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 Coma Coma is defined as a deep state of unarousable unresponsiveness, characterized by a score of 3 points on the GCS. A comatose state can be caused by a multitude of conditions, making the precise epidemiology and prognosis of coma difficult to determine. Coma in that individuals in a persistent vegetative state have intermittent sleep Sleep Sleep is a reversible phase of diminished responsiveness, motor activity, and metabolism. This process is a complex and dynamic phenomenon, occurring in 4-5 cycles a night, and generally divided into non-rapid eye movement (NREM) sleep and REM sleep stages. Physiology of 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 Cardiac arrest Cardiac arrest is the sudden, complete cessation of cardiac output with hemodynamic collapse. Patients present as pulseless, unresponsive, and apneic. Rhythms associated with cardiac arrest are ventricular fibrillation/tachycardia, asystole, or pulseless electrical activity. 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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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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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 Coma Coma is defined as a deep state of unarousable unresponsiveness, characterized by a score of 3 points on the GCS. A comatose state can be caused by a multitude of conditions, making the precise epidemiology and prognosis of coma difficult to determine. Coma and recovery or between coma Coma Coma is defined as a deep state of unarousable unresponsiveness, characterized by a score of 3 points on the GCS. A comatose state can be caused by a multitude of conditions, making the precise epidemiology and prognosis of coma difficult to determine. 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 Sleep Sleep is a reversible phase of diminished responsiveness, motor activity, and metabolism. This process is a complex and dynamic phenomenon, occurring in 4-5 cycles a night, and generally divided into non-rapid eye movement (NREM) sleep and REM sleep stages. Physiology of Sleep–wake cycles
    • Sufficiently preserved hypothalamic and brain stem Brain Stem The brain stem is a stalk-like structure that connects the cerebrum with the spinal cord and consists of the midbrain, pons, and medulla oblongata. It also plays a critical role in the control of cardiovascular and respiratory function, consciousness, and the sleep-wake cycle. 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 Cerebral cortex The cerebral cortex is the largest and most developed part of the human brain and CNS. Occupying the upper part of the cranial cavity, the cerebral cortex has 4 lobes and is divided into 2 hemispheres that are joined centrally by the corpus callosum. Cerebral Cortex and spares the brain stem Brain Stem The brain stem is a stalk-like structure that connects the cerebrum with the spinal cord and consists of the midbrain, pons, and medulla oblongata. It also plays a critical role in the control of cardiovascular and respiratory function, consciousness, and the sleep-wake cycle. Brain Stem
  • Traumatic brain injury (most common)
  • Nontraumatic brain injury
    • Hypoxic–ischemic injury ( hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension, cardiac arrest Cardiac arrest Cardiac arrest is the sudden, complete cessation of cardiac output with hemodynamic collapse. Patients present as pulseless, unresponsive, and apneic. Rhythms associated with cardiac arrest are ventricular fibrillation/tachycardia, asystole, or pulseless electrical activity. Cardiac Arrest, arrhythmia, near- drowning Drowning Drowning occurs due to respiratory impairment from submersion or immersion in a liquid medium. Aspiration of water leads to hypoxemia, which affects all organ systems, resulting in respiratory insufficiency and acute respiratory distress syndrome (ARDS), cardiac arrhythmias, and neuronal damage. Drowning)
    • Hemorrhagic or thrombotic cerebrovascular event
    • Toxins:
      • Uremia
      • Ethanol
      • Opiates
      • Lead
    • Bacterial, viral, or fungal infection
    • Increased intracranial pressure Increased Intracranial Pressure Normal intracranial pressure (ICP) is defined as < 15 mm Hg, whereas pathologically increased ICP is any pressure ≥ 20 mm Hg. Increased ICP may result from several etiologies, including trauma, intracranial hemorrhage, mass lesions, cerebral edema, increased CSF production, and decreased CSF absorption. Increased Intracranial Pressure (ICP) (e.g., tumor or abscess)
    • Electrolyte imbalance:
      • Hyponatremia Hyponatremia Hyponatremia is defined as a decreased serum sodium (sNa+) concentration less than 135 mmol/L. Serum sodium is the greatest contributor to plasma osmolality, which is very tightly controlled via antidiuretic hormone (ADH) release from the hypothalamus and by the thirst mechanism. Hyponatremia or hypernatremia Hypernatremia Hypernatremia is an elevated serum sodium concentration > 145 mmol/L. Serum sodium is the greatest contributor to plasma osmolality, which is very tightly controlled by the hypothalamus via the thirst mechanism and antidiuretic hormone (ADH) release. Hypernatremia occurs either from a lack of access to water or an excessive intake of sodium. Hypernatremia
      • Hypoglycemia Hypoglycemia Hypoglycemia is an emergency condition defined as a serum glucose level ≤ 70 mg/dL (≤ 3.9 mmol/L) in diabetic patients. In nondiabetic patients, there is no specific or defined limit for normal serum glucose levels, and hypoglycemia is defined mainly by its clinical features. Hypoglycemia or hyperglycemia
      • Hypocalcemia Hypocalcemia Hypocalcemia, a serum calcium < 8.5 mg/dL, can result from various conditions. The causes may include hypoparathyroidism, drugs, disorders leading to vitamin D deficiency, and more. Calcium levels are regulated and affected by different elements such as dietary intake, parathyroid hormone (PTH), vitamin D, pH, and albumin. Presentation can range from an asymptomatic (mild deficiency) to a life-threatening condition (acute, significant deficiency). Hypocalcemia or hypercalcemia Hypercalcemia Hypercalcemia (serum calcium > 10.5 mg/dL) can result from various conditions, the majority of which are due to hyperparathyroidism and malignancy. Other causes include disorders leading to vitamin D elevation, granulomatous diseases, and the use of certain pharmacological agents. Symptoms vary depending on calcium levels and the onset of hypercalcemia. Hypercalcemia
    • Endocrine disorders:
      • Adrenal insufficiency Adrenal Insufficiency Adrenal insufficiency (AI) is the inadequate production of adrenocortical hormones: glucocorticoids, mineralocorticoids, and adrenal androgens. Primary AI, also called Addison’s disease, is caused by autoimmune disease, infections, and malignancy, among others. Adrenal insufficiency can also occur because of decreased production of adrenocorticotropic hormone (ACTH) from disease in the pituitary gland (secondary) or hypothalamic disorders and prolonged glucocorticoid therapy (tertiary). Adrenal Insufficiency and Addison’s Disease 
      • Thyroid disorders
    • Degenerative and metabolic diseases:
      • Urea cycle disorders Urea cycle disorders Urea cycle disorders (UCDs) are caused by genetic defects and result in deficiencies of enzymes and transporters of the urea cycle. As a result of the defects, individuals are unable to rid the body of nitrogen waste. Common symptoms include vomiting, lethargy, seizures, and respiratory alkalosis. Urea Cycle Disorders
      • Reye syndrome
      • Mitochondrial diseases
    • Hepatic encephalopathy Hepatic Encephalopathy Hepatic encephalopathy is a reversible condition in which elevated ammonia levels cause impaired brain function in patients with advanced liver disease. Hepatic encephalopathy can be precipitated by conditions that affect the normal absorption, metabolism, or clearance of ammonia, including dehydration, renal failure, infections, and gastrointestinal bleeding. 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 Coma Coma is defined as a deep state of unarousable unresponsiveness, characterized by a score of 3 points on the GCS. A comatose state can be caused by a multitude of conditions, making the precise epidemiology and prognosis of coma difficult to determine. 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 Coma Coma is defined as a deep state of unarousable unresponsiveness, characterized by a score of 3 points on the GCS. A comatose state can be caused by a multitude of conditions, making the precise epidemiology and prognosis of coma difficult to determine. 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 Teeth Normally, an adult has 32 teeth: 16 maxillary and 16 mandibular. These teeth are divided into 4 quadrants with 8 teeth each. Each quadrant consists of 2 incisors (dentes incisivi), 1 canine (dens caninus), 2 premolars (dentes premolares), and 3 molars (dentes molares). Teeth are composed of enamel, dentin, and dental cement. 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 Electrolytes Electrolytes are mineral salts that dissolve in water and dissociate into charged particles called ions, which can be either be positively (cations) or negatively (anions) charged. Electrolytes are distributed in the extracellular and intracellular compartments in different concentrations. Electrolytes are essential for various basic life-sustaining functions. Electrolytes
    • CBC
    • Arterial or venous blood gas analysis
    • Toxicologic tests
    • CSF analysis
  • Imaging: 
    • MRI: shows generalized reduction of cerebral blood flow Flow Blood flows through the heart, arteries, capillaries, and veins in a closed, continuous circuit. Flow is the movement of volume per unit of time. Flow is affected by the pressure gradient and the resistance fluid encounters between 2 points. Vascular resistance is the opposition to flow, which is caused primarily by blood friction against vessel walls. Vascular Resistance, Flow, and Mean Arterial Pressure
    • Fluorodeoxyglucose–positron emission tomography (FDG–PET) scan → generalized and markedly reduced cerebral metabolism of glucose
  • Other testing:
    • Quantitative EEG: to assess sleep Sleep Sleep is a reversible phase of diminished responsiveness, motor activity, and metabolism. This process is a complex and dynamic phenomenon, occurring in 4-5 cycles a night, and generally divided into non-rapid eye movement (NREM) sleep and REM sleep stages. Physiology of 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 Cardiac arrest Cardiac arrest is the sudden, complete cessation of cardiac output with hemodynamic collapse. Patients present as pulseless, unresponsive, and apneic. Rhythms associated with cardiac arrest are ventricular fibrillation/tachycardia, asystole, or pulseless electrical activity. 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 Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. 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 Deep vein thrombosis Deep vein thrombosis (DVT) usually occurs in the deep veins of the lower extremities. The affected veins include the femoral, popliteal, iliofemoral, and pelvic veins. Proximal DVT is more likely to cause a pulmonary embolism (PE) and is generally considered more serious. Deep Vein Thrombosis ( DVT DVT Deep vein thrombosis (DVT) usually occurs in the deep veins of the lower extremities. The affected veins include the femoral, popliteal, iliofemoral, and pelvic veins. Proximal DVT is more likely to cause a pulmonary embolism (PE) and is generally considered more serious. Deep Vein Thrombosis) prophylaxis
  • Physical therapy 
  • Treatment of seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures if needed

Ethical considerations

  • Decision-making capacity Decision-making capacity Decision-making capacity describes a patient's ability to make autonomous decisions regarding their care, as determined by a physician. Decision-making Capacity and Legal Competence 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 Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables.
    • 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 Locked-in syndrome Locked-in syndrome (LIS) is a rare neurological disorder in which patients are awake and conscious but are unable to move their limbs or speak. The disorder is a result of brain injury to the ventral aspect of the pons and caudal ventral midbrain; etiologies include brainstem stroke, tumors, intracranial bleeding, and demyelinating disorders. Locked-in Syndrome: This is a state of quadriplegia (inability to move the limbs) and anarthria (inability to articulate speech) resulting from brain stem Brain Stem The brain stem is a stalk-like structure that connects the cerebrum with the spinal cord and consists of the midbrain, pons, and medulla oblongata. It also plays a critical role in the control of cardiovascular and respiratory function, consciousness, and the sleep-wake cycle. Brain Stem injury. Locked-in syndrome Locked-in syndrome Locked-in syndrome (LIS) is a rare neurological disorder in which patients are awake and conscious but are unable to move their limbs or speak. The disorder is a result of brain injury to the ventral aspect of the pons and caudal ventral midbrain; etiologies include brainstem stroke, tumors, intracranial bleeding, and demyelinating disorders. 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 Brain death is a legal and clinical term describing the irreversible cessation of all cerebral and brainstem functions, including the ability of the brain stem to regulate vegetative and respiratory activities. Brain Death: Brain death Brain death Brain death is a legal and clinical term describing the irreversible cessation of all cerebral and brainstem functions, including the ability of the brain stem to regulate vegetative and respiratory activities. Brain Death” is a legal and clinical term that describes the irreversible cessation of all cerebral and brain stem Brain Stem The brain stem is a stalk-like structure that connects the cerebrum with the spinal cord and consists of the midbrain, pons, and medulla oblongata. It also plays a critical role in the control of cardiovascular and respiratory function, consciousness, and the sleep-wake cycle. Brain Stem functions, including the ability of the brain stem Brain Stem The brain stem is a stalk-like structure that connects the cerebrum with the spinal cord and consists of the midbrain, pons, and medulla oblongata. It also plays a critical role in the control of cardiovascular and respiratory function, consciousness, and the sleep-wake cycle. 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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