Persistent Vegetative State

Leif Gustafson

March 15, 2000

Introduction

Persistent vegetative state (PVS) has been at the center of much controversy in recent years. Most of this controversy comes from the difficulty in defining and understanding this condition, and this has led to discussion over how people in this state are to be treated. The controversy with the greatest public exposure stems around the euthanasation of patients with this condition. This paper, however, focuses on what PVS is and what types of therapy patients with this condition receive.

Determining PVS

The first difficulty in PVS is determining a definition. PVS is a condition in which a person loses the higher cerebral powers of the brain, but maintains sleep-wake cycles with full or partial hypothalamic and brain stem autonomic functions. Persistent vegetative state is also often referred to a permanent vegetative state (although this is currently losing preference because there is the possibility of recovery) and has also been referred to as apallic syndrome or wachkoma in the past. A Multi-Society Task Force defined diagnostic criteria for PVS in 1994. These criteria include the lack of awareness of self or environment and the inability to interact with others. The lack of sustained, reproducible, purposeful or voluntary behavioral responses to visual auditory, tactile or noxious stimuli, and a lack of evidence of language comprehension or expression. There is intermittent wakefulness manifested by the presence of sleep-wake cycles, a sufficient hypothalamic and brain-stem autonomic function for survival with medical and nursing care, bowel and bladder incontinence, and finally there are variably preserved cranial-nerve reflexes and spinal reflexes. In short, a wakeful unconscious state that lasts longer that a few weeks is referred to as a persistent vegetative state. (Borthwick MSTF 1). This state can last for more than fifteen years, however the longer a patient is in PVS the less likely they are of recovering from it.

This definition includes difficult to define terms such as awareness, and this problematic definition has led some people to question the validity of the syndrome. It has also lead to problems in the diagnosis of PVS. The crux of the problem lies in the determination of a person’s internal mental state using external proof. Different tests have been used in an attempt to determine criteria for its diagnosis, because in using conventional methods of observation of function it takes weeks to diagnose a patient as being in PVS. Glucose metabolism, EEG, CT scans, and positron-emission tomography (PET) have all been used to increase understanding and diagnostic ability for PVS. However, information from these tests have not been able to provide any conclusive diagnostic information. It is possible that these tests or a combination of them will be useful as diagnostic tools in the future, but more data must be collected before any determinations can be made.

This lack of diagnostic certainty has led to the misdiagnosis of many patients as being PVS when they actually are not. One study showed that in a sample of 62 patients in nursing homes who were diagnosed with PVS eleven had been misdiagnosed and another study showed that eighteen of 49 patients were misdiagnosed (Borthwick). These errors have come from the lack of information about the criteria that are necessary for a person to be considered PVS as well as a lack of time and methods used for determining a patient as having PVS.

A large number of people in the U.S. are diagnosed with PVS. These patients range in age from infant to elderly, and can become PVS for many different reasons. PVS can be brought about through traumatic injury, degenerative disease, or metabolic disease. Each of these are responsible for similar damage to the cortex of the brain, however each leads to a different likelihood of recovery. This is true because with degenerative diseases the body is not able to reverse the disease process, and recovery does not occur. With traumatic injury, on the other hand, the body is often relatively healthy, and will be more likely to recover and bring the patient out of PVS.

Treatment

There is another factor that adds to the controversy surrounding PVS, and that is that there has been no conclusive evidence of an effective treatment. There have been a few attempts, such as the use of deep brain stimulation, the use of drugs to increase neurological recovery, and the use of sensory stimulation. However, as mentioned, there is no conclusive evidence that these therapies have any ultimate affect on neurological recovery.

One study was performed in which deep brain stimulation was performed in an attempt to stimulate the cortex of the brain. This was done using stereotaxically implanted electrodes in the centrum medianum-parafascicularis complex. The tests showed that there were cases of positive change. However, there are also cases of spontaneous long-term recovery which leaves this study inconclusive, and at best only minimally effective (Cohadon and Richer).

Drug therapies are important for the treatment of most medical problems, and therefore have been looked at in the treatment of patients in PVS. Drug categories which are thought to have positive effects on the recovery of patients with PVS include cholinergic agonists and catecholaminergic agonists, both of which assist in increasing the activity of neurotransmitter systems. Cholinergic agonists act like cholinergic neurotransmitters which are the neurotransmitters for many neurons controlling muscle activity as well as many neurons in the central nervous system (CNS). The catecholamine agonists also act like neurotransmitters, and they work on the receptors of catecholaminergic neurotransmitters such as dopamine, epinephrine, and norepinephrine which are present in many CNS neurons. These drugs are thought to be beneficial through stimulating neurons in the CNS leading to greater neurological activity that will hopefully aide in bringing the patient to a state of awareness beyond the vegetative state.

One group of agents which have been studied are dopaminergic agents which act as catecholaminergic agonists, and have been shown to have positive effects on patients with other disorders including akinetic mutism, hepatic coma, and brain damage with avolitional states. Because of this, there have been studies on the effect of levodopa (L-dopa) and combined carbidopa/levodopa therapies. These therapies do seem to have positive effects, and individuals treated with this drug therapy have shown significant recovery. For example one 51-year-old man who was diagnosed with PVS several months following an automobile accident was administered L-dopa. Remarkable neurological recovery occurred though this treatment which helps in repairing damaged dopaminergic systems (Matsuda, et.al.). However, these tests have not been performed in a large enough scale to provide definitive information. There has been a lack of controlled trials in determining the effectiveness of these drugs. Along with this there is the previously mentioned fact that there are different levels of spontaneous recovery for patients that are diagnosed as being in PVS.

There is also much thought that certain drugs can have negative effects on the recovery of patients in PVS. Drug categories such as catecholaminergic antagonists, anticholinergics, GABA agonists and serotonergic agonists are thought to inhibit recovery for patients in PVS. These drugs are thought to have negative effects because they work against the stimulation of neurons in the CNS, and it is the stimulation of the CNS that is thought to be beneficial to the recovery of persons in PVS. Because of the adverse affects of some drugs, there is caution in using them for the treatment of clinical conditions for patients in PVS. For example, drugs that are used in the treatment of epilepsy and spasticity fall into the category of drugs that are considered to be detrimental to the recovery of patients in PVS.

Another form of therapy that seems to have some benefit for patients in PVS, is the use of structured sensory stimulation. This form of therapy stems from the concept that mental function is adversely affected with sensory deprivation. The idea behind this therapy is actually similar to the idea surrounding the drug categories which are hypothesized to have beneficial affects on patients in PVS. That is, the cholenergic and catacholenergic agonists are used to stimulate neurons in the CNS. Structured sensory stimulation, like drug therapy, has not given conclusive information due to the lack of structured and controlled testing.

In sensory stimulation the environment of the patient is kept under control. Patients are exposed to a minimal amount of stimulation to keep from being overloaded with sensory input, and are also given time with no sensory input so that they are able to rest. This leads to another problem, and that is whether or not there is other sensory stimulation that is not being controlled which is affecting the patient. It is also interesting to note that there is no evidence to determine whether enjoyable stimulation and unpleasant stimulation is more effective. The idea of enjoyable and unpleasant stimulation comes from information provided about the patient prior to their being in PVS.

Because of the lack of treatment guidelines for patients in PVS, the medical treatment given to persons in PVS turns to keeping the patient's body in good health, which means treatment similar to that of patients in comatose states. PVS patients are treated to prevent infections, bed sores, and with physical therapy to prevent contractures and orthopedic disformities. In addition patients are given necessary balanced nutrition and hydration, and the administration of these items has been at the center of the euthanasia controversy mentioned at the beginning of the paper.

Recovery

Eye tracking and Emotional responses are the most common ways of determining whether a patient is responding, and therefore no longer in a vegetative state. The first sign of a patient emerging from PVS is the localizing of the eyes on a visual stimulus. This can be observed because persons in a vegetative state are unable to track moving objects or fixate their vision on an object, and as a patient recovers they regain this ability. This type of a response if most often detected by family members or caregivers that have worked directly with the patient. Eye tracking is not necessarily enough to show that a person is recovering from PVS because patients may not show any other evidence of other meaningful response to the environment. More difficulties with eye tracking may come into play because of the possibility of other neurological or ophthalmological damage that may prevent a patient from tracking stimuli. This means that a patient may actually have a degree of recovery that will be missed because it cannot be detected through eye tracking. Emotional response is also difficult to determine because a response must be directly related to specific stimulus. This can be difficult because patients in PVS can scream, cry, grunt or have other actions associated with emotional responses, which are not done in response to stimuli. Therefore significant testing must be done to determine that emotional responses are not being done randomly, but are performed as responses.

A patient recovering from PVS usually recovers in a progressive manner where they move into a post vegetative state. Some patients have recovered significantly. Individuals with relatively short periods of time in PVS have been able to regain nearly normal physical and mental capabilities. There has also been documentation of individuals recovering from periods of PVS lasting over a year who have been able to regain the ability to think, communicate and recover a fair level of physical independence (move without a wheelchair, and feed themselves) (CRA 54).

Future

As has been mentioned throughout this paper there is a lack of information, and a lack of studies on patients in PVS. There are a number of factors that have lead to this. One is the relatively low number of patients in any one place, which leads to difficulty in comparing and testing of therapies carried out on PVS patients. Another factor is that it has been generally agreed that there is no effective treatment, and this thought has possibly deterred individuals from undertaking research efforts in this area. In relation to this, the therapies that are thought to be beneficial seem to have only minimal effect on the recovery of the patient. A final important factor that has probably kept research in this area to a minimum is a lack of finances. Money is needed for research to take place, and if there is no money, then there is no research. At the current time people have not pushed for more research in the area of treatment for PVS and therefore research companies have not seen benefit in persuing these avenues. One area where money does play a factor in PVS, and which may eventually lead to greater research in assist patients in PVS, is the cost of care for patients in PVS. It is estimated that between $1 billion-$7 billion is spent on the care of patients in PVS annually in the United States (Borthwick 3). This is for the medical care that these patients must receive to ensure health, and is at the center of the controversy surrounding euthanasia for patients with this condition. Euthanasia is seen as a cost benefit, and has therefore been looked at in much greater detail than have any of the treatment methods. In fact, ethical controversy has likely detracted from the scientific research that is necessary in determining whether or not there are any treatments that bring significant benefit to patients in PVS.

Along with the possible treatments that have been mentioned and studied to a certain degree, there are other possible treatments which may come to the forefront in the near future. One with great potential, and in an early stage of development, is gene therapy. This type of therapy is being examined for use in recovery form neurological damage. As mentioned, this therapy is still in early stages, but there have been promising animal studies. One such study showed that nerve growth factor which could be secreted by genetically engineered fibroblasts could modulate neruoplasticity in the adult mammalian CNS, and may favor the recovery of cortical function following injury. This type of therapy could prove to be very beneficial in the recovery of cortical function of patients in PVS and therefore prove to bring about the recovery of these patients. This would be a very exciting advancement in the treatment of not only PVS, but other neurological problems, because to this point medical technology is not able to "resuscitate the brain" (Stell).

A final technique that is being examined is the grafting of fetal brain tissue into an adult host. This type of therapy is being explored in animal models and has been performed with rats in the grafting of dopamine and norepinephrine containing neurons into the cerebral cortex, hippocampus and caudate nucleus of an adult rat brain. This therapy has shown to work by generating areas of dense yet defined catecholaminergic projections. It is too early to tell whether or not this technology will be of any benefit to persons with PVS, but it does show that there is research going on in the field of neurophysiology , and it is research in this area that will help in finding treatments for persons with PVS.

There is one point to bring up with these emerging technologies of gene therapy and fetal tissue research, and that is that there are ethical issues which must be addressed before therapies that utilize these technologies are going to be used. Although the techniques that these use are on the cutting edge of medical technology there is the multifaceted view of medicine that must be taken into consideration.

Conclusion

Persistent vegetative state is a condition that will continue to be at the center of controversy until a greater understanding of the condition is found, and more accurate definitions and methods for diagnosis it are determined. It is also true that until money is put into researching this disorder the search for a definitive treatment will not be found. At this point in time the only known hope for recovery is the chance, spontaneous, natural recovery of patient. As with all medical conditions there will be a continued interaction between government, business, academia, medical practitioners, and the public to form the thoughts and treatments surrounding PVS.

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