Research is pointing to new treatments for the millions of North Americans who suffer from sleep disorders.
Anne Meda was exhausted. Barely able to drag one foot in front of the other, the Toronto elementary school music teacher had to stop working because she no longer had the energy to teach, sing or get through a school day. She’d been diagnosed with heart failure, a sometimes fatal condition in which the heart can no longer pump enough blood to meet the body’s needs. Her heart, struggling to compensate, had enlarged to such an alarming degree that the only solution, she was told, would be a transplant. At 52, Meda felt she was dying.
And then her cardiologist suggested she join a U of T sleep study that was investigating a possible link between heart failure and sleep disorders. Meda was doubtful – her husband, a physician, had never complained that she snored – but she agreed. After spending a night in a sleep lab, she received a diagnosis that astounded her: sleep apnea, a disorder that was causing her to stop breathing at least five times an hour for 10 seconds or more each time, repeatedly making her oxygen levels plummet, her blood pressure soar and her heart work far too hard. She began nightly treatment with a small, bedside CPAP (continuous positive airway pressure) machine with a nose mask to supply a steady flow of pressurized air. It wasn’t easy – she cried the first time she used it – but her heart has gradually reverted to its normal size and today, 10 years later, Meda no longer has heart failure. “I just joined a gym,” she says, “and I hadn’t been able to do that for years.”
It’s been a tough sell, but only recently is sleep beginning to receive the recognition it deserves. It’s gradually catching up to its more popular cousins, balanced diet and regular exercise, as one of the pillars of good health. Beyond that, more and more studies are showing a strong correlation between sleep disorders and a whole range of illnesses and conditions, including heart disease, stroke, high blood pressure, diabetes, Parkinson’s disease, sudden infant death syndrome and even attention-deficit hyperactivity disorder in children and teens. While the importance of sleep is still underestimated in our 24-7 society, Dr. Douglas Bradley, director of U of T’s Centre for Sleep Medicine and Circadian Biology and director of the Sleep Research Laboratory at the Toronto Rehabilitation Institute, says, “A lot of people still have trouble seeing that disorders specific to sleep can contribute to so many illnesses, but I think the barriers are gradually being broken down.”
U of T sleep scientists such as Bradley are waking us up to the stark reality that the distinctive snoring of sleep apnea is more than a noisy nuisance, or that the sudden napping of narcolepsy is not just a comic quirk. The implications of sleep disorders are staggering both in their severity and in their scope. An estimated 40 million North Americans have chronic sleep problems, costing the Canadian and American economies billions of dollars a year in health-care expenses and lost productivity. Many sleep disorders cause chronic daytime sleepiness. One study found that, in 2000, more than 800, 000 drivers were involved in vehicle crashes related to sleep apnea.
A common sleep disorder, and Bradley’s particular area of interest, is obstructive sleep apnea. The typical pattern involves many cycles of snoring and cessations of breathing, punctuated by loud snorts to restart the flow of air. The struggle to breathe, which is like trying to suck air through a soggy straw, causes oxygen levels to drop, which forces the person to wake up briefly to breathe, often hundreds of times a night. Each arousal makes heart rate and blood pressure soar. Bradley says that among people who have difficult-to-control high blood pressure, 85 to 90 per cent have sleep apnea. The disorder can be a problem at any age; it’s thought that some crib deaths may be caused by apnea in infants who lack the ability to wake up to breathe.
Identified as a clinical disorder only in the 1960s, sleep apnea was considered a problem mainly of obese men (and their long-suffering bed partners). Now it’s known that apnea can also affect people with small jaws, overbites, recessed chins, thick tongues or big tonsils. Four to nine per cent of men and two to four per cent of women aged 30 to 60 have obstructive sleep apnea combined with daytime sleepiness, which makes the condition as prevalent as asthma but far less recognized. In fact, 80 to 90 per cent of people with sleep apnea go undiagnosed, especially women and children, people of normal weight, and those who sleep alone and are unaware of their breathing problems while sleeping.
The consequences are serious. Bradley estimates that at least half of people with heart failure, which is a leading cause of cardiovascular death, also have sleep apnea, and that people with sleep apnea have three to four times the risk of stroke. He adds that just as treating high blood pressure has resulted in a decrease in heart attacks over the past generation, treating sleep apnea could also make a significant difference, since it improves cardiovascular function in people who have heart failure as effectively as the most potent heart medicines. “Sleep apnea might be the hypertension of the 21st century,” he says.
One of the biggest difficulties, however, is identifying sleep apnea before someone has a heart attack or stroke. There simply aren’t enough facilities (or money) for every Canadian to undergo a sleep study; while Ontario has more than 100 sleep clinics, other provinces have far fewer. Wait times often exceed a year. Bradley’s clinic is developing a user-friendly home device so people can record their breathing patterns in their own beds. He predicts it will become commercially available in the next two years.
Another problem is treatment. The CPAP machine, invented in 1981 by Colin Sullivan, an Australian who did some of his research at the University of Toronto, is extremely effective, but there’s a catch. Only about two-thirds of the people prescribed one actually use it regularly, citing discomfort, dry nose and mouth, or headaches. That is why there’s a push to find alternate treatments, such as drug therapies. It’s a huge challenge because not only is sleep a very different physical state from wakefulness, but the stages of sleep are diverse, too.
We tend to think of sleep as a time of rest and recovery for the whole body and brain, but in truth it’s a time of dynamic activity. Typically we cycle through four stages of progressively deeper sleep and then back before entering REM (rapid eye movement) or dreaming sleep. The whole cycle repeats about every 90 to 120 minutes. Everyone’s respiratory muscles relax during sleep – we can instantly tell when someone is asleep by the slightly laboured breathing – but the airway stays open. In people with sleep apnea, the airway collapses when their respiratory muscles relax. The tongue can also go slack and block the airway. In order to study what drugs might be beneficial, researchers first needed to understand why the brain signals the muscles that affect breathing, such as in the tongue and diaphragm, to become inactive, and why this never happens when someone is awake.
“I wanted to learn what there is about the brain that is causing breathing to change during sleep,” says Richard Horner, an associate professor of medicine and physiology at U of T who holds the Tier 1 Canada Research Chair in Sleep and Respiratory Neurobiology. Horner’s lab was the first in the world to study how cells in the medulla area of the brain stem affect the muscles that are critically involved with breathing during wakefulness and during sleep, and which chemicals are chiefly involved in the process. Horner says, “We’ve successfully used this knowledge to increase respiratory activity in sleep.”
Using rats, Horner’s lab has been identifying the chemicals involved in the brain when there is a loss of breathing muscle activity in sleep. Based on this knowledge, he is devising and testing new pharmacological ways of reactivating these muscles. The chemicals Horner is examining include histamine, noradrenalin and serotonin, which are involved in producing a state of wakefulness in the brain. (That’s why antihistamines cause tiredness and some antidepressants disturb sleep.)
His research points the way to further study. “This work offers proof in principle that it is possible to reactivate these important breathing muscles in sleep when they are normally suppressed,” Horner says. “However, the next challenge is to achieve this in a clinical setting.” While drug therapy may be a few years in the future, Horner’s results may eventually be extrapolated to understand other conditions where breathing is suppressed, such as the shallow, slow or irregular breathing that results from the use of opioid medications for pain management.
brain, but in truth it’s a time of dynamic activity
There may also be some low-tech treatments on the horizon. Researchers have established that obesity worsens apnea, as it places extra weight on the throat. But in a new study of 23 normal-weight men, Bradley’s lab found a surprising link between sleep apnea and fluid retention. During normal sleep, fluid moves out of the legs and into the upper body. But among these men with apnea, the amount of fluid that moved related directly to how much time each day they spent sitting. In men who sat for most of the day, so much fluid moved that it increased their neck size by up to a full inch, worsening apnea. The study, published in November, attracted worldwide attention. Future treatments might include a simple diuretic or even a prescription for daily walking, which reduces fluid retention in the legs.
Another sleep disorder under scrutiny at U of T is narcolepsy. It’s a neurological condition that causes excessive daytime sleepiness. People with narcolepsy may sleep a normal amount at night, but because they don’t get enough deep sleep – they often go immediately into REM sleep, complete with vivid dreams – they experience an overwhelming urge to nap throughout the day and often in inappropriate situations. “I can fall asleep talking, sitting at the lunch table, getting a root canal or having sex,” says Lee Lyons, 49, of Toronto. “I’ll get this weird crawly feeling at the back of my neck and I know I can’t fight it. If you offered me a million dollars I couldn’t stay awake.”
Lyons (BA 1981 Trinity) first experienced the problem as an adolescent but, like many narcoleptics, went undiagnosed throughout her teens and young adulthood. As a history student at U of T, she loved school but couldn’t stay awake in class or during exams. Between classes she’d sneak naps on a couch in the women’s washroom. She says, “I had professors glare at me because I fell asleep in every class. Everyone thinks you’ve been partying too much or you’re irresponsible.” She just barely got her degree, and then, forced to abandon her plans to continue in academia, took a series of jobs, including driving a truck and operating machinery at a nuclear plant. Luckily her sleepiness never caused a serious accident. But when she was finally diagnosed with narcolepsy and told her boss, he said, “Thank God! We thought you must be an alcoholic or a heroin addict.” After trying various medications, Lyons now takes the psychostimulant modafinil, which helps her manage her condition. It’s not a cure – she had her commercial driver’s license revoked, can no longer work and receives disability benefits. Moreover, Health Canada has issued warnings about modafinil’s dangerous side-effects, including a life-threatening skin condition and adverse psychological symptoms.
To complicate the issue, narcoleptics generally also have cataplexy, a condition of sudden muscular weakness, ranging anywhere from a barely perceptible slackening of the jaw to a total body collapse, even as the person remains awake and aware. The attacks, often triggered by emotional events such as surprise, excitement or laughter, last seconds to minutes and can occur up to several times a day. “Sarah” a 32-year-old U of T graduate with a BA in anthropology, developed narcolepsy at 14 but didn’t have her first experience of cataplexy until her mid-20s when one day, while she was laughing, her knees buckled under her. “I can’t even watch America’s Funniest Home Videos,” she says. “I can never have a really hearty laugh.”
Today, Sarah takes a psychostimulant for the narcolepsy and an antidepressant for the cataplexy. Volunteering in a school and still searching for a full-time teaching position, she’s only too aware that the stigma of her condition could prevent her from landing a job – which is why she’s afraid to use her real name for this article.
Aiming to help the estimated three million narcoleptics in the world is John Peever, an assistant professor in U of T’s department of cell and systems biology. Peever’s research seeks to understand exactly how the brain regulates motor activity during sleep. “We’re trying to figure out what brain chemicals change in narcolepsy and particularly cataplexy,” Peever says. What is known is that narcoleptics have a deficiency of a group of cells in the brain’s hypothalamus that make the peptide orexin, which promotes wakefulness. Symptoms of narcolepsy appear in adolescence, which is also the time that scientists believe orexin cells may begin to degenerate, though there is still no evidence to link them. Adult narcoleptics may have lost up to 90 per cent of their orexin. “We’re trying to find out why those cells are dying,” Peever says.
There’s evidence that physical damage to that part of the brain may trigger the process – Lee Lyons suffered eight concussions as a child – but in most narcoleptics, why orexin cells die is unknown. They could be pre-programmed to die, or they could die as the result of an autoimmune disorder. That narcolepsy is significantly more prevalent in Japan than in North America suggests that there may be a genetic, cultural or environmental piece to the puzzle. Recently, Peever’s lab studied the brainwave and muscle activity of mice bred without orexin, and screened drugs to see what treatment works best for narcolepsy and cataplexy. “The real direction the field is moving in is why these cells get lost in the first place,” he says. “Then we could work on coming up with neuroprotective drugs to stop the death of those cells.” Evidence so far indicates that the dopamine system may be an important neurotransmitter to target. “Drugs that act on the dopamine system are miraculous at suppressing cataplexy in mice,” says Peever.
There’s promise, too, for a sleep problem called REM behaviour disorder, which causes violent thrashing as people act out their dreams, often resulting in physical injury. Peever and PhD student Patti Brooks have discovered that mice lacking glycine receptors in the brain exhibit behaviour that strongly resembles REM disorder in humans. They are working to establish whether abnormalities in the glycine system in humans are involved in this disorder. Scientists believe it’s possible that REM disorder is an early warning sign of Parkinson’s disease, a progressive neurological disease that affects more than a million North Americans. If this is the case, then treatment for Parkinson’s could begin upon a diagnosis of REM disorder, rather than several years later. So far, 80 to 90 per cent of people diagnosed with REM disorder go on to develop Parkinson’s or other neurodegenerative disorders such as Alzheimer’s. Peever believes that over time, the REM disorder-neurodegenerative disorder correlation will likely become even stronger. “I would be shocked if those numbers don’t turn out to be higher – even up to 100 per cent,” he says.
For anyone who still doubts the seriousness of sleep and its disorders, surely that’s a wake-up call. But knowing that some of the world’s leading scientists are working on solution a may help all of us rest a little easier.
Marcia Kaye (marciakaye.com) of Aurora, Ontario, is a magazine journalist and bestselling author specializing in health issues.