Review of REM Sleep: Part Two – Pathophysiology

by Amalia A. Geller, MD

Part two of this article will review the fascinating pathophysiology of REM Behavior Disorder (RBD) and provide an update on treatment and management of RBD.

Diagnosis of REM Behavior Disorder

As mentioned in part one of this article, brain activity accelerates during REM sleep showing markedly different types of brain waves. The EEG will return to a relatively low-voltage, mixed-frequency pattern. No sleep spindles, K-complexes, or NREM findings will be seen. The chin EMG will also fall to its lowest level. The classic finding will be seen on electrooculography (EOG) channels showing rapid eye movements. Other sleep architecture we see during REM sleep include Sawtooth EEG waves (7-8 Hz in the posterior dominant region) as well as basic muscle twitches.

RBD is listed as a parasomnia. The hallmark of RBD is vigorous motor activity during REM sleep in the total absence of muscle atonia. Another name for REM behavior disorder is REM sleep without atonia (RSWA), which is defined as increased tone during REM sleep using EMG of the chin and/or limb leads (either sustained increased chin EMG during sleep or increased chin or limb twitching).

Home sleep testing cannot be used to evaluate RBD. In cases when abnormal behavior does not occur during the sleep study, RSWA is required for the diagnosis.

The scoring of RSWA requires at least one of the following features developed by the American Academy of Sleep Medicine:

1. Sustained muscle activity in the chin EMG during REM sleep stage.
2. Excessive transit muscle activity in the chin or limb EMG during REM sleep.

The International Classification of Sleep Disorders, third edition, states the diagnostic criteria for RBD must include the following:

1. Repeated episodes of sleep-related behaviors, including vocalization and/or complex motor behaviors.
2. Documenting behaviors by PSG during REM sleep or based on clinical history.
3. Recordings of PSG that demonstrate REM sleep without atonia on submental or limb leads.
4. Behaviors are not better explained by another sleep disorder, mental disorder, medication, substance use, or epilepsy.

Questionnaires for Evaluating RBD

Validated questionnaires include:

1. Mayo Sleep Questionnaire – 98% sensitivity and 74% specificity.
2. REM Sleep Behavior Disorder Single- Question Screen (RBD1Q) – 98% sensitivity and 87% specificity.

Other useful questionnaires include:

1. REM Sleep Behavior Disorder – Hong Kong Questionnaire (RBDQ-HK) – 82% sensitivity and 87% specificity
2. REM Behavior Disorder Screening Questionnaire (RBDSQ) – 96% sensitivity and 56% specificity
3. Innsbruck REM Sleep Behavior Disorder Inventory – 91% sensitivity and 86% specificity

A critical finding we see during REM sleep that would indicate evidence of behavior disorder is an increase above normal of chin EMG, and clinically, when the patient completely acts out or moves and has dream enactment.

Four Categories of RBD

1. Idiopathic RBD: RBD without an identifiable underlying cause; this form is uncommon.
2. Drug-induced RBD: Mainly caused by MAO-inhibitors, tri-cyclic anti-depressants, and serotonin reuptake inhibitors. Serotonergic RBD can also be present in those with alpha-nuclear neuro degeneration. This would involve abnormalities like color vision, anomia, constipation, and motor impairments. It is thought that the serotonergic in a depressant may unmask RBD in individuals who are at increased risk for underlying Neuro degeneration.
3. Secondary RBD due to medical condition: Neurodegenerative synucleinopathies (dementia with Lewy bodies, Parkinson disease, olivopontocerebellar degeneration, multiple system atrophy, and Shy-Drager Syndrome), Traumatic Brain Injury (TBI), PTSD, Narcolepsy Type 1, and congenital and neurodevelopmental disorders are the main causes of this form of RBD. Less common causes include non-synucleinopathies: Progressive supranuclear palsy (PSP), familial amyotrophic lateral sclerosis (ALS), frontotemporal dementia, and myotonic dystrophy. Secondary RBD has also been seen with Wilson’s disease, cerebral degeneration, and autoimmune encephalitis. These are usually due to paraneoplastic cerebellar degeneration that is immune mediated; often, these conditions can improve after immunotherapy.
4. Autoimmune RBD: The autoimmune disorder known as anti-IgL0N5 disease is a rare neurodegenerative encephalitis involving bulbar symptoms, gait abnormalities, and cognitive dysfunction. In addition to sleep manifestations such as sleep apnea, non-rapid movement sleep parasomnia, and RBD, serotonergic agents can lead to dream enactment. Histopathology studies in these forms of autoimmune-mediated RBD show neuron loss and extensive deposits of tau in the tegmentum of the brainstem and hypothalamus.

Other classifications of behavior disorder include:

• Subclinical REM sleep behavior disorder.
• Clinically probable REM behavior disorder.
• Idiopathic, cryptogenic REM sleep behavior disorder.
• Secondary or symptomatic REM sleep behavior disorder.

The prevalence of REM behavior disorder in the general population overall is unknown, but it is estimated to be about 0.5%. RBD can occur in either gender or age group even during childhood or adolescence. Most often, we find it occurring in middle-aged or older adult men.

Acute RBD can be related to medication side effects as listed above or underlying toxic-metabolic derangement. Also, benzodiazepine withdrawal and alcohol withdrawal can increase the risk for RBD.

RBD is thought to be a prodrome for degenerative diseases, in particular, diffuse Lewy body dementia, Parkinson disease, as well as multiple system atrophy. These are all listed as alpha-synuclein degeneration regulating nuclei in the brain – specifically in the pontine tegmentum area.

Studies have shown that up to 81% of men with RBD over the age of 50 had delayed emergence of Parkinson disease dementia over a decade after the initial REM behavior diagnosis. Other conditions that overlap with RBD are the disorder of arousal, rhythmic movement disorder, insomnia, or sleep-related eating disorders.

RBD can also occur with narcolepsy (30% of young individuals with narcolepsy type 1), brain tumors, brain trauma, psychiatric disorders, substance abuse, and muscular sclerosis.

During dream acting, patients are acting out their dreams and have increased risk for injury to themselves and others. The dreams are usually associated with being chased or attacking themes, but they are not specific for behavior disorder.

Nightmares are frightening dreams that wake us up from REM sleep. In RBD, the patients are acting out the dreams and usually do not awaken themselves out of sleep. If they do awaken, it is because they have harmed themselves such as falling out of the bed. In general, the patient will have a memory of nightmares; they are very detailed and vivid, and they occur with emotions of fear. This is usually not as strong in patients experiencing RBD.

Differential Diagnosis

• Substance abuse/withdrawal
• Benign childhood epilepsy
• Complex partial seizures
• Confusional arousals
• Delirium
• Epilepsia partialis continua
• Epileptic encephalopathy
• Juvenile myoclonic epilepsy
• Malingering
• Sleep apnea
• Parasomnia overlap syndrome
• Periodic limb Movement disorder
• PTSD
• Psychogenic non-epileptic seizure
• Sleep terror
• Sleep walking/Trauma-associated sleep disorder

Clinical Management and Treatment of RBD

Management of RBD should focus on injury prevention and treating the underlying disorder in addition to psychological treatment for severe cases. Recommended actions:

• To prevent fall risk, lower bed closer to the floor
• Safeguard firearms, knives, and other weapons
• Sleep in sleeping bag/restraining clothes
• Separate the partner from the patient to decrease risk of injury.

Medical Treatment of Idiopathic/Isolated RBD

RAMELTEON (melatonin M1/M2 receptor agonist) dose 8mg at bedtime. A study on idiopathic RBD at this dose showed no impact on the RBD or RSWA, but subjective improvement was reported.

MELATONIN typical dosing is 5-15mg. Sustained release preferred over immediate release since REM sleep events cluster at greater frequency in the second half of the sleep cycle.

CLONAZEPAM (long-acting with half-life of 30-40 hours) dose 0.25mg 30 minutes prior to bedtime. Dose can be increased to maximum 4mg. Side effects include: residual AM sleepiness, increased fall risk, memory dysfunction, impotence, and unstable gait. There can be an initial period of suppression in the RBD followed by re-emergence of more complex behavior.

Other agents: dopaminergic agents, paroxetine, acetylcholinesterase inhibitors and anti-convulsants: carbamazepine and levetiracetam, anti-HTN medications (prazosin AND clonidine).

Management of Drug-induced RBD

Treatment for drug-induced RBD may require discontinuation, dose reduction, or earlier medication intake.

Pharmacological Treatment of Secondary RBD

Treatment medications could include slow-release melatonin, clonazepam, or transdermal rivastigmine. Treating co-morbid OSA with CPAP can help reduce RBD. When RBD is due to Parkinson disease, managing the PD with dopaminergic agents, PPE, and deep brain stimulation are investigational.

New Updates on RBD

Mount Sinai Medical Center has developed a model showing there is a neurodegenerative link with Tau protein and that the dual orexin receptor antagonist drugs that are used for insomnia can decrease REM behavior disorder. This was published in The Journal of Neuroscience. Their model shows an early biomarker which could guide prevention and treatment. The dual orexin receptor antagonist when given twice a day within a 24-hour period, decreased sleep latency, increased the quality and duration of sleep, and decreased REM behavior disorder.

 

Videos Showing RBD

https://bit.ly/4hPcFRl
https://bit.ly/4iEDCIt
https://bit.ly/4iEHo4H