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Reborn
We have always been told there is no recovery from persistent vegetative state - doctors can only make a
sufferer's last days as painless as possible. But is that really the truth? Across three continents, severely
brain-damaged patients are awake and talking after taking ... a sleeping pill. And no one is more bafed
than the GP who made the breakthrough. Steve Boggan witnesses these 'strange and wonderful' rebirths
Steve Boggan
Tuesday 12 September 2006 11.47BST

For three years, Riaan Bolton has lain motionless, his eyes open but unseeing. After a
devastating car crash doctors said he would never again see or speak or hear. Now his mother,
Johanna, dissolves a pill in a little water on a teaspoon and forces it gently into his mouth.
Within half an hour, as if a switch has been icked in his brain, Riaan looks around his home in
the South African town of Kimberley and says, "Hello." Shortly after his accident, Johanna had
turned down the option of letting him die.
Three hundred miles away, Louis Viljoen, a young man who had once been cruelly described
by a doctor as "a cabbage", greets me with a mischievous smile and a streetwise four-move
handshake. Until he took the pill, he too was supposed to be in what doctors call a persistent
vegetative state.
Across the Atlantic in the United States, George Melendez, who is also brain-damaged, has lain
twitching and moaning as if in agony for years, causing his parents unbearable grief. He, too, is
given this little tablet and again, it's as if a light comes on. His father asks him if he is, indeed,
in pain. "No," George smiles, and his family burst into tears.
It all sounds miraculous, you might think. And in a way, it is. But this is not a miracle
medication, the result of groundbreaking neurological research. Instead, these awakenings
have come as the result of an accidental discovery by a dedicated - and bewildered - GP. They
have all woken up, paradoxically, after being given a commonly used sleeping pill.
Across three continents, brain-damaged patients are reporting remarkable improvements after
taking a pill that should make them fall asleep but that, instead, appears to be waking up cells
in their brains that were thought to have been dead. In the next two months, trials on patients
are expected to begin in South Africa aimed at nding out exactly what is going on inside their
heads. Because, at the moment, the results are baing doctors.
The remarkable story of this pill and its active ingredient, zolpidem, begins in 1994 when
Louis Viljoen, a sporty 24-year-old switchboard operator, was hit by a truck while riding his
bike in Springs, a small town 30 minutes' drive east of Johannesburg. He suered severe brain
injuries that left him in a deep coma. He was treated in various hospitals before being settled in
the Ikaya Tinivorster rehabilitation centre nearby. Doctors expected him to die and told his
mother, Sienie Engelbrecht, that he would never regain consciousness. "His eyes were open
but there was nothing there," says Sienie, a sales rep. "I visited him every day for ve years and
we would speak to him but there was no recognition, no communication, nothing."
The hospital ward sister, Lucy Hughes, was periodically concerned that involuntary spasms in
Louis's left arm, that resulted in him tearing at his mattress, might be a sign that deep inside he
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might be uncomfortable. In 1999, ve years after Louis's accident, she suggested to Sienie that
the family's GP, Dr Wally Nel, be asked to prescribe a sedative. Nel prescribed Stilnox, the
brand name in South Africa for zolpidem. "I crushed it up and gave it to him in a bottle with a
soft drink," Sienie recalls. "He couldn't swallow properly then, but I helped him and sat at his
bedside. After about 25 minutes, I heard him making a sound like 'mmm'. He hadn't made a
sound for ve years.
"Then he turned his head in my direction. I said, 'Louis, can you hear me?' And he said, 'Yes.' I
said, 'Say hello, Louis', and he said, 'Hello, mummy.' I couldn't believe it. I just cried and cried."
Hughes was called over and other sta members gathered in disbelief. "Sienie told me he was
talking and I said he couldn't be - it wasn't possible," she recalls. "Then I heard him. His mother
was speechless and so were we. It was a very emotional moment."
Louis has now been given Stilnox every day for seven years. Although the eects of the drug
are supposed to wear o after about two and a quarter hours, and zolpidem's power as a
sedative means it cannot simply be taken every time a patient slips out of consciousness, his
improvement continues as if long-dormant pathways in his brain are coming back to life.
I see Louis before his daily medication, yet he is conscious where once he would have been
comatose. Almost blind because of a separate and deteriorating condition, there is a droop to
one side of his mouth and brow because of brain damage. His right arm is twisted awkwardly
into his side.
Louis is given a pill, and I watch. It is 8.30am. After nine minutes the grey pallor disappears
and his face ushes. He starts smiling and laughing. After 10 minutes he begins asking
questions. His speech is impaired because of the brain damage and the need, several years ago,
to remove all his teeth, but I can understand him. A couple of minutes later, his right arm
becomes less contorted and the facial drooping lessens. After 15 minutes he reaches out to hug
Sienie. He pulls o her wedding ring and asks what it is. "It's a suer-ring," she jokes. And he
says, "Well, if you're suering, you should make a plan!" The banter continues and he
remembers conversations from the previous day and adds to them.
"Louis," I ask, "do you feel any change in awareness before and after the pill?" "No," he says.
"None whatsoever." Whatever is happening, he feels the same. "How do you know this is your
mother?" I ask, referring to Sienie. Remember, Louis cannot see. He says: "Because I recognise
her voice and I know she loves me."
Nel was as amazed at Louis' awakening as everyone else. A GP in Springs for 40 years, when he
isn't seeing up to 100 patients a day, he spends his time restoring vintage cars. Married with
three grown-up children, he has lived in the same house all his life.
"Something strange and wonderful is happening here, and we have to get to the bottom of it,"
he says. "Since Louis, I have treated more than 150 brain-damaged patients with zolpidem and
have seen improvements in about 60% of them. It's remarkable."
After Louis' awakening was publicised in the South African media, Dr Ralf Clauss, a physician
of nuclear medicine - the use of radioactive isotopes in diagnostic scans - at the Medical
University of Southern Africa, contacted Nel to suggest carrying out a scan on Louis. "The
results were so unbelievable that I got other colleagues to check my ndings," says Clauss, who
now works at the Royal Surrey County Hospital in Guildford. "We did scans before and after we
gave Louis zolpidem. Areas that appeared black and dead beforehand began to light up with
activity afterwards. I was dumbfounded - and I still am."
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Clauss says immediate improvements in the left parietal lobe and the left lentiform nucleus
were visible. In lay terms, these are important for motor function, sight, speech and hearing.
"I remember saying to Dr Nel that we were witnessing medical history," says Clauss.
No one yet knows exactly how a sleeping pill could wake up the seemingly dead brain cells, but
Nel and Clauss have a hypothesis. After the brain has suered severe trauma, a chemical
known as Gaba (gamma amino butyric acid) closes down brain functions in order to conserve
energy and help cells survive. However, in such a long-term dormant state, the receptors in the
brain cells that respond to Gaba become hypersensitive, and as Gaba is a depressant, it causes a
persistent vegetative state.
It is thought that during this process the receptors are in some way changed or deformed so
that they respond to zolpidem dierently from normal receptors, thus breaking the hold of
Gaba. This could mean that instead of sending patients to sleep as usual, it makes dormant
areas of the brain function again and some comatose patients wake up.
In Kimberley, the once booming home of the De Beers diamond empire, Riaan Bolton's family
heard of Nel's work after he and Clauss had papers published in the medical journal
NeuroRehabilitation and the New England Journal of Medicine several months ago. Riaan
suered severe brain trauma when he was thrown from a car in a trac accident in July 2003.
A keen cricketer and rugby player, the 23-year-old was studying to become an industrial
engineer but still found time to play guitar in a band.
"One specialist said he had a 5% chance of recovering, another said he had no chance
whatsoever of regaining consciousness," says his mother, Johanna. She and her husband,
Tinus, spend about 1,000 a month on round-the-clock care for their son in a converted garage
at their home, but until June they had seen no sign of awareness in him. Then they asked their
doctor, Clive Holroyd, to contact Nel for advice.
"There was no movement, no recognition, just nothing," says Tinus. "Then we gave him the pill
and we noticed him moving the ngers in his left hand and touching them against each other.
His eyes went big and he began looking from left to right.
"The doctor started asking Riaan questions. He said, 'Look at me, Riaan' and Riaan looked
straight at him and focused on his face. Then the doctor asked him to move his hand and he
moved it. And then he lifted his head from the pillow and began looking around. I couldn't
believe it."
I watch as Riaan is given his medication. As with Louis, his face ushes and his eyes begin to
sparkle and focus within minutes. Gone is the 1,000-yard stare. He hugs his mother and looks
at her face, but even though I am amazed, the family reckon this isn't his best day so far. They
show me a number of DVDs they shot in July. In them, Riaan responds to questioning, nods
and shakes his head, drinks through a straw, often laughs and says, 'Hello.' He remains severely
brain damaged, but there is clear evidence of understanding and communication.
"It has given us hope," says Johanna. "To have communication with him again, to know he
becomes aware of us and to tell him we love him - knowing he can hear us - is simply beyond
belief. It has been a very moving experience."
Holroyd remains perplexed. "There is a measurement of the depths of coma called the Glasgow
scale, with three being the worst and 15 being normal," he says. "Riaan was six, but within 10
minutes of taking the pill he is up to nine. It's simply unbelievable. And the mind-boggling
thing about this is that it's done with a sleeping pill.
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"Some time ago, Riaan had a cardiac arrest and it was a dicult call as to whether or not to
resuscitate him. His mother insisted he should be, and look at him now. From now on, this will
cause serious ethical issues over whether to let such coma victims die." Those issues became
even more complicated last week, when a British woman believed to be in a persistent
vegetative state astonished doctors by responding to their voices.
Although these awakenings are the most dramatic aspect of the zolpidem phenomenon, Percy
Lomax, the chief executive of ReGen Therapeutics, the British company funding the South
African trials, believes Nel's work with less brain-damaged patients could be the most
signicant. Many stroke victims, patients with head injuries and those whose brains have been
deprived of oxygen, such as near-drowning cases, have reported signicant improvement in
speech, motor functions and concentration after taking the drug.
"The potential for this drug is enormous," says Lomax. "ReGen has applied for a patent to use
the drug, now out of patent and generically available, for the treatment of secondary brain
injury after brain trauma. The object of the clinical trial is to scientically establish that the
compound works in the way it has been shown to work in individual cases. It will be carried
out on patients known to react well to zolpidem, and by lowering the dosage it is hoped that
the sedative side-eects will be reduced but the brain stimulation will still continue.
"It may be that further research will allow us to better understand the way the drug works and
to develop a new generation of better-targeted pharmaceuticals." He says market research
estimates the potential market for zolpidem in brain-damaged patents could top $4.3bn
(2.3bn).
The company that rst developed zolpidem, Sano-Aventis, was contacted by Nel and Clauss
but appears to have chosen not to become involved in the trials or the use of the drug on braindamaged patients. Instead, the brain scans on up to 30 patients will be carried out at the
Pretoria Academic Hospital by Professor Mike Sathekge, head of nuclear medicine, and
Professor Ben Meyer, one of South Africa's most renowned physicians.
"The results so far could be potentially very important," says Meyer. "We have never before
spoken of damaged cells in the brain going into hibernation - we have thought of them as
necrotic, or dead, cells. But we know cells can go into hibernation in the heart and thyroid, so
why not the brain? If there are hibernating cells in damaged brains, it may be that this drug
helps to wake them in some people."
In South Africa, I meet a procession of brain-damaged patients who feel the drug has changed
their lives for the better. There is 32-year-old Miss X, who can't be named for legal reasons. She
suered four cardiac arrests and hypoxia, a lack of oxygen to the brain, when a hospital's
apparent failure to diagnose a gall bladder problem resulted in her contracting septicaemia
four years ago. She can barely stand, her arms are in spasm, she cannot speak - although her
intelligence has not been aected - and the left side of her face droops. She was given zolpidem
for the rst time just a week before I see her and her parents say the improvement was such
that she has come back for more.
Miss X is given a pill by Nel at 4.37pm. By 4.50 the left side of her face is no longer drooping,
her eyes sparkle and she smiles broadly. At 5.02, her arms have relaxed enough for her to fold
them and she is laughing with her parents. Ten minutes later, she stands up, stretches to her
full height and claps her hands.
Using a card keyboard, she spells out answers to questions I have for her. "Can you use the
keyboard more quickly with the medication?" She answers: "Yes." Does she feel an
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improvement? "Yes, I am not falling over. I am not coughing so much. I can swallow easier. I
feel my limbs are much more relaxed." But does she feel more tired? "No". What is she hoping
for? "To talk again. I'd love to be able to call my cats to come to me."
At 5.22pm, Miss X issues a long, drawn-out "Wall-eeee!" and hugs Nel.
Then there is Wynand Claasens, 22, who suered severe brain damage ve years ago when he
was assaulted outside his school. A series of subsequent strokes left him wheelchair-bound,
depressed and aggressive. He used to be a long-distance runner. Nel gave him Stilnox for the
rst time in early July this year. "I was struggling to walk, my left eye was hanging lower and
was smaller than my right eye, I was feeling very angry, I had pains in my knees and I was
having trouble going to the toilet," Wynand says. "Now I'm walking with one stick, my face has
evened up, I can go to the toilet when I'm ready and the pain in my knees has gone. I take one
10mg tablet each night and I feel about 60% better."
The list goes on. Heidi Greven, who is now 21, was starved of oxygen to her brain at birth. Her
mother, Babs, says she used to sit in silence, locked inside her own head, never
communicating and looking terribly unhappy. When I meet Heidi, she is walking around,
curious about everything. She examines the shorthand in my notebook. Although too shy to
speak (she will always be brain damaged), she jokes with Nel. At home, she now chats with her
parents.
"I'll never forget the rst time she was given the medication," says Babs. "It was in July 2002.
After 10 to 15 minutes it was like a curtain being lifted from her eyes. I couldn't believe it. She
suddenly started looking around and ddling with magazines. Then she went outside the door
and looked into the other rooms in the surgery. She found a portable radio and put it up to her
shoulder and began listening to it. Beforehand, she would just sit there doing nothing.
"That was a Saturday. When she went to [a special] school on the Monday, her teacher sent a
note home asking what we had done to make Heidi come alive."
There are others, too: Paul Ras, a 69-year-old runner who suered brain damage after a trac
accident. Now he is convinced zolpidem is responsible for a recovery that allows him to run
races up to 50km - with only one hip.
And Theo van Rensburg, a 43-year-old lawyer who suered severe brain injuries in a car crash
in 1991. He also suered a stroke while in a coma for three months. He took Stilnox in 1999
and reported an improvement in balance, co-ordination, speech and hearing.
"I go horse-riding now," he says. He still has diculty speaking, but I can understand him. "It's
really good for my balance."
Finally, I meet 22-year-old Janli de Koch, whose eyesight was damaged in a car accident in
Switzerland in December 2004. The injury resulted in a restriction of her visual eld to two
corners of her eyes; she cannot see below a certain point, so that she bumps into things and
falls over. Last month, she was prescribed zolpidem and now says she can already see more
than she used to. She hopes the improvements will continue.
In 1969 the neurologist Dr Oliver Sacks used the then new drug L-Dopa to awaken a group of
catatonic patients who had survived the 1917-1928 epidemic of the mysterious "sleeping
disease", known as encephalitis lethargica. The 1990 lm Awakenings chronicles Sacks' delight
at his patients' progress and his despair when the medication stops working and they slip back
into a catatonic state. The hope with zolpidem is that the improvements will continue and
there will be no regression. In the patients who have used the medication longest - such as
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Louis Viljoen and Theo van Rensburg - the signs are that progress continues. But time will tell.
Perhaps the last word should go to Pat Flores, the mother of George Melendez, the 31-year-old
coma patient who reassured his parents that he wasn't in pain after taking Ambien, as
zolpidem is known in the US. He was starved of oxygen when his car overturned and he landed
face down in a garden pond near his home in Houston, Texas, in 1998. "The doctors said he
was clinically dead - one said he was a vegetable," says Pat. "After three weeks he suered
multi-organ failure and they said his body would ultimately succumb. They said he would
never regain consciousness."
He survived and four years later, while visiting a clinic, Pat gave him a sleeping pill because his
constant moaning was keeping her and her husband, Del, awake in their shared hotel room.
"After 10 to 15 minutes I noticed there was no sound and I looked over," she recalls. "Instead of
nding him asleep, there he was, wide awake, looking at his surroundings. I said, 'George', and
he said, 'What?' We sat up for two hours asking him questions and he answered all of them. His
improvements have continued and we talk every day. He has a terric sense of humour and he
carries on running jokes from the day before.
"It is dicult to describe how it feels to get someone back who you were told you had lost for
ever. There is a bond that has been restored and it validates our absolute belief that all along
George was locked inside there somewhere. It tells us that we were right and the doctors were
wrong. George, and his personality, were in there the whole time".
What is persistent vegetative state?
Though it sounds unkind to refer to a human in such terms, even medical dictionaries dene
persistent vegetative state (PVS) as the condition of living like a vegetable: in other words,
existing without consciousness or the ability to initiate voluntary action. Though people in this
state may occasionally give the impression of being awake and sentient, making random
movements and opening their eyes and even appearing to smile or cry, they are unable to
respond to communication or demonstrate awareness of their environment. This is dierent
from an ordinary coma, in which the patient's eyes are closed, and which rarely last more than
four weeks. The other key dierence is that a person in a coma hasn't necessarily lost all
cognitive function (ie, brain power); they are just temporarily unable to access it. If they
recover - and many do - they may have cognition afterwards.
PVS is the result of irreparable damage to the cerebral cortex - the "thinking, feeling" part of
the brain - but it is not to be confused with brain death. And while the "persistent" bit in the
title indicates that the condition, unlike coma, is generally deemed permanent, there are
intermittent reports of "recoveries". Last week, it was reported that a 23-year-old woman who
has been in a vegetative state since suering devastating brain damage in a trac accident was
suddenly able to understand speech. And in 2003 an Arkansas man, Terry Wallis, returned to
consciousness 19 years after he was injured in a car accident, stunning his mother by saying
"Mom" and then asking for a drink of zzy pop. Such breakthroughs are controversial, in both
medical and legal circles. The British Medical Association, for example, currently deems such
miraculous events not as recoveries from PVS, but as an indicator of an earlier misdiagnosis.
Because legal systems do not generally equate PVS with death, and diagnosis is dicult, there
have been several famous court cases involving people in this condition. The most high-prole
centred on Terri Schiavo, a 26-year-old Florida woman who went into a PVS after collapsing
and suering a heart attack in 1990. In 1998 her husband, Michael Schiavo, petitioned for her
gastric feeding tube to be removed; her parents did not believe the diagnosis and took the case
to court to prevent medical care being withdrawn. Ultimately, the court challenges were
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unsuccessful and in 2005 Schiavo's feeding tube was removed, leading to her death.
There is no treatment for PVS. Instead, the medical team concentrate on preventing infections
and maintaining the patient's physical state as much as possible. The most common cause of
death for a person in a vegetative state is infection such as pneumonia. For most such patients,
life expectancy ranges from two to ve years; survival beyond 10 years is unusual.
Helen Pidd

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