EFFECT OF MELATONIN ON PAIN SYNDROME IN DELAYED SLEEP PHASE DISORDER IN PATIENTS WITH PARKINSON'S DISEASE

Parkinson’s disease is characterized mainly by damage to the neurons of the substantia nigra and other brain structures and manifested by motor and non-motor symptoms. In patients with Parkinson’s disease receiving dopaminergic therapy, a later onset of sleep has been identified that is associated with the development of the delayed sleep phase disorder. The delayed sleep phase disorder is characterized by a persistent delay in the circadian rhythm that causes a delay in the desired time of falling asleep and waking up. According to clinical guidelines for the treatment of delayed sleep phase disorder, exogenous melatonin is recommended. Along with this, its analgesic properties have been reported. At the same time circadian regulation of fluctuations of painful sensations transmission by either peripheral or central alarm system has been reported. In particular, the two-way connection between the nociceptive system and the circadian rhythm in the human body determines the possibility of mutual influence between these systems. However, the question of the therapeutic effect of melatonin in the presence of concomitant pathology on the circadian rhythm disorders, and, in particular, delayed sleep phase disorder that is a topical issue for patients with Parkinson's disease, is still remaining unexplored. The aim of the study is to compare the changes in subjective perception of pain in patients with Parkinson's disease, who received melatonin therapy and who did not, in delayed sleep phase disorder. We conducted a prospective study that included 48 patients with Parkinson's disease. Circadian rhythm disorders were diagnosed according to the criteria of the International Classification of Sleep Disorders-3. The diagnosis of delayed sleep phase disorder was made on the basis of a clinical interview, filling in a sleep diary and daily thermometry for 7 days. The examined patients were divided into 2 groups according to the chosen method of treatment: group 1 - patients with Parkinson's disease and delayed sleep phase disorder receiving melatonin; group 2 - patients with Parkinson's disease and delayed sleep phase disorder receiving only general recommendations for improving sleep quality and daily functioning without medical intervention. The Unified Parkinson's Disease Rating Scale was used to assess the severity of patients’ clinical condition. The intensity of the pain syndrome was assessed on a visual-analogue scale. The McGill Questionnaire was used to analyze subjective experiences of pain. The patients of group 1 were prescribed to take melatonin, 1 tablet in a dose of 3 mg at 22:00. Individuals in group 2 received general recommendations on the schedule of sleep-wake cycles, light regime and sleep hygiene. Patients with Parkinson's disease and delayed sleep phase disorder have been diagnosed with mild to moderate pain. Treatment of delayed sleep phase disorder in patients with Parkinson's disease reduces the intensity and modality of the pain syndrome, which may be due to improved functioning of the descending pain modulation system and restoration of rhythmic expression of internal clock genes. The administration of melatonin as part of a comprehensive approach to the treatment of circadian rhythm disorders helps to reduce sensory sensations and affective experiences caused by pain that indicates the potential antinociceptive effect of melatonin in the treatment of circadian disorders.

Circadian Disorders, Insomnia, and Parasomnias

Circadian rhythm disorders have misalignment between the desired sleep schedule and the circadian (24-hour) sleep-wake rhythm. Many persons experience this misalignment with jet lag. Other common circadian rhythm disorders include delayed sleep-phase disorder, advanced sleep-phase disorder, and shift-work sleep disorder. Insomnia is one of the most common medical concerns, and its prevalence increases with age. Patients may have difficulty initiating sleep or maintaining sleep and generally have a poor quality of sleep. Causes of insomnia are multifactorial.

The human CRY1 tail controls circadian timing by regulating its association with CLOCK:BMAL1

Circadian rhythms are generated by interlocked transcription–translation feedback loops that establish cell-autonomous biological timing of ∼24 h. Mutations in core clock genes that alter their stability or affinity for one another lead to changes in circadian period. The human CRY1Δ11 mutant lengthens circadian period to cause delayed sleep phase disorder (DSPD), characterized by a very late onset of sleep. CRY1 is a repressor that binds to the transcription factor CLOCK:BMAL1 to inhibit its activity and close the core feedback loop. We previously showed how the PHR (photolyase homology region) domain of CRY1 interacts with distinct sites on CLOCK and BMAL1 to sequester the transactivation domain from coactivators. However, the Δ11 variant alters an intrinsically disordered tail in CRY1 downstream of the PHR. We show here that the CRY1 tail, and in particular the region encoded by exon 11, modulates the affinity of the PHR domain for CLOCK:BMAL1. The PHR-binding epitope in exon 11 is necessary and sufficient to disrupt the interaction between CRY1 and the subunit CLOCK. Moreover, PHR–tail interactions are conserved in the paralog CRY2 and reduced when either CRY is bound to the circadian corepressor PERIOD2. Discovery of this autoregulatory role for the mammalian CRY1 tail and conservation of PHR–tail interactions in both mammalian cryptochromes highlights functional conservation with plant and insect cryptochromes, which also utilize PHR–tail interactions to reversibly control their activity.

1109 Broadly Assessing Sleep Complaints In A Sample Of Patients With ADHD

Introduction It is commonly observed in clinical settings that patients with ADHD regularly present with comorbid “sleep disturbances”. In the absence of broad based sleep disorders assessments, it is thought that this represents Delayed Sleep Phase Disorder (DSPD). Recently, a surveillance study was undertaken in a university-based, outpatient specialty clinic for adults with ADHD, by adding a comprehensive sleep disorders screener (SDS-CL-25) to the clinical intake procedures. These data were used to ascertain which sleep disorders symptoms are common in this clinical cohort. Methods SDS-CL-25 data were collected in 150 subjects (93/57 male/female, mean age 32.8, age range 18-79). The SDS-CL-25 is a 25 item instrument developed to screen for 13 sleep disorders at one time (Sleep Dx symptoms are endorsed on Likert-scales; 0 [never] 4 [>5x/week]). For the purposes of this study, the percentage of subjects endorsing frequent symptomatology (sum of the percent of endorsements for columns 3 & 4)was calculated per symptom. Sums of >20% were considered, a priori, to be of clinical significance. Results Patients endorsed: increased fatigue (59%); SL or WASO or EMA’s >30 minutes (40%; 26%; 21%, respectively); late preferred time to bed (31%); work & school limits sleep opportunity (30%); variable time to and out of bed (27%); and snoring (21%). The average percent endorsement was 15% (range 0-59%). Conclusion These results suggest that, consistent with clinical observations, adult patients diagnosed with ADHD frequently endorse late preferred time to bed, variable sleep wake schedules, work/school limitations on sleep opportunity, and sleep onset problems that are accompanied by daytime fatigue. This constellation of symptoms is consistent with the notion that patients with ADHD tend to have comorbid DSPD. The high prevalence of middle and late insomnia was unexpected and suggests that Insomnia Disorder (proper) may also be a feature of ADHD. Support No support was provided for this abstract.

1191 Development of a Clinically-Validated Questionnaire and Scoring Algorithm Designed to Identify Common Sleep Problems Among Adults

Introduction Although sleep is critical to maintaining health and quality of life, inadequate sleep duration and/or quality is common. It can be difficult to distinguish sleep problems that may be addressed through adjustments to lifestyle versus issues that may represent a more serious condition requiring medical intervention. SmartSleep Analyzer is a cloud-based questionnaire and scoring algorithm designed to categorize respondents according to likely sleep problems as follows: obstructive sleep apnea (OSA), snoring, trouble falling asleep or staying asleep, delayed sleep phase disorder (DSPD), shift work disorder (SWD), chronic sleep restriction (CSR), or no sleep problem. Primary, secondary, and tertiary categorizations are provided, where applicable. The objective of this study was to validate the questionnaire scoring algorithm categorization/s against a sleep physician assessment. Methods From 2,316 available records, 90 complete questionnaires were randomly selected for this analysis. The questionnaire scoring algorithm categorization was compared against the consensus assessment of three independent sleep physicians who each reviewed the answers to all questions before arriving at a diagnosis. Results The questionnaire respondents (70% female) were aged 42.2±14.5 years, had a mean BMI of 32.0±7.7 kg/m2, and self-reported sleep duration of 6.5±1.4 hours/night. The primary, secondary, or tertiary categorization of the questionnaire scoring algorithm matched the primary consensus categorization of the physicians 90.6% of the time (95% confidence interval (CI): 82.6 to 95.7). When OSA and snoring were grouped, agreement increased to 98.9% (95% CI: 94.0 to 100). In all analyses undertaken, the accuracy of questionnaire scoring algorithm against the physicians exceeded the accuracy of the physicians when compared to each other. Conclusion These results demonstrate that our questionnaire and scoring algorithm performs well in identifying sleep problems that may impact adult respondents, using physician-review as the comparison standard. Support Philips