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IS PARASOMNIA THE FIRST SIGN OF NEURODEGENERATIVE DISORDER?

REM (rapid eye movement) sleep behavior disorder may be the first sign of Parkinson disease and related neurodegenerative diseases, researchers at a sleep research center say.

REM sleep behavior disorder is rapidly becoming one of the most studied of the misunderstood and under-recognized sleep-related disorders known collectively as parasomnias. From sleep eating and sleepwalking to night terrors and sleep sex, “parasomnias are things that go bump in the night – unusual, out-of-the-ordinary events that occur during sleep or arousal from sleep,” said Colin M. Shapiro, MD, PhD, Professor of Psychiatry at the University of Toronto and author of a case series of 11 patients with sexsomnia in the Canadian Journal of Psychiatry (2003;48:311–317).

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Dr. Mark W. Mahowald: “If you follow people with REM sleep behavior disorder, at least two-thirds develop a synucleinopathy – Parkinson disease, multiple system atrophy, or dementia with Lewy body disease.”

As its name implies, REM sleep disorder is a parasomnia that strikes during REM sleep, when most dreaming occurs. “Normally during REM sleep, all the muscles except the diaphragm are paralyzed, so if you dream you are killing your mother-in-law, you're not actually going to do it,” said Christian Guilleminault, MD, Professor of Sleep Medicine at Stanford University.

But people with REM sleep behavior disorder do not show the normal paralysis of REM sleep, said Mark W. Mahowald, MD, Director of the Minnesota Regional Sleep Disorders Center at Hennepin County Medical Center and Professor of Neurology at the University of Minnesota in Minneapolis.

The result: Victims act out their dreams – thrashing, yelling, swearing, punching, kicking, running out of bed, even hitting their bed partners.

“If you follow people with REM sleep behavior disorder, at least two-thirds develop a synucleinopathy – Parkinson disease, multiple system atrophy, or dementia with Lewy body disease,” Dr. Mahowald said.

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Dr. Carlos H. Schenck is credited, along with Dr. Mark W. Mahowald, with discovering REM sleep disorder in 1986.

“From a treatment standpoint, if and when we develop a neuroprotective agent for Parkinson disease, people who have a REM sleep behavior disorder would probably be immediate candidates for the drug.”

DISCOVERING THE DISORDER

Working with Carlos H. Schenck, MD, Senior Staff Psychiatrist at the Minnesota Regional Sleep Disorders Center at Hennepin County Medical Center and Associate Professor of Psychiatry at the University of Minnesota in Minneapolis, Dr. Mahowald is credited with first discovering REM sleep behavior disorder in 1986 (Sleep 1986;9:293–308).

“There had been isolated cases before, but no one really knew what it was,” Dr. Mahowald recalled. “We had six patients with the exact same behavior during REM sleep – violent behavior associated with dream enactment – and recalled an animal model for it that was created in 1965. In the cat model, researchers made a lesion in the brain stem and instead of the typical paralysis of REM sleep, saw the same complex motor behavior we were seeing in our patients.”

Diagnosis is based on a clinical history of violent and injurious behavior during REM sleep that is associated with sleep enactment, coupled with polysomnographic findings of persistence of muscle activity during REM sleep, Dr. Mahowald said.

Loss of REM paralysis alone is insufficient to generate REM sleep behavior disorder, he said; “There also must be disinhibition of motor pattern generators in the mesencephalic loco-motor region to result in overexcitation of phasic motor activity with behavioral release.”

LINK TO NEURODEGENERATIVE DISEASE

Of the 29 otherwise healthy people initially diagnosed with idiopathic REM sleep behavior disorder that Drs. Mahowald and Schenck have followed since the 1980s, two-thirds have gone on to develop Parkinson disease or other related neurodegenerative disorders, Dr. Mahowald said. Most are men, over 50 years old, with the average time between the development of the sleep problem and the neurological disorder being 10 years (Neurology 1996;46(2):388–393).

Also, another study found that one-third of 33 patients with Parkinson disease met the diagnostic criteria of REM sleep behavior disorder based on polysomnography recordings, only half of whom would have been detected by history (Neurology 2002;59:585–589). Another study of 93 consecutive patients with REM sleep behavior disorder at the Mayo Clinic showed that neurological disorders were present in 57 percent of patients; Parkinson disease, dementia without parkinsonism, and multiple system atrophy accounted for all but 14 percent of these. REM sleep behavior disorder developed before parkinsonism in 52 percent of the patients with Parkinson disease, the researchers reported (Brain 2000;123:331–339).

According to Dr. Mahowald, telephone surveys suggest that 0.5 percent of the population suffers from symptoms consistent with REM sleep behavior disorder, making “it quite common.”

Writing last year (Schweiz Arch Neurol Psychiatr 2003;154:363–368), Drs. Mahowald and Schenck described a “typical” case. A 57-year-old police officer and avid recreational hunter had a 5-year history of progressively severe and injurious dream-enacting behaviors. He would frequently shout obscenities, kick the wall, punch his pillow, and sometimes hit his wife in bed while dreaming he was being attacked by unfamiliar people or animals. One night be nearly broke his wife's wrist while dreaming of putting a wounded deer out of its misery.

An overnight polysomnography study demonstrated classic REM sleep behavior disorder findings, with intermittent loss of REM-atonia and increased phasic twitching during REM sleep of all monitored muscles.

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Dr. Christian Guilleminault: “Normally during REM sleep, all the muscles except the diaphragm are paralyzed, so if you dream you are killing your mother-in-law, youre not actually going to do it.”

Treatment with clonazepam immediately controlled the parasomnia – a benefit that has been maintained for 15 years at the original 1 mg dose at bedtime, Dr. Mahowald said. However, 18 years after the onset of the REM sleep behavior disorder, the man was diagnosed with recent-onset Parkinson disease, with bradykinesia, rigidity, and resting tremor.

While it was initially thought that the majority of cases of REM sleep behavior disorder were idiopathic, “that may not be the case,” Dr. Mahowald said. “It is becoming apparent that spontaneous REM sleep behavior disorder is a harbinger of degenerative neurological conditions, and that in some patients, it may take more than 10 years for the neurodegenerative disease to develop.”

While there have been no controlled trials of drug therapy, Dr. Mahowald said that clonazepam works in about 90 percent of patients. In the Mayo trial, clonazepam treatment of REM sleep behavior disorder was completely or partially successful in 87 percent of the patients who took the drug (Brain 2000;123:331–339).

OUTSIDE COMMENTARY

Sid Gilman, MD, Chairman of the Department of Neurology at the University of Michigan School of Medicine in Ann Arbor, agreed that REM sleep behavior disorder is a possible herald of neurodegenerative disorders with parkinsonism, but he said that further research is still needed.

“Mark Mahowald is the clinical sleep specialist who first discovered REM sleep behavior disorder and he is quite right in saying that some percentage of patients with REM sleep behavior disorder go on to develop Parkinson disease or similar disorders,” he said. “But I don't think we can yet say everyone with REM sleep behavior disorder will develop Parkinson disease,” he said, adding that he plans to study how many do.

Studies of otherwise healthy people with REM sleep behavior disorder by the University of Michigan's Roger Albin showed reduced dopamine levels in the striatum, the part of the brain very involved with movement (Neurology 2000;55:1410–1412), Dr. Gilman said. In the study, the researchers determined the density of striatal dopaminergic terminals with [11C]dihydrotetrabenazine PET in six elderly subjects with chronic idiopathic REM sleep behavior disorder and 19 age-appropriate controls.

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Dr. Sid Gilman: “I dont think we can yet say everyone with REM sleep behavior disorder will develop Parkinson disease.”

“That gave us a little evidence that this is a structure important in the development of REM sleep behavior disorder and raises the possibility that these people will go on to develop Parkinson disease, multiple system atrophy (MSA), or dementia with Lewy body disease.”

Taking the research a step further, Dr. Gilman studied 13 patients with MSA and 27 healthy controls (Neurology 2003;61(1):29–34). Dr. Gilman said he chose patients with MSA because they also tend to have REM sleep behavior disorder and obstructive sleep apnea.

“Our findings were dramatic,” he said. There was no relationship of dopamine to obstructive sleep apnea but a strong relationship between dopamine and REM sleep behavior disorder.

“The worse the REM sleep behavior disorder, the lower the dopamine stores,” said Dr. Gilman.

Conversely, while the researchers found no relationship of acetylcholine levels in the thalamus to REM sleep behavior disorder, there was “a reasonable correlation to obstructive sleep apnea,” he said.

Parkinson disease, MSA, and dementia with Lewy bodies also show the same biochemical abnormality in alpha synuclein, he said. “I suspect that in some way, primarily through dopamine, these disorders include the same sleep problem.”

FUTURE RESEARCH

Assuming the results can be replicated, Dr. Gilman said he plans to evaluate the same biochemical abnormality in people with REM sleep behavior disorder who do not have an identifiable neurological problem. “A study has been initiated of healthy people, but we're still blinded to the results,” he said.

One puzzling issue, he said, is that drugs that raise dopamine levels help REM sleep behavior disorder some, but other drugs do it better. Why is that if dopamine is the key? “Only when we study large numbers of otherwise healthy people with REM sleep behavior disorder can we answer the question of whether REM sleep behavior disorder is always a harbinger of neurodegenerative disease,” he said.

Dr. Guilleminault agreed. “There are more and more suspicions that neurodegenerative disease may be evolving in people with REM sleep behavior disorder,” he said. “But there are still a lot of unanswered questions.”

ARTICLE IN BRIEF

✓ REM (rapid eye movement) sleep behavior disorder may be the first sign of Parkinson disease and related neurodegenerative diseases, sleep researchers say. But experts say more research is needed to identify just how many people with the sleep disorder develop neurodegenerative disease.

THE QUEST TO UNDERSTAND SLEEP BEHAVIOR DISORDERS

Knowledge of parasomnias has exploded in recent years, with new disorders recognized and known disorders reported to occur more frequently than previously thought, said Carlos H. Schenck, MD, Senior Staff Psychiatrist at the Minnesota Regional Sleep Disorders Center at Hennepin County Medical Center and Associate Professor of Psychiatry at the University of Minnesota in Minneapolis.

Left untreated, or misdiagnosed as psychiatric problems, parasomnias can have dire consequences: The sleepwalker may hurl himself out the window; the sexsomniac may actually rape his or her own spouse. The good news, the sleep specialists say, is that a better understanding of parasomnias' roots has led to new treatments – and in some cases, even cures.

For years, physicians had no idea what caused even the most common and well known of the parasomnias, sleepwalking and night terrors. But researchers at the Stanford University Sleep Disorders Clinic found that, at least in some children, sleep-disordered breathing is to blame.

Even more importantly, said Christian Guilleminault, MD, Professor of Sleep Medicine at Stanford University: “If you treat the breathing disorder” – with tonsillectomy, for example – “you can eliminate sleepwalking or sleep terrors. It's a cure.”

In the study, the researchers found that more than half of the 84 children with recurring sleepwalking or sleep terrors also suffered sleep-disordered breathing – habitual snoring, a history of upper respiratory infection, earaches, or mouth breathing. In contrast, virtually none of 36 children without sleep disturbances experienced sleep-related breathing problems (Pediatrics 2003;111:e17–e25).

Dr. Guilleminault said that all of the children with sleep-disordered breathing who underwent a tonsillectomy or adenoidectomy were cured of sleepwalking and night terrors. Meanwhile, the six children whose sleep-time breathing problems were left untreated continued to suffer from their parasomnias, he said.

Dr. Guilleminault isn't suggesting that surgery be done to prevent these sleep disturbances in all children. “Most children have an occasional sleepwalking episode or night terror,” he said. The children in the study represent a “very small group” that suffers persistent problems – once or several times a week, on a regular basis, he said.

While Dr. Guilleminault has completed a similar study in adults, he is reluctant to share the results, pending acceptance and publication in a scientific journal. But, he hinted, in the future, “we will be able to treat the underlying cause of sleepwalking.”

Dr. Mahowald agreed that physicians shouldn't worry if their pediatric patients occasionally sleepwalk or suffer night terrors. Even in adults, about 5 to 10 percent of whom sleepwalk and 1 percent of whom have sleep terrors, the condition is generally harmless, he said.

In contrast to REM sleep behavior disorder, sleepwalking and night terrors result from an abnormal and abrupt arousal out of slow wave sleep. The normal transition from deep sleep to a lighter sleep stage having been bypassed, “the brain is not fully conscious; it is almost as if it's half awake and half asleep,” he said. “You can perform a complex behavior such as driving a car, but you're not aware enough to know what you are doing.”

Sleep Sex, Sleep Eating

Less well known and more recently recognized than the other types of parasomnia are sleep sex and sleep eating disorder. “They have some characteristics of each of the other categories, but don't quite fit the mold,” Dr. Shapiro said.

Drs. Shapiro and Guilleminault have each published research describing 11 patients with symptoms of sexsomnia that ranged from loud, disruptive moaning to sexual assault. Regardless of how unusual or violent the behavior, Dr. Guilleminault says his patients had no memory of the events the next morning.

He noted that often, people who engage in atypical sexual behavior during sleep have a history of sleepwalking, REM behavior disorders, apnea, bed wetting, or other sleep-related problems, to name a few. Some even have seizure disorders.

“That's a big find,” Dr. Guilleminault said. “It suggests we can treat the seizures and eliminate the problem.”

Dr. Shapiro urges physicians to ask patients about any abnormal sexual behavior during sleep. “Just recognizing that sexsomnia is a sleep disorder is a step in the right direction,” he said. “Now that we know it is possible and doctors start to ask the right questions, we will start to learn more about it.”

The medical community has also been slow to recognize sleep eating as a medical condition, said Lea Montgomery, RN, MS, an instructor at Texas Christian University Harris School of Nursing in Fort Worth, who has written review articles on the disorder. “I had one woman frantic to get help; she had been sleep eating for 13 years. She tried to get help but wasn't taken seriously.”

Sleep eaters get up to eat as many as 12 times a night, Ms. Montgomery said. “It's messy primitive eating – butter right out of the butter dish, salt out of the saltshaker – not what they would normally eat during the day,” she said.

If symptoms of any parasomnia persist, physicians may want to seek a consultation at an accredited sleep center, the specialists say. The American Academy of Sleep Medicine (www.aasmnet.org/listing.asp) maintains a list of accredited sleep centers around the country.

REFERENCES

• Gilman S, Koeppe RA, Chervin RD, et.al. REM sleep behavior disorder is related to striatal monoaminergic deficit in MSA. Neurology 2003;61:29–34.
• Boeve BF, Silber MH, Parisi JE, et.al. Synucleinopathy pathology & REM sleep behavior disorder plus dementia on parkinsonism. Neurology 2003;61(1):40–45.
• Gagnon J, Bedard M, Petit D, et.al. REM sleep behavior disorder & REM sleep without atonia in Parkinson's disease. Neurology 2002;59:585–589.
• Schenck CH, Bundlie SR, Mahowald MW. Delayed emergence of a parkinsonian disorder in 38% of 29 older men initially diagnosed with idiopathic rapid eye movement sleep behavior disorder. Neurology 1996;46:388–393.
• Albin R, Koeppe R, Chervin R, et.al. Decreased striatal dopaminergic innervation in REM sleep behavior disorder. Neurology 2000;55:1410–1412.
• Schenck CH, Bundlie SR, Ettinger MG, Mahowald MW. Chronic behavior disorders of human REM sleep: a new category of parasomnia. Sleep 1986;9:293–308.