A vegetative state is absence of responsiveness and awareness due to overwhelming dysfunction of the cerebral hemispheres, with sufficient sparing of the diencephalon and brain stem to preserve autonomic and motor reflexes and sleep-wake cycles. Patients may have complex reflexes, including eye movements, yawning, and involuntary movements to noxious stimuli, but show no awareness of self or environment. A minimally conscious state is characterized by some evidence of awareness of self and/or the environment, and patients tend to improve. Diagnosis is based on history and findings of the physical examination, including the use of a quantitative behavioral assessment, typically using the Coma Recovery Scale–Revised. Treatment is mainly supportive. Prognosis must be formulated carefully with consideration of time after injury and the underlying etiology. A high rate of misdiagnosis of vegetative state in patients demonstrating clinical features of minimally conscious state has significant prognostic implications as prognosis is improved for MCS.
The vegetative state (VS)—sometimes called unresponsive wakefulness syndrome (UWS)—is a condition that preserves the ability to maintain blood pressure (BP), respiration, and cardiac function, but not cognitive function. Hypothalamic and medullary brain stem functions remain intact to support cardiorespiratory and autonomic functions and are sufficient for survival if medical and nursing care is adequate. The cortex is severely damaged (eliminating cognitive function), but the brain stem arousal systems remain functional, producing periods of eyes open during the day that appear "wakeful" but are unlinked to the normal sleep-wake features of neuronal activity. Midbrain or pontine reflexes may or may not be present. Patients usually have no awareness of self and interact with the environment only via reflexes. Seizure activity may be present but not be clinically evident.
Terminology no longer in use described a "persistent" vegetative state (1).
The most common causes of a vegetative state and minimally conscious state are
Diffuse cerebral hypoxia
The minimally conscious state (MCS) is defined as "a condition of severely altered consciousness in which minimal but definite behavioral evidence of self- or environmental awareness is demonstrated" (2). In MCS, limited but clearly discernible evidence of self- or environmental awareness must be demonstrated on a reproducible or sustained basis by 1 or more of the following behaviors:
Evidence of language comprehension (designated MCS+)
Ability to follow simple commands
Ability to give gestural or verbal "yes"/"no" responses (independent of accuracy)
Ability to produce intelligible verbalization, or other purposeful behaviors (with a contingent relationship to environmental stimuli), such as visual tracking, purposeful withdrawal from painful stimuli, localizing of auditory stimuli (designated as "MCS" if no evidence of following commands is identified)
The category "emergence from MCS" is operationally identified by demonstration of functional interactive communication or functional use of 2 different objects.
The natural history of recovery from VS/UWS and MCS is different, with the highest percentage of recovery seen in patients with MCS and within the first year after injury (1).
Cognitive motor dissociation (CMD) is a condition that describes the state of individuals who have the following characteristics (3):
They appear unresponsive following a severe brain injury.
They have bedside examination results that are consistent with either VS/UWS or MCS (without evident ability to follow behavioral commands).
They nonetheless successfully perform complex cognitive linguistic tasks, such as following a motor imagery command when assessed with task-based functional magnetic resonance imaging (fMRI) or electroencephalography (EEG) paradigms.
The presence of CMD may influence goals of care and treatment decisions.
Cognitive motor dissociation has been identified in 25% of patients with disorders of consciousness in acute or chronic settings (3). In a single center study, patients who met criteria for CMD in the intensive care setting showed a 4-fold increased likelihood of independence at 1 year compared with patients without CMD (4).
General references
1. Giacino JT, Katz DI, Schiff ND, et al. Practice guideline update recommendations summary: Disorders of consciousness: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology; the American Congress of Rehabilitation Medicine; and the National Institute on Disability, Independent Living, and Rehabilitation Research. Neurology. 2018;91(10):450-460. doi:10.1212/WNL.0000000000005926
2. Giacino JT, Ashwal S, Childs N, et al. The minimally conscious state: definition and diagnostic criteria. Neurology. 2002;58(3):349-353. doi:10.1212/wnl.58.3.349
3. Bodien YG, Allanson J, Cardone P, et al. Cognitive Motor Dissociation in Disorders of Consciousness. N Engl J Med. 2024;391(7):598-608. doi:10.1056/NEJMoa2400645
4. Claassen J, Doyle K, Matory A, et al. Detection of Brain Activation in Unresponsive Patients with Acute Brain Injury. N Engl J Med. 2019;380(26):2497-2505. doi:10.1056/NEJMoa1812757
Symptoms and Signs
Vegetative state
Patients in a vegetative state show no evidence of awareness of self or environment and cannot interact with other people. Purposeful responses to external stimuli are absent, as are contingent responses to language.
The following are present in patients in a vegetative state (1, 2):
Signs of patterned brain stem arousal (eg, periods of eye opening) and intact brain stem reflexes (eg, reactive pupils, oculocephalic reflex)
Apparent periods of sleep and wake, not necessarily reflecting a specific circadian rhythm nor associated with electrophysiologically intact sleep
Some complex brain stem reflexes, including yawning, chewing, swallowing, and, uncommonly, guttural vocalizations
Sometimes arousal and startle reflexes (eg, loud sounds or blinking with bright lights may elicit eye opening)
Sometimes watering and tearing of the eyes
Sometimes the appearance of a smile or frown, or more complex but stereotyped limbic displays
Spontaneous roving eye movements—usually slow, of constant velocity, and without saccadic jerks
The spontaneous roving eye movements may be misinterpreted as volitional tracking and can sometimes be misinterpreted as evidence of awareness.
Patients cannot react to visual threat and cannot follow commands. The limbs may move but, by definition, purposeful motor responses do not occur. Pain usually elicits a motor response (typically decorticate or decerebrate posturing) but no purposeful avoidance. Patients have fecal and urinary incontinence. Cranial nerve and spinal reflexes are typically preserved.
Minimally conscious state
Fragments of meaningful interaction with the environment are preserved. Patients in a minimally conscious state may do the following:
Establish eye contact and sustained fixation
Purposefully grasp at objects (eg, turn hand over to grasp a ball rolled on dorsal surface)
Respond to commands reliably using a consistent motor channel (eg, upward eye movement, flexion of foot, head nod or shake)
Localize noxious stimuli
Exhibit automatic movements (eg, extending arm and hand to shake hand)
Localize sound (eg, turn head to sound of keys jangled on one side of the head)
Exhibit sustained visual tracking
Contingent vocalization (eg, makes a sound in reaction to speech or questions)
Symptoms and signs references
1. Giacino JT, Katz DI, Schiff ND, et al. Practice guideline update recommendations summary: Disorders of consciousness: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology; the American Congress of Rehabilitation Medicine; and the National Institute on Disability, Independent Living, and Rehabilitation Research. Neurology. 2018;91(10):450-460. doi:10.1212/WNL.0000000000005926
2. Giacino JT, Ashwal S, Childs N, et al. The minimally conscious state: definition and diagnostic criteria. Neurology. 2002;58(3):349-353. doi:10.1212/wnl.58.3.349
Diagnosis
History (from family/observers) and physical examination
Findings, after sufficient observation period, consistent with clinical criteria
Neuroimaging
A vegetative state (VS) is suggested by lack of response to all stimuli despite an eyes-open appearance during some periods of the day in a patient with intact brain stem function. Diagnosis is based on clinical criteria. However, neuroimaging is indicated to exclude treatable disorders.
The vegetative state must be distinguished from the minimally conscious state (MCS). Both states can be permanent or temporary, and the physical examination may not reliably distinguish one from the other (1). Sufficient observation is needed. If observation is too brief, evidence of awareness may be overlooked; up to 5 separate examinations using the Coma Recovery Scale–Revised (CRS, the standard quantitative behavioral assessment tool) are necessary for accurate diagnosis (2). Some patients with severe Parkinson disease are misdiagnosed as being in a vegetative state due to marked akinesia.
CT or MRI can differentiate an ischemic infarct, an intracerebral hemorrhage, and a mass lesion involving the cortex or the brain stem. Magnetic resonance angiography can be used to visualize the cerebral vasculature after exclusion of a cerebral hemorrhage. Diffusion-weighted MRI is becoming the preferred imaging modality for following ongoing ischemic changes in the brain.
Positron emission tomography (PET), functional MRI, and single-photon emission computed tomography (SPECT) can be used to assess cerebral function. In research settings, a wide range of measurements of brain function using these tools can distinguish VS/UWS from MCS (3). Since functional studies can also identify cognitive motor dysfunction (CMD), the American Academy of Neurology (AAN) guidelines indicate that specialized functional imaging or electrophysiologic studies may be used to assess for evidence of awareness not identified on neurobehavioral assessment that might prompt consideration of an alternate diagnosis (4). However, these tools are not widely available and their use may be limited mostly to specialized centers.
EEG is useful in assessing cortical dysfunction and identifying occult seizure activity.
Diagnosis references
1. Schnakers C, Vanhaudenhuyse A, Giacino J, et al. Diagnostic accuracy of the vegetative and minimally conscious state: clinical consensus versus standardized neurobehavioral assessment. BMC Neurol. 2009;9:35. Published 2009 Jul 21. doi:10.1186/1471-2377-9-35
2. Wannez S, Heine L, Thonnard M, Gosseries O, Laureys S; Coma Science Group collaborators. The repetition of behavioral assessments in diagnosis of disorders of consciousness. Ann Neurol. 2017;81(6):883-889. doi:10.1002/ana.24962
3. Edlow BL, Claassen J, Schiff ND, Greer DM. Recovery from disorders of consciousness: mechanisms, prognosis and emerging therapies. Nat Rev Neurol. 2021;17(3):135-156. doi:10.1038/s41582-020-00428-x
4. Giacino JT, Katz DI, Schiff ND, et al. Practice guideline update recommendations summary: Disorders of consciousness: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology; the American Congress of Rehabilitation Medicine; and the National Institute on Disability, Independent Living, and Rehabilitation Research. Neurology. 2018;91(10):450-460. doi:10.1212/WNL.0000000000005926
Treatment
Supportive care
Supportive care is the mainstay of treatment for patients in a vegetative state or minimally conscious state; it should include the following:
Preventing systemic complications due to immobilization (eg, pneumonia, urinary tract infection, thromboembolic disease)
Providing good nutrition
Providing physical therapy to prevent limb contractures
Several medications can lead to improvement in neurologic responsiveness in patients with vegetative state and minimally conscious state following traumatic brain injury. The best evidence supports the use of amantadine (1, 2). Other medications that have demonstrated benefit for as long as the medication is continued include zolpidem (3), apomorphine (4), and levodopa (5). In general, time trials of these medications should be employed in patients with disorders of consciousness, independent of etiology of injury, to attempt to improve responsiveness (6).
Decisions about life-sustaining care should involve social services, the hospital ethics committee, and family members. Advance directives should guide decisions about life-supporting care for patients in a prolonged vegetative state.
Several studies suggest that providing music interventions for patients with impaired consciousness may lead to positive behavioral effects and improved physiologic responses (7). However, results should be interpreted with caution because of limited research in this area.
Treatment references
1. Giacino JT, Whyte J, Bagiella E, et al. Placebo-controlled trial of amantadine for severe traumatic brain injury. N Engl J Med. 2012;366(9):819-826. doi:10.1056/NEJMoa1102609
2. Giacino JT, Katz DI, Schiff ND, et al. Practice guideline update recommendations summary: Disorders of consciousness: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology; the American Congress of Rehabilitation Medicine; and the National Institute on Disability, Independent Living, and Rehabilitation Research. Neurology. 2018;91(10):450-460. doi:10.1212/WNL.0000000000005926
3. Du B, Shan A, Zhang Y, et al: Zolpidem arouses patients in vegetative state after brain injury: Quantitative evaluation and indications. Am J Med Sci. 347 (3):178–182, 2014. doi: 10.1097/MAJ.0b013e318287c79c
4. Fridman EA, Krimchansky BZ, Bonetto M, et al. Continuous subcutaneous apomorphine for severe disorders of consciousness after traumatic brain injury. Brain Inj. 24 (4):636–641, 2010. doi: 10.3109/02699051003610433
5. Fridman EA, Osborne JR, Mozley PD, Victor JD, Schiff ND. Presynaptic dopamine deficit in minimally conscious state patients following traumatic brain injury. Brain. 2019;142(7):1887-1893. doi:10.1093/brain/awz118
6. Fridman EA, Schiff ND. Organizing a Rational Approach to Treatments of Disorders of Consciousness Using the Anterior Forebrain Mesocircuit Model. J Clin Neurophysiol. 2022;39(1):40-48. doi:10.1097/WNP.0000000000000729
7. Li X, Li C, Hu N, Wang T. Music interventions for disorders of consciousness: A systematic review and meta-analysis. J Neurosci Nurs. 52(4): 146–151, 2020. doi: 10.1097/JNN.0000000000000511
Prognosis
General recommendations for determining prognosis for patients with disorders of consciousness are the following (1):
Clinicians should perform serial behavioral evaluations.
Clinicians should counsel families that individual outcomes vary. In general, outcomes are more favorable for patients with disorders of consciousness due to traumatic etiology than nontraumatic causes; patients diagnosed with MCS within 5 months of injury have a more favorable outcome than those with VS/UWS at 5 months.
Clinicians should perform the Coma Recovery Scale–Revised and use somatosensory evoked response to assist prognostication for recovery of consciousness at 24 months for patients in VS/UWS following anoxic brain injury.
Prognostic counseling should be provided when patients enter the chronic phase of VS/UWS that emphasizes the likelihood of permanent severe disability and need for long-term assistive care.
Vegetative state
Prognosis varies by etiology and duration of the vegetative state. The majority of cases result from traumatic brain injury or hypoxic-ischemic or anoxic injuries; prognosis differs for these etiologies and differs for adults versus children. Following traumatic brain injuries, an adult patient remaining in VS for 6 months retains a 16% chance of functional independence at 1 year; a child retains a 32% chance of functional independence at 1 year. In comparison, following anoxic brain injury, no adults or children remaining vegetative at 6 months regained functional independence (2).
In 5-year follow-up studies of patients who had been in a vegetative state for 1 year, some patients showed recovery of functional communication, indicating recovery past the level of minimally conscious state (3, 4).
Mortality is high within the first year; approximately one-third of patients die (1). The cause of death is usually pulmonary infection, urinary tract infection, or multiple organ failure, although death may also be sudden and of unknown cause. For those who survive the first year, life expectancy is about 2 to 5 years (2). A few patients live for decades.
Aggregate data for patients with VS/UWS and MCS shows median survival rates of 9.1 years for traumatic etiology and 2.2 years for anoxic etiology (3).
Minimally conscious state
The prognosis in MCS versus VS/UWS appears to vary by etiology. Studies suggest that patients with MCS have better outcomes than those with VS/UWS in both traumatic and nontraumatic injuries, but the prognostic advantage is more pronounced when the underlying cause is traumatic brain injury rather than nontraumatic brain injury (1).
Recovery from MCS can extend well beyond 12 months, with some patients emerging from MCS as late as 2 years or more after injury (5). However, even after emerging from MCS, most patients remain severely disabled, with only about 20% achieving functional independence (6). Earlier transition to MCS and earlier initiation of rehabilitation are associated with better functional outcomes.
Prognosis references
1. Giacino JT, Katz DI, Schiff ND, et al. Practice guideline update recommendations summary: Disorders of consciousness: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology; the American Congress of Rehabilitation Medicine; and the National Institute on Disability, Independent Living, and Rehabilitation Research. Neurology. 2018;91(10):450-460. doi:10.1212/WNL.0000000000005926
2. Posner J, Saper C, Schiff ND, Claassen J. Plum and Posner's Diagnosis and Treatment of Stupor and Coma. 5th Edition. Oxford University Press; 2019.
3. Estraneo A, Moretta P, Loreto V, Lanzillo B, Santoro L, Trojano L. Late recovery after traumatic, anoxic, or hemorrhagic long-lasting vegetative state. Neurology. 2010;75(3):239-245. doi:10.1212/WNL.0b013e3181e8e8cc
4. Luauté J, Maucort-Boulch D, Tell L, et al. Long-term outcomes of chronic minimally conscious and vegetative states. Neurology. 2010;75(3):246-252. doi:10.1212/WNL.0b013e3181e8e8df
5. Giacino JT, Katz DI, Schiff ND, et al. Comprehensive systematic review update summary: Disorders of consciousness: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology; the American Congress of Rehabilitation Medicine; and the National Institute on Disability, Independent Living, and Rehabilitation Research. Neurology. 2018;91(10):461-470. doi:10.1212/WNL.0000000000005928
6. Luauté J, Maucort-Boulch D, Tell L, et al. Long-term outcomes of chronic minimally conscious and vegetative states. Neurology. 2010;75(3):246-252. doi:10.1212/WNL.0b013e3181e8e8df
Key Points
Vegetative state is typically characterized by absence of responsiveness and awareness due to overwhelming dysfunction of the cerebral hemispheres, intact brain stem function, and appearance of awareness despite its absence.
Minimally conscious state differs from vegetative state in that the patients have definite evidence of self- and/or environmental awareness.
Diagnosis requires repeated and often prolonged observation, particularly to differentiate vegetative state (VS) from minimally conscious state (MCS).
Prognosis is significantly improved for MCS versus VS across all etiologies and durations of the condition.
Treatment is indicated with amantadine for all VS and MCS patients.
To detect cognitive motor dysfunction, clinicians may use multimodal assessments, including specialized functional imaging or electrophysiologic studies, to identify covert awareness not apparent on neurobehavioral assessment, which might prompt an alternate diagnosis.
Drug Information for the Topic
