[Fwd: COMA: People are waking up!!??]

[Guest guest]

*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 <http://www.guardian.co.uk/>*

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, 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, " 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 , 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. "

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: 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 , the mother of

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, '', 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 was locked

inside there somewhere. It tells us that we were right and the doctors

were wrong. , 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,

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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