Kanika Bagai

Estimation of sleep disturbances using wrist actigraphy in patients with postural tachycardia syndrome

STUDY OBJECTIVES Patients with postural tachycardia syndrome (POTS) commonly complain of fatigue, unrefreshing sleep, daytime sleepiness and diminished quality of life. The study objective was to assess sleep quality in POTS patients using wrist actigraphy. DESIGN Prospective study with control group. METHODS Patients with POTS (n = 36) and healthy subjects (n = 36) completed a detailed sleep log and actigraphy for 7 days. RESULTS Compared with healthy subjects, POTS patients have more self-reported problems including days with restless sleep (53 ± 30% vs. 21 ± 20%; P<0.001) and tiredness (75 ± 23% vs. 39 ± 27%; P<0.001). Using actigraphy, POTS patients have lower sleep efficiency (73 ± 13% vs. 79 ± 6%; P = 0.01). Actigraphy determined sleep onset latency (SOL) did not vary significantly in the two groups, but subjective SOL was higher in POTS patient (56 ± 66 min vs. 1 3 ± 9 min; P = 0.001). In POTS patients, there was a significant correlation between subjective complaints of tiredness and actigraphic sleep efficiency (Rs = -0.36; R(2) = 0.15; P = 0.01), significant correlations between actigraphic SOL and upright norepinephrine levels (P = 0.040), and between wake after sleep onset and standing heart rate (P = 0.02). CONCLUSIONS POTS patients have more sleep-related symptoms and poor sleep efficiency. The pattern of subjective vs. objective SOL mismatch is suggestive of sleep-state misperception. High norepinephrine correlated with actigraphic SOL, and this activation of the stress system may contribute significantly to a hyperarousal state with consequent insomnia, poor mental and physical health in POTS patients.

Circadian variability of fibrinolytic markers and endothelial function in patients with obstructive sleep apnea.

STUDY OBJECTIVES Obstructive sleep apnea (OSA) is strongly associated with cardiovascular disease, including stroke and acute coronary syndromes. Plasminogen activator inhibitor-1 (PAI-1), the principal inhibitor of tissue-type plasminogen activator (t-PA), has a pronounced circadian rhythm and is elevated in both OSA and cardiovascular disease and may be an important link between the two conditions. Endothelial dysfunction is one of the underlying pathophysiological mechanisms of cardiovascular disease, and may be altered in OSA. Our primary aim was to compare circadian variability of PAI-1 and t-PA in patients with OSA and normal controls by determining the amplitude (peak level) and mesor (rhythm adjusted mean) of PAI-1 and t-PA in serial blood samples over a 24-h period. The secondary aim was to measure markers of endothelial function (brachial and radial artery flow) in patients with OSA compared with normal controls. SETTING Cross-sectional cohort study. PATIENTS OR PARTICIPANTS Subjects age 18 y or older, with a body mass index of 25-45 kg/m(2), with or without evidence of untreated OSA. INTERVENTIONS Plasma samples were collected every 2 h, in OSA patients and matched controls, over a 24-h period. PAI-1 and t-PA antigen and activity were measured. The presence or absence of OSA (apnea-hypopnea index of 5 or greater) was confirmed by overnight polysomnography. Endothelial function was measured via brachial artery flow mediated vasodilatation and computerized arterial pulse waveform analysis. MEASUREMENTS AND RESULTS The rhythm-adjusted mean levels of PAI-1 antigen levels in the OSA group (21.8 ng/mL, 95% confidence level [CI], 18 to 25.7) were significantly higher as compared to the non-OSA group (16 ng/mL, 95% CI, 12.2 to 19.8; P = 0.03). The rhythm-adjusted mean levels of PAI-1 activity levels in the OSA group (23.9 IU/mL, 95% CI, 21.4 to 26.5) were also significantly higher than in the non-OSA group (17.2 IU/ mL, 95% CI, 14.6 to 19.9; P < 0.001).There were strong correlations between amplitude of PAI-1 activity and severity of OSA as measured by AHI (P = 0.02), and minimum oxygen levels during sleep (P = 0.04). Endothelial function parameters did not differ significantly between the two groups. CONCLUSION The presence of obstructive sleep apnea adversely affects circadian fibrinolytic balance with higher mean plasminogen activator inhibitor-1 activity and antigen, and significantly lower mean tissue-type plasminogen activator activity compared with controls. This perturbation may be an important mechanism for increased cardiovascular events in patients with obstructive sleep apnea. Intermittent hypoxia and changes in circadian clock gene activity in obstructive sleep apnea may be responsible for these findings and warrant further study. Favorable changes in fibrinolytic balance may underlie the reduction in cardiovascular events observed with the treatment of obstructive sleep apnea.

Silent Cerebral Small Vessel Disease in Restless Legs Syndrome.

STUDY OBJECTIVES Growing literature suggests that patients with restless legs syndrome (RLS) may be at increased risk for hypertension, heart disease, and stroke. Cerebral small vessel disease (SVD) is a known risk factor for clinical stroke. This study evaluated silent cerebral SVD by MRI in patients with RLS, in the absence of a history of previous clinical stroke or known stroke risk factors and taking into account disease duration. METHODS Fifty-three patients with RLS < 10 y were prospectively recruited along with 44 with RLS > 10 y and 74 normal controls. A magnetic resonance imaging study was obtained from all subjects and scans were analyzed for area and volume of SVD. RESULTS There was a significant increase in SVD area in the entire group of RLS patients compared to controls (P = 0.036); this was almost entirely driven by the group with RLS > 10 y. SVD area and volume were significantly increased in patients with RLS > 10 y with respect to both controls (P < 0.0001 and P < 0.0014, respectively) and RLS < 10 y (P < 0.00022 and P < 0.003, respectively). Age, duration of RLS, and the interaction of age and duration of RLS were independent predictors of SVD disease. Duration of RLS was an independent predictor of the burden of cerebral SVD (area P < 0.00012 and volume P < 0.0025), whereas sex and insomnia were not. CONCLUSION RLS duration should be taken into account when analyzing the association between RLS and cerebrovascular disease; our data support the hypothesis that a long-lasting RLS and its accompanying periodic limb movements in sleep are a risk factor for silent SVD and perhaps for the development of clinical stroke.

Melatonin reduces tachycardia in postural tachycardia syndrome: a randomized, crossover trial.

BACKGROUND Postural tachycardia syndrome (POTS) induces disabling chronic orthostatic intolerance with an excessive increase in heart rate (HR) upon standing, and many POTS patients have a hyperadrenergic state. Medications that restrain HR are a promising approach to this problem. OBJECTIVE We tested the hypothesis that melatonin will attenuate the tachycardia and improve symptom burden in patients with POTS. METHODS Patients with POTS (n = 78) underwent acute drug trials with melatonin 3 mg orally and placebo, on separate mornings, in a randomized crossover design. Blood pressure, HR, and symptoms were assessed while seated and after standing for up to 10 min prior to, and hourly for 4 h following study drug administration. RESULTS The reduction in standing HR was significantly greater 2 h after melatonin compared with placebo (P = 0.017). There was no significant difference in the reduction of systolic blood pressure between melatonin and placebo, either with standing or while seated. The symptom burden was not improved with melatonin compared with placebo. CONCLUSION Oral melatonin produced a modest decrease in standing tachycardia in POTS. Further research is needed to determine the effects of regular night-time use of this medication in POTS.

Restless Legs Syndrome: Current Concepts about Disease Pathophysiology

Background In the past few decades, much has been learned about the pathophysiology of restless legs syndrome (RLS). Investigators have studied neuropathology, imaging, electrophysiology, and genetics of RLS, identifying brain regions and biological systems affected in RLS. This manuscript will review RLS pathophysiology literature, examining the RLS state through consideration of the neuroanatomy, then the biological, organ, and genetic systems. Methods Pubmed (1966 to April 2016) was searched for the term “restless legs syndrome” cross-referenced with “pathophysiology,” “pathogenesis,” “pathology,” or “imaging.” English language papers were reviewed. Studies that focused on RLS in relation to another disease were not reviewed. Results Although there are no gross structural brain abnormalities in RLS, widespread brain areas are activated, including the pre- and post-central gyri, cingulate cortex, thalamus, and cerebellum. Pathologically, the most consistent finding is striatal iron deficiency in RLS patients. A host of other biological systems are also altered in RLS, including the dopaminergic, oxygen-sensing, opioid, glutamatergic, and serotonergic systems. Polymorphisms in genes including BTBD9 and MEIS1 are associated with RLS. Discussion RLS is a neurologic sensorimotor disorder that involves pathology, most notably iron deficiency, in motor and sensory brain areas. Brain areas not subserving movement or sensation such as the cingulate cortex and cerebellum are also involved. Other biological systems including the dopaminergic, oxygen-sensing, opioid, glutamatergic, and serotonergic systems are involved. Further research is needed to determine which of these anatomic locations or biological systems are affected primarily, and which are affected in a secondary response.

Objective Sleep Assessments in Patients with Postural Tachycardia Syndrome using Overnight Polysomnograms.

STUDY OBJECTIVES Patients with postural tachycardia syndrome (POTS) commonly complain of fatigue, unrefreshing sleep, daytime sleepiness, and diminished quality of life. The study objective was to assess objective sleep quality in POTS patients using overnight polysomnography. METHODS We studied 16 patients with POTS and 15 healthy control subjects performing daytime autonomic functions tests and overnight polysomnography at the Vanderbilt Clinical Research Center. RESULTS There were no significant differences in the objective sleep parameters including sleep efficiency, sleep onset latency, wake time after sleep onset, REM latency, percentage of time spent in N1, N2, N3, and REM sleep, arousal index, apnea-hypopnea index, or periodic leg movement index in POTS patients as compared with healthy control subjects. There were significant negative correlations between sleep efficiency and the change in HR from supine to stand (rs = -0.527; p = 0.036). CONCLUSIONS POTS patients do not have significant differences in objective sleep parameters as compared to control subjects based on overnight polysomnograms. Activation of the sympathetic nervous system may contribute significantly to the hyper arousal state and worsening of subjective estimates of sleep quality as previously reported in POTS patients.

Cardiovascular comorbidity in patients with restless legs syndrome: current perspectives

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A Pilot Study Assessing the Effects of Pallidal Deep Brain Stimulation on Sleep Quality and Polysomnography in Parkinson's Patients.

Deep Brain Stimulation (DBS) is an established adjunctive surgical intervention to treat poorly controlled motor symptoms in Parkinsons disease (PD). Both surgical targets (the subthalamic nucleus and globus pallidus) have proven equally efficacious in treating motor symptoms but unique differences may exist in effects on nonmotor symptoms. Sleep dysfunction, a common disabling symptom in PD, has only been examined directly in the subthalamic target, demonstrating some beneficial changes in sleep quality. We aimed to explore sleep changes after pallidal stimulation; hypothesizing similar benefits would be seen.

Refining duration and frequency thresholds of restless legs syndrome diagnosis criteria

Objective: This study assesses the prevalence of restless legs syndrome (RLS) using DSM-5 criteria and determines what is the most appropriate threshold for the frequency and duration of RLS symptoms. Methods: The Sleep-EVAL knowledge base system queried the interviewed subjects on life, sleeping habits, and health. Questions on sleep and mental and organic disorders (DSM-5, ICD-10) were also asked. A representative sample of 19,136 noninstitutionalized individuals older than 18 years living in the United States was interviewed through a cross-sectional telephone survey. The participation rate was 83.2%. Results: The prevalence of the 4 leg symptoms describing RLS occurring at least 1 d/wk varied between 5.7% and 12.3%. When the frequency was set to at least 3 d/wk, the prevalence dropped and varied between 1.8% and 4.5% for the 4 leg symptoms. Higher frequency of leg symptoms was associated with greater distress and impairment with a marked increase at 3 d/wk. Symptoms were mostly chronic, lasting for more than 3 months in about 97% of the cases. The prevalence of RLS according to DSM-5 was 1.6% (95% confidence interval 1.4%–1.8%) when frequency was set at 3 d/wk. Stricter criteria for frequency of restless legs symptoms resulted in a reduction of prevalence of the disorder. The prevalence was further reduced when clinical impact was taken into consideration. Conclusions: In order to avoid inflation of case rates and to identify patients in whom treatment is truly warranted, using a more conservative threshold of 3 times or greater per week appears the most appropriate.

Depth and Distribution of Symptoms in Restless Legs Syndrome/ Willis-Ekbom Disease

STUDY OBJECTIVES To determine the depth and distribution of sensory discomfort in idiopathic restless legs syndrome/Willis-Ekbom disease (RLS) and RLS concurrent with other leg conditions, specifically peripheral neuropathy, sciatica, leg cramps, and arthritis. METHODS RLS subjects (n = 122) were divided into 71 idiopathic RLS and 51 RLS-C, or Comorbid, groups. All subjects were examined by an RLS expert, answered standardized RLS questionnaires, and received a body diagram to draw the location and depth of their symptoms. RESULTS Age was 63.04 ± 12.84 years, with 77 females and 45 males. All patients had lower limb involvement and 43/122 (35.25%) also had upper limb involvement. Of the 122 subjects, 42.62% felt that the RLS discomfort was only deep, 9.84% felt that the discomfort was only superficial, and 47.54% felt both superficial and deep discomfort. There were no defining characteristics in depth or distribution of RLS sensations that differentiated those patients with idiopathic RLS from those patients with RLS associated with other comorbid leg conditions. The sensation of arthritis was felt almost exclusively in the joints and not in the four quadrants of the leg, whereas the exact opposite was true of RLS sensations. CONCLUSIONS Depth and distribution cannot be used as a discriminative mechanism to separate out idiopathic RLS from RLS comorbid with other leg conditions. Although seen in clinical practice, the total absence of patients with non-painful RLS only in the joints in the current study attests to the rarity of this presentation and raises the possibility of misdiagnosis under these circumstances. We recommend that such patients not be admitted to genetic or epidemiological studies.