Picture Becomes Clearer on Etiology of Rapid Eye Movement Behavior Disorder, Saper Says

BY JOHN R. BELL
Elsevier Global Medical News

BOSTON (EGMN) - Neurologists are making great strides in describing the mechanisms by which movement disorders, such as rapid eye movement behavior disorder, occur, Dr. Clifford Saper, chairman of the department of neurology at Beth Israel Deaconess Medical Center, Boston, said in a plenary presentation at the annual meeting of the American Academy of Neurology.

Patients with rapid eye movement behavior disorder (RBD) can injure themselves or their bed partners with their involuntary movements made during sleep in correlation with dreamed events, he noted. But the physiologic basis for their disorder is similar to that underlying narcolepsy with cataplexy.

In RBD, the cholinergic system fires back up to a nearly waking level, but the activity of the monoamine system goes to zero. "In the absence of preparedness of the cortical neurons to receive this flood of sensory information, the information that is received is interpreted as a dreaming state," Dr. Saper explained.

A switching mechanism allows the brain to transition between wakefulness and sleep; changes to the anatomical underpinnings of this mechanism have been identified as being associated with not only parkinsonism but also RBD and narcolepsy.

Dr. Saper described recent discoveries from his lab and others in the last decade.

The interaction between arousal-inhibiting neurons in the ventrolateral preoptic nucleus (VLPO) and the arousal systems constitutes a "flip-flop switch," a term borrowed from electrical engineering, Dr. Saper said.

Degeneration of VLPO neurons over a lifetime can be significant. Starting with roughly 30,000 cells in this group, the number often dwindles to half that by age 65 years (J. Anat. 1989;164:55-72). "This is very important, because with the loss of neurons in this population, predictable effects on the flip-flop switch will be seen," Dr. Saper said.

In animal models, the effect of this has been observed via a decline in delta power (slow waves) on EEG (J. Neurosci. 2000;20:3830-42). But with three-fourths of the VLPO neurons intentionally removed, the rats' sleep decreased, and much less time was spent in deep slow-wave sleep, with more awakenings and longer times to falling asleep. The effect was similar to that seen in aging in humans, who over the course of a lifetime lose an hour of total sleep time per night, Dr. Saper said.

Loss of VLPO neurons also leads to an increasing tendency to fall asleep more often during the day, with more transitions from wakefulness to sleep and from sleep to wakefulness, because the brain is more often near the flip flop switch's transition point.

To prevent this, more neurons are needed to reinforce the waking state. The neurons that fill this role are the orexin neurons in the lateral hypothalamus. "The VLPO [area] is kind of like an off switch for the brain, and the orexin neurons more like an on switch for the arousal systems in the brain," Dr. Saper explained. Moreover, the orexin neurons send signals to the entire cerebral cortex, preparing it to receive information. "The result is that the orexin neurons add weight to the 'on' side of the flip-flop switch and give it stability. And that stability allows you to maintain a waking state for an entire 16-hour day."

Removal of the orexin neurons in animal models has induced sleep instability in which REM-like atonia suddenly intrudes upon wakefulness. Again, studies have shown that humans lose orexin cells with age (Neuron 2000;27:468-74).

Given the delicate balance between VLPO neurons and orexin neurons, "one could predict that their outputs should intersect at a part of brain that should inhibit REM sleep." Dr. Saper's lab has looked for this area in animals and found it in the pons at the level of the dorsal raf A nucleus.

"So what we found in the brain stem is essentially a GABAergic, double-inhibitory switch again, where the REM-on neurons inhibit the REM-off [neurons] and vice versa." Lesions on either side of the switch result in disinhibition of the switch, so that it spends more time in the opposite state but also reverses unpredictably.

"It turns out that if you look at [RBD] patients, over a period of 5 years or so, about half of them develop parkinsonism. In fact, [RBD] is now considered to be one of the earliest signs of developing parkinsonism, long before the movement disorder occurs," Dr. Saper said in an interview.

Despite the growing body of evidence establishing a link between neuronal loss and the development of sleep disorders, several more common disorders - particularly those occurring in childhood - have other etiologies.

"Sleepwalking, which is most common in young people, is not the same as RBD," Dr. Saper noted in an interview. "Sleepwalking occurs during non-REM sleep, when the body ordinarily is not paralyzed. You can show the difference by recording the EEG and EMG during sleepwalking, vs. RBD, and also because they occur at very different parts of life. RBD behavior is typically struggling or fighting, and the associated dreams tend to be unpleasant social interactions of that sort," said Dr. Saper, who is also professor of neurology and neuroscience at Harvard University, Boston.

Patients with RBD "describe the dreams as especially vivid," he added. "Sleepwalkers typically have a much less active dream, in which they are not struggling - although some children get night terrors, in which the dream does frighten them, and they call out in their sleep, but they are not actively struggling or fighting."

Possibly delaying diagnosis and treatment is the fact that patients with RBD usually are not noticed until they are fairly disruptive. "It may start with only a few smaller movements during REM sleep - when you record the patient in the sleep lab, that is often all you see - but would generally not be reported until it got much worse."

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