Medical Miracle

A sleeping pill is waking up many patients in persistent vegetative states. [Link]

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.