Parasomnia overlap disorder, Parkinson’s disease and subthalamic deep brain stimulation: three case reports

Background Parasomnia overlap disorder (POD) is a distinct parasomnia and characterized by concomitant manifestation of rapid-eye-movement (REM)- and non-REM (NREM)-parasomnias. Although not uncommon among patients with Parkinson’s disease, POD is often under-investigated. Case presentation This is the first report of patients with PD and features of POD that underwent deep brain stimulation. Our patients exhibited different outcomes of POD features after subthalamic deep brain stimulation. Conclusions We expect that the reporting of these first patients will open the discussion about the need for more detailed and broad-spectrum assessments regarding parasomnias in PD patients that undergo deep brain stimulation. The implications of our observations are both clinical and neurobiological.


Background
Parasomnia overlap disorder (POD) is a distinct parasomnia and characterized by concomitant manifestation of rapid-eye-movement (REM)-and non-REM (NREM)parasomnias. There are only limited data on the prevalence of POD in the course of Parkinson's disease (PD), and a previous questionnaire-based study reported that 26 out of 417 (6%) PD patients reported sleepwalking and also features of REM behavior disorder (RBD), suggesting the presence of POD. [1] To the best of our knowledge, this is the first report of PD patients with POD features in the context of subthalamic deep brain stimulation (STN-DBS).
Levodopa equivalent daily dose (LEDD) was calculated as previously described (including all commonly used medications in PD patients such as dopamine agonists, MAO-B inhibitors, COMT-inhibitors etc.) [3].

Case presentations
Case 1 Patient 1, female, age 70 was diagnosed in 1999 with tremor-dominant PD, underwent bilateral STN-DBS in 2015. Since 2012, the quality of sleep gradually deteriorated mainly due to disrupted night sleep and early morning awakening resulting in daytime sleepiness (Epworth Sleepiness Scale, ESS:12/24). She reported weekly sleep-talking but no sleep-walking or dreamenacting behavior (DEB).
In v-PSG prior to STN-DBS, quantification of EMGactivity [4] showed increased phasic/tonic muscle activity and several episodes of DEB during REM-sleep. NREM-parasomnia included repeated mumbling, sleep-talking and confusional arousals.
STN-DBS was well received and 1 year after surgery, motor signs, assessed by Unified Parkinson's Disease Rating Scale (UPDRS) part III, were ameliorated (57%) and LEDD was reduced by 91% (from 885 mg to 75 mg). Pregabaline 50 mg (prescribed due to very mild restless legs symptoms) and quetiapine 25 mg were gradually stopped after DBS surgery. The rest of medication (levothyroxine and painkillers) remained unchanged.
Sleep quality and daytime sleepiness (ESS 5/24) improved and sleep-talking became rare. Sleep architecture improved markedly (Fig. 1, a1-2). Awakenings from stage 3 NREM were present but showed no episodes of DEB or confusional arousals. Compared to baseline, EMG showed a 44% reduction in tonic and 8% reduction in phasic activity. Apnea-Hypopnea Index (AHI) improved from 19.2/h to 9.2/h.  v-PSG prior to STN-DBS revealed increased phasic/ tonic muscle activity [4] and several episodes of DEB during REM sleep as well as NREM-parasomnia including bruxismus, movements of all four extremities, sleeptalking, sounds of laughing/crying and grimacing several times throughout the night.
STN-DBS was well received and 1 year after surgery, motor signs, assessed by UPDRS part III, improved (50%) and LEDD was reduced by 70% (from 1500 mg to 460 mg). The rest of the medication (painkillers) remained unchanged. Sleepiness slightly improved (ESS 3/24), however, sleep quality deteriorated and his wife reported that frequency of sleepwalking and DEB doubled after DBS. In v-PSG, sleep architecture showed no significant changes ( Fig. 1, b1-2). During REM sleep, while tonic activity was reduced (from 36 to 15% of total REM sleep), phasic activity increased (from 22 to 28%). During stage 3 NREM, episodes of confusional arousal were captured. AHI changed from 7/h to 2/h. v-PSGs in 2012 and 2014 illustrated a progressive increment in phasic/tonic muscle activity during REM sleep. NREM-parasomnia in 2012 included axial myoclonus, mumbling, sleep-talking, chewing, and spitting. In 2016, v-PSG showed a status dissociatus with constant movements of all extremities, sleep-talking, laughing, grimacing and tongue-clicking throughout the whole night (Fig. 1, c1-2). DEB-episodes coincided with "saw tooth waves" in EEG and REM, without associated muscle atonia. AHI gradually increased from normal in 2012 to 10

Discussion and Conclusions
DBS is a well-established treatment for motor symptoms in PD. Despite the impact of sleep disturbances on quality of life of patients with PD, [5] only few DBS studies included sleep and polysomnographic assessments prior to and after surgery (for review see Eugster et al. [6]). Considering sleep-wake functions as an integral part of the DBS outcome in PD patients, we report the first three PD patients with features of POD that underwent STN-DBS.
The pathological substrate of POD in PD remains unclear. Previous studies implicated neurodegeneration at the brainstem, possibly Lewy pathology, [7] involving the ascending control of state transition and the descending control of muscle tone. [8] At the neural level, gross motor phenomena during REM or NREM sleep may arise from a dissociated activity between serotonergic neurons that modulate tonic motor activity and those in the raphe nuclei regulating REM-NREM states, [9] implicating serotonergic system in the motor activity during REM and NREM sleep that characterizes POD. Changes in sleep quality and behavior after STN-DBS can be attributed to improved mobility or respiration and changes in medication. However, STN-related neuronal pathways may also directly be involved in sleep physiology mainly through reciprocal projections to structures involved in generation and modulation of sleep stages (including raphe nucleus, pedunculopontine nucleus and laterodorsal tegmentum), [10][11][12] and to regions that regulate circadian rhythms, mainly the thalamus [13,14].
In the presented cases, it is difficult to disentangle the impact of STN-DBS, medication and disease progression itself on POD outcome. In cases 1 and 2, the very different course regarding outcome of POD features after STN-DBS underlies the important role of DBS itself or even differences in the stimulation parameters (e.g. bipolar vs monopolar stimulation) since in both cases there was a prominent LEDD reduction (90% and 70% respectively) and a comparable improvement in motor signs. In case 3, the alterations in sleep behavior, including deterioration of sleep quality, progressive development of POD and status dissociatus were observed only several years after STN-DBS and 2 years after readmission of dopaminergic therapy, underlying the important role of disease progression and possibly of the medication.
We expect that the reporting of these first patients will open the discussion about the need for more detailed and broad-spectrum assessments regarding parasomnias in PD patients that undergo DBS, with the goal of including these assessments in future prospective studies. This, not only will advance pre-DBS selection procedures, it will contribute to the improvement of postoperative therapeutic practice and may give new insights into the neurobiology of motor and sleep-wake control.

Funding
Not available.

Availability of data and materials
The datasets used and/or analyzed for the current report are available from the corresponding author on reasonable request.
Authors' contributions PB participated in the design and coordination of the study, participated in the acquisition of data, performed the analysis/interpretation of data and wrote the manuscript. JM participated in the acquisition of data, in the analysis/interpretation of data and in the writing of the manuscript. WMMS participated in the design of the study and provided critical revision of the report for intellectual content. CLB conceived of and supervised the study, participated in its design and provided critical revision of the report for intellectual content. All authors have read and approved the final version of the manuscript.

Authors' information
The scoring and the quantification of phasic and tonic muscle atonia were performed by a single scorer, blinded to subject and time of examination. Sleep staging and respiratory event scoring were made according to ICSD-III.

Ethics approval and consent to participate
The protocol for the retrospective analysis of the data was approved by the local ethics committee (Kantonale Ethikkommission Bern). All three participants of this case report gave their consent to participate, have seen and read the submitted material and have signed a written consent for the publication of this manuscript.

Consent for publication
Written informed consent was obtained from all three patients for publication of this Case Report and any accompanying data. A copy of the written consent is available for review by the Editor of this journal.