Persistent vegetative state

# Overview
A persistent vegetative state (PVS) is a condition of patients with severe brain damage in whom coma has progressed to a state of wakefulness without detectable awareness.

# Definition

## Medical definition
Recent functional neuroimaging results have shown that some parts of the cortex are still functioning in 'vegetative' patients. Such studies are disentangling the neural correlates of the vegetative state from the minimally conscious state, and have major clinical consequences in addition to empirical importance for the understanding of consciousness (Laureys, 2000). The minimally conscious state (MCS) is a recently defined clinical condition that differs from the persistent vegetative state (PVS) by the presence of inconsistent, but clearly discernible, behavioral evidence of consciousness (Boly, 2004). Researchers have analyzed functional neuroimaging results and demonstrated that cerebral activity observed in patients in an MCS is more likely to lead to higher-order integrative processes, thought to be necessary for the gain of conscious auditory perception. (Sara et al, 2007).

## Legal/ethical definition
As opposed to brain death, PVS is not recognized as death in any legal system. This legal grey area has led to several court cases involving people in a PVS, those who believe that they should be allowed to die, and those who are equally determined that, if recovery is possible, care should continue. This ethical issue raises questions about autonomy, quality of life, appropriate use of resources, the wishes of family members, professional responsibilities, and many more.

# History
The syndrome was first described in 1940 by Ernst Kretschmer who called it apallic Syndrome.
The term persistent vegetative state was coined in 1972 by Scottish spinal surgeon Bryan Jennett and American neurologist Fred Plum to describe a syndrome that seemed to have been made possible by medicine's increased capacities to keep patients' bodies alive.

# Classification
Terminology in this area is somewhat confused.  While the term persistent vegetative state is the most frequent in media usage and legal provisions, it is discouraged by neurologists, who favour the terminology of the Royal College of Physicians (RCP) which refers only to the vegetative state, the continuing vegetative state, and the permanent vegetative state.
The vegetative state is a chronic or long-term condition. This condition differs from a persistent vegetative state (PVS, a state of coma that lacks both awareness and wakefulness) since patients have awakened from coma, but still have not regained awareness. In the vegetative state patients can open their eyelids occasionally and demonstrate sleep-wake cycles. They also completely lack cognitive function. The vegetative state is also called coma vigil. The continuing vegetative state describes a patient's diagnosis prior to confirmation of the permanence of the condition. The permanent vegetative state occurs when the vegetative state is deemed permanent; a prediction is being made that the patient will never recover awareness. This prediction cannot be made with absolute certainty. However, the chances of regaining awareness diminish considerably as the time spent in the vegetative state increases (Royal College of Physicians, 1996).
This typology distinguishes various stages of the condition rather than using one term for them all. In his most recent book The Vegetative State, Jennett himself adopts this usage, on the grounds that "the 'persistent' component of this term ... may seem to suggest irreversibility". The Australian National Health and Medical Research Council has suggested "post coma unresponsiveness" as an alternative term.

# Signs and symptoms
Most PVS patients are unresponsive to external stimuli and their conditions are associated with different levels of consciousness. Some level of consciousness means a person can still respond, in varying degrees, to stimulation. A person in a coma, however, cannot. In addition, PVS patients often open their eyes, whereas patients in a coma subsist with their eyes closed (Emmett, 1989).
PVS patients' eyes might be in a relatively fixed position, or track moving objects, or move in a disconjugate (i.e. completely unsynchronised) manner. They may experience sleep-wake cycles, or be in a state of chronic wakefulness. They may exhibit some behaviors that can be construed as arising from partial consciousness, such as grinding their teeth, swallowing, smiling, shedding tears, grunting, moaning, or screaming without any apparent external stimulus.
Individuals in PVS are seldom on any life-sustaining equipment other than a feeding tube because the brainstem, the center of vegetative functions (such as heart rate and rhythm, respiration, gastrointestinal activity), is relatively intact (Emmett, 1989).

# Causes
There are three different causes of PVS: brain injuries which may be either acute and traumatic, or non-traumatic; degenerative and metabolic brain disorders, and severe congenital abnormalities of the central nervous system.
Medical books (such as Lippincott, Williams, and Wilkins. (2007). In A Page: Pediatric Signs and Symptoms ) dictate several potential causes of PVS, which are as follows:
- Bacterial, viral, or fungal infection, including Meningitis
- Increased intracranial pressure, such as a tumor or abscess
- Vascular pressure which causes intracranial hemorrhaging or stroke
- Hypoxic ischemic injury (hypotension, cardiac arrest, arrhythmia, near-drowning)
- Toxins such as uremia, ethanol, atropine, opiates, lead, substance abuse, colloidal silver
- Trauma: Concussion, contusion
- Seizure, both nonconvulsive status epilepticus and postconvulsive state (postictal state)
- Electrolyte imbalance, which involves hyponatremia, hypernatremia, hypomagnesimia, hypoglycemia, hyperglycemia, hypercalcemia, and hypocalcemia
- Postinfectious: Acute disseminated encephalomyelitis (ADEM)
- Endocrine disorders such as adrenal insufficiency and thyroid disorders
- Degenerative and metabolic diseases including urea cycle disorders, Reye syndrome, and mitochondrial disease
- Systemic infection and sepsis
- Hepatic encephalopathy
- Psychogenic
In addition, these authors claim that doctors sometimes use the mnemonic device AEIOU-TIPS to recall portions of the differential diagnosis: Alcohol ingestion and acidosis, Epilepsy and encephalopathy, Infection, Opiates, Uremia, Trauma, Insulin overdose or inflammatory disorders, Poisoning and psychogenic causes, and Shock.

# Diagnosis
Despite converging agreement about the definition of persistent vegetative state, recent reports have raised concerns about the accuracy of diagnosis in some patients, and the extent to which, in a selection of cases, residual cognitive functions may remain undetected and patients are diagnosed as being in a persistent vegetative state. Objective assessment of residual cognitive function can be extremely difficult as motor responses may be minimal, inconsistent, and difficult to document in many patients, or may be undetectable in others because no cognitive output is possible (Owen et al, 2002). In recent years, a number of studies have demonstrated an important role for functional neuroimaging in the identification of residual cognitive function in persistent vegetative state; this technology is providing new insights into cerebral activity in patients with severe brain damage. Such studies, when successful, may be particularly useful where there is concern about the accuracy of the diagnosis and the possibility that residual cognitive function has remained undetected.

## Diagnostic experiments
Researchers have begun to use functional neuroimaging studies to study covert cognitive processing in patients with a clinical diagnosis of persistent vegetative state. Activations in response to sensory stimuli with positron emission tomography (PET), functional magnetic resonance imaging (fMRI), and electrophysiological methods can provide information on the presence, degree, and location of any residual brain function. However, use of these techniques in people with severe brain damage is methodologically, clinically, and theoretically complex and needs careful quantitative analysis and interpretation.
For example, PET studies have shown the identification of residual cognitive function in persistent vegetative state. That is, an external stimulation, such as a painful stimulus, still activates 'primary' sensory cortices in these patients but these areas are functionally disconnected from 'higher order' associative areas needed for awareness. These results show that parts of the cortex are indeed still functioning in 'vegetative' patients (Matsuda et al, 2003).
In addition, other PET studies have revealed preserved and consistent responses in predicted regions of auditory cortex in response to intelligible speech stimuli. Moreover, a preliminary fMRI examination revealed partially intact responses to semantically ambiguous stimuli, which are known to tap higher aspects of speech comprehension (Boly, 2004).
Furthermore, several studies have used PET to assess the central processing of noxious somatosensory stimuli in patients in PVS. Noxious somatosensory stimulation activated midbrain, contralateral thalamus, and primary somatosensory cortex in each and every PVS patient, even in the absence of detectable cortical evoked potentials. In conclusion, somatosensory stimulation of PVS patients, at intensities that elicited pain in controls, resulted in increased neuronal activity in primary somatosensory cortex, even if resting brain metabolism was severely impaired. However, this activation of primary cortex seems to be isolated and dissociated from higher-order associative cortices (Laureys et al, 2002).
Also, there is evidence of partially functional cerebral regions in catastrophically injured brains. To study five patients in PVS with different behavioral features, researchers employed PET, MRI and magnetoencephalographic (MEG) responses to sensory stimulation. In three of the five patients, co-registered PET/MRI correlate areas of relatively preserved brain metabolism with isolated fragments of behavior. Two patients had suffered anoxic injuries and demonstrated marked decreases in overall cerebral metabolism to 3040% of normal. Two other patients with non-anoxic, multifocal brain injuries demonstrated several isolated brain regions with relatively higher metabolic rates, that ranged up to 5080% of normal. Nevertheless, their global metabolic rates remained <50% of normal. MEG recordings from three PVS patients provide clear evidence for the absence, abnormality or reduction of evoked responses. Despite major abnormalities, however, these data also provide evidence for localized residual activity at the cortical level. Each patient partially preserved restricted sensory representations, as evidenced by slow evoked magnetic fields and gamma band activity. In two patients, these activations correlate with isolated behavioral patterns and metabolic activity. Remaining active regions identified in the three PVS patients with behavioral fragments appear to consist of segregated corticothalamic networks that retain connectivity and partial functional integrity. A single patient who suffered severe injury to the tegmental mesencephalon and paramedian thalamus showed widely preserved cortical metabolism, and a global average metabolic rate of 65% of normal. The relatively high preservation of cortical metabolism in this patient defines the first functional correlate of clinical pathological reports associating permanent unconsciousness with structural damage to these regions. The specific patterns of preserved metabolic activity identified in these patients reflect novel evidence of the modular nature of individual functional networks that underlie conscious brain function. The variations in cerebral metabolism in chronic PVS patients indicate that some cerebral regions can retain partial function in catastrophically injured brains (Schiff et al, 2002).

## Misdiagnoses
Misdiagnosis of PVS is not uncommon. One study of 40 patients in the United Kingdom reported that 43% of those patients classified as in a PVS were misdiagnosed and another 33% able to recover whilst the study was underway. Some cases of PVS may actually be cases of patients being in an undiagnosed minimally conscious state. Since the exact diagnostic criteria of the minimally conscious state were formulated only in 2002, there may be chronic patients diagnosed as PVS before the notion of the minimally conscious state became known.
Can there be conscious awareness in vegetative state? Three completely different aspects of this issue should be distinguished. First, some patients can be conscious simply because they are misdiagnosed. In fact, they are not in vegetative state. Second, sometimes a patient was correctly diagnosed but, then, examined during a beginning recovery. Third, perhaps some day the very notion of the vegetative state will change so as to include elements of conscious awareness. Inability to disentangle these three cases leads to confusion. An example of such confusion is the response to a recent experiment using magnetic resonance imaging which revealed that a woman diagnosed with PVS was able to activate predictable portions of her brain in response to the tester's requests that she imagine herself playing tennis or moving from room to room in her house. The brain activity in response to these instructions was indistinguishable from those of healthy patients. Because such activations can be obtained only if a patient has clear awareness and concentrated attention, the diagnosis of PVS was obviously an error. Therefore, the experiment did not show awareness in vegetative state in any reasonable sense of the word; rather, it showed that magnetic resonance imaging, combined with sophisticated stimulation, can effectively be used to disclose major diagnostic errors.

# Recovery
Many patients emerge spontaneously from a vegetative state within a few weeks. The chances of recovery depend on the extent of injury to the brain and the patient's age  younger patients having a better chance of recovery than older patients. Generally, adults have a 50 percent chance and children a 60 percent chance of recovering consciousness from a PVS within the first 6 months. After a year, the chances that a PVS patient will regain consciousness are very low and most patients who do recover consciousness experience significant disability. The longer a patient is in a PVS, the more severe the resulting disabilities are likely to be. Rehabilitation can contribute to recovery, but many patients never progress to the point of being able to take care of themselves.Recovery after long periods of time in a PVS has been reported on several occasions and are often treated as spectacular events.
There are two dimensions of recovery from a persistent vegetative state: recovery of consciousness and recovery of function. Recovery of consciousness can be verified by reliable evidence of awareness of self and the environment, consistent voluntary behavioral responses to visual and auditory stimuli, and interaction with others. Recovery of function is characterized by communication, the ability to learn and to perform adaptive tasks, mobility, self-care, and participation in recreational or vocational activities. Recovery of consciousness may occur without functional recovery, but functional recovery cannot occur without recovery of consciousness (Ashwal, 1994).

# Possible treatment and cures
As of April 2007, no treatment for vegetative state exists that would satisfy the efficiency criteria of evidence-based medicine. Several methods have been proposed which can roughly be subdivided into four categories: pharmacological methods, surgery, physical therapy, and various stimulation techniques. Pharmacological therapy mainly uses activating substances such as tricyclic antidepressants or methylphenidate. Promising results have been reported on dopaminergic drugs, particularly amantadine. Presently the first randomized controlled trial amantadine versus placebo is running; its results have not been published yet. Surgical methods such as deep brain stimulation are rarely used. Stimulation techniques include sensory stimulation, sensory regulation, music and musicokinetic therapy, social-tactile interaction, etc.  Below are some details related to treatments that have demonstrated some hope.

### Zolpidem (stilnox/ambien)
There is currently limited evidence that the imidazopyridine hypnotic drug zolpidem (stilnox/ambien) can have positive behavioral effects in some PVS patients. The first such putative case is Louis Viljoen who was hit by a vehicle in 1994 leaving him in a PVS state. Five years later when Viljoen was having involuntary spasms in his left arm, his physician, H Wally Nel, treated him with zolpidem. 25 minutes after the treatment, Viljoen started murmuring and then conversing, albeit not fluently, with his mother. In magnetic resonance images of his brain before and after treatment with zolpidem, the damaged brain regions, which appeared black and dead before treatment, began to light up with neural activity afterwards. Following seven years of further treatment with zolpidem, Viljoen can now speak in complex sentences and move his head and arms. The physician, Nel, who treated Viljoen claims to have treated 150 further PVS patients with zolpidem and seen improvements in approximately 60% of them.
Additionally, stroke victims and patients with head injuries or brain damage following oxygen deprivation, such as near-drowning victims, have reported significant improvements in speech, motor functions, and concentration after treatment with zolpidem.
A clinical trial of zolpidem involving over 360 PVS patients worldwide is currently underway, and 60% of these patients are showing signs of improvement, although no results have yet been published.
There is one other published case series on the long-term effects of zolpidem on patients in PVS, also authored by Nel & Clauss. The first patient, "L", is a 31 year old male who, before treatment with zolpidem, had been in PVS for three years with a Glasgow Coma Scale of 9. They report that after receiving 10mg of zolpidem, L is able to engage in meaningful conversation. The maximum effect of the zolpidem is seen one hour after application and wears off after about four hours. By the date of publication in 2006, L had been receiving zolpidem therapy for six years, with no decrease in the effectiveness of treatment, and some gradual long-term improvement in short- and long-term memory. The other two patients in the case series were male, of similar age, and had similar though somewhat lessened responses to zolpidem  the zolpidem worked maximally one hour after application, its effects wore off after four hours, and there was no decrease in effectiveness after several years of daily use.
As yet, no scientific studies have been published on the effectiveness of zolpidem as a treatment for PVS.

### Levodopa
In addition, there have been several case studies analyzed that emphasize another pharmacological possibility of treatment for patients in a persistent vegetative state. Three patients, whose brains had been damaged by severe head injury, recovered from a persistent vegetative state after the administration of a drug called levodopa. In all three cases the patients were deeply comatose on arrival to the hospital, remained unresponsive to simple verbal commands, and their condition was unchanged for a lengthy period of time even after intensive treatment including surgery. All three patients were diagnosed as being in a persistent vegetative state for three, seven, and twelve months respectively (Matsuda et al, 2003).
Case 1 describes a 14 year old boy who, three months after his trauma, could not follow moving objects with his eyes and experienced tremor-like involuntary movements as well as hypertonicity (increased tension of the muscles, meaning the muscle tone is abnormally rigid, hampering proper movement). Levodopa was recommended to relieve the patients parkinsonian features. Surprisingly, after nine days of treatment the patients involuntary movements were reduced and he began to respond toward voices. Three months after treatment, he was able to walk and obtained the intelligence of an elementary school child. One year after his trauma, he was able to walk to high school by himself. Case 2 involves a young adult who underwent deep brain stimulation one year after the trauma and showed no improvement. Levodopa was administered and one year later, once his tubes were removed, he said, I want to eat sushi and drink beer! Case 3 describes a middle-aged man who experienced spasticity of his extremities, was administered levodopa, and was able to say his name and address correctly after only two months. 
After neurological evaluation, all three cases revealed asymmetrical rigidity or tremor and presynaptic damage in the dopaminergic (uses dopamine as neurotransmitter) systems. In conclusion, levodopa should be considered for patients in a persistent vegetative state with atypical features in their limbs and who have MRI evidence of lesions in the dopaminergic pathway, particularly presynaptic lesions in areas such as the substantia nigra or ventral tegmentum. Data shows that only 6% of adult patients recover after being in a vegetative state for six to twelve months. This poor recovery rate demonstrates the significance in the rapid recovery of patients that begin levodopa treatment, particularly in those who were in a vegetative state for almost a year.

### Baclofen
This unexpected and late recovery of consciousness raises an interesting hypothesis of possible effects of partially regained spinal cord outputs on reactivation of cognition. Other case studies have shown that recovery of consciousness with persistent severe disability 19 months after a non-traumatic brain injury was at least in part triggered and maintained by intrathecal baclofen administration (Sara et al, 2007).

### Removal of cold intubated oxygen
Another documented case reports recovery of a small number of patients following the removal of assisted respiration with cold oxygen.  The researchers found that in many nursing homes and hospitals unheated oxygen is given to non-responsive patients via tracheal intubation. This bypasses the warming of the upper respiratory tract and causes a chilling of aortic blood and chilling of the brain. The researchers describe a small number of cases in which removal of the chilled oxygen was followed by recovery from the PVS and recommend either warming of oxygen with a heated nebulizer or removal of the assisted oxygen if it is no longer needed. The authors further recommend additional research to determine if this chilling effect may either delay recovery or even may contribute to brain damage.

# Epidemiology
In the United States, it is estimated that there may be between 15,000-40,000 patients who are in a persistent vegetative state, but due to poor nursing home records exact figures are hard to determine.