IN JULY 2005, a 23-year-old British woman was involved in a horrific road accident. She was taken to hospital in a deep coma with a serious head injury. After an operation to relieve the pressure on her brain, she gradually woke up, but only to what’s been called a “living death” – a condition known as a persistent vegetative state.
PVS is an unnerving name and equally disturbing to witness. The patient is clearly alive, breathing unaided, but the person who was once there seems to have gone. They sleep and wake and move, though their movements are erratic. They may speak or make noises, even smile, cry or grimace, but they seem to do nothing of their own free will. They respond to neither pain nor stimulation.
It was a shock, then, when neuroscientists examining the woman – let’s call her patient X – claimed to have detected unmistakable flickers of consciousness during a brain scan. If they were right, although she met the hospital’s clinical criteria for PVS – most importantly, wakefulness but total lack of awareness in a standardised bedside test – she was not entirely unconscious.
Advertisement
The discovery is just one of several recent cases that seem to defy medical understanding. As well as unexpected flickers of awareness there have been seemingly impossible “awakenings”, such as the case of Terry Wallis, who suddenly came round 19 years after he became unconscious. There are also growing numbers of reports of drugs that can rouse otherwise unresponsive patients. PVS and other disorders of consciousness (see Diagram) have long been among the most medically and ethically challenging conditions, but this has turned them into a minefield.
What do these awakenings mean for the hundreds of thousands of patients diagnosed with PVS and other disorders of consciousness? Could some of them be aware of their predicament, trapped inside a body they can no longer control? Can standard tests distinguish between those who are still “in there” and those who are truly unaware and unlikely ever to recover? Are patients who have a chance of waking up being allowed to die because doctors assume they have no future (see “A right to die?”)?
Most cases of PVS come about as a patient claws their way out of a coma after a head injury, or after their brain has been deprived of oxygen in a heart attack or stroke. The early stages are defined simply as a “vegetative state”, and many patients pass through this on their way to some form of recovery. Those who languish for longer than 30 days are generally diagnosed with PVS – though “persistent” doesn’t necessary mean permanent, and a handful of patients regain consciousness months later. After a year following brain injury, or three to six months after a stroke or heart attack, the chances of recovery are slim, and the patient is often declared to be in a permanent vegetative state.
PVS has always been difficult to diagnose and manage largely because it is not so much a diagnosis as a symptom, and no single brain region or function is lost. (For typical diagnostic criteria, as used in the UK, see .) It is also incredibly hard to predict an individual patient’s chances of recovery. So do the recent events really change the picture, and if so, how?
The team who studied patient X now have more clues as to what their discovery might mean. PVS patients often have reflex-like responses in the brain to words, sounds, faces and painful stimuli, but these register only in the outermost sensory areas and never reach regions that might become aware of them. What Adrian Owen from the Medical Research Council Cognition and Brain Sciences Unit in Cambridge, UK, and colleagues at the University of Cambridge and University of Liège in Belgium wondered was whether patient X’s response could be more sophisticated than that. Could she respond to instructions to perform a mental task that a brain scanner could pick up?
Normally just thinking about actions produces similar patterns of brain activation to actually performing them. So Owen and his colleagues picked two actions involving very different brain regions: walking around your home, which uses spatial awareness and memory regions; and playing tennis, which uses regions that control limb movement. Having established that functional MRI could identify these thought patterns in normal volunteers, they asked patient X either to imagine playing tennis or to imagine walking around her house. Sure enough, they found that she showed the same distinctive patterns of brain activity Owen believes this can only mean one thing: “This patient was consciously aware and purposefully following the instructions given to her, despite her diagnosis of vegetative state.”
In subsequent tests of around a dozen patients the team has found only one other who responds to instructions in a similar way. So patient X’s condition looks like a rarity, though by no means a one-off.
What does this mean for other PVS patients? Patient X is still under observation, and Owen says she has shown some signs of improvement. She is now considered to be in a ““, a recently defined category which allows for sporadic signs of awareness and attempts to communicate. It seems likely that her early signs of awareness reflected the first stirrings of recovery.
It therefore seems unlikely that legions of PVS patients are suffering in silence, aware of their predicament but unable to communicate. It may simply be that brain scanning is capable of picking up signs of recovery earlier than clinical tests, Owen says. He thinks it won’t be long before brain imaging becomes a standard diagnostic tool.
Terry Wallis is one person whose story might have run a little differently if routine scanning had been available. In 1984, at the age of 19, he was thrown from his pick-up truck near his home in Massachusetts, and was found in a coma the next day. A few weeks later, he was diagnosed with PVS and released into family care. He didn’t see a neurologist again for 19 years. His mother always maintained that there was something of Terry still inside, and apparently she was right. In 2003, she was rewarded when Wallis uttered his first word since the accident: “Mom”. Over the next three days, he regained the ability to move and communicate a little, and had the shock of coming to terms with the fact that it was no longer 1984, he was no longer a teenager, and that his baby daughter was now 20.
To find out more about Wallis’s apparently miraculous recovery – the latest awakening on record – neurologist Nicholas Schiff from the Weill Medical College of Cornell University in New York twice scanned Wallis’s brain using diffusion tensor imaging. This technique reveals the connectivity patterns in the brain rather than just anatomy or activity. The scans showed that while his brain structure was relatively intact the connections between regions, especially those between the two hemispheres, were torn apart.
Comparing scans from eight months and 26 months after his awakening, Schiff found some clues as to why Wallis may have resurfaced. The normal connections between the hemispheres were much less substantial than usual – “like a small wispy string”, says Schiff. But a completely novel structure had developed towards the back of his brain and was showing strong connectivity between the two hemispheres . Developing this new structure was clearly a very long and slow process that could well have taken 19 years.
If it can take two decades for the brain to recover, just how persistent is PVS, and how long might unconsciousness last? How might doctors decide which patients warrant a lengthy vigil, and make sure that families seeking the right to die for their loved ones are not denying them a late awakening?
It’s hard to say. When Schiff studied the case notes, he found that Wallis had not been in a vegetative state after all. His diagnosis, certainly from around three months after the accident, fitted better with the minimally conscious state. Schiff argues that nobody properly diagnosed as being in a PVS has ever experienced a late recovery.
Even if Wallis wasn’t in a PVS, his late awakening from minimal consciousness is still baffling. And there are other, similar cases that defy medical understanding. Take 49-year-old Christa Lilly from Colorado, who suffered a stroke and heart attack in 2000 and lies unconscious in what was originally diagnosed as PVS, except for three days earlier this year and another five occasions beforehand when she has woken up and picked up where she left off. Her doctors now consider her to be minimally conscious, but do not know why she slips in and out of this state. In January, a 44-year-old man in Italy awoke 19 months after a brain haemorrhage, even though recovery from this type of injury is usually considered impossible after three months. And last month a Polish rail worker, Jan Grzebski, woke from what media reports called a 19-year coma, though chances are he actually had locked-in syndrome, in which the patient is aware but completely paralysed.
Sleeping pill paradox
Even more astonishing is the case of , who lives in a rehabilitation centre near Johannesburg, South Africa. Every morning he wakes up from his PVS, enjoys a period of alertness and then lapses back into unconsciousness. His secret is a sleeping pill called zolpidem, which paradoxically seems to rouse him.
In 1996, when he was 25, Viljoen was hit by a truck while riding his bike. Initially his brain injuries left him in a coma, but gradually he settled into what his doctors called PVS. In 1999 his doctor, Wally Nell, prescribed him zolpidem in an attempt to stop him harming himself as he thrashed about in bed.
His mother was there the first time he received the drug. She was also there to witness his miraculous first words less than half an hour later. Though he was blind, he could recognise his mother’s voice. His daily dose of zolpidem now gives him roughly 10 hours of alertness. He remembers his previous awakenings and has retained his sense of humour. He is still blind, and has short-term memory problems, but his mental functions are improving all the time.
“Louis’ mother was there the first time he woke up”
Nell has since tried zolpidem on around 200 people with various brain injuries and claims that around half show some benefit, though very few were as seriously injured as Viljoen. However, other institutions, including Schiff’s, have had nowhere near such high success rates. Some suggest that the successes may not have been true cases of PVS, but something more like minimal consciousness. Either way, neuroscientists are now studying the zolpidem effect and several clinical trials are getting under way. The first results should be in later in the year.
Zolpidem is not the only promising drug. Others have shown success in informal trials, including antidepressants, Parkinson’s drugs such as l-dopa, and stimulants such as ritalin.
John Whyte of the Moss Rehabilitation Research Institute in Philadelphia, Pennsylvania, says it is high time that these anecdotal treatments were tested more rigorously, though he cautions that doing so is difficult. Because PVS is a long-term condition and varies from patient to patient, huge groups are needed to get significant results. What’s more, families that enrol in trials need to accept the possibility that their loved one will be given a placebo rather than the drug itself. Whyte himself is in the process of recruiting 180 PVS patients for a clinical trial for amantadine, a Parkinson’s drug which seems to have had some success.
Drugs may not be the only treatment option. Deep brain stimulation (DBS), using implanted electrodes that work a bit like a pacemaker for the brain, has shown some promise. On the basis of one small trial, researchers at Nihon University School of Medicine in Japan claim that PVS patients who receive DBS are more likely to regain consciousness than those who don’t. Using a slightly different technique, Schiff has found that DBS can produce brain activity rather like wakeful arousal, though not actual awakening. He is planning a bigger trial on patients in the minimally conscious state.
Even low-tech options such as physical rehab are producing results. The Leijpark Rehabilitation Centre in Tilburg, the Netherlands, is a model of how effective it can be. The centre places great importance on daily routine, with separate living rooms and bedrooms, for example. Patients sit up and are given physiotherapy and sensory stimulation up to three times a day.
Treatment does not come cheap – upwards of ¬1000 a day – but it does seem to pay off. Although the centre has not done formal clinical trials, it claims about twice as many of its patients regain consciousness compared with published averages – though the odds may be stacked in its favour as its patients are all children or young adults and are often at the most favourable end of the spectrum. Unfortunately, Leijpark is a rarity. Physiotherapy is expensive and is generally seen as unnecessary for patients who are not expected to wake up.
Joseph Fins, who heads the division of medical ethics at Weill, says that patients in minimal consciousness are among the most neglected of all patients in long-term care. “We spend hundreds of thousands of dollars saving their lives, then we let them linger in suboptimal care,” he says. “They have no rehab and no supportive care. If their brains recover, their bodies have deteriorated.” Schiff agrees that the care of brain-injured patients is “a disaster”.
As knowledge about disorders of consciousness improves, however, the prospects for patients can only get better. The US Institute of Medicine recently convened a meeting of researchers, ethicists, legal experts and policy-makers to discuss the . All agreed that improving treatment and research into disorders of consciousness is an urgent priority. They described a “silent epidemic” of brain-injured patients who are being neglected for want of medical care – and research. For those in search of a miracle, the odds are still long. But awareness at last seems to be rising, in more ways than one.
A right to die?
Late awakenings from apparently persistent vegetative states have created concern about decisions to allow some patients to die on the basis that they have no hope of recovery. Should the right to die still exist?
The right to die was hard-won, established in law in the US in 1976 and in UK case law in 1993. Right-to-die cases now only go to court if doctors or family members disagree.
So far all right-to-die decisions have been supported by autopsy results. Yet even where there is unequivocal evidence that PVS is irreversible, the right to die can be controversial, as in the case of Terri Schiavo in 2005. She had been in a PVS for 15 years and had shown no signs of recovery. Yet the White House and the Vatican got involved, and Schiavo’s feeding tube was removed and reinserted four times before she was allowed to die.
Recent discoveries are having an effect. In one case a UK judge issued an order to try zolpidem on a PVS patient against her family’s wishes, before considering the right to die.
Researchers generally agree that the right to die should remain an option, and that a correct diagnosis of PVS usually goes along with irreversible neural death. The problem, it seems, is not with the right itself, or even challenging the persistence of true PVS, but with recognising patients who might instead be in the twilight of the minimally conscious state.
