Few human diseases or disabilities generate more confusion and dread than does the condition commonly called the persistent vegetative state (PVS). Health professionals who care for patients in PVS have called this "the ultimate curse".1
The perplexing syndrome PVS was given its unfortunate name by Jennett and Plum in 1972.2 They described a state of "wakefulness without awareness" in which a patient, due to head trauma, anoxic event or degenerative disease has lost all cortical (upper brain) functions. Since 1972, others have attempted to subdivide the diagnosis based on time elapsed since the precipitating event. There is little agreement regarding how much time must elapse before a diagnosis of PVS is made, and as to when the diagnosis of "persistent" vegetative state becomes a diagnosis of a "permanent" vegetative state.3
Generally agreed-upon indications of PVS include:
Other clinical features of PVS include bowel and bladder incontinence, spontaneous blinking and usually retained pupillary responses along with occasional purposeless movements of the head, trunk and eyes.4
The term "Persistent Vegetative State" has come to be used generically and often inappropriately. It could reasonably be said that the term itself, taken in the commonly understood sense of the term "vegetable", is dehumanizing as well as biologically nonsensical. A human can no more "become" a vegetable than a vegetable can "become" a human being.
Despite a search for a better term, the designation of "persistent vegetative state" is still in common usage.5 Andrews (1997) states that "the term 'permanent' does not signify that recovery is impossible, only that the statistical chance of further recovery is very small". The Royal College of Physicians, in setting guidelines on the vegetative state has suggested that the term 'persistent' be replaced by 'continuing'. Additionally, it has been recommended that the word "persistent" be deleted, and that instead the term "vegetative state" be used with the addition of the duration i.e., vegetative state of 4 months duration.6 The term "persistent vegetative state" still has general acceptance in both medical and legal forums7,8 despite acknowledgement that the term "vegetative" does have unwanted connotations. It is only because of the general acquaintance with the terms "Persistent Vegetative State" (PVS) and "Vegetative State" (VS) that they are used in this paper.
The term PVS is often confused with "brain death", even by some health professionals, but especially by a public which gets much of its medical information from prime-time television shows and ill-informed news anchors. Brain death actually refers to a condition in which both upper (cortical) and lower (brainstem) brain functions are irreversibly absent. Thus, the patient who is brain dead is not capable of breathing on his own. Circulation can be maintained with medical assistance for a relatively short time, perhaps hours or a few days, but will ultimately cease despite the most "heroic" or intensive measures9. Patients in the PVS, however, do not require assistance with breathing and circulation, are not "dead" (although some would argue for the extension of the term "brain death" to include patients whose brainstems are intact10) or imminently dying, and can be maintained with routine nursing care for relatively extended periods of time.11,12 People in the PVS are not dead in the way that those fulfilling the criteria of brain death are regarded as being. They are not separated off by some qualitative step from those very severely damaged by head injury and are not in a state much worse than the elderly with advanced dementia or children afflicted with severe brain injury at birth.
The exact number of persons in the PVS is unknown, but it is estimated that 10,000-25,000 adults and 4,000-10,000 children in the United States are in the "vegetative" state.13 Problems with determining the precise number of cases arise from non-standard reporting, as well as inexactness in definition and diagnosis.14 Whereas more specific and measurable medical criteria have been established for brain death by numerous organizations around the world, no comparably exact criteria have been established for the PVS.15 Unlike the diagnosis of brain death, which typically can be determined over several hours' time, the diagnosis of PVS (and declarations regarding irreversibility) can take months to establish.16 Although positron emission tomography (PET) scans, computerized axial tomography (CAT) scans and electroencephalography (EEG) are all used to try to establish the diagnosis, none of these tests are definitive in confirming the existence of the PVS.17 The fact that subcortical and brainstem structures remain functional allows prolonged survivals if caregivers attend to nutrition and hygiene. This potential for "indefinite" survival, observed Jennet and Plum, "presents a problem with humanitarian and socioeconomic implications which society as a whole will have to confront."18
Several other disorders can result from severe brain injury, and these neurologic conditions can be confused with the PVS as well. Therefore, it is essential to distinguish the "vegetative" state from coma (unawareness in the absence of wakefulness) and the locked-in syndrome, in which the patient is aware of his surroundings, but cannot respond to stimuli due to the absence of motor function.19 Coma is a state of unconsciousness in which the eyes are closed and sleepwake cycles absent. It is usually transient, but one potential outcome is the VS. The locked-in syndrome results from brainstem lesions which disrupt voluntary control of movement without abolishing either arousal or the content of awareness. Patients who are "locked in" are usually able to communicate using movements of the eyes or eyelids.
Treatment and rehabilitation for individuals in the PVS vary widely among centers in the U.S. and abroad. Differences in predicted outcomes in PVS are quite pronounced, with some authors reporting uniformly dismal outcomes, while others report much more favorable recovery rates.20,21 Late recovery from the PVS, dismissed as non-existent by many authors, is reported by a number of neurologists and rehabilitation specialists.22,23,24 Misdiagnosis appears to be quite common, due to lack of agreement on features of PVS, heterogeneity of the PVS population, and the inherent diagnostic and prognostic uncertainty of the syndrome.25,26,27 These factors combine to cast doubt on the "permanence" of unconsciousness in those diagnosed as being in the PVS and may indicate that the actual population of individuals in truly permanent unawareness is quite small.
The mechanisms of PVS are not yet well understood. Prior to the death of Karen Ann Quinlan, whose 10 years in the PVS helped launch the "right-to die" movement, scientists believed that diffuse brain cell damage in the cerebral cortex was responsible for the syndrome. Studies of Quinlan's brain on autopsy, however, revealed that the most extensive damage occurred in the thalamus, which consists of two egg-shaped structures buried deep within the brain. This seems to support an emerging theory that the thalamus is critical for thought and awareness.28 McLellan et al (1986) identified diffuse axonal injury, extensive hypoxic damage to the neocortex, and secondary damage to the brain stem as the principal neuropathological bases of the vegetative state.29 Kinney and Samuel (1994) report that in diffuse axonal injury, retrograde thalamic degeneration occurs as a result of widespread axonal damage and takes some three months to develop (e.g.in traumatic injury). On the other hand, in thalamic damage associated with ischemia there is diffuse thalamic neuronal loss as a result of hypoxia and the changes are apparent a very short time after the episode (e.g., in non-traumatic or hypoxic injury).30 The neuropathology of PVS cannot be fully determined except in postmortem examinations of the brain. Adams et al (1999) state "the structural basis of the vegetative state can only be defined post mortem if... appropriate histological studies are undertaken. Only then can the amount and distribution of diffuse axonal injury and damage caused by ischemia or raised intracranial pressure be established and their contribution to the vegetative state determined."31
Adams et al (2000) sum up the variance of recovery between traumatic vs. hypoxic (nontraumatic) PVS as follows: In acute hypoxic episodes the neurons that are lost have undergone ischemic necrosis and will therefore never function again. In contrast, in diffuse axonal injury (DAI) there is no actual loss of neurons, only transneuronal degeneration. If there is any delayed restoration of function in the axons damaged at the time of the original injury, the substrate of thalamic neurons is still there and conceivably, may be able to function again.32 Another difference between the traumatic and the non-traumatic cases described by Adams et al was the frequency of diffuse ischemic damage in the neocortex: this occurred in 64% of the nontraumatic cases but in only 11% of the traumatic cases. They go on to say that "we also have considerable experience of the neuropathological abnormalities in patients who remained severely disabled but not vegetative as a result of an acute brain insult. In some of these brains there were lesions similar to those found in some of the vegetative patients, particularly in the traumatic group, in that some severely disabled patients had grades 2 or 3 DAI (diffuse axonal injury) including damage to the thalamus. "The severity of the damage may have been more severe in the vegetative patients but as yet, we have been unable to devise a quantitative method to measure damage to axons".33
In summary, present data indicate that the three main patterns of pathology seen in the brains of patients who have died in a vegetative state are: a.) diffuse axonal injury, typically as a sequel to severe closed head trauma, b.) extensive laminar necrosis of the cerebral cortex, usually following global cerebral hypoxia or ischemia and c.) thalamic necrosis, which is occasionally the most conspicuous finding. Mixtures of these findings are not uncommon.34
Several studies of local cerebral blood flow and glucose metabolism have compared patients in coma, in vegetative states of various durations and in the locked-in state with healthy controls. The lowest values occur in patients with the PVS at between one-half and one-third of those of controls.35 However,until neurophysiological tests can give more precise results, their role in this complex neurological disorder remains supportive rather than diagnostic in individual cases.
It has, however been well established that those parts of the brain which control movement and behavior are not the same as those that control thought and awareness. Andrews (1997) points out that a person with severe neurological disabilities that affect motor responses can face enormous difficulties in demonstrating awareness.36 In his unit at the Royal Hospital for Neurodisability in London, 40% of those admitted with a diagnosis of vegetative state were found to have been misdiagnosed, some for several years.37 The main feature contributing to the misdiagnosis was blindness or severe visual impairment (60%) together with "profound physical disablement".38 In a study by Childs, Mercer and Childs (1993), behavior indicative of cognitive responsiveness was found in 37% of the patients admitted diagnosed to be in "coma" or VS.39 These studies suggest that physicians' assessment measures may be insufficiently sensitive to reach a correct diagnosis of VS.
Giacino and Zasler (1995) have pointed out that there is no method yet available to clinically assess "internal awareness" in a patient who is otherwise unable to express awareness relative to external environmental stimuli.40 We are only able to infer the presence or absence of conscious experience, as pointed out by Bernat (2002) and the Multi-Society Task Force on the Persistent Vegetative State.41,42 Furthermore, "consciousness" is not an all-or-nothing phenomenon, but rather part of a continuum.43
Andrews (1997) lists several criteria that need to be met in making the diagnosis of PVS. The first is that the patient should be otherwise generally healthy. The maintenance of good nutrition is essential. He further notes that percutaneous gastrostomy (PEG) feeding has made nutritional management simpler and has greatly decreased the risk of aspiration pneumonia. Control of urinary tract infections has been made easier by removal of indwelling (Foley) catheters and the better management of bowel activity has decreased problems associated with fecal impaction.
The second principle is that patients should be assessed out of bed in a well supporting seating system, which is specifically designed to meet their needs. Patients tend to be more alert when sitting up, perhaps helping to activate the reticular system. A good seating system also helps control muscle tone; thereby releasing whatever function the patient has to enable him or her to communicate, by for example pressing a buzzer. The patient should have as many sedating drugs as possible withheld (this can include anti-spasticity and anti-epileptic drugs which should be reduced to the lowest possible dose. Drugs with the lowest sedative effect should be used whenever possible.) Complications and consequences of neurological injury should be prevented; this includes high muscle tone and contractures, by skin care, good seating and posture control.44
The ability to generate a behavioral response can fluctuate from day-to-day and hour-to-hour and even minute-to-minute in the neurologically impaired patient depending on fatigue, general health and the underlying neurological condition. Andrews describes the assessment as ideally being conducted by a skilled team, without over-stimulation. The team should exploit "windows of opportunity" and carry out the assessment for short intervals during the day over a period of time (usually 4-6 weeks). Andrews emphasizes that the assessment of awareness and responsiveness cannot be made on a "one-off assessment at the bedside by even the most eminent neurologist".45
Andrews (1998) lists other difficulties that may be encountered in making the diagnosis of PVS. In addition to the physical ability of the patient to respond, they include the desire or willingness (if the patient is aware) of the patient to respond, the abilities of the observer to make rapport with the patient, the ability to observe accurately, the time available for observation and assessment and the lack of available and reliable assessment tools.46
Even with ideal physical assessment procedures, it should be kept in mind that failure to establish command following does not necessarily mean that the patient is vegetative. It may mean that there is a profound hearing or language impairment or paralysis of the muscle groups required to generate the behavior. Therefore, assessment protocols should be conducted taking into consideration all available information about the patient's injury, including the presence of any focal lesions (e.g. left language areas) or fractures (e.g. eighth nerve lesions from basilar skull fractures) that may indicate compromised auditory comprehension. Evoked response studies may be helpful for demonstrating the integrity of sensory pathways required for response (e.g. brainstem auditory evoked responses [BAERS]). If there is little evidence of volitional limb movement, assessment of eye or facial movements should be incorporated into the assessment protocol.47
Since the patient thought to be in the VS may exhibit behavioral responses at infrequent and unpredictable intervals, the type of assessments that are one time only, even if more than one physician is involved, may easily miss signs of awareness.48 Gill-Thwaites (1997) states that in light of the results of available studies and considering the controversial issue of withdrawal of nutrition and hydration from patients diagnosed in the PVS, it is clear that more stringent guidelines on the method, frequency and duration of assessment must be established in the case of PVS patients in order to give the patient an optimal opportunity to demonstrate their level of awareness.49
The available data seem to indicate that careful long-term observation can often reveal signs of awareness, if awareness exists. Unfortunately, this is often not the way in which such assessments are carried out in day-to-day practice. It is important to understand, however, that medically, we can only measure movement and behavior, not "thought" or "awareness". Since the judgment of "lack of awareness" is necessarily highly subjective, and since previously "unaware" individuals do at times become aware, it is fraught with peril to designate an individual as incognizant or "permanently" unconscious. There is simply no way to be medically certain that a person lacks awareness or will not regain it.50
Some 6-14% of patients admitted with a severe head injury are in a vegetative state one month later.51 Analysis by the Multi-Society Task Force on the Persistent Vegetative State (1994) of over 700 published cases of patients in a vegetative state one month after an acute brain insult found that some of these patients recover consciousness over the next few months, with recovery being more common after traumatic than non-traumatic damage.52
Prediction of recovery from the VS based on neuroradiologic findings is inherently complex. Although statistically significant differences have been found among groups of patients who remained in the VS versus patients who recovered some awareness, the overlap between groups is often too high to help in the management of the individual patient.53 That being said, a number of studies have attempted to discover and quantify findings that are prognostic for recovery from the PVS, although agreement does not yet exist as to the strongest indicators for recovery or nonrecovery. Laureys et al (2000) found that functional connectivity between intralaminar thalamic nuclei and prefrontal and anterior cingulate cortices was altered during VS but not after recovery of consciousness.54 Reider-Groswasser et al (1997) found that values of over 8mm for the width of the third ventricle and over 11 mm for the septum caudate distance on CT scan are suggestive of catastrophic injury and poor prognosis for recovery.55 In a study of the PET scans of 9 patients diagnosed as being in the acute vegetative state (i.e. less than one month post-injury), Rudolf, et al (2000) report that overall reduction of cortical flumazenil binding to below five times average white matter activity is related to extremely small possibility of recovery from an acute vegetative state.56 Kampfl et al (1998) report that cerebral MRI findings in the sub acute stage after head injury can predict the outcome of the post-traumatic VS and that corpus callosum and dorsolateral brainstem lesions are highly significant in predicting non-recovery.57
Zandbergen et al (1998) report in a systematic review that somatosensory evoked potentials (SSEP) is the most useful method to predict poor outcome in non-traumatic anoxic-ischemic coma. Evoked potentials are also the least susceptible to metabolic changes and drugs. In the studies they reviewed, the following factors were 100% specific in all studies -- i.e. no patients had a good outcome (identified as anything other than death or VS) in the presence of any of these factors: absence of pupillary reactions to light on the third day, absent motor response to pain on the third day, and bilateral absence of cortical response to median nerve SSEP within the first week. They also reported that late recovery, with severe mental and motor disability in most patients, has been reported in 11% of patients who have been in non-traumatic coma for 1 month. In their analysis, 179 of the 189 patients with absent N20-responses died during follow-up.58 This finding help might identify a subgroup of patients who will not recover. However, this study needs replication since SSER's only look at one point in time and are generally thought to be of questionable prognostic value.
There are a number of problems inherent in prognostic studies and in applying their findings to the clinical situation. Problems with prognostic studies occur when sample size is unrepresentative, when patients are not homogenous with respect to prognostic risk, when follow-up is insufficient to minimize the possibility that the missing patients could alter the interpretation of the results, and when health outcomes are not evaluated using objective and unbiased criteria.59 All these factors must be taken into account when evaluating prognostic data.
One interesting area of investigation is research into the regenerative capacity of the central nervous system. Laureys et al (2000) state that "residual cerebral plasticity" during VS has been largely overlooked and deserves further investigation. The cellular mechanisms which underlie this functional normalization over time remain putative, but may include axonal sprouting, neurite outgrowth, cell division (known to occur predominantly in associative cortices in normal primates) or even apoptosis.60 This becomes more intriguing when considering the example of anencephalic children, often used as analogous to PVS in the adult. Plum and Posner (1983) note that the content of consciousness is widely held to be mediated by the cerebral cortex, with subcortical structures serving merely an arousal function.61 However, in a small study of 4 children aged 5 to 17 born with congenital brain malformations involving total or near-total absence of cerebral cortex (anencephalic), the investigators found that in spite of the overwhelming brain malformations, the children nevertheless possessed discriminative awareness -- for example distinguishing familiar from unfamiliar people and environments, social interaction, functional vision, orienting, musical preferences, appropriate affective responses and associative learning. These abilities may reflect 'vertical' plasticity of brainstem and diencephalic structures. Shewman (1999) postulates that the relative rarity of reported consciousness in congenitally decorticate children could be due to an inherent tendency of the label 'developmental vegetative state' to become self-fulfilling.62 Such "vertical plasticity" has been demonstrated in animal studies (Bjursten, 1976)63. It should be noted that children are thought to possess more potential for such "plasticity" than are adults.
There are few effective medical treatments for the patient in PVS, with most being rehabilitative in nature. However, in a single case study, Zafonte, Watanbe and Mann (1998) presented an apparent profound dose-related response to the pro-dopaminergic medication Amantadine. Dopaminergic pathways have been thought to play a significant role in arousal.64 Ritalin administered to one patient showed an equivocal result in another single case study.65
The PVS has served as a model for withdrawing medical treatment and care from patients since the 1976 case of Karen Ann Quinlan.66 On April 15, 1975, twenty-one year old Karen Quinlan, in what was described as a "coma of mysterious origin", was admitted to a New Jersey hospital. Five months later, on September 12, after Karen's physicians refused her parents' request that their still-unconscious daughter be removed from the ventilator, Karen's parents began legal proceedings. On November 10, New Jersey Superior Court Judge Robert Muir, Jr. denied the Quinlans their request. Karen remained on the ventilator. The Quinlans appealed to the New Jersey Supreme Court which on March 31, 1976 handed down In the Matter of Karen Quinlan, an Alleged Incompetent (70 N.J. 10; 355A. 2d 647, 1976). The decision held that Karen's "right to privacy" now included her right to be removed from the machine.
The legal opinion in that case referred to Roe v. Wade as to a right to privacy and held that the state's interest in preserving life diminishes as the patient's condition deteriorates. Ironically, the family petitioned to remove the ventilator in the Quinlan case -- a technology that, by definition of her being in the PVS (with intact respiratory and circulatory function), and by her survival for 10 years after its removal, she did not need. M.L. Stevens has noted that the legal process can nurture misconceptions about medical practice and the role of medical technology.67
Removing unwanted medical treatment was extended to basic care in the aftermath of the 1986 AMA Judicial Council statement which held that nutrition and hydration could be ethically withheld from the "permanently comatose".68 Within a few years several patients had been legally starved and dehydrated, including Nancy Cruzan and Christine Busalacchi (who was, accordina to many observations aware of and responsive to her environment and thus, not in the PVS).69,70,71 The Cruzan and Busalacchi cases, in particular, led to the redefinition of food and water as "medical treatment" under many state laws.
In 1990, the U.S. Supreme Court decided its first right-to-die case in a matter involving Nancy Cruzan.72 In that case, it was held that the state of Missouri could require the continued treatment of a patient in the persistent vegetative state in the absence of "clear and convincing" proof that the patient explicitly authorized the termination of treatment.73 The so-called "clear and convincing evidence" was soon pronounced found and was presented by former co-workers of Nancy Cruzan who maintained that she would not want to be "kept alive", citing comments made by a group of young people over a decade earlier concerning the use of a baby bottle (an Infafeeder bottle used to give pureed food) to a severely disabled child. The media characterized this as Nancy's obvious revulsion at "forced feeding". Nancy Cruzan died 12 days after her food and water were withdrawn.74
Christine Busalacchi was a young woman severely brain injured in an automobile accident. She was not dying, nor was she brain dead. Her father, Pete, posed with her on the cover of Time magazine to illustrate the "right to die" during his fight to move her out of the state of Missouri so that her food and water could be withdrawn.75 However, during this same time, Christine was reported by her nurses to be improving -- smiling, waving, following people with her eyes and even apparently forming some words.76 Her father finally succeeded in his effort and Christine died March 7, 1993 at Barnes Hospital in St. Louis, MO after her food and water were withdrawn. In defending his decision, Pete Busalacchi cited a priest's opinion that Christine had "actually died in the accident" and withdrawing her food and water was just a way of "letting her body go" as well.77
The cases of Karen Quinlan, Nancy Cruzan and Christine Busalacchi illustrate how medical incoherence and legal activism have become a deadly combination for the very severely disabled. These cases further demonstrate the striking inability of both the healthcare and legal systems to get at the truth about the patients' medical conditions, about PVS itself, and the human rights of disabled persons. Despite significant diagnostic and prognostic uncertainty, courts seem to be accepting guidelines issued by the medical profession as highly persuasive 'expert' evidence.
Unfortunately, the Quinlan case was just the beginning of what has become a tragic history of the legal process and medical practice falling over each other in their apparent rush to deny ordinary human care to this particular class of helpless humans. Cranford (1998) states that modern medical technology has created new syndromes of severe and permanent brain damage. In the first 25 years of the right to die debate the permanent vegetative state has been the "paradigmatic neurologic syndrome" for decisions to discontinue treatment. In the near future however, a far more problematic syndrome may be even more important in the right-to-die debate, the minimally conscious state (MCS).78 (Ronald Cranford is the neurologist who agreed to discontinue nutrition and hydration for Nancy Cruzan when her Missouri physician initially refused.) The Aspen Neurobehavioral Conference, a multi-society task force similar in composition to the Multi-Society Task Force that developed the criteria for PVS, convened in Aspen CO in 1995 and began meeting annually. The work group defined "minimally conscious state" as a "condition of severely altered consciousness in which the person demonstrates minimal but definite behavioral evidence of self or environmental awareness." The Aspen work group proposed the following criteria for MCS:
One or more of the following clinical features must be present on a reproducible or sustained basis:
As is the case with the PVS criteria, all the criteria for the MCS require motor ability to varying degrees, and can be dependent upon sensory deficits such as loss of hearing and blindness.
MCS patients can be separated into three groups based on the nature of their disease or injury:
The MCS is further subdivided into "temporary" and "permanent". The temporary MCS is one in which the patient is emerging from a vegetative state to a higher degree of consciousness. A permanent MCS may be the final product of an acute insult to the brain, such as traumatic or anoxic-ischemic insult or the end state of a progressive degenerative neurologic disorder such as Alzheimer's disease. Cranford relates that some see the MCS as "worse" than the PVS because the patient has some awareness of his own limitations and may be suffering.79 From a neurologic standpoint, MCS patients are thought to function at the level of a patient with severe or profound dementia. According to the Aspen Working Group, the estimated number of MCS patients in the US is 112,000 to 180,000 compared with previous estimates of 14,000 to 35,000 patients in the vegetative state.80 Unfortunately, the designation MCS is even less specific than the PVS. Although the delineation of this new clinical entity (MCS) has been put forth, unlike the Multi-Society Task Force on the PVS, the Aspen Neurobehavioral Consensus Conference could not identify evidence-based guidelines for the diagnosis, prognosis and management of the MCS and therefore developed "consensus" guidelines.81,82
Strauss (2000) divides the MCS further in to "mobile" and "immobile" and observed little difference in survival between pediatric patients in the VS and in the "immobile" MCS, suggesting that the presence of consciousness may not be a critical variable in determining life expectancy. Furthermore, survival was much greater for patients in the mobile MCS than in the immobile MCS, suggesting that mobility is possibly more important in predicting survival than the level of consciousness.83
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