-benzodiazepine sedative drug, may improve arousal and cognition of brain-injured patients (Clauss and Nel, 2006).

An other non-pharmacological treatment consist on the deep brain stimulation of the thalamus. A recent case report by Nicholas Schiff and colleagues from New York showed its efficacy in a chronic post-traumatic minimally conscious patient (Schiff et al., 2007). However, at present, this remains research and awaits further confirmation. It has not been shown effective in the vegetative state.

Future challenges

Brain death, comatose, vegetative and minimally conscious states represent different pathological alterations of both dimensions of consciousness (involving arousal and awareness) or, for locked-in states, of the motor signs of consciousness. The clinical evaluation of conscious perception and cognition in these patients is difficult and erroneous in 40% of case. Electrophysiological and functional neuroimaging studies are increasing our understanding of the neural correlates of arousal and awareness and will improve the diagnosis, prognosis and management these challenging patients. At present, much more data and methodological validation is awaited before functional neuroimaging studies can be proposed to the medical community as a tool to disentangle conscious from unconscious patients. In the same line, we need much more data before we make any assertive conclusions about the effect of pharmacological and non-pharmacological treatment in patients in altered state of consciousness.

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Recommended Reading

Laureys, S.; Owen, A.M.; and Schiff, N.D. (2004a) Brain function in coma, vegetative state, and related disorders. Lancet Neurol, 3(9):537-46

Laureys, S. (2005) The neural correlate of (un)awareness: lessons from the vegetative state. Trends Cognitive Science, 9(12):556-9 Fins, J.J. Constructing an ethical stereotaxy for severe brain injury: balancing risks, benefits and access. Nat Rev Neurosci, 4(4):323-7, 2003.

Laureys, S. Science and society: death, unconsciousness and the brain. Nat Rev Neurosci, 6(11):899-909, 2005.

Owen, A.M.; Coleman, M.R.; Boly, M.; Davis, M.H.; Laureys, S.; and Pickard, J.D. Detecting awareness in the vegetative state. Science, 313(5792):1402, 2006.

Bernat, JL. Chronic disorders of consciousness. Lancet, 367 (9517): 1181-92, 2006.

Laureys, S. Eyes open, brain shut. Sci Am, 296(5):84-9, 2007.

Posner JB, Saper CB, Schiff N and Plum F: The diagnosis of stupor and coma, 4th ed., 2007.

Owen, AM. Disorders of consciousness. Ann N Y Acad Sci. 1124: 225-38, 2008.

External Links

Coma Science Group http://www.comascience.org

American Academy of Neurology http://aan.com/professionals/practice/pdfs/pdf_1995_thru_1998/1995.45.1012.pdf

American Medical Association http://www.ama-assn.org/ama/pub/category/8457.html

United Network for Organ Sharing http://www.unos.org

See also

Consciousness, Glasgow coma scale

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