[Commons-Law] Generic Sleeping Pill Awakens "Persistent Vegetative State" Brain Cells
Via: Seth Johnson
> http://www.guardian.co.uk/science/story/0,,1870286,00.html
Relevant snippet:
"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
scientifically 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-effects 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 first developed zolpidem, Sanofi-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
brain-damaged 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.
> http://www.guardian.co.uk/science/story/0,,1870286,00.html
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
baffled than the GP who made the breakthrough. Steve Boggan
witnesses these 'strange and wonderful' rebirths
Tuesday September 12, 2006
The Guardian
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 flicked 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 finding out exactly what is going on inside their heads.
Because, at the moment, the results are baffling 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
suffered 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 five 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
might be uncomfortable. In 1999, five 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 five 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 staff 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 effects of the drug are supposed to wear off 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 flushes. 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 off her wedding ring and
asks what it is. "It's a suffer-ring," she jokes. And he says,
"Well, if you're suffering, 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 findings," 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."
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 suffered 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
differently 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 suffered severe brain trauma when he
was thrown from a car in a traffic 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
fingers 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
flushes 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.
"Some time ago, Riaan had a cardiac arrest and it was a difficult
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 significant. Many stroke victims, patients with
head injuries and those whose brains have been deprived of
oxygen, such as near-drowning cases, have reported significant
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
scientifically 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-effects 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 first developed zolpidem, Sanofi-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
brain-damaged 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
suffered 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 affected -
and the left side of her face droops. She was given zolpidem for
the first 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 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 suffered severe brain
damage five 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 first 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 first 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 fiddling 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
suffered brain damage after a traffic 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 suffered severe
brain injuries in a car crash in 1991. He also suffered 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 difficulty
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 field 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 film 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 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 suffered 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 finding 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 terrific sense of humour and he carries on
running jokes from the day before.
"It is difficult 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 define 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 different from an
ordinary coma, in which the patient's eyes are closed, and which
rarely last more than four weeks. The other key difference 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 suffering devastating brain damage in
a traffic 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 fizzy 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 difficult, there have been several famous court
cases involving people in this condition. The most high-profile
centred on Terri Schiavo, a 26-year-old Florida woman who went
into a PVS after collapsing and suffering 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
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 five years; survival beyond 10 years is unusual.
Helen Pidd
> http://www.guardian.co.uk/science/story/0,,1870286,00.html
Relevant snippet:
"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
scientifically 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-effects 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 first developed zolpidem, Sanofi-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
brain-damaged 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.
> http://www.guardian.co.uk/science/story/0,,1870286,00.html
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
baffled than the GP who made the breakthrough. Steve Boggan
witnesses these 'strange and wonderful' rebirths
Tuesday September 12, 2006
The Guardian
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 flicked 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 finding out exactly what is going on inside their heads.
Because, at the moment, the results are baffling 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
suffered 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 five 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
might be uncomfortable. In 1999, five 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 five 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 staff 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 effects of the drug are supposed to wear off 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 flushes. 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 off her wedding ring and
asks what it is. "It's a suffer-ring," she jokes. And he says,
"Well, if you're suffering, 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 findings," 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."
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 suffered 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
differently 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 suffered severe brain trauma when he
was thrown from a car in a traffic 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
fingers 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
flushes 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.
"Some time ago, Riaan had a cardiac arrest and it was a difficult
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 significant. Many stroke victims, patients with
head injuries and those whose brains have been deprived of
oxygen, such as near-drowning cases, have reported significant
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
scientifically 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-effects 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 first developed zolpidem, Sanofi-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
brain-damaged 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
suffered 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 affected -
and the left side of her face droops. She was given zolpidem for
the first 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 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 suffered severe brain
damage five 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 first 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 first 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 fiddling 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
suffered brain damage after a traffic 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 suffered severe
brain injuries in a car crash in 1991. He also suffered 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 difficulty
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 field 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 film 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 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 suffered 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 finding 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 terrific sense of humour and he carries on
running jokes from the day before.
"It is difficult 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 define 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 different from an
ordinary coma, in which the patient's eyes are closed, and which
rarely last more than four weeks. The other key difference 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 suffering devastating brain damage in
a traffic 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 fizzy 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 difficult, there have been several famous court
cases involving people in this condition. The most high-profile
centred on Terri Schiavo, a 26-year-old Florida woman who went
into a PVS after collapsing and suffering 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
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 five years; survival beyond 10 years is unusual.
Helen Pidd
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Harish Singh
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