Persistent Vegetative State

The term “persistent vegetative state,” also called unresponsive wakefulness, describes the condition of individuals with severe anoxic brain injury who have progressed to a state of wakefulness without any meaningful response to their environment. A persistent vegetative state is distinguished from a coma in that individuals in a persistent vegetative state have intermittent sleep–wake cycles. The individual’s eyes may be open and there may be some yawning, grunting, or other vocalizations. In both cases, the individual is alive, but the brain does not function fully. Persistent vegetative state is most commonly associated with anoxic brain injury due to cardiac arrest, trauma, metabolic causes, or infections. Diagnosis is made by fulfilling specific diagnostic criteria. Treatment is controversial and ethically challenging. Recovery of consciousness from a posttraumatic persistent vegetative state is unlikely after 12 months, while recovery from a nontraumatic persistent vegetative state after 3 months is exceedingly rare.

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Overview

Definition

Persistent vegetative state, also called unresponsive wakefulness, describes the condition of individuals with severe anoxic brain injury who have progressed to a state of wakefulness without any meaningful response to their environment.

  • The definition requires permanence of vegetative state, which is established:
    • 3 months after a hypoxic brain injury
    • 1 year after a traumatic brain injury
  • The persistent vegetative state represents a transition between coma and recovery or between coma and death.
  • The following criteria need to be present for the diagnosis:
    • 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
    • Intermittent wakefulness manifested by the presence of sleep–wake cycles
    • Sufficiently preserved hypothalamic and brain stem autonomic function to permit survival with medical and nursing care
    • Bowel and bladder incontinence
    • Variably preserved cranial nerve reflexes and spinal reflexes

Epidemiology

  • In the United States, there are 15,000–40,000 individuals in a persistent vegetative state.
  • Prevalence varies widely: estimated at 0.2–6.1 individuals per 100,000

Etiology

  • Anything that causes extensive damage to the cerebral cortex and spares the brain stem
  • Traumatic brain injury (most common)
  • Nontraumatic brain injury
    • Hypoxic–ischemic injury (hypotension, cardiac arrest, arrhythmia, near-drowning)
    • Hemorrhagic or thrombotic cerebrovascular event
    • Toxins:
      • Uremia
      • Ethanol
      • Opiates
      • Lead
    • Bacterial, viral, or fungal infection
    • Increased intracranial pressure (e.g., tumor or abscess)
    • Electrolyte imbalance:
      • Hyponatremia or hypernatremia
      • Hypoglycemia or hyperglycemia
      • Hypocalcemia or hypercalcemia
    • Endocrine disorders:
      • Adrenal insufficiency 
      • Thyroid disorders
    • Degenerative and metabolic diseases:
      • Urea cycle disorders
      • Reye syndrome
      • Mitochondrial diseases
    • Hepatic encephalopathy

Pathophysiology

Arousal and wakefulness are supported by neurons that project to both thalamic and cortical neurons.

  • In persistent vegetative state:
    • Brain stem function is mostly spared → maintains arousal and autonomic functions
    • Gray and white matter of both cerebral hemispheres are severely damaged.
    • Cortical metabolism of individuals in a vegetative state is 30%–40% of the normal range of values → may be irreversible structural neuronal loss or potentially reversible damage
  • In a coma, the individual:
    • Does not open the eyes, even with vigorous stimulation
    • Displays no evidence of awareness of their surroundings, even after the discontinuation of sedative drugs 
    • In the transition from a coma to persistent vegetative state → eyes are open intermittently (wakefulness), but there is no evidence of awareness of consciousness 

Clinical Presentation

Individuals may present with persistent vegetative state several months after a traumatic or anoxic brain injury.

Clinical features

  • Compatible with persistent vegetative state: 
    • Generally able to breathe without mechanical support
    • Cardiovascular, GI, and renal function may be normal.
    • Stool and urine incontinence are present.
    • The individual appears to be asleep with their eyes closed at times and awake but unaware with their eyes open at other times.
    • Individuals in a persistent vegetative state may:
      • Make a range of spontaneous movements, including chewing, teeth grinding, and swallowing
      • Grimace or move their extremities in response to external stimuli
      • Have emotional responses (smile, shed tears, scream) with no discernible reason
      • Turn their head and eyes fleetingly to follow a moving object or loud sound 
      • Have spontaneous roving movements of the eyes
    • Neurologic exam:
      • Brain stem reflexes (pupillary, oculocephalic, corneal, and gag) are usually intact. 
      • Painful stimulation may provoke an extensor or flexor response of the extremities.
      • Grasp reflexes may be present.
  • Incompatible with persistent vegetative state:
    • Any unambiguous sign of conscious perception or deliberate action 
    • Any evidence of purposeful movement, communication, or consistent response to a command:
      • Can easily be missed, especially in individuals whose motor capacities are limited
      • Fluctuating arousal or motivation may prevent this evidence from being detected during a single examination.
      • Repeated exams are necessary before concluding that an individual’s wakefulness is unaccompanied by awareness.
      • The rate of misdiagnosis of persistent vegetative state has been estimated at 37%–43%.

Testing

  • Labs: To rule out other conditions causing decreased responsiveness (e.g., profound electrolyte disturbances, toxic substances, infection): 
    • Electrolytes
    • CBC
    • Arterial or venous blood gas analysis
    • Toxicologic tests
    • CSF analysis
  • Imaging: 
    • MRI: shows generalized reduction of cerebral blood flow
    • Fluorodeoxyglucose–positron emission tomography (FDG–PET) scan → generalized and markedly reduced cerebral metabolism of glucose
  • Other testing:
    • Quantitative EEG: to assess sleep architecture
    • Event-related potentials: records small changes in EEG signals in response to external stimuli
Fdg pet scan to evaluate brain metabolism in a 66-year-old woman with pvs

Fluorodeoxyglucose–positron emission tomography (FDG–PET) scan to evaluate brain metabolism in a 66-year-old woman in a persistent vegetative state 10 months after intraoperative cardiac arrest and severe cerebral hypoxemia:
Scan shows massive cortical and subcortical brain atrophy with dilated ventricles (normal intracranial pressure).

Image: “FDG PET scan PVS full stage. Indication: Brain metabolism 10 months after insult” by Wild K. et al. License: CC BY 2.0

Management and Ethical Considerations

Individuals in a persistent vegetative state require ongoing supportive care for the prevention of complications as well as treatment of seizures if they occur.

Supportive care

  • Nutrition via nasogastric or gastrostomy tube
  • Adequate hydration
  • Establishment of secure airway and tracheostomy if needed
  • Pressure ulcer prophylaxis
  • Deep vein thrombosis (DVT) prophylaxis
  • Physical therapy 
  • Treatment of seizures if needed

Ethical considerations

  • Decision-making capacity or power of attorney is transferred to the family, who may choose to:
    • Continue life-supporting measures 
    • Discontinue life-supporting measures: considered ethical by the American Academy of Neurology
  • If the individual has an advance directive, this should be honored.

Prognosis

  • Potential for recovery:
    • Spectrum of regaining consciousness to functional living:
      • Some individuals have regained consciousness after years of being in a persistent vegetative state, but with major, persistent physical impairment.
      • Determination of what constitutes “worthwhile” recovery is highly subjective and variable.
    • In 15% of nontraumatic injury cases and 50% of traumatic injury cases, the individual will recover consciousness by 12 months.
    • Persistent vegetative state of traumatic origin has a better prognosis in general than one of nontraumatic origin.
  • Younger individuals have a more favorable prognosis.
  • 80% mortality after 5 years

Differential Diagnosis

  • Minimally conscious state: This term is used to describe individuals who are not in a vegetative state but are unable to communicate consistently. They can reproducibly demonstrate ≥ 1 of the following behaviors: visually tracking, following simple commands, gestural or verbal yes/no response to questions, intelligible speech, purposeful behavior. Further improvement is more likely than in individuals in a persistent vegetative state; however, some people remain in a minimally conscious state permanently. 
  • Locked-in syndrome: This is a state of quadriplegia (inability to move the limbs) and anarthria (inability to articulate speech) resulting from brain stem injury. Locked-in syndrome is defined by sustained eye opening, awareness of the environment, aphonia or hypophonia, quadriplegia or quadriparesis, and vertical or lateral eye movement or blinking of the upper eyelid to signal yes/no responses. Eye or eyelid movements are the only method of communication. These individuals characteristically retain alertness and cognitive ability.
  • Brain death: “Brain death” is a legal and clinical term that describes the irreversible cessation of all cerebral and brain stem functions, including the ability of the brain stem to regulate vegetative and respiratory activities. In addition to the bedside neurologic exam, additional ancillary studies may occasionally be needed to support the diagnosis. A diagnosis of brain death must be established prior to considering organ donation. 

References

  1. Bender, A., Jox, R.J., Grill, E., Straube, A., Lulé, D. (2015). Persistent vegetative state and minimally conscious state: a systematic review and meta-analysis of diagnostic procedures. Deutsches Arzteblatt International 112:235–242. Retrieved September 29, 2021, from https://www.aerzteblatt.de/int/archive/article/169020
  2. Berger, J.R., Price, R. (2021). Stupor and coma. In Jankovic J., Mazziotta, J.C., Pomeroy, S. L., & Newman, N. J. (Eds.), Bradley and Daroff’s Neurology in Clinical Practice, pp. 34–51.e1. 
  3. Ferri, F. F. (2021). V – differential diagnosis. In Ferri, F. F. (Ed.), Ferri’s Clinical Advisor 2022. Elsevier, pp. 1765–1770.
  4. Weinhouse, G.L., Young, B. (2020). Hypoxic-ischemic brain injury in adults: evaluation and prognosis. UpToDate. Retrieved September 29, 2021, from https://www.uptodate.com/contents/hypoxic-ischemic-brain-injury-in-adults-evaluation-and-prognosis

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