The Terri Schiavo story that was widely publicized in early 2005 was one in which clinical issues were at best misunderstood and at worst overshadowed by political posturing and media sensationalism.
The Terri Schiavo story that was widely publicized in early 2005 was one in which clinical issues were at best misunderstood and at worst overshadowed by political posturing and media sensationalism. The subtle distinctions between vegetative state, minimally conscious state (MCS), and locked-in syndrome-difficult to differentiate even for physicians-were too often misused or glossed over. Commentators were more interested in such ethically loaded questions as whether remarks once made by Schiavo while watching television constituted an expressed wish that her life not be prolonged artificially, or whether Schiavo's husband Michael, as her guardian, could be acting in her best interests while living with another woman.
Schiavo's 15 years of impaired consciousness, diagnosed by most consulting neurologists as a vegetative state, ended on March 31, 2005, 2 weeks after her percutaneous endoscopic gastrostomy tube was removed. More than a year later, her story is still a topic of public discussion. Schiavo's husband and her parents each published a book on the anniversary of her death, while US politicians and activists on both sides of the "feeding tube" debate continue to battle over more than 40 proposed pieces of legislation that would restrict the withdrawal of artificially administered nutrition and hydration.
But the past year also has seen an intensification of interest in issues of impaired consciousness on the part of researchers and clinicians. Dozens of papers on the diagnosis and management of vegetative state and minimally conscious state have appeared in the medical literature during that time, including a 555-page special issue of the international journal Neuropsychological Rehabilitation published in the fall of 2005.1 Furthermore, the American Academy of Neurology held a breakfast seminar on vegetative state at its annual meeting in April.
Although functional imaging techniques are helping researchers differentiate vegetative state from MCS by teasing out evidence of cognitive processes in outwardly unresponsive patients, making this critical distinction remains a profound diagnostic challenge for clinicians who lack access to such technology.
"We can't get inside somebody's mind. All we can do is try to stimulate them and gauge their reactions," said James L. Bernat, MD, professor of neurology at Dartmouth Medical School in Hanover, New Hampshire.
Indeed, the ability to measure a patient's responsiveness is the key to the differential diagnosis of vegetative state, MCS, or locked-in syndrome, and the inability to recognize very low levels of awareness is what accounts for the number of minimally conscious or locked-in patients who receive a misdiagnosis of vegetative state. A 1993 study by Nancy L. Childs, MD, and colleagues at the Healthcare Rehabilitation Center in Austin, Texas, found that a misdiagnosis of coma or persistent vegetative state was made in 37% of 49 patients.2 In 1996, Keith Andrews, MD, and colleagues at the Royal Hospital for Neuro-disability in London reported misdiagnosis of vegetative state in 43% of 40 patients-including one man thought to have been in a vegetative state for 7 years who, 2 weeks after admission to Andrews' rehabilitation unit, was able to "dictate" letters to his wife with the aid of a computer.3
No more recent data on misdiagnoses of vegetative state are available in the medical literature, and it is possible that the numbers have come down since the 2002 publication of a definition and diagnostic criteria for MCS by a collaborative group of authors led by Joseph T. Giacino, PhD, associate director of neuropsychology at the New Jersey Neuroscience Institute of the JFK Johnson Rehabilitation Institute in Edison.4 But the consensus among experts is that misdiagnosis rates are still unacceptably high.
"Anecdotally, I think most clinicians who focus in this area would still acknowledge that there are a lot of misdiagnoses being applied,"Giacino said. "Many of us see patients who get admitted to our centers with a diagnosis of vegetative state, and on the first examination, it becomes apparent that they do actually have some awareness."
Published criteria for diagnosing vegetative state (also historically referred to as "persistent vegetative state" or "permanent vegetative state"-terms that Bernat and other experts feel are misleading) and MCS are listed in Tables 1 and 2. The key difference between them is that a patient in a vegetative state demonstrates no evidence of conscious behavior at any time, whereas a patient in an MCS demonstrates clear evidence of conscious behavior at least some of the time. Locked-in syndrome, which is not a disorder of consciousness, can be difficult to distinguish from vegetative state because of the locked-in patient's inability to communicate his or her awareness other than by eye blinking. However, locked-in syndrome is typically characterized by quadriplegia or more extensive paralysis, whereas patients in a vegetative state are not paralyzed and often make reflexive movements, although not purposeful ones.5
|Table 1 - Criteria for diagnosis of vegetative state|
|No evidence of awareness of self or environment|
|Incapable of interacting with others|
|No sustained, reproducible, or purposeful voluntary behavioral responses to visual, auditory, tactile, or noxious stimuli|
|No evidence of language comprehension or expression|
|Intermittent wakefulness characterized by sleep-wake cycles|
|Preserved autonomic and hypothalamic function sufficient for survival with medical or nursing care|
|Bowel and bladder incontinence|
|Preserved cranial nerve reflexes|
|Table 2 - Criteria for diagnosis of minimally conscious state|
|Limited but clearly discernable evidence of self-awareness or environmental awareness, as demonstrated in a sustained or reproducible manner by 1 or more of the following behaviors:|
|Follows simple commands|
|Gestures or verbalizes yes/no responses (regardless of accuracy)|
|Purposeful behavior that occurs in response to relevant environmental stimuli and is not merely reflexive.|
|Appropriate smiling or crying in response to the linguistic or visual content ofemotional topics or stimuli, but not to neutral topics or stimuli|
SUBTLETIES AND SERIAL ASSESSMENTS
The biggest potential pitfall in differentiating vegetative state from MCS is the variability with which minimally conscious patients exhibit conscious behavior. Because such behaviors can fluctuate from one hour to the next or from one day to the next and may be affected by a patient's level of fatigue or by medications, they can be easily missed in a single consultation period.
"If you only do a single assessment, your chances of getting the correct diagnosis are not so hot," Giacino said. "You have to do it more than once in order to be confident in your assessment."
The other significant challenge in diagnosing MCS is that the conscious behaviors that patients exhibit may be extremely subtle; it may be difficult for the clinician to determine whether a behavior is in fact a response to a command or a reflex. Blinking, which is seen reflexively in vegetative patients but responsively (eg, in response to threat) in minimally conscious patients, can be particularly confusing both to clinicians and to a patient's loved ones.
"The public is very confused by eye opening and eye blinking," said Jerome E. Kurent, MD, associate professor of medicine and neurology at the University of South Carolina in Columbia. "It needs to be explained that this is part of the vegetative state."
A slower rate of spontaneous blinking over time, in fact, may help differentiate between vegetative state and MCS. In a study of 13 patients, researchers from the University of Pisa found that the blinking rate remained stable over a 2-week period in vegetative patients, but the blinking rate gradually decreased as cognitive scores increased in minimally conscious patients.6
Communicating with the patient's family and caregivers about typical behaviors and times of day when the patient seems to be most responsive can help boost clinicians' confidence in their assessments, Giacino said. He and colleagues at the JFK Johnson Rehabilitation Institute are currently involved in a multicenter effort with researchers from New York's Columbia and Cornell universities that uses functional magnetic resonance imaging (fMRI) to determine the underlying cause of the behavioral variability in minimally conscious patients-not only to help avoid misdiagnoses but also to provide a basis for intervention.
"The thing we're actually most interested in is whether the brain is experiencing neurophysiologic fluctuations, up-regulating at certain points in time and down-regulating at other points," he said. "If we can stabilize these abnormal oscillations using some intervention, then the result may be a patient who has the capacity for sustained cognitive processing."
Preliminary results of that multicenter study, which compared 2 minimally conscious patients with 7 healthy volunteers, were published in February 2005.7 The study authors found that when the patients and volunteers were exposed to a familiar voice reciting a coherent narrative in a normal manner, fMRI maps of the cortical responses to the auditory stimulation were similar for both groups. When the narrative was recited backward, the fMRI map was similar to that associated with the normally read narrative in volunteers, but cortical activity, although intact, was reduced in the minimally conscious patients. This suggests that the cortical systems associated with language processing, while intact, are functionally down-regulated in MCS, which raises the possibility that an intervention to excite those cortical systems might improve auditory cognition in minimally conscious patients.
In another functional neuroimaging study published in 2005, British researchers found similar responses to auditory stimuli in a single patient with a diagnosis of vegetative state.8 Positron emission tomography (PET) conducted 9 months apart revealed preserved cortical responses to intelligible auditory stimuli, while fMRI maps obtained at the time of the second test indicated partial responses to semantically ambiguous auditory stimuli. However, Belgian researchers who used functional PET imaging to identify residual cortical activation in the vegetative state in response to auditory and somatosensory stimuli9-11 characterized those activations as being restricted to the primary cortices and not indicative of awareness.
Although functional imaging may indeed aid in differentiating vegetative state from MCS, researchers are careful to emphasize that residual cortical activity identified in a clinically vegetative patient does not necessarily mean that the patient's condition has been misdiagnosed or that the patient will progress to higher levels of consciousness. Conversely, however, functional imaging could potentially help identify patients whose intact sense of awareness has been masked by physical limitations. Vegetative state was misdiagnosed in one such patient for more than a year until a new seating system provided him with enough postural support that he was able to use the muscles of one shoulder to shrug in response to stimuli.3
"The inherent problem in treating patients with disorders of consciousness is that we have no litmus test of consciousness. We have behavior," Giacino said. "One of the ways in which functional imaging can be useful as a diagnostic aid is in cases where we see dissociation between the behavioral profile that we generate at the bedside and the neurophysiologic profile that we generate in the scanner."
Because of frequent misdiagnoses and few outcome measures that are applicable to the population, it is often difficult to accurately assess the benefits of rehabilitation in patients with diagnoses of impaired consciousness. Takamitsu Yamamoto, MD, and colleagues from the Department of Neurological Surgery at Nihon University School of Medicine in Tokyo reported that 8 of 21 patients with diagnoses of vegetative state were able to obey verbal commands following treatment with deep brain stimulation (DBS) and that 4 of 5 minimally conscious patients who received the treatment were no longer bedridden.12,13 But limitations of the study's design have left experts unconvinced of the benefits of DBS in patients with impaired consciousness.14
The possibility that levodopa could play a therapeutic role in patients with impaired consciousness has been studied for years and was introduced to the general public in the 1990 film Awakenings, based on the 1973 memoir of the same name by neurologist Oliver Sacks, MD. More recently, Ben-Zion Krimchansky, MD, and colleagues at the Loewenstein Hospital Rehabilitation Center in Ra'anana, Israel, found that 7 of 8 traumatically brain-injured patients, in whom vegetative state with a mean duration of 104 days had been diagnosed, fully regained consciousness after 13 days of levodopa/carbidopa therapy; the eighth patient improved to an MCS.15 But Wakoto Matsuda, MD, and colleagues at Kyoto University in Japan suggested that levodopa may only be effective in a subgroup of patients with vegetative state, including those with concomitant symptoms of parkinsonism.16
Zolpidem (Ambien), an omega 1-specific indirect gamma-aminobutyric acid agonist that is typically prescribed for treatment of insomnia, was in the media spotlight in June 2006 following the publication of a study suggesting it may have additional benefits for patients with impaired consciousness.17 Ralf Clauss, MD, now at the Royal Surrey County Hospital in the United Kingdom, and fellow investigators at the University of Zululand in KwaDlangezwa, South Africa, found that 3 patients in whom vegetative state was diagnosed experienced a transient period of awareness for about 4 hours after taking the drug. The effect was seen daily for 3 to 6 years, with no long-term adverse effects reported.
Giacino is currently leading a multicenter, double-blind, randomized controlled trial to investigate the effectiveness of amantadine in more than 180 patients with a diagnosis of vegetative state or MCS following traumatic brain injury. The study is expected to take 5 years to complete, due in part to difficulty in recruiting patients.
"Insurance companies don't want to admit these patients to a hospital for rehabilitation because they don't believe the patients can be helped," Giacino said. "Scientifically, it's extremely frustrating. How can we find out if we can help these patients if we can't get access to them?"
The rehabilitation options for patients with impaired consciousness at many facilities are focused on sensory stimulation, physical therapy, occupational therapy, and facilitating the constructive involvement of family members. In the 13 years since implementation of the Early Intensive Neurorehabilitation Programme (EINP) for patients age 25 years and under at the Rehabilitation Centre Leijpark in the Netherlands, 62% of patients regained full consciousness within 3 months of admission to the program.18 Of the 63 patients who were in a vegetative state when admitted, 9 remained vegetative after 3 months in the program; of the 82 minimally conscious patients, 13 remained minimally conscious at the same end point.
The success of the EINP is multifactorial, said Henk Eilander, a developmental psychologist and neuropsychologist at the Rehabilitation Centre Leijpark, who led the investigation of the facility's outcomes.
"Although sensory stimulation was the center of the program when we started it in 1987, I nowadays think that all parts are evenly important," Eilander said. "The cohesion and tuning in to each other by all therapists is very important; fine-tuning on each individual patient is essential; and last but not least, the way families can cope and behave has great influence on the basic emotions of the patient, which is one of the conditions for good recovery."
In its report published in 1994, the Multi-Society Task Force on Persistent Vegetative State concluded that the prognosis for patients in whom vegetative state resulted from a nontraumatic cause was worse than for those in whom vegetative state was associated with traumatic injuries.19 The task force estimated that the chance of recovery was less than 1% after 3 months for patients in a vegetative state not associated with traumatic injury, whereas this dire prognosis could be expected after 12 months has elapsed for patients in a vegetative state associated with trauma. However, a study by Giacino and Kalmar of 55 patients with a diagnosis of vegetative state and 49 patients with a diagnosis of MCS found no significant difference in outcomes between patients whose vegetative state was associated with trauma and those whose condition was unrelated to traumatic injury.20 The study did find that minimally conscious patients whose condition was associated with trauma fared significantly better at 1 year than did minimally conscious patients whose condition was not associated with trauma.
"[Patients with] medical causes of brain damage-such as anoxia, encephalitis, hypoglycemia, or subarachnoid hemorrhage-do less well than [patients with] traumatic causes, mainly because in medical causes, the whole of the brain tends to be affected rather than the bits of the brain in traumatic causes," said Andrews.
THE CLINICIAN'S ROLE
Despite the diagnostic, prognostic, and therapeutic challenges posed by patients with impaired consciousness, Bernat emphasized that physicians treating these patients must try to be as honest and accurate as possible to avoid additional confusion.
"The doctor's job should be to state the diagnosis, the prognosis, and the level of certainty we have, which can be very low," Bernat said. "Prognosis is a statistical phenomenon. People don't like that and it makes us anxious, but that's the way it is."
One of the worst things a clinician can do, Kurent said, is to ask a patient's family how they would like the patient's case to be managed. "We're trained professionals. We should be able to offer patients our support, rather than throwing the ball back in their court," he said. "We don't want to send the message that the patient and their family are being abandoned."
Physicians can take some comfort in the fact that, although the Schiavo case was undeniably clouded by confusion and sensationalism, many experts were able to take advantage of the opportunity to educate the public about issues related to consciousness.
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Jordana Bieze Foster is a freelance writer in Stow, Massachusetts, and former editorial director of Applied Neurology.