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Neurology Today:
doi: 10.1097/01.NT.0000350666.41650.05
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REM Sleep Behavior Disorder Associated with Progressive Neurological Disorders: Largest Longitudinal Study to Date

TALAN, JAMIE

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ARTICLE IN BRIEF

Canadian investigators reported that at five years 20 percent of patients with a REM sleep behavior disorder developed signs of a neurodegenerative condition.

During REM sleep, during which memories are consolidated, dreamers are paralyzed and their limbs cannot act out their imaginary mental states. But some people have a condition called REM sleep behavior disorder, which is marked by thrashing, kicking, and punching during threatening moments in dream life. It turns out that there is something wrong with the body's natural defense to shut down the limbs so people don't act out on their dreams.

Now, a team of Canadian scientists report from the largest and longest follow-up study of people with the sleep disorder who are at high risk of developing a progressive neurological disorder. At present, no one knows why. The findings were reported online Jan. 7 in advance of the April 21 print edition of Neurology.

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STUDY PROTOCOLS

Ronald B. Postuma, MD, assistant professor of neurology at McGill University, and colleagues at the Hopital du Sacre-Coeur in Montreal followed 93 patients with REM-sleep behavior disorder annually since 1999 to determine their risk for neurodegenerative diseases. Other centers, including sleep teams at the University of Minnesota and the Mayo Clinic in Rochester, MN, have also linked the condition to an increased risk for Parkinson disease (PD) and Lewy Body dementia (LBD) — both of which involve the neuronal deposition of alpha-synuclein.

The Canadian investigators reported that at five years, 26 patients, or 20 percent, had signs of a neurodegenerative condition: 14 had PD; seven, LBD; four, Alzheimer disease, and one, multiple system atrophy. Computer modeling showed that the risk at ten years was 40 percent; and by 12 years, about half of the patients with complaints of bizarre sleep-time behavior were now grappling with a serious brain disease.

Work done at the Sacre-Coeur hospital almost a decade ago found that 38 percent of PD patients have REM sleep behavior disorder, and another 20 percent have other signs of REM sleep disturbance.“We are now examining our patients carefully to look at markers that can predict neurodegenerative disease,” said Dr. Postuma.

Figure. DR. RONALD B...
Figure. DR. RONALD B...
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CONNECTION TO PD PATHOLOGY

The findings dovetail with work by the German anatomist Heiko Braak, MD, who suggested in 2003 in the Neurobiology of Aging that PD does not begin in the motor system — and that strong evidence suggests the disease begins in the olfactory tract and spreads up to the pontine nuclei, which are known to regulate sleep and mood. Some studies have shown that lesions to the pons result in decreased REM sleep. Over time, PD pathology appears in the substantia nigra, where it has been linked to the classic symptoms of tremor, rigidity, and bradykinesia.

“We are interested in finding out more about these pre-clinical stages,” said Dr. Postuma. “We recognize that we can pick up neurological diseases before their full blown clinical manifestations. This is a potential opportunity to intervene early in a neurodegenerative process.”

Dr. Postuma wants his colleagues to be aware of the association and asks patients to come in annually for a check-up — with this caveat: “On one hand you do not want to alarm patients who may remain normal, but on the other hand, it is important to have patients followed to detect and treat disease manifestations promptly,” he said. “I usually begin by telling patients only that there is evidence for a link between sleep and movement disorders, and so they should be followed to make sure everything is ok.”

Clearly, more work needs to be done. Only a few studies have linked the REM sleep behavior disorder to neurodegenerative diseases. The first report — in 1996 in Neurology — by a group led by Carlos Schenk, MD, of the University of Minnesota found 38 percent of their REM sleep behavior disorder patients — 29 patients followed for five years — developed PD; at ten years, 65 percent of them had neurological symptoms. In 2006, Spanish neurologist Alex Iranzo, MD, and his colleagues reported in the Lancet Neurology that 45 percent of 44 patients developed a neurodegenerative condition. And Mayo Clinic investigators reported in a 2006 edition of Sleep that 65 percent of patients with REM sleep behavior disorder developed some neurodegenerative condition over an 11-year study period.

But Maja Tippmann-Peikert, MD, an assistant professor of neurology at the Mayo Clinic Center for Sleep Medicine, said that this latest Canadian study had gone the extra mile “in an exceptionally well designed study …They wanted to account for any possible artifacts that could occur.”

She said that the implications are critical. “Patients have to be aware that there could be a problem down the road,” she said. She performs a neurological exam every year and cautions her patients to get in touch if tremors or other neurological symptoms develop. At the same time, she agrees with Dr. Postuma that she does not want to scare patients.

“Not everyone will get neurological complications. There have been two REM sleep behavior disorder patients whose brains were autopsied and while they had lived their lives out with no neurological deficits the classic pathological signs of deterioration were there. There was obvious and extensive Lewy-body damage in the brain stem.

The hope is that future neuroprotective agents may ultimately be used to prevent these neurodegenerative problems in patients with REM sleep behavior disorder.

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REFERENCES

Postuma RB, Gagnon JF, Monplaisir J, et al. Quantifying the risk of neurodegenerative disease in idiopathic REM sleep behavior disorder. Neurology 2009; E-pub 2009 Jan.7.

Braak H, Del Tredici K, Rub U, de Vos RA, Jansen Steur EN, Braak E. Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol Aging 2003;24(2):197–211.

Schenck CH, Bundlie SR, Mahowald MW, et al. 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.

Iranzo A, Molinuevo JL, Tolosa E, et al. Rapid-eye-movement sleep behaviour disorder as an early marker for a neurodegenerative disorder: A descriptive study. Lancet Neurol 2006;5(7):572–577.

Tippmann-Peikert M, Olson EJ, Silber MH, et al. Idiopathic REM sleep behavior disorder: A follow-up of 39 patients. Sleep 2006;29:A272Abs.

©2009 American Academy of Neurology

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