Neuroimaging: Visualizing Brain Structure and Function

Coma to Brain Death:
Recognizing Disorders of Consciousness

• 1. Introduction to neuroethics
• 2. Coma
• 3. Vegetative State
• 4. Minimally conscious state
• 4.1. Emergence from minimally conscious state
• 5. Distinguishing between Vegetative State and Minimally Conscious State
• 6. Prognostication and the notion of late recovery
• 7. Statistical likelihood of further recovery for patients in a vegetative or minimally conscious state
• 8. Meaningful Recovery -- Ethical Implications
• 9. Future directions in research
• 10. Case Study
• 11. Conclusion
• 12. References

Definitions, diagnostic criteria, and inclusion categories for the different disorders of consciousness are changing as neurologists and scientists gain a greater understanding of levels of consciousness, their duration, and their progression. We present below a discussion of these levels, what they mean, how they are determined, common prognoses, and some ethical implications of meaningful recovery, as well as future directions in research.

2. Coma

Among profound disorders affecting consciousness, the best-known is probably coma. Plum and Posner lastingly described coma in 1980 as "a state of unarousable unresponsiveness in which the eyes remain continuously closed and there is no understandable response to environmental or intrinsic stimulation."² Unlike brief depressed consciousness from concussion, syncope, or other causes, coma persists for at least an hour. Patients in coma are not aware. They have a reduced cerebral metabolic rate of oxygen, distinguishing coma from sleep. (Sleep is further distinguished from coma by arousability.)

Comatose patients cannot speak, follow commands, move purposefully, or visually fixate. The condition has dozens of causes. Some are reversible, including the over-administration of sedating medications or continuous non-convulsive seizures, while others, such as prolonged anoxia, are not. Four major categories of coma can be delineated clinically using a scheme first proposed by Plum and Posner based on the examination of a patient's pupils, eye movements, respiratory patterns, and motor response to external stimuli.³ The comatose patient may require life-support such as artificial ventilation to live, at least in the short term. Neuroimaging results are not part of the coma definition, but imaging is usually obtained in the diagnostic workup.

Coma is transient. A patient in a coma progresses within 2-4 weeks to one of several conditions including death, recovery to some degree, or progression to the vegetative state. Some assessments during coma can predict an eventual vegetative state or death. Somatosensory evoked potentials in particular have good predictive value: if they show bilaterally absent N20 responses, there is a near-100% chance of a patient progressing to death or a vegetative state. Patients may or may not awaken further from a vegetative state to higher levels of consciousness, such as the minimally conscious state or a higher level of recovery.

Part of the difficulty in discussions of disorders of consciousness stems from their shifting definitions over the past 50 years. These definitions have undergone even greater change in the last few decades. A benchmark article by Giacino in the Journal of Head Trauma and Rehabilitation in 2005 (summarized below) reviewed these developments.⁴

3. Vegetative State

Defining the vegetative state was itself a major challenge. In 1963, Arnaud and colleagues first described patients as "vegetative," referring to debilitated survivors of head trauma.⁵ The addition of the word "persistent" by Jennet and Plum in 1972 in their Lancet publication "Persistent Vegetative State after Brain Damage: A Syndrome in Search of a Name"⁶ described prolonged unresponsiveness as a phenomenon distinct from transient coma. Subsequently, Plum and Posner in 1982 defined the vegetative state as irreversible and not just persistent, but permanent.⁷

A diagnosis of Vegetative State requires that all the following criteria be met:⁸

• 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
• Sufficient preservation of autonomic functions to permit survival with adequate medical care
• Bowel and bladder incontinence
• Variable preservation of cranial nerve and spinal reflexes

Subsequent efforts have focused on defining the prognosis for patients in the vegetative state. Between 1994 and 1996, three different working groups [the American Academy of Neurology (AAN), the American Congress of Rehabilitation Medicine (ACRM), and a multi-specialty group called the International Working Part on the Management of the Vegetative State (IWP)], all deliberating in parallel, published three separate positions papers that contained conflicting definitions of this condition they were established to help clarify. Each featured differing statements of exactly when a vegetative state could be called persistent or permanent. The AAN, for example, defined a persistent vegetative state as diagnosable after one month, while the ACRM required a duration of 12 months for diagnosis, and the IWP gave no discrete criteria.

The Multi-Society Taskforce on the Persistent Vegetative State (MSTF) meanwhile undertook an evidence-based review of the subject, published in the New England Journal of Medicine in 1994.⁹ The Task Force's review of the world literature on PVS importantly contributed information about the effect of etiology on the likelihood of recovery.

Head trauma and non-traumatic anoxic-ischemic injury are the two most common causes of the vegetative state in the United States. The MSTF reviewed 434 cases of patients in a vegetative state one month after injury and found that about half of adults and 60% of children eventually regained consciousness if the cause was trauma, whereas only 15% of adults and 13% of children regained consciousness if the initial injury was non-traumatic. Notably, of those who did recover, most did so within six months of traumatic injury, or three months of anoxic/ischemic injury. Of all 434 patients, only seven regained consciousness after 12 months. Thus the MSTF review concluded that recovery was extremely unlikely in trauma after 12 months and in non-traumatic causes after three months. They recommended calling the vegetative state "permanent" after these times.

The MSTF contended that patients in the vegetative state are not aware according to three factors:

1. the presence of stereotypical ocular, facial, and motor movements seen only with the destruction of higher cortical structures, accompanied by the absence of any voluntary movements;
2. PET studies that show decreased glucose metabolism in these patients; and
3. post-mortem autopsy studies showing extensive structural damage that is probably incompatible with consciousness.

Despite compelling scientific evidence supporting these patients' unawareness, many people are surprised by the variety of behaviors patients in a vegetative state can exhibit, including crying, turning the head, and moving limbs. These result from primitive motor programs or brainstem or spinal reflexes that are normally suppressed by higher cortical structures that have been interrupted or destroyed, allowing the primitive involuntary motor programs to emerge. These same patterns can be observed in newborns whose entire cortex has been destroyed by ischemic injury during birth, but who nevertheless may appear to a casual observer quite similar to healthy newborns whose cerebral cortex is still immature. In both of these cases, as well as in the persistently vegetative adult with a destroyed cortex, the cortex is not suppressing these primitive motor programs. By definition, however, they do not reflect awareness.

4. Minimally Conscious State

Questions about the temporal label of "permanent" remained contentious after the MSTF's report because of the handful of cases of delayed recovery cited in the MSTF report, and because of the small number of cases for whom follow-up data beyond 12 months were even available. Thus another body, the Aspen Neurobehavioral Group, convened to understand why prior recommendations had been so discrepant. The Aspen Group published a series of three seminal papers over an eight-year period on the subject of disorders of consciousness. Their final publication,¹⁰ a 2002 consensus guideline published in Neurology, was endorsed by the American Academy of Neurology, American Congress of Rehabilitation Medicine, American Academy of Physical Medicine and Rehabilitation, American Academy of Neurosurgeons, Child Neurology Society, and the Brain Injury Association of America. It described a distinction between vegetative patients who fit the criteria above, and those who seemed intermittently aware, a condition they termed the minimally conscious state. Looking back at studies of patients previously called vegetative, they identified some who had been minimally conscious and found they had better recovery at one year than their truly vegetative counterparts. Importantly, and in keeping with the findings of the MSTF, the Aspen Group's review found that even among minimally conscious patients, those whose brain injury was traumatic were significantly more likely to recover to at least moderate disability, versus those with non-traumatic injury, whose disability was always severe.

In their series, the Aspen group also re-examined the extent to which the vegetative state was, in fact, permanent. Their review included all published cases of late recovery from the vegetative state for which sufficient data were available. The group removed the designation of "permanent," recommending instead that patients be diagnosed with "vegetative state," with a description of its cause (traumatic or non-traumatic) and duration.

The Aspen group described minimal consciousness as "a condition of severely altered consciousness in which minimal but definite behavioral evidence of self or environmental awareness is demonstrated."^{11 12} A diagnosis of a minimally conscious state requires that a patient meet at least one of the following diagnostic criteria:

1. Following simple commands
2. Gestural or verbal yes/no responses
3. Intelligible verbalization
4. Purposeful behavior, including movements or affective behaviors that occur in contingent relation to the relevant environmental stimuli and are not due to reflexive activity. Examples of qualifying behavior include:

1. Appropriate crying or smiling in response to the linguistic or visual content of emotional topics or stimuli but not to neutral topics or stimuli
2. Vocalizations or gestures that occur in direct response to the linguistic content of questions
3. Reaching for objects that demonstrates a clear relationship between object location and direction of reach
4. Touching or holding objects in a manner that accommodates the size and shape of the object
5. Eye movement or sustained fixation that occurs in direct response to moving or salient stimuli.

Unlike the vegetative state, long-term natural history studies of the minimally conscious state are lacking. Therefore, although doctors can make a clinical distinction between minimally conscious patients and patients in the vegetative state, implications for eventual progression to higher levels of consciousness for patients in the minimally conscious state are unknown. Differences in mechanism of injury are clearly important, as described above. Other differences in adult versus pediatric patients probably exist, but more research is required to know that definitively.

4.1. Emergence from Minimally Conscious State

Some patients do "emerge" from the minimally conscious state to a higher level of consciousness. Such a diagnosis requires the patient perform one or both of the following behaviors reliably and consistently.¹³

1. Functional interactive communication: Accurate yes/no responses to 6 of 6 basic situational questions on two consecutive evaluations.
2. Functional object use: Use of at least two different objects on at least two consecutive evaluations.

5. Distinguishing between Vegetative State and Minimally Conscious State

Even to a trained neurologist, distinguishing between the vegetative and minimally conscious states can be difficult.¹⁴ Distinguishing between reflexive and responsive crying, for example, is enough to change a diagnosis from vegetative state to minimal consciousness, but can be challenging in practice. Current guidelines, therefore, recommend that someone experienced in diagnosing disorders of consciousness perform the examinations, that exams be repeated over time, and that a second opinion be requested if a major decision, such as withdrawal of life-support, is at stake and the diagnosis is unclear.¹⁵

6. Prognostication and the notion of late recovery

Diagnostic accuracy is always important, but it becomes more urgent when coupled with the issue of prognosis. This pairing is important for neuroimaging investigation of disorders of consciousness and related prognostication, including the notion of late recovery from the vegetative or minimally conscious states.

This issue gained attention in 2003 with the case of Terry Wallis, who in 1984 suffered a traumatic brain injury, and resided in an Arkansas nursing facility with the diagnosis of vegetative state. After 19 years, without being seen by a neurologist or undergoing any neuroimaging, he unexpectedly regained speech in 2003.

Wallis's case raised the question of how many other patients might be in a similar predicament. As importantly, it pointed to the question of recovery from the vegetative or minimally conscious state (at the time he was institutionalized, the latter was not a formal diagnosis). The Multi-Society Task Force review, conducted before there was a formal distinction between vegetative and minimally conscious patients and whose sample probably included some patients who were minimally conscious, did note a tiny number of cases (7 out of 434) of late recovery in their survey. Advocates have seized upon these data to argue that the frequency of late recovery may be underestimated.

This in turn leads to the question of predicting which patients are likely to recover eventually. At present, no study has validated a predictive model, but efforts to form one continue. A 2007 study by Di et al.¹⁶ used fMRI to study seven vegetative patients and four minimally conscious ones while the patients' own names were read to them by a familiar voice. Two of the clinically vegetative patients unexpectedly showed activation not only of the auditory cortex but of temporal and association areas as well, suggesting the structural possibility of higher thought. These two individuals later went on to improve to minimal consciousness. Other investigators are using fMRI to examine patients already minimally conscious whose brains may have the structural integrity needed eventually to emerge to sustained awareness. The goal of these experiments is to devise individualized assessments, similar to those used to identify patients appropriate for neurosurgery¹⁷ to treat epilepsy, which will help evaluate whether patients have the potential for recovery from minimal consciousness.

Because of the lack of radiographic diagnostic, outcome, or prognostic data, there is no current recommendation, for example, to use fMRI or PET scanning as a screening tool for patients in either a vegetative or a minimally conscious state. At present both are still mostly research techniques. Patients are currently being enrolled in trials to elucidate these points, and recommendations may change as the results of these studies emerge. If there has been a noticeable change in practice resulting from the recent reports of unexpected radiographic evidence of neural activity, especially auditory, it is probably clinicians' increased sensitivity and discretion regarding what is said at the patient's bedside. Increasingly, minimally conscious patients in particular are given the benefit of the doubt in terms of their capacity to hear and understand.

7. Statistical likelihood of further recovery for patients in a vegetative or minimally conscious state

Ideally, physicians and families would like to know the statistical likelihood of further recovery for patients in a vegetative or minimally conscious state. As discussed above, data are available for vegetative patients and are used by physicians and families to decide the appropriateness of continuing life- supporting medical care and artificial nutrition and hydration for vegetative patients.

In contrast, large-scale long-term outcome data on minimally conscious patients are lacking, as are tools shown reliably to predict which minimally conscious patients may emerge from this state, when they might do so, and what level of recovery they might ultimately attain, so there is less to guide discussions about their care. Honest discussions with these patients' families would plainly describe the patients' devastated status and acknowledge the current limitations of medical certainty regarding outcomes.¹⁸

8. Meaningful Recovery -- Ethical Implications

Crucial to keep in focus when discussing disorders of consciousness is the distinction not just between the aware and unaware patient, but the overall severity of injury these patients have suffered. Recovery of consciousness is different from recovery of other kinds of function. Despite misleading media portrayals of individuals who emerge from vegetative and minimally conscious states to resume their former lives, the reality is that all such patients will continue to be moderately to severely disabled at best, if they ever do regain consciousness.

For decades, before the distinction was drawn between vegetative and minimally conscious states, neurologists relied on a description of the patient's neurological exam and a statement regarding the potential for "meaningful recovery." Many still do. Many neurologists continue to believe that despite the major differences between the vegetative and minimally conscious person, the gulf may ultimately be less salient for the patient and family than that between a permanent loss of most abilities and a more robust level of function. As Richard Mayeux, MD, Professor of Neurology at Columbia University's Neurological Institute, expressed it, "What the family wants to know is, 'Will this person be sitting at the Thanksgiving dinner table next year? Will he be interacting with the children?'" In a former and more nihilistic era, the neurologist might gloss over the uncertainties of prognosis for a minimally conscious patient, and push a family toward a decision to withdraw life support. A cultural trend away from paternalism in medicine has altered this practice somewhat, but the neurologist's assessment is still influential. The doctor must help families understand what the patient has lost and realistically describe the patient's new needs.

The definition of "meaningful recovery" requires exploration, as do the recommendations doctors offer to families given different diagnoses and prognoses. The neurologist's perspective is influenced by prior experience, knowledge of the potential for contractures, skin breakdown, recurrent infection and other complications of chronic care, and an understanding of the likely emotional and financial cost of chronic care to the family. Patients may have previously expressed written (e.g., an Advance Directive) or verbal wishes regarding their idea of "meaningful existence" in such a situation. Absent that, family members may know (or claim to know) what the patient would consider "meaningful." For some, the knowledge that a patient is intermittently aware will lead them to decide to pursue chronic care that, without any pre-existing statement to the contrary from the patient, may be the only option.¹⁹ It is important for doctors to help people distinguish between the hopeless persistent vegetative state and the unknown prognosis of minimal consciousness.²⁰

Religious belief can also play a role in life support decisions for the minimally conscious patient. While some traditions hold that life in any form is intrinsically meaningful and sacred and should be preserved, others maintain that it is wrong to prolong life artificially in a vegetative individual. Unfortunately, there are also highly politicized cases where the religious beliefs of vocal groups not immediately connected to the individual patients, or their doctors and families, intervene in the decision-making. This occurred most recently in the well- publicized case of Terri Schiavo, when lay as well as medical individuals offered diagnoses and prognoses for a patient none of them had seen personally.²¹

Functional neuroimaging offers a fresh, increasingly literal interpretation of "meaningful." Using fMRI, researchers can visualize the activity levels of the brain structures commonly used to produce thoughts and to synthesize meaning from sensory experience. Scans of vegetative patients showing destroyed connections between their receptive and processing areas support the idea that vegetative patients are disconnected from the parts of their brains that integrate sensory experience into meaning.²²

9. Future directions in research

Neurology investigators and researchers must keep pace with the seemingly relentless acceleration in speed and power of imaging technology. In 2007, an international group of leading experts has convened to review the current state of scientific knowledge on disorders of consciousness and prepare a new consensus statement. This will likely incorporate a recommendation on the role of neuroimaging in the diagnosis and management of vegetative and minimally conscious patients.

Regardless of advances in neuroimaging, however, there still remains no substitute for a trained neurologist to explain the physical findings and interpret increasingly complex data to arrive at an appropriate diagnosis and prognosis for any given patient.

Use of imaging technology for research on disorders of consciousness is intensifying. Well-publicized medical-legal cases like Terri Schiavo (and her medical-legal predecessors Karen Ann Quinlan and Nancy Cruzan), focused public attention on the problem of disorders of consciousness and the difficulties with accurate diagnosis and prognosis, and advocates on both sides of the public debate used neuroimaging results to bolster their cases.

More recently, the prevalence of traumatic brain injury in soldiers returning from the war in Iraq has made understanding disorders of consciousness, and the potential inclusion of neuroimaging for accurate diagnosis and prognosis, a public health priority. Large and costly imaging equipment and procedures are among the barriers to their use. Also important is the historical nihilism toward minimally conscious patients that is rooted in profound ethical judgments about the overall value of their lives. Some question the research ethics of neuroimaging patients with impaired consciousness because participants are unable to provide consent for these tests, particularly for PET scans that involve radiation. The long follow-up period needed to answer the most important questions of future possibilities is a further obstacle to funding and research.

10. Case Study

Susan Shin, a 24-year-old healthy graduate student is crossing the street to attend class when a delivery truck runs a red light and hits her. She is thrown several feet, hits her head on the curb, and loses consciousness. EMTs have difficulty obtaining blood pressure and her oxygen saturation is below normal. In the Emergency Department (ED) she is still unconscious and is intubated. She is found to have multiple rib fractures, a collapsed lung, and is markedly hypotensive from internal bleeding. A non-contrast CT scan of her brain shows diffuse subarachnoid blood and contusions of her frontal and temporal lobes. Neck CT shows no fractures.

A chest tube is inserted, helping Susan's lung reinflate. She is attached to a ventilator. She is transfused and rushed to emergency surgery which normalizes her blood pressure. After surgery she enters the ICU. Forty hours later, well after the anesthesia was worn off, she still has not regained consciousness. A neurologist is called.

The neurologist examines Susan, finding her unresponsive to any unpleasant stimuli. She is breathing faster than the ventilator setting. She has equal, reactive pupils and her eyes move appropriately when ice water is instilled in each ear. Tickling her throat causes a cough and gag. She flexes slightly from painful pressure on her nails.

Imaging is appropriate at this point for diagnostic purposes. Further structural imaging can help identify the cause of Susan's coma. Although a repeat CT scan would probably also have been done to follow up on the blood in the brain, MRI will show more detail of which structures are injured. MRI of the spinal cord would be done to exclude a cord injury from the trauma.

The neurologist recommends MRIs of the brain and its vasculature and of the cervical spine. Overnight the ICU nurse notices some quick jerks of the fingers that could represent seizure, so the resident physician obtains an electroencephalogram (EEG). The study shows diffuse slowing of the brain's normal electrical activity as is often seen in comatose patients, but no evidence of seizures.

The MRI of the brain and cervical spine are performed the next day. The cervical spine is normal. There are no injuries to the cerebral vasculature. The brain scan shows improvement in the subarachnoid blood and contusions. However, there is swelling and evidence of traumatic damage to the white matter connecting the cortex (outermost layer) and deeper parts of the brain, and brightness of part of the cortex consistent with ischemic and hypoxic injury. The traumatic white matter damage is confirmed by an MR SPECT study.

Susan does not have an advance directive in the form of a designated health care proxy or a living will. She also has no spouse and no children, so her parents are the next in line as her surrogates to make medical decisions for her. They say that she was a competitive athlete and active in her church and would want "to fight this out."

Susan receives state of the art intensive care. She has not become infected, her laboratory values reflect normal metabolic function, and she is receiving no sedating medications. Follow-up neuroimaging at appropriate intervals shows a complete resolution of the swelling and the blood. However, the traumatic axonal injury and the hypoxic/ischemic injury persist. A week after injury, Susan still has all brainstem reflexes, has eye opening and occasional spontaneous eye movements, and withdraws slightly from pain. She has no language, but sometimes smiles for no clear reason. The ICU team requests a neurologist's opinion on her prognosis.

What it means to have positive outcome in this setting is not well defined overall, but one attempt is the Glasgow Outcome Scale, which defines "moderate disability" as independence in daily living with physical or mental limitations preventing return to one's previous level of function. For traumatic and non- traumatic coma, detailed tables based on studies with large sample sizes exist, correlating the different features seen on neurological exams with the percentages of patients who go on to recover neurological function to various extents (ranging from none to resumption of former activities). , These numbers can be cited to families who want to know overall odds and to prepare them for the possibility of severe disability if expected. However, except for some scenarios, the percentages cannot foretell the outcome for any one individual patient.

Susan has two different types of injury, both traumatic and anoxic/ischemic, making her prognosis more difficult and complex, because it is not clear which is more severe or contributing most to her current condition.

She is currently in a vegetative state (VS), "awake but unaware." It is too early to comment on its permanence. Data on the likelihood of recovery from the vegetative state collected by the Multi-Society Task Force described outcomes beginning from one month of ongoing VS, after which the term persistent may apply. This patient could remain vegetative or could go on to recover to a higher level of awareness such as minimal consciousness.

Although they are not required for diagnosis of a vegetative state, electrodiagnostic studies can sometimes aid in prognosis. EEG can exclude seizures or demonstrate other patterns known to be associated with poor outcome. Somatosensory evoked potentials (SSEPs) and Brainstem auditory- evoked responses (BAERs) can test the integrity of different circuits in the cortex and brainstem, respectively.

It is a month later. Susan now makes eye contact with her mother, follows her face with her eyes, and turns to the sound of a voice. She can hold a ball.

Functional imaging is limited by both technical factors and our current knowledge of its correct interpretation. A study done at different times on the same patient could show activation of different areas based on the patient's own fluctuating awareness that day, so may not accurately identify functional integrity. Even if intact networks were identified, it would be unclear how robust a subjective experience of consciousness or self-awareness the radiographically observed activity actually reflected. The neurologist can inform the family that the patient has recovered some neurological function, but that she is still severely brain injured, based on her history and physical examination.

The parents want to know if Susan knows that they are there at her bedside, if she can hear them talking to her, and if she is in pain. The neurologist explains that it is not known how much of what healthy people would recognize as conscious awareness is present in minimally conscious individuals. It is probably not the case that she is living an active mental life inside her severely limited body, the way a person with a neuro-degenerative disease might.

The neurologist further explains that patients who recover from MCS do not recall the period of minimal consciousness. Rather, it is thought, and imaging has supported the idea, that MCS involves a fluctuating limited ability to interact, and that these patients have limited activation of selected areas of cortex permitting some interaction without the full integration required for complete awareness. What exactly is intact is highly individual and dependent on the injury each patient sustains. Large areas of pain networks may be preserved, so it is reasonable to ensure patients' comfort, including pain medication. Several studies have shows preservation of auditory networks and at least one has shown evidence of auditory processing and cognitive command following, so although it is unlikely that the patient has total awareness of her family's presence, her brain could be processing their speech rudimentarily.

The neurologist reassures the Shins that Susan will continue to be examined at regular intervals for evidence of neurological recovery. He also provides them with a realistic explanation of her likely severe degree of permanent disability.

The family accepts the lack of indication for functional imaging in diagnosis. Just then a nearby research neuroscientist decides that Susan is eligible for her experimental study of functional imaging using PET scanning in minimally conscious patients.

The proposed neuroimaging studies will be experimental and descriptive. They are not validated for prognosis in Susan's case. Currently, there are many research studies but no large, validated set of prognostic data using fMRI or PET for patients in MCS, so even if it were performed, the test's results would be of uncertain significance. The results might enter a database which in aggregate data could be used to prospectively or retrospectively correlate eventual outcome with features seen on such imaging, and thus might eventually help scientists form prognostic schemes such as those currently in existence for coma. The benefit will not be for this patient or family, but for others in the future. Eventually, physicians may be able to construct a functional, neuroimaging profile of a particular injured patient that gives good information about likely recovery. However, that is a future direction, not a current reality.

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Columbia University