Behavioral Sleep Syndrome is one of the major predictors of Parkinson’s disease. Symptoms include vivid dreams, which are typically characterized by threatening sleep content and muscle activity. Characteristic of the syndrome is the preservation of muscle tension during REM sleep and sleep-related behaviors shown by video registration in sleep polysomnography. The risk of injury during seizures is increased. Melatonin or clonazepam can be used as treatment.
Definition of RBD (REM Behavior Disorder)?
In idiopathic RBD, movements are often violent. They involve sleep talking, laughing, screaming, singing, hitting or kicking. They are not unintentionally stereotyped, which distinguishes them from nocturnal epilepsy and periodic limb movements. Getting up, walking, and using objects on the bedside table are more indicative of sleepwalking, especially if the attack occurs within 1-3 hours after falling asleep. Patients describe themselves as defending themselves against external threats.
Patients are more likely to experience disturbances in attention and control than linguistic memory problems. In screening for mild memory impairment (MCI) in RBD patients, the Montreal Cognitive Assessment (MoCA) test showed memory loss in 50% of new RBD patients, compared with 8% in the control group. The abnormal score was considered to be 25/30 for MoCA.
Differential diagnostics should include obstructive sleep apnea, intermittent limb movement, sleepwalking, night terror, and nocturnal epilepsy. As a result, extensive criteria for EEG-sleep polysomnography and simultaneous video registration in a sleep laboratory are included in current criteria.
It is a sleep or movement disorder associated with REM sleep. Of the ICD-10 diagnosis numbers, G47.8 (Other sleep disorders, Periodic limb movement disorder) is best suited for RBD. Accurate diagnosis of RBD requires extensive sleep polysomnography and simultaneous video registration. Various questionnaires have been developed for RBD screening and preliminary diagnostics. Currently, there are mainly three different methods:
RBD screening questionnaire developed in Marburg, MSQ created at Mayo Clinic, and RBDQ-HK form in Hong Kong.
What are different forms of RBD?
Acute RBD can be caused by medication. A selective serotonin reuptake inhibitor, mirtazapine, tricyclic antidepressants, selective MAO-A inhibitors, and beta-blockers, bisoprolol and atenol, may cause symptoms. Symptoms may also be due to the sudden withdrawal of lamotrigine or alcohol.
Chronic RBD can be of primary idiopathic form or secondary. In narcolepsy and neurodegenerative synucleinopathies (such as Parkinson’s disease), RBD is common and in neurodegenerative tauopathies (Alzheimer’s disease, forehead lobe dementia, corticobasal degeneration and progressive supranuclear palsy) it is clearly less common. The presence of RBD in a dementia patient may thus be a differential diagnosis – if it is found out.
In progressive series, RBD can predict the development of Parkinson’s disease or dementia. The amount of tonic atony calculated from sleep polysomnography in the follow-up distinguished 50% of patients with these disease groups.
In retrospective sets of Parkinson’s patients, RBD precedes detection of Parkinson’s disease in 3 to 11 years in 27-50% of patients. In addition to RBD, visco-constructive difficulties, autonomic nervous system disorders, constipation, loss of sense of smell, or EEG retardation are precursor findings. It has been estimated that a 55-year-old RBD patient with additional findings would have a 70% risk of developing Parkinson’s disease or dementia within 5 to 10 years. The use of melatonin or modafinil has been suggested to prevent this development, but there is no clear evidence of the neuroprotective effect of these drugs.
The classic motoric symptoms of Parkinson’s disease appear when 60% of the black nucleus cells are destroyed by lewyn body accumulation (Grade 3 of Braak’s classification). Even before this, disease changes occur in the lower parts of the brainstem (stage 2), the olfactory bulb and the autonomic nervous system (stage 1). Therefore, Parkinson’s disease can be termed centrosympathomyenteric neuropathy. Based on the pathological synuclein accumulation, the clinical picture may be Parkinson’s disease, dementia or just autonomic degeneration. Also, 20 years of RBD may be the only manifestation of this accumulation of Lewy bodies.
RBD Patient Examples
A fifty-two year old man has been suffering from Restless Legs Syndrome and nocturnal periodic limb disorder for about three years. In addition, he has had depression. The medication has been ropinirole for restless legs and agomelatine for poor quality sleep and depression. Extensive sleep polysomnography done two years earlier showed restless sleep and suspicion of REM sleep without muscle atony. The result of the RBD screening survey was abnormal. Magnetic resonance imaging (MRI) of the brain and dopamine carrier protein imaging have been normal. The result of the quantitative odor threshold measurement was slightly different, which fits in with the microsm. The stomach is functioning normally. The patient is still at work and has no evidence of Parkinson’s disease (Hoehn-Yahr Grade 0). At this point, the finding refers to idiopathic RBD. Because agomelatine also acts as a melatonin agonist, no separate melatonin treatment has been initiated to date.
A 66-year-old healthy woman developed extrapyramidal symptoms about 10 years earlier. Decreased sense of smell began at age 54 and there has been a tendency for constipation for years. The diagnosis of Parkinson’s disease was made at age 59 on the basis of symptoms and a brain dopamine transporter protein profile. Magnetic resonance imaging (MRI) of the brain and neurophysiological examinations of the peripheral nervous system were normal. Hoehn-Yahr’s stage is still 2, meaning Parkinson’s disease is mild.
From the very beginning of the illness, limb pains and poor sleep have become a real problem. Due to moderate depression, the patient retired at the age of 60 two years after the diagnosis. Initially done polysomnography showed intermittent movement of the legs. At first there were difficulties in falling asleep, and then there was an abnormal waking up and staying awake for hours. The content of dreams has become very vivid. RBD symptoms and REM sleep without muscle atony were found four years ago at age 62 in extensive video sleep polysomnography. The woman was prescribed 2 mg of long-acting melatonin for the evening. With this medication her night’s sleep was restored. The situation is being monitored.
The 63-year-old retired woman’s sense of smell and Parkinson’s disorder began to develop before the age of 50. The diagnosis of Parkinson’s disease was made at the age of 50. Clear RBD symptoms began at age 56 and have been progressively worsening.
Two years after their onset, a brain pacemaker was installed in the basal ganglia of the brain. RBD symptoms have worsened over the last five years, and the woman has repeatedly beaten her husband while asleep. The diagnosis was confirmed by extensive sleep polysomnography. Long-term treatment with melatonin helped. Hoehn-Yahr’s stage is now 3, meaning Parkinson’s disease is moderate.
The physiological model of RBD birth can be summarized from animal models and human pathology. The generation of REM sleep (paradoxical sleep, PS) requires the interaction of both triggering (PS-on) and inhibitory (PS-off) neurons in the brainstem.
Figure 1. The paths that trigger and suppress paradoxical sleep. PS-on lanes are marked with a red solid line and PS-off lanes are marked with a green dashed line. NSC = nucleus subcaeruleus, LC = locus caeruleus, PAG = periacveductal gray matter, TMN = tuberomamillary nucleus, RMg = raphe magnus nucleus, PeF = perifornical nucleus, GiV = reticular gigantocellular nucleus.
In RBD formation, cell death occurs either in the NSC nucleus or at lower levels in the GiV and RMG nuclei. Lewy bodies accumulation occurs when the protein alpha-synuclein is folded incorrectly in protein synthesis. RBD patients are accumulating a wide variety of related conditions. Behavioral sleep syndrome and neurodegenerative disorders thus appear to have common birth mechanisms.
What is the treatment of RBD (REM Behavior Disorder)?
No high quality double-blind studies have been published for any of the drugs used to treat RBD. The publications concern individual cases or small patient records.
Clonazepam and melatonin are the most prominent drugs in the treatment of RBD. In the evening, melatonin seems to correct the missing atonia at night and clonazepam prevents excessive phase motor activity. A few studies have been published on the use of short-acting melatonin in the treatment of RBD. Doses have ranged from 3 to 12 mg. There are no publications on the use of long-acting melatonin, for example, at a dose of 2 mg. The disadvantages of clonazepam (0.25-2 mg) are its long half-life, sedation, risk of accidents in the elderly and the development of addiction.
Pramipexole may be helpful. One series of 11 patients has been published on Zopiclone; eight patients seemed to benefit from a 3.75-7.5 mg dose. The use of levodopa and cholinesterase inhibitors has not been studied. Because many antidepressants worsen the symptom, concomitant depression in RBD patients has been proposed to be treated with bupropion or agomelatine.