REM sleep behavior disorder, autonomic dysfunction and synuclein-related neurodegeneration: where do we stand?

Rapid eye movement (REM) sleep consists of a dreaming state in which there is activation of the cortical and hippocampal electroencephalogram (EEG), rapid eye movements, and loss of muscle tone. Although REM sleep was discovered more than 50 years ago, the neuronal circuits responsible for switching between REM and non-REM (NREM) sleep remain poorly understood. Here we propose a brainstem flip-flop switch, consisting of mutually inhibitory REM-off and REM-on areas in the mesopontine tegmentum. Each side contains GABA (gamma-aminobutyric acid)-ergic neurons that heavily innervate the other. The REM-on area also contains two populations of glutamatergic neurons. One set projects to the basal forebrain and regulates EEG components of REM sleep, whereas the other projects to the medulla and spinal cord and regulates atonia during REM sleep. The mutually inhibitory interactions of the REM-on and REM-off areas may form a flip-flop switch that sharpens state transitions and makes them vulnerable to sudden, unwanted transitions-for example, in narcolepsy.

Rapid-eye-movement (REM) sleep behaviour disorder (RBD) is a parasomnia characterised by dream-enacting behaviours related to unpleasant dreams and loss of muscle atonia during REM sleep. RBD may be idiopathic or associated with neurological disease. Available data suggest that in some cases RBD might be the initial manifestation of a neurodegenerative disease. We sought to determine the frequency and nature of neurological disorders developing in patients diagnosed with idiopathic RBD at our sleep centre. We retrospectively assessed 44 consecutive patients (39 men and five women with a mean age of 74 years), with at least 2 years of clinical follow-up after a diagnosis of idiopathic RBD, through a detailed clinical history, complete neurological examination, rating scales of parkinsonism, and neuropsychological tests. 20 (45%) patients developed a neurological disorder after a mean of 11.5 years from the reported onset of RBD and a mean follow-up of 5.1 years from the diagnosis of idiopathic RBD at our sleep centre. Emerging disorders were Parkinson's disease in nine patients, dementia with Lewy bodies in six, multiple system atrophy with predominant cerebellar syndrome in one, and mild cognitive impairment in four in whom visuospatial dysfunction was prominent. Patients with longer clinical follow-up developed a neurological disease (OR 1.512, 95% CI 1.105-2.069; p=0.010). Our study indicates that in people presenting to sleep centres, RBD often antedates the development of a neurodegenerative disorder. Close follow-up of patients with idiopathic RBD could enable early detection of neurodegenerative disease. This finding may be of great interest when early effective treatment strategies and neuroprotective drugs become available.

Four men, aged 67-72 years, had 4-month to 6-year histories of injuring themselves or their spouses with aggressive behaviors during sleep, often during attempted dream enactment. A 60-year-old woman had disruptive though nonviolent sleep and dream behaviors. Polysomnography did not detect seizures but did document REM sleep pathology with variable loss of chin atonia, extraordinarily increased limb-twitch activity, and increased REM ocular activity and density. A broad range of REM sleep behaviors was recorded on videotape, including stereotypical hand motions, reaching and searching gestures, punches, kicks, and verified dream movements. Stage 3-4 slow wave sleep was elevated for age in all patients. NREM sleep was devoid of harmful behaviors, although three men had periodic myoclonus. There was no associated psychiatric disorder, whereas serious neurologic disorder was closely associated in four cases: olivo-ponto-cerebellar degeneration, Guillain-Barré syndrome, subarachnoid hemorrhage, and an atypical dementia. Two patients had immediate and lasting sleep behavioral suppression induced by clonazepam, and another patient had the same response with desipramine. All instances of drug discontinuation prompted immediate relapse. In four cases there was associated dream hyperactivity, which resolved with behavioral control. These REM sleep neurobehavioral disorders constitute another category of parasomnia, replicate findings from 21 years ago in cats receiving pontine tegmental lesions, and offer additional perspectives on human behavior, neurophysiology, pharmacology, and dream phenomenology.