Donald Dorff could sleep hear the crowd roaring as he snatched the quarterback’s pitch from the air and sprinted toward the goal line.
“There was a 280-pound tackle waiting for me, so I decided to give him my shoulder,” the 67-year-old told National Geographic magazine in 1987.
“When I came to sleep, I was on the floor in my bedroom,” Dorff said. “I had smashed into the dresser and knocked everything off it and broke the mirror and just made one heck of a mess. It was 1:30 a.m.”
Five years earlier, Dorff had become the first patient diagnosed with an unusual disease called rapid eye movement sleep behavior disorder, or RBD.
There’s more. Dorff’s case also launched researchers on a journey that uncovered one of the earliest signs of two devastating diseases: Parkinson’s and a unique form of dementia called Lewy body.
Symptoms include screaming, kicking and throwing punches
The discovery of RBD was made in 1982 when Dorff, after years of experiencing “violent moving nightmares,” became a patient of psychiatrist and sleep specialist Dr. Carlos Schenck, then working at the Minnesota Regional Sleep Disorders Center in Minneapolis.
“During rapid eye movement or REM sleep, the brain basically paralyzes the body so that we cannot act out our dreams,” Schenck, now a professor and senior staff psychiatrist at the Hennepin County Medical Center at the University of Minnesota, told CNN recently.
“But Dorff was able to get up and hurt himself while dreaming, a very odd behavior. We were scratching our heads about it,” he said. “Then we put him in a sleep lab, and lo and behold, all his physical behaviors came out of REM sleep, which had never been reported before.”
More patients with the unusual disorder were identified, many exhibiting a disturbing set of violent symptoms, Schenck said.
“They start kicking in bed, throwing punches at their bed partners, talking or screaming loudly, things like ‘Get the hell out of here!’ Then the wife has to scream really loudly to stop the episode,” he said.
“Limb jerking, twitching, throwing out your arm, throwing punches, kicking, sitting up, standing, jumping out of bed and running. Those behaviors are very typical with RBD,” he added.
One 70-year-old patient, described by his wife as having a gentle nature during the day, would punch and kick her as many as five times a night, Schenck said. On one occasion, he tried to strangle his wife while dreaming of fighting off a mauling bear.
Another patient, also 70, dreamed he had just taken down a deer and was going to break its neck. In reality it was his wife’s neck, which he discovered when he woke up. (She quit sleeping in the same bed.)
RBD can affect women, too
Lewy body dementia can refer to two different types of dementia: Parkinson’s disease dementia and dementia with Lewy bodies, which both affect cognition.
Parkinson’s disease, however, is a slowly progressive disorder that inhibits muscle control, balance and movement — although about 4 in 5 people with Parkinson’s ultimately develop dementia, according to Johns Hopkins Medicine.
In both Parkinson’s and the two dementias, cells in and around the stalk-like stem at the bottom of the brain begin to die. In addition to breathing, swallowing, heart rate and eye and facial movements, the brain stem also controls the sleep-wake cycle.
Early damage to the brain stem caused by Parkinson’s can interfere with the body’s innate ability to freeze the muscles while dreaming, thus allowing the body to sit up, scream, flail or otherwise act out a dream.
Hallucinations, which are common in Parkinson’s, can also occur, according to case studies. A 67-year-old man would see faceless, hooded or cloaked figures or animals while awake during the night. The images vanished when the man turned on a light or got up to investigate.
Such nighttime behaviors can often be controlled with medication, including high doses of melatonin or the drug clonazepam, which stops seizures and relaxes tense muscles, Schenck said.
“Either one alone or both in combination works 80% to 90% of the time, and there are a long list of alternative treatments,” said Schenck, who first published the connection between RBD and Parkinson’s in February 1996.
“We know the mechanism for RBD very well, and we know how to treat it,” he said. “The next step is to slow down or halt the progression to Parkinson’s disease and dementia with Lewy bodies.”
At first, researchers believed RBD only affected men but then realized that women are equally impacted.
“Just as many women have this problem, but because it’s much milder and doesn’t cause injury as often, they frequently don’t come in to seek help,” Schenck said. “Yet they have lost that muscle paralysis in REM sleep, and they’re just as much at risk for future Parkinson’s disease as the men.”
A clinical trial is underway at nine medical centers in the United States, Schenck said. Called the North American Prodromal Synucleinopathy Consortium, the research hopes to identify potential treatments for rapid eye movement sleep behavior disorder and slow its progression into Parkinson’s and dementia.
Seek medical treatment if violent dreams begin
As a child, Donald Dorff shared a room with three brothers and never had any signs of a sleep disorder. On his wedding night, however, he scared his new bride with loud talking, groaning, teeth grinding and minor movements, according to Schenck’s case study.
About 41 years later, however, he began to have vivid, violent dreams that he would act out. In one dream, he was riding a motorcycle when another motorcyclist tried to ram him.
“I decided I’m going to kick his motorcycle away and at that point my wife woke me up and said, ‘What in heavens are you doing to me?’ because I was kicking the hell out of her,” Dorff told Schenck during treatment.
In another dream Dorff was under attack by a man with a rifle and preparing to shoot back when he suddenly woke up. “I was kneeling alongside the bed with my arms extended like 1 was holding the rifle up and ready to shoot.”
One night Dorff dived into a bedside dresser and cut himself, Schenck said. It was then that he found Schenck’s clinic and went there for treatment.
While some people with RBD develop full-blown Parkinson’s rather quickly, Dorff was not one of them. He died of prostate cancer, Schenck said, and was able to control his violent nighttime behavior until his death as long as he remained on medication.
Dorff’s case helped physicians discover an early key to two devastating disorders, allowing earlier diagnosis and treatment.
“If you’ve never been a sleepwalker or sleep talker throughout your life and suddenly, after the age of 50, you start and the talking becomes louder and more frequent, then you really should be evaluated by your primary care doctor,” Schenck said.
“Your doctor should consider neurological evaluation because that could be the first sign of a neurodegenerative disorder.”
Sleep: Scientific Progress
First steps: Discovery of the electroencephalogram and stages of sleep
The development of modern Sleep Medicine is closely linked to the discovery of the electrical activity of the brain. Caton was the first to record brain electrical activity of animals in England in 1875,11 but it was Berger who discovered and reported the “electroencephalogram of man” in Germany in 1929.12 In 1937 Loomis in the US first documented the characteristic electroencephalogram (EEG) patterns of what is now called NREM sleep: vertex waves, sleep spindles, K complexes, and delta slowing.13 He divided sleep into 5 stages of increasing depth from A through E, which form the basis for the current classification of NREM sleep.
In 1951 Kleitman, a professor of physiology at the University of Chicago, studied eye movements during sleep with the assistance of his graduate student, Aserinsky. This work culminated in a seminal paper in 1953 in which a new sleep state, REM sleep, was described and a correlation with dreaming hypothesized.14 In 1957, Dement and Kleitman described the human sleep cycle of NREM sleep stages of increasing depth followed by periods of REM sleep, with the cycles repeating through the night.15 They proposed a new classification of sleep stages, using four stages of NREM sleep1–4 and REM sleep, a schema still used today with very few alterations. This understanding of the electrophysiologic substrate of human sleep has been the basis for the vast literature on sleep that has accumulated over the ensuing half century.
Narcolepsy: From bedside to bench
The story of narcolepsy is an example of the major advances that Sleep Medicine has made in the last 50 years. It clearly indicates how scientific progress in the neurobiology of sleep has resulted in novel understanding of a strange and disabling disease known clinically for over a century. Narcolepsy was first described in 1880 by Gelineau,16 a neuropsychiatrist in France, who recognized a group of patients with irresistible sleep. The disorder consists clinically of excessive daytime sleepiness in combination with cataplexy, a loss of muscle tone in response to laughter and other emotional stimuli. Some patients also experience paralysis or hallucinations at sleep onset and on awakening.
The first breakthrough in understanding the disease came in 1960, when Vogel recognized that REM sleep commenced near sleep onset in narcoleptics, rather than 1 to 2 hours later.17 This insight led to the concept that cataplexy and sleep paralysis represent the muscle atonia of REM sleep intruding into wakefulness, while hypnagogic hallucinations are dissociated dreams occurring without loss of consciousness. The next phase in unraveling narcolepsy was triggered by the observation that Japanese narcoleptics were highly likely to carry the HLA haplotype DR2,18 a finding that was later confirmed in American Caucasians. A lower frequency of HLA DR2 in African-Americans led to the conclusion that the actual predisposing antigen was DQ1 rather than DR2.19 Finally, the responsible subtype was identified as HLA DQB1*0602,20 present in 85% to 90% of narcoleptics who have cataplexy.21
The major breakthrough, however, occurred in the last 6 years and is a fascinating story of scientific discovery. In 1998, two peptides were identified in the hypothalamus and named hypocretin (Hcrt)-1 and Hcrt-2,22 names reflecting their hypothalamic origin and homology to secretin. Almost simultaneously, another group of investigators independently identified the same peptides, which they named orexin-A and orexin-B, based on their appetite-stimulating effect.23 These molecules arise from a precursor, preprohypocretin, synthesized by a small number of cells in the posteri- or and lateral hypothalamus, especially the perifornical area. They project to a diverse set of targets in the brain and spinal cord, especially the monoaminergic and cholinergic fields of the brainstem tegmentum comprising the ascending reticular activating system.24,25 Two membrane receptors have been identified, Hcrt receptor-1 with a high affinity for Hcrt-1, and Hcrt receptor-2, with a high affinity for Hcrt-1 and Hcrt-2.
Narcolepsy in dogs is transmitted as an autosomal recessive trait. Painstaking research by the Stanford Center for Narcolepsy under the direction of Mignot reached fruition in 1999 with the discovery that the disorder was caused by a deletion in the Hcrt receptor-2 gene.26 Another group of investigators, working with a Hcrt knockout mouse model, serendipitously recognized that the mutant mice developed episodes of either REM sleep or cataplexy while awake.27 Following these seminal observations, studies of narcoleptic patients revealed low or undetectable Hcrt-1 in the cerebrospinal fluid (CSF) of most (87%) patients with cataplexy and in some patients without cataplexy (14%). In contrast, low levels were not found in control subjects (0%) and observed rarely in patients with other neurological conditions (<2%).28 Autopsy studies of the brains of human narcoleptics have revealed that Hcrt is absent in the hypothalamus, cortex, and pons, and Hcrt neurons are reduced by 90% compared to controls.29,30 Clinical manifestations of the disease, such as cataplexy, appear to reflect a lack of Hcrt-mediated synaptic excitation of serotonergic and noradrenergic pathways normally responsible for REM-sleep inhibition. The sleepiness of narcolepsy more likely reflects lack of Hcrt’s excitatory influences upon histaminergic, dopaminergic, and cholinergic components of the ascending reticular activating system (ARAS), which normally function to promote thalamocortical arousal.
The next step in understanding the disorder will involve probing the mechanism of reduced Hcrt production by the hypothalamus. Despite the animal data, the search for human mutations has been disappointing and only a single point mutation in the Hcrt signal peptide has been described in one patient.30 The strong association with HLA DQB1*0602 has led to the hypothesis that narcolepsy may be due to a localized autoimmune attack on the hypothalamus, but there is as yet no direct proof of this. Further advances are expected to lead to novel therapies and, thus, complete the loop from bedside to bench and back to bedside.
Restless legs syndrome: The dopamine-iron connection
Restless legs syndrome (RLS) was first described by Ekbom in Sweden more than 50 years ago, but for many years was thought to be a rare curiosity. However, current epidemiologic studies suggest it may be one of the most common sleep-related disorders, with a prevalence as high as 10%.31 Patients complain of severe discomfort in their legs while sitting or lying in bed, associated with an uncontrollable desire to move to obtain relief. Almost 90% of patients experience regular jerks of their legs while asleep, known as periodic limb movements (PLM) of sleep.
In humans, RBD occurs overwhelmingly in men, commencing in middle or older age. A range of epidemiologic, psychometric, radiologic, and pathologic data has shown that the disease is linked with certain specific neurodegenerative disorders. At least 50% of patients in large studies carry diagnoses of Parkinson’s disease, multiple system atrophy, or dementia.45 Clinical and psychometric data have suggested that dementia associated with RBD indicates the presence of Lewy body pathology (with or without associated Alzheimer changes) rather than that of Alzheimer’s disease alone.46,47 This is confirmed by the available autopsy data on 14 patients with RBD: 13 have shown Lewy bodies (including 1 case with no neurologic signs clinically) and 1, the pathology of multiple system atrophy.48 Thus RBD appears to be associated with those neurodegenerative disorders with alphasynuclein positive inclusion bodies. There is also retrospective and prospective evidence that RBD may sometimes be the first manifestation of one of these neurologic disorders,49 and thus at least some patients with apparently idiopathic RBD may with time evolve to develop a neurodegenerative disease. Further evidence to support this contention comes from two radionuclide studies showing that neurologically normal RBD patients have reduced striatal dopamine activity, suggesting they may be in the presymptomatic stages of Parkinson’s disease.50,51 These insights may provide a way of identifying patients at high risk of developing serious neurologic disease, perhaps allowing preventive therapies to be administered in the future.
Obstructive sleep apnea: Discovery to epidemic
In 1956, Burwell et al published their classic description of the obesity hypoventilation (Pickwickian) syndrome.52 Following publication of this article, pulmonologists believed that alveolar hypoventilation (respiratory failure) was responsible for the excessive daytime somnolence observed in these patients. This misconception was not corrected until 1966 when Gastaut et al polysomnographically monitored the sleep of these patients.53 They documented repetitive episodes of upper-airway obstruction terminated by brief arousals that in turn fragmented nocturnal sleep. Obstructive sleep apnea (OSA) was discovered, and it was correctly postulated that sleep fragmentation was responsible for the excessive daytime somnolence observed in these patients. Subsequently, it has been determined that reductions in tidal volume (hypopneas) as well as increases in upper airways resistance also produce sleep fragmentation and daytime sleepiness.
This major new concept in medical science stimulated considerable research in the area of sleep and breathing. By 1978, Remmers et al had documented the relationship between intralumial airway pressure and EMG activity of the genioglossus muscle in the pathophysiology of upper-airway collapse in the pharyngeal segment of the airway,54 and tracheostomy was recognized as an effective treatment. Three years later, Sullivan et al demonstrated that the application of continuous positive airway pressure (CPAP) via the nose would prevent upper-airway collapse, normalize nocturnal sleep, and alleviate daytime hypersomnolence.55 This latter discovery revolutionized the treatment of OSA and has resulted in the use of nasal CPAP as the most commonly used treatment of this condition. Initially, OSA was felt to be a rather uncommon condition affecting only severely over-weight men. However, the small number of sleep specialists and pulmonologists interested in this condition in the early 1980s soon realized that OSA was a common condition affecting women as well as men. The first major epidemiologic study of the prevalence of OSA was published in 1993 by Young et al.56 They found OSA to be present in 2% and 4% of middle-aged women and men respectively. Subsequent epidemiologic studies have confirmed that obesity remains one of the major risk factors for OSA, but also have shown familial aggregation and differences among different age and ethnic groups, and between genders.
This high prevalence in the population combined with evidence suggesting adverse cardiovascular consequences led the National Institutes of Health (NIH) to fund studies investigating these important relationships. Resulting publications have established a clear association between sleep-disordered breathing and the development of hypertension,57,58 along with an increased prevalence of coronary heart disease, heart failure, and stroke at levels of an apnea-hypopnea index equal to or greater than 5 per hour.59 Based on these recent findings, the Centers for Medicare and Medicaid Services (CMS) have recently published guidelines for the reimbursement of nasal CPAP therapy in symptomatic patients with an apnea-hypopnea index equal to or greater than 5 per hour or asymptomatic patients with an apnea-hypopnea index equal to or greater than 15 per hour.
Insomnia: Progress toward relief for many
Insomnia is the most prevalent of all sleep problems. Although its etiology and pathogenesis remain elusive, significant strides have been made in terms of its epidemiology, phenomenology, and treatment. Insomnia is the subjective complaint of difficulty falling asleep, difficulty staying asleep, poor quality sleep, or inadequate sleep duration despite having an adequate opportunity for sleep. Two points in this definition deserve specific attention. First, insomnia is a subjective complaint and is not defined by laboratory test results or by a specific duration of sleep or wakefulness. Second, the insomnia symptom occurs despite the individual having adequate opportunity to sleep. This factor distinguishes insomnia from sleep deprivation, which has different causes, consequences, and clinical presentations.
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