REM sleep behavior disorder (RBD) is common among veterans with PTSD

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Military veterans with post-traumatic stress disorder or concussion suffer from a thrashing form of sleep behavior at a rate that is far higher than the general population, according to a new study by researchers at the VA Portland Health Care System and Oregon Health & Science University. The finding was published online this week in the journal SLEEP.

Researchers next want to probe whether the disorder, known as REM sleep behavior disorder or RBD, might provide an early signal of the development of neurodegenerative conditions such as Parkinson’s disease.

Normally during sleep that coincides with rapid eye movement, or REM sleep, muscles are effectively paralyzed.

In cases of RBD, brain control of muscle paralysis is impaired, resulting in people acting out dreams during REM sleep, sometimes causing injuries to themselves or their partners. It is estimated to affect less than 1% of the general population.

That proportion rose to 9% of the 394 veterans in this study and further swelled to 21% among those with PTSD.

“This is important because, in the general population, RBD has been linked to Parkinson’s disease, and RBD often precedes classic symptoms of Parkinson’s by years,” said senior author Miranda Lim, M.D., Ph.D., a staff physician at the VA and assistant professor of neurology, medicine and behavioral neuroscience in the OHSU School of Medicine. “We don’t know whether veterans who have PTSD and higher rates of RBD will go on to develop Parkinson’s, but it is an important question we need to answer.”

Researchers suspect chronic stress on the brain may play a role in causing the sleep disorder in veterans with PTSD, as many veterans have been exposed to concussion which potentially accelerates neurodegenerative processes.

Each study participant underwent an overnight sleep study at the VA Portland Health Care System between 2015 and 2017 to determine the presence of dream enactment during episodes of REM sleep.

Muscle activity was monitored continuously during the 8 hours of the study in order to diagnose RBD.

The study found that those with PTSD had over 2-fold increased odds of RBD compared to veterans without PTSD.

“RBD seems to be highly prevalent in veterans with a history of trauma,” said lead author Jonathan Elliott, Ph.D., a research physiologist at the Portland VA and assistant professor of neurology in the OHSU School of Medicine.

Doctors involved in the study, including co-authors Kristianna Weymann, Ph.D., R.N., a clinical assistant professor in OHSU School of Nursing, and Dennis Pleshakov, a student at the OHSU School of Medicine, will continue to track research participants with RBD, looking for early signs of Parkinson’s or other neurodegenerative conditions.

Although there are several therapies to ease some of the symptoms of Parkinson’s, including tremor and fatigue, so far there has been no definitive therapy to prevent it.

Researchers suspect chronic stress on the brain may play a role in causing the sleep disorder in veterans with PTSD, as many veterans have been exposed to concussion which potentially accelerates neurodegenerative processes.

Clinical trials for promising therapies are usually conducted well after patients have been diagnosed with Parkinson’s, at a stage which may be too late to reverse the symptoms. Lim said that identifying patients with RBD presents an opportunity to identify people earlier in the disease course, and potentially provides a more viable window to test promising interventions.

“By the time a patient shows classic symptoms of Parkinson’s, it may be too late,” Lim said. “If you could intervene when people first start to show RBD, maybe you could prevent later symptoms of Parkinson’s.”

Funding: The study was supported with resources and the use of facilities at the VA Portland Health Care System, VA Career Development Award No. 1K2 BX002712; National Institutes of Health EXITO institutional core grant No. UL1GM118964; Portland VA Research Foundation; NIH grant No. T32 AT002688; VA Career Development award No. 1K2 RX002947; OHSU Medical Research Foundation; and VA OAA Post-doctoral Nursing Research Fellowship.

Interpretations and conclusions are those of the authors and do not represent the views of the U.S. Department of Veterans Affairs or the U.S. government.


Trauma survivors with and without posttraumatic stress disorder (PTSD) frequently report a variety of sleep disturbances, consisting of trauma-related nightmares, autonomic hyperarousal, and excessive movements.1 

Sleep disturbances following a traumatic experience are predictors for physical and psychiatric symptoms, and there appear to be bidirectional relationships between sleep, mood, anxiety, and PTSD.24 Trauma-associated sleep disorder (TASD) is a proposed parasomnia distinct from nightmare disorder (NMD), non-rapid eye movement (NREM) sleep disorders of arousal, and rapid eye movement (REM) sleep behavior disorder (RBD), although TASD has some overlapping clinical features with each of these entities.1,5,6 

The most notable distinction between patients with NMD and TASD is the occurrence of dream enactment behavior (DEB) with excessive movements and complex vocal and motor behaviors during sleep, similar to those seen in RBD.6 

Patients with TASD have been described to have variable features of excessive muscle activity in both NREM and REM sleep.

Loss or dysregulation of normal REM sleep atonia in TASD appears similar to that seen in RBD. In TASD, however, a distinctive patient history of an acute onset of DEB and nightmares occurs in close temporal proximity to trauma and other features that are unusual or inconsistent with RBD, such as a nightmare theme that is specifically linked to the personally-experienced traumatic event or exposure that is similar to the “flashbacks” seen in PTSD, and TASD often presents at a considerably younger age than is typical for RBD.6 

We present a case of probable TASD, describe other detailed neurological and polysomnography (PSG) features, and discuss implications for the understanding of TASD and further steps needed to delineate its standing as a possible unique parasomnia distinct from RBD and NMD, and discuss considerations about whether TASD may be a separable entity from PTSD.

The proposed diagnostic criteria for trauma-associated sleep disorder include:1,6

  1. Inciting traumatic experience.
  2. A history of altered dream mentation that is related to prior traumatic experience.
  3. Self or witnessed reports of DEB including abnormal vocalizations or abnormal motor behaviors in sleep.
  4. Symptoms of autonomic hyperarousal or monitoring that demonstrate tachycardia, tachypnea, or diaphoresis not due to sleep-disordered breathing.
  5. A PSG demonstrating RSWA or DEB in REM sleep.
  6. Absence of electroencephalographic epileptiform activity on PSG.

Our patient fulfilled most of the proposed diagnostic criteria for TASD, lacking only clear signs of autonomic hyperarousal. Following the inciting traumatic military experience, DEB was observed by his wife and reportedly involved nightmares that directly paralleled his traumatic military experience, and he had features of RSWA, albeit in a somewhat atypical distribution from “traditional” idiopathic/isolated or symptomatic RBD, which is usually presumed to be caused by synucleinopathy. In this case, the strong temporal relationship between a history of directly preceding inciting traumatic experience in the military prior to onset of DEB, the specificity of traumatic dream content and themes linked to the patient’s own individual traumatic military exposures, and DEB-mirroring dream content of a traumatic nature all support the diagnosis of the proposed parasomnia TASD. Some might argue that the case is simply a PTSD case, and indeed, our case had been previously diagnosed with PTSD by a psychiatrist. The diagnosis of PTSD by DSM-5 criteria requires the following elements: direct exposure to a significantly traumatic event involving actual or threatened death or injury; persistent re-experiencing of the event including nightmares and/or flashbacks; avoidance of trauma-related stimuli; negative thoughts or feelings beginning or worsening after the traumatic exposure; trauma-related arousal and reactivity including irritability, aggression, hypervigilance, and difficulty with concentration and/or sleeping; symptoms causing significant distress or impairment; and a duration of at least one month.19 However, our case had significantly greater complex dream enacting motor behaviors that are atypical for a PTSD diagnosis alone. Other features that argue for the coexistence of a parasomnia disorder include the complex motor and vocal dream-enactment behaviors accompanying his dreams, the prominence of the REM sleep atonia loss (RSWA) which excludes “pseudo-RBD” (ie, complex motor behaviors associated with sleep apnea arousal that mimic RBD),20 and the absence of features of hypervigilance or re-experiencing of the event (“flashbacks”) in the daytime. Additionally, to further differentiate this patient from “pseudo-RBD,” abnormal sleep behaviors occurred spontaneously, not during apnea-induced arousals, and did not improve during administration of continuous positive airway pressure therapy.20 However, the alternative diagnosis of idiopathic/isolated RBD could also be very reasonably applied to this patient and is, in fact, the correct diagnosis according to current ICSD-3 criteria and nomenclature.

A potential common pathophysiology linking PTSD with RBD has been suggested by overlap of clinical phenomena and by evidence from neurophysiologic, neuroimaging, and neuropathological studies.21,22 Sleep disturbance is common among patients with PTSD. One study found decreased slow-wave sleep in patients with PTSD.23 Additionally, discrepancies between self-reported and objectively-measured sleep parameters have also been associated with trauma exposure or PTSD, challenging prior assertions that individuals with PTSD over-report their sleep disturbances.24 One study found Vietnam combat veterans with PTSD had a higher percentage of REM-sleep epochs with at least one prolonged twitch burst, although RSWA was not formally analyzed.25 Severe anxiety disorders such as PTSD have shown altered cortical thickness and regional brain volumes and post-mortem neuronal counts of structures involved in or closely related to REM sleep control and dreaming.2631 Alterations in amygdala and hippocampal volumes have been found in PTSD, with consistent findings of smaller hippocampi and either increased or decreased amygdalar volumes compared with controls.27,30,31 In particular, right amygdala volume loss has been associated with anxious arousal symptomatology in PTSD.32 Several human and animal studies have suggested altered noradrenergic functioning in the locus ceruleus (LC) in patients with PTSD, with evidence pointing to stress-induced LC neuronal loss and altered compensatory function in the LC region causing behavioral symptoms of anxious arousal and hypervigilance.3234 One theory of the bidirectional relationship between sleep and PTSD holds that patients with PTSD have enhanced REM-on and wake-promoting amygdala and medial prefrontal cortex network activity, with corresponding decreased REM-off and anterior hypothalamic sleep-facilitating network activity.35

Patients with PTSD have decreased neuronal counts in the LC and peri-locus ceruleus nuclei located in the dorsal pontine tegmentum, corresponding closely to a directly neighboring region where the REM-onset neurons of the subceruleus/sub-lateral dorsal nucleus are located, which also regulates REM sleep atonia.21,22,36 Decreased LC regional neurons could result in decreased neuronal output of the LC and neighboring structures to other REM sleep-modulating nuclei such as the pedunculopontine and magnocellularis nuclei, subsequently altering the output of these structures,22 similar to the pathophysiologic process underlying RBD and accounting for both loss of normal REM sleep atonia regulation and increased motor activity during REM sleep as seen in RBD.37

Further research will be necessary to determine if TASD is a distinct disorder that evolves from PTSD or if it is, instead, a special interaction between PTSD and RBD, possibly caused by an interaction between PTSD symptoms in an individual harboring covert preexisting synuclein pathology in the dorsal pons that would otherwise be asymptomatic. In the latter possibility of interaction between PTSD and RBD, pathophysiology of PTSD in the dorsal pons and traumatic nightmares could facilitate expression of enactment of PTSD dreams. This is a similar scenario to theories in which antidepressant medications are associated with RBD. The development of antidepressant-associated RBD has been proposed as an early signal of an underlying covert neurodegenerative disease, since patients who are either receiving or not receiving antidepressants show a similar frequency of neurodegenerative biomarkers. However, patients receiving antidepressants phenoconverted to overt neurodegenerative disorders at a lower frequency than those who did not receive antidepressants.38 This study suggested that antidepressant medications act to promote and unveil RBD symptoms at an earlier timeframe and, through lead-time bias, lead to earlier detection of RBD in the setting of antidepressant use, in comparison to patients with RBD who do not receive antidepressant medications.38 Others have interpreted these data differently, pointing out that a neuroprotective effect of the antidepressants might delay the progression of underlying neurodegenerative disease.39 Alternatively, antidepressants may have a more directly causal role in RBD, possibly producing a functional, reversible disturbance of REM sleep atonia regulation.40

A proposed treatment for TASD is prazosin, a centrally active alpha-1-adrenergic receptor antagonist, which is also a standard treatment for PTSD-associated trauma nightmares.41 Several clinical trials, including a meta-analysis of placebo-controlled studies on PTSD sleep disturbances, found prazosin significantly improves nightmare frequency, PTSD severity, and sleep quality. These findings support the efficacy of this medication for the treatment of combat veterans and trauma survivors.4244 Due to improvement in symptoms following treatment with prazosin, TASD could be driven by hyperadrenergic function, which may aid diagnostic distinction from RBD, since prazosin would not be expected to be effective in RBD (although systematic treatment trials are currently lacking in either TASD or RBD). On the other hand, a recent large multi-center trial of prazosin for alleviating distressing dreams or improving sleep quality of military veterans with chronic PTSD showed no beneficial outcomes for prazosin.45 In our case, prazosin 4 mg prior to bedtime was similarly not beneficial in reducing DEB frequency or severity, although it remains unclear if our case was an unusual variant of PTSD, or more likely was the distinctive parasomnia TASD for which prazosin is as yet unproven. It has been suggested that prazosin may not be effective in patients with chronic PTSD with obstructive sleep apnea due to interference of the drug’s mechanism or masking of its beneficial effects.45 In our patient, melatonin was also ineffective, at least when dosed to the average effective dose of 6 mg nightly.46 Further controlled studies of prazosin and other treatments typically effective for RBD (melatonin, clonazepam) will need to be done to clarify which treatment strategies are safe and effective for the management of TASD.

The fundamental mechanisms of TASD and its overlapping symptoms with other parasomnias and PTSD are complex and poorly understood. TASD may be part of the spectrum of idiopathic RBD that onsets before age 60, in relationship to mood, anxiety, or PTSD, with or without antidepressant treatment. Such cases might be considered distinct from “traditional” idiopathic/isolated RBD in older adults, when RBD is presumably associated with underlying synucleinopathy in most cases. Such younger age-onset RBD cases associated with antidepressants have been described as “psychiatric RBD,” an interesting, possibly distinct subset of patients who develop RBD symptoms at a younger age and who may have a different ultimate prognosis (or at least, a considerably longer time course) for the risk of developing overt neurodegenerative disease. Further prospective and longitudinal follow-up of this and other cases will be necessary to determine whether TASD is a distinct parasomnia or simply a variant “mash-up” of PTSD and RBD and to determine phenoconversion risk in this interesting subset of patients presenting with dream enactment.


Source:
Duke Universtiy
Media Contacts:
Erik Robinson – Oregon Health & Sciences University
Image Source:
The image is in the public domain.

Original Research: Open access
“Post-traumatic stress disorder increases odds of REM sleep behavior disorder and other parasomnias in Veterans with and without comorbid traumatic brain injury”. Jonathan E Elliott, Ryan A Opel, Dennis Pleshakov, Tara Rachakonda, Alexander Q Chau, Kristianna B Weymann, Miranda M Lim.
Sleep doi:10.1093/sleep/zsz237.

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