Elevated C-reactive protein is associated with severe periodic leg movements of sleep in patients with restless legs syndrome

BackgroundRestless legs syndrome (RLS) is a common sleep disorder in which urges to move the legs are felt during rest, are felt at night, and are improved by leg movement. RLS has been implicated in the development of cardiovascular disease. Periodic leg movements (PLMs) may be a mediator of this relationship. We evaluated systemic inflammation and PLMs in RLS patients to further assess cardiovascular risk.Methods137 RLS patients had PLM measurements taken while unmedicated for RLS. Banked plasma was assayed for high sensitivity C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-alpha).ResultsMean (SD) PLM index was 19.3 (22.0). PLMs were unrelated to TNF-a and IL-6, but were modestly correlated with log CRP (r(129) = 0.19, p = 0.03). Those patients with at least 45 PLMs/h had an odds ratio of 3.56 (95% CI 1.26–10.03, p = 0.02, df = 1) for having elevated CRP compared to those with fewer than 45 PLMs/h. After adjustment for age, race, gender, diabetes, hypertension, hyperlipidemia, inflammatory disorders, CRP-lowering medications, and body mass index, the OR for those with ?45 PLMs/h was 8.60 (95% CI 1.23 to 60.17, p = 0.03, df = 10).ConclusionsPLMs are associated with increased inflammation, such that those RLS patients with at least 45 PLMs/h had more than triple the odds of elevated CRP than those with fewer PLMs. Further investigation into PLMs and inflammation is warranted.     

Leg movements during wakefulness in restless legs syndrome: time structure and relationships with periodic leg movements during sleep

Background and objectiveApproximately one third of patients with restless legs syndrome (RLS) also show periodic leg movements (PLM) during relaxed wake fulness (PLMW). In contrast with the large amount of data published on periodic leg movements during sleep (PLMS), PLMW have received less attention from the scientific community. The objective of this study was to evaluate the correlations/differences of time–structure and response to a dopamine-agonist between PLMW and PLMS in patients with RLS.MethodsNinety idiopathic RLS patients and 28 controls were recruited. Subjects underwent clinical and neurophysiological evaluation, hematological screening, and one or two consecutive full-night polysomnographic studies. A subset of patients received 0.25 mg of pramipexole or placebo before the second recording. Polysomnographic recordings were scored and LM activity was analyzed during sleep and during the epochs of wakefulness occurring during the first recording hour.ResultsRLS patients had higher LM activity during wakefulness than controls, but with a similar periodicity. Even if correlated, the ability of the PLMW index to predict the PLMS index decreased with increasing LM activity. Intermovement intervals during wakefulness showed one peak only at approximately 4 s, gradually decreasing with increasing interval in both patients and controls. The effect of pramipexole was very limited and involved the small periodic portion of LM activity during wakefulness.ConclusionsPLMW index and PLMS index were correlated; however, the magnitude of this correlation was not sufficient to suggest that PLMW can be good predictors of PLMS. Short-interval LM activity during wakefulness and sleep might be linked to the severity of sleep disruption in RLS patients and the differences between their features obtained during wakefulness or sleep might be relevant for the diagnosis of sleep disturbances in RLS.     

PLM detection by actigraphy compared to polysomnography: a validation and comparison of two actigraphs

ObjectiveTo compare periodic leg movement (PLM) counts obtained with polysomnography (PSG) to those obtained from actigraphy with two devices (Actiwatch and PAM-RL).MethodsTwenty-four patients underwent full night actigraphy with Actiwatch from both legs and simultaneous PSG. Out of these patients, 10 had additional actigraphy with PAM-RL. Bilateral and unilateral PLM indices (PLMI) for both actigraphs were calculated for time in bed and compared to polysomnographic PLMI. Additionally, a comparison between the two different actigraphs was performed.ResultsPLMI obtained with Actiwatch were significantly lower than those obtained with PSG (21.2 ± 25.6/h versus 34.4 ± 30.7/h; p < 0.001), whereas the PLMI from PAM-RL were significantly higher than in PSG (63.6 ± 39.3/h versus 37.0 ± 33.5/h; p = 0.009). In direct comparison, Actiwatch gave significantly lower PLMI than the PAM-RL (p = 0.005). The correlations between Actiwatch and PSG (rho = 0.835, p < 0.001), PAM-RL and PSG (rho = 0.939, p < 0.001), and Actiwatch and PAM-RL (rho = 0.915, p < 0.001) were significant. Unilateral actigraphy compared to standard PSG gave less consistent findings. When comparing different settings of the PAM-RL, manual threshold setting resulted in PLMI that were no longer different from PSG (p = 0.074), in contrast to the default threshold setting.ConclusionsThe Actiwatch underestimated and the PAM-RL overestimated PLMI compared to PSG. Whereas PLMI obtained with two actigraphs and PSG were highly correlated, they differed in mean values. Therefore, PSG, actigraphy and also the different actigraphs cannot be interchanged in longitudinal studies, and actigraphy should not be used for diagnostic decision making based on PLM indices. The best approximation to PSG PLMI was achieved by using manual threshold setting with the PAM-RL.     

The validity of the PAM-RL device for evaluating periodic limb movements in sleep and an investigation on night-to-night variability of periodic limb movements during sleep in patients with restless legs syndrome or periodic limb movement disorder using this system

BackgroundThe status of night-to-night variability for periodic limb movements in sleep (PLMS) has not been clarified. With this in mind, we investigated the validity of PLMS measurement by actigraphy with the PAM-RL device in Japanese patients with suspected restless legs syndrome (RLS) or periodic limb movement disorder (PLMD) and the night-to-night variability of PLMS among the subjects.MethodsForty-one subjects (mean age, 52.1 ± 16.1 years) underwent polysomnography (PSG) and PAM-RL measurement simultaneously. Thereafter, subjects used the PAM-RL at home on four more consecutive nights.ResultsThe correlation between PLMS index on PSG (PLMSI-PSG) and PLM index on PAM-RL (PLMI-PAM) was 0.781 (P < .001). When the PLMSI cutoff value on PSG was set at 15 episodes per hour, the cutoff value for predicting this PLMSI level was 16.0 episodes per hour. When the condition was set to the level in which the mean interclass correlation coefficient reached ⩾0.9, the number of required nights for repeated measurements was 26 nights for subjects with PLMI of <15 episodes per hour and three nights for those with PLMI ⩾15 episodes per hour on PAM-RL.ConclusionsPAM-RL is thought to be valuable for assessing PLMS even in Japanese subjects. Recording of PAM-RL for three or more consecutive nights may be required to ensure the screening reliability of a patient with suspected pathologically frequent PLMS.     

Cortical involvement in the sensory and motor symptoms of primary restless legs syndrome

BackgroundRestless legs syndrome (RLS) is characterized by closely interrelated motor and sensory disorders. Two types of involuntary movement can be observed: periodic leg movements during wakefulness (PLMW) and periodic leg movements during sleep (PLMS). Basal ganglia dysfunction in primary RLS has often been suggested. However, clinical observations raise the hypothesis of sensorimotor cortical involvement in RLS symptoms. Here, we explored cortical function via movement-related beta and mu rhythm reactivity.MethodsTwelve patients with idiopathic, primary RLS were investigated and compared with 10 healthy subjects. In the patient group, we analyzed event-related beta and mu (de)synchronization (ERD/S) for PLMS and PLMW during a suggested immobilization test (SIT). An ERD/S analysis was also performed in patients and controls during self-paced right ankle dorsal flexion at 8:30 PM (i.e., the symptomatic period for patients) and 8:30 AM (the asymptomatic period).ResultsBefore PLMS, there was no ERD. Intense ERS was recorded after PLMS. As with voluntary movement, cortical ERD was always observed before PLMW. After PLMW, ERS had a diffuse scalp distribution. Furthermore, the ERS and ERD amplitudes and durations for voluntary movement were greater during the symptomatic period than during the asymptomatic period and in comparison with healthy controls, who presented an evening decrease in these parameters. Patients and controls had similar ERD and ERS patterns in the morning.ConclusionOn the basis of a rhythm reactivity study, we conclude that the symptoms of RLS are related to cortical sensorimotor dysfunction.     

Power spectral analysis of surface electromyography (EMG) at matched contraction levels of the first dorsal interosseous muscle in stroke survivors

ObjectiveThe objective of this study was to help assess complex neural and muscular changes induced by stroke using power spectral analysis of surface electromyogram (EMG) signals.MethodsFourteen stroke subjects participated in the study. They were instructed to perform isometric voluntary contractions by abducting the index finger. Surface EMG signals were collected from the paretic and contralateral first dorsal interosseous (FDI) muscles with forces ranging from 30% to 70% maximum voluntary contraction (MVC) of the paretic muscle. Power spectral analysis was performed to characterize features of the surface EMG in paretic and contralateral muscles at matched forces. A Linear Mixed Model was applied to identify the spectral changes in the hemiparetic muscle and to examine the relation between spectral parameters and contraction levels. Regression analysis was performed to examine the correlations between spectral characteristics and clinical features.ResultsDifferences in power spectrum distribution patterns were observed in paretic muscles when compared with their contralateral pairs. Nine subjects showed increased mean power frequency (MPF) in the contralateral side (>15 Hz). No evident spectrum difference was observed in 3 subjects. Only 2 subjects had higher MPF in the paretic muscle than the contralateral muscle. Pooling all subjects’ data, there was a significant reduction of MPF in the paretic muscle compared with the contralateral muscle (paretic: 168.7 ± 7.6 Hz, contralateral: 186.1 ± 8.7 Hz, mean ± standard error, F = 36.56, p < 0.001). Examination of force factor on the surface EMG power spectrum did not confirm a significant correlation between the MPF and contraction force in either hand (F = 0.7, p > 0.5). There was no correlation between spectrum difference and Fugl–Meyer or Chedoke scores, or ratio of paretic and contralateral MVC (p > 0.2).ConclusionsThere appears to be complex muscular and neural processes at work post stroke that may impact the surface EMG power spectrum. The majority of the tested stroke subjects had lower MPF in the paretic muscle than in the contralateral muscle at matched isometric contraction force. The reduced MPF of paretic muscles can be attributed to different factors such as increased motor unit synchronization, impairments in motor unit control properties, loss of large motor units, and atrophy of muscle fibers.SignificanceSurface EMG power spectral analysis can serve as a useful tool to indicate complex neural and muscular changes after stroke.     

Sleep laboratory diagnosis of restless legs syndrome

Polysomnographic recordings and the Suggested Immobilization Test (SIT) are frequently used to support the clinical diagnosis of restless legs syndrome (RLS). The present study evaluated the discriminant power of 5 different parameters: (1) index of periodic leg movements during sleep (PLMS), (2) index of PLMS with an associated microarousal (PLMS-arousal), (3) index of PLM during nocturnal wakefulness (PLMW), (4) SIT PLM index and (5) mean subjective leg discomfort score during the SIT (SIT MDS) in 100 patients with idiopathic RLS and 50 healthy control subjects. Both groups differed significantly on each parameter studied. Furthermore, while the SIT PLM, the PLMS and the PLMS-arousal indices revealed a poor ability to discriminate patients from controls, the PLMW index and the MDS both showed high sensitivity (87 +/- 7 and 82 +/- 8, respectively) and specificity (80 +/- 11 and 84 +/- 10, respectively) for diagnosing RLS. The combination of these 2 parameters correctly classified 88% of all subjects with a sensitivity of 82% and a specificity of 100%.     

Investigation into the correlation between sensation and leg movement in restless legs syndrome.

We evaluated rest effects on restless legs syndrome (RLS) sensory and motor symptoms. During two 60-minute Suggested Immobilization Tests (SIT) subject's signals of RLS leg sensations and periodic leg movements while awake (PLMW) were recorded. Sensations, PLMW, sensations preceding or after PLMW, sensations occurring without following PLMW, and PLMW occurring without preceding sensation were determined. The RLS patients were divided into equal-sized high and low PLMW groups for further analysis. Data from 46 subjects (28 RLS and 18 controls) revealed sensations increased linearly with rest in RLS patients and controls. Movement rate increased linearly with rest for controls but increased rapidly for the first 45 minutes for all RLS patients. PLMW/hour increased with further rest for low but not high PLMW patients. Sensations followed by PLMW and PLMW without preceding sensations followed similar patterns. Sensations without subsequent PLMW increased dramatically in the last 15 minutes of the SITs. Whereas both sensory and motor signs of RLS increase with rest, there is minimal increase for controls. Patients with higher but not lower PLMW rates reached a ceiling for PLMW after 35 to 40 minutes. The temporal dissociation between sensory and motor events supports viewing these motor and sensory events as separate but loosely linked manifestations of RLS.     

Sertraline and periodic limb movements during sleep: an 8-week open-label study in depressed patients with insomnia

BackgroundPrevious studies have reported that selective serotonin reuptake inhibitors (SSRIs) might induce or exacerbate periodic limb movements during sleep (PLMS). However, most of these studies were retrospective and cross-sectional studies with small sample sizes on a selective SSRI, fluoxetine. Because different SSRIs have different pharmacologic profiles, it was not certain if other SSRIs also might lead to PLMS.MethodsData were taken from an open-label 8-week trial of sertraline in depressive patients with insomnia (n = 31). Depressed patients were administered sertraline 50 mg at 8:00 am on the first day, and the dosage was subsequently titrated up to a maximum of 200 mg daily during the 8-week trial. All participants were tested by repeated polysomnography (PSG) (baseline, first day, 14th day, 28th day, and 56th day). Periodic leg movements (PLM) were visually counted and the PLM index (PLMI) was calculated. PLMS was defined as PLMI ⩾5, and significant PLMS was defined as PLMI ⩾15.ResultsCompared with baseline (PLMI, 3.6 ± 1.5), all PLMI indices increased on the immediate administration of sertraline on the first day (PLMI, 5.1 ± 3.9). From the 14th day onward, PLMI became stable and significantly higher than baseline and the first day (8.7 ± 3.1 on the 14th day, 8.3 ± 3.7 on the 28th day, and 8.5 ± 3.6 on the 56th day; F[11.81]; P = .003). The clinical responses and PSG characteristics continuously improved during the 8-week trial. The PLMS group (PLMI ⩾5) had a higher arousal index (AI) than the non-PLMS group on the 14th day (9.4 ± 5.5 vs 5.2 ± 3.7; t test, 4.22; P = .03) and the 56th day (8.1 ± 5.5 vs 4.3 ± 3.7; z score, 3.11; P = .04); albeit, there was no significant clinical disturbances in the PLMS group.ConclusionsPLMS were increased during sertraline treatment, but only a few of the PLMS reached the significant level. This effect of sertraline on PLMS might be dosage dependent. Although the sertraline-induced PLMS did not seem to cause significant clinical disturbance, the PLMS group (PLMI ⩾5) had a higher AI than the non-PLMS group. Thus clinicians should pay more attention to PLMS during SSRI antidepressant treatment.     

Blood pressure changes associated with periodic leg movements during sleep in healthy subjects

Background and objectivesPeriodic leg movements during sleep (PLMS) are associated with important blood pressure (BP) increases in restless legs syndrome (RLS) patients. These movements also are highly prevalent in the healthy elderly population. The aims of our study were to evaluate if heart rate (HR) and BP changes associated with PLMS are present in healthy subjects with no report of health concerns and to compare the amplitude of cardiovascular changes in healthy subjects to that of RLS subjects.MethodsFourteen healthy subjects (six men, eight women; 46.6 ± 9.7 y) and 14 RLS subjects (six men, eight women; 47.6 ± 11.8 y) matched for age and gender participated in our study. Beat-to-beat noninvasive BP was continuously recorded during one night of polysomnography. HR, systolic BP (SBP) and diastolic BP (DBP) were measured for 10 beats before and 15 beats after onset of PLMS with and without microarousals (MA).ResultsPLMS were associated with sudden and significant increases of HR, SBP and DBP in both groups; however, cardiovascular increases were more pronounced in RLS subjects than in healthy subjects.ConclusionsBecause PLMS index increases with age in healthy subjects and aging is associated with higher cardiovascular risk, further studies should investigate the impact of PLMS-related BP changes on the development of cardiovascular diseases in healthy elderly populations.     

A dose-ranging study of pramipexole for the symptomatic treatment of restless legs syndrome: Polysomnographic evaluation of periodic leg movements and sleep disturbance

Objective: To evaluate, both polysomnographically and by subjective scales, the efficacy and safety profile of pramipexole for restless legs syndrome (RLS) via a 3-week, double-blind, placebo-controlled, parallel-group, dose-ranging study.Methods: At baseline and after 3 weeks, periodic limb movements (PLM) and sleep parameters were assessed by polysomnography, and patients self-assessed their sleep disturbance and overall RLS severity using the international RLS study group rating scale (IRLS). Four pramipexole doses were evaluated: 0.125, 0.25, 0.50, and 0.75 mg/d. Data from 107 patients were included in the intent-to-treat (ITT) analysis.Results: For pramipexole recipients, the primary outcome measure, PLM per hour in bed asleep or awake (the PLM index, or PLMI), decreased by a median of ?26.55 to ?52.70 depending on dosage group, vs. ?3.00 for placebo (p < 0.01 or ?0.001 for each group vs. placebo; Wilcoxon–Mann–Whitney test). Improvements in the secondary endpoints of PLM while asleep and while awake were also significantly superior for pramipexole. At 3 weeks, all pramipexole doses reduced the median for PLM while asleep to levels considered normal (<5 PLM/h). Except for delta-sleep time and awakenings/arousals, sleep parameters remained unchanged or favored pramipexole. Median sleep latency was reduced by ?5.00 to ?11.75 min in the pramipexole groups, vs. ?2.00 for placebo (p < 0.05 for all groups except 0.25 mg/d). Median total sleep time increased by 25.75–66.75 min, vs. 25.50 (p < 0.05 for 0.50 mg/d), and median time in stages 2–4/rapid eye movement (REM) sleep increased by 37.00–68.00 min, vs. 26.75 (p < 0.05 for 0.50 mg/d). By subjective IRLS ratings, all pramipexole doses were significantly superior to placebo. Safety analysis demonstrated no dose-dependent increase in adverse events, and no drug-related increase in daytime somnolence was observed.Conclusions: Pramipexole is effective and well tolerated in RLS, most notably among objective measures, for reducing PLM and decreasing sleep latency. Although other sleep parameters showed lesser, usually insignificant change, patients’ subjective ratings of RLS severity and sleep disturbance were significantly improved (p ? 0.0023).     

Age-at-onset in restless legs syndrome: A clinical and polysomnographic study

ObjectiveTo determine the distribution of age-at-onset in a large cohort of patients with restless legs syndrome (RLS) and to compare clinical and polysomnographic characteristics of patients with early and late age-at-onset of RLS.MethodsTwo hundred and fifty patients with RLS were studied. Information on age-at-onset, etiology, familial history and symptoms severity of RLS was obtained. Age-at-onset density functions were determined from bootstrap methods and kernel density estimators.ResultsAge-at-onset showed a significant bimodal distribution with a large peak occurring at 20 years of age and a smaller peak in the mid-40s. Early- and late-onset RLS could be separated with a cut-off at 36 years of age. Distributions of age-at-onset differed as a function of presence/absence of a familial history and etiology of RLS. Age-at-onset clearly differentiated patients with a primary RLS (early onset) from those with secondary RLS. Finally, early-onset RLS was associated with increased RLS severity with higher indices of periodic leg movements in sleep (PLMS) associated with microarousals and periodic leg movements during wakefulness (PLMW).ConclusionsEarly- and late-onset RLS could be distinguished depending on familial history and etiology of RLS. Our data suggest that different pathological processes are involved in these two groups, the early-onset group being highly genetically determined.     

Intra-rater reliability of motor unit number estimation and quantitative motor unit analysis in subjects with amyotrophic lateral sclerosis

ObjectivesTo assess the intra-rater reliability of decomposition-enhanced spike-triggered averaging (DE-STA) motor unit number estimation (MUNE) and quantitative motor unit potential analysis in the upper trapezius (UT) and biceps brachii (BB) of subjects with amyotrophic lateral sclerosis (ALS) and to compare the results from the UT to control data.MethodsPatients diagnosed with clinically probable or definite ALS completed the experimental protocol twice with the same evaluator for the UT (n = 10) and BB (n = 9).ResultsIntra-rater reliability for the UT was good for the maximum compound muscle action potential (CMAP) (ICC = 0.88), mean surface-detected motor unit potential (S-MUP) (ICC = 0.87) and MUNE (ICC = 0.88), and for the BB was moderate for maximum CMAP (ICC = 0.61), and excellent for mean S-MUP (ICC = 0.94) and MUNE (ICC = 0.93). A significant difference between tests was found for UT MUNE. Comparing subjects with ALS to control subjects, UT maximum CMAP (p < 0.01) and MUNE (p < 0.001) values were significantly lower, and mean S-MUP values significantly greater (p < 0.05) in subjects with ALS.ConclusionsThis study has demonstrated the ability of the DE-STA MUNE technique to collect highly reliable data from two separate muscle groups and to detect the underlying pathophysiology of the disease.SignificanceThis was the first study to examine the reliability of this technique in subjects with ALS, and demonstrates its potential for future use as an outcome measure in ALS clinical trials and studies of ALS disease severity and natural history.     

Psychometric properties of the French Version of the Social Responsiveness Scale in autism spectrum disorder with or without attention deficit hyperactivity disorder

ObjectivesThe Social Responsiveness Scale (SRS) is an instrument that is commonly used to screen for Autism Spectrum Disorder (ASD). Attention Deficit Hyperactive Disorder (ADHD) frequently occurs with ASD and both disorders share some phenotypic similarities. In the present study, we aimed to determine the psychometric properties of the French version of the Social Responsiveness Scale (SRS) and its 5 subscales (social awareness, social cognition, social communication, social motivation, and autistic mannerisms) to discriminate between children with ADHD and those with ASD (differential diagnosis) and children with ADHD from those with a dual diagnosis of ADHD and ASD (comorbid diagnosis).MethodSRS total scores and the 5 subscores of the SRS were compared between 4 groups of children: ADHD (n = 32), ASD + ADHD (n = 30), ASD (n = 31) and typical neurodevelopment (TD; n = 30) children. The discriminant validity was estimated using the Area Under the ROC Curves (AUC).ResultsSRS Social cognition (AUC = 0.73) and Autistic mannerisms (AUC = 0.70) subscores were the most discriminating for differential diagnosis of ASD and ADHD. SRS total scores (AUC = 0.70), and Social communication (AUC = 0.66) and Autistic mannerisms (AUC = 0.75) subscores were the most discriminating for comorbid diagnosis of ASD among ADHD children.ConclusionThe SRS autistic mannerisms subscore was found to be clinically relevant for both differential diagnosis of ASD and ADHD and comorbid diagnoses of ASD among ADHD children but with a modest discriminant power.     

Modulation of neck muscle activity induced by intra-oral stimulation in humans

ObjectiveTo investigate the effect of painful electrical stimuli applied to intra-oral tissues around the teeth on the neck muscle activity in healthy humans.MethodsElectromyographic (EMG) responses of the dorsal neck muscles evoked by intra-oral electrical stimulation were recorded before and after local anesthesia to the stimulus site in 17 healthy volunteers.ResultsInhibition of dorsal neck muscle EMG activities on average 80% compared to baseline level was observed with a latency around 50 ms after the electrical stimulation before anesthesia, and the EMG activity inhibition decreased after anesthesia of the intra-oral stimulus site. The perceived intensity of the electrical stimuli as scored on a visual analogue scale (VAS) was 6.1 ± 0.4 cm before anesthesia and 1.5 ± 0.2 cm after anesthesia.ConclusionIntra-oral stimulation can inhibit neck muscle activity. This modulation might be attributed mainly to nociceptive afferent nerves however, non-nociceptive fibers could also be responsible.SignificanceIntra-oral information including nociceptive activity can inhibit neck muscle activity. From a clinical viewpoint, the present findings demonstrate the neural connectivity between the trigeminal region and the cervical region raising the possibility that orofacial pain conditions could influence head, neck and shoulder activity.     

Quantification of subfield pathology in hippocampal sclerosis: A systematic review and meta-analysis

BackgroundThe utility of MRI-based hippocampal subfield volumetry as a diagnostic test for hippocampal sclerosis (HS) is based on the hypothesis that specific hippocampal subfields are differentially affected in HS. While qualitative studies suggest selective involvement of certain hippocampal subfields in this condition, whether quantifiable differences exist remains unclear. Neuronal density measurement is the most widely used technique for measuring subfield pathological change in HS. Therefore, a systematic review and meta-analysis of studies reporting neuronal densities in temporal lobe epilepsy was performed in order to quantify subfield pathology in hippocampal sclerosis.MethodsStudies were identified by searching the Medline and Embase databases using the search terms: cell count, hippocampus, and epilepsy. Of the 192 studies identified by the literature search, seven met all inclusion and exclusion criteria. Random effects meta-analyses were performed, comparing: (i) neuronal densities in control (n = 121) versus HS (n = 371) groups for subfields CA1-4; and (ii) amount of neuronal loss in HS between subfields CA1-4.ResultsStatistically significant neuronal loss was observed comparing HS to control groups in all subfields CA1-4 (p < 0.001 for all comparisons). Significantly greater neuronal loss was demonstrated in HS comparing CA1 versus CA2 (p < 0.001), CA3 (p = 0.005), and CA4 (p = 0.003). Greater pyramidal cell loss was also demonstrated in CA3 relative to the CA2 subfield (p = 0.003). No significant differences were identified comparing CA2 and CA4 (p = 0.39); or comparing CA3 and CA4 (p = 0.64).ConclusionsHS is characterized by pathology in all hippocampal subfields. Quantifiable differences exist in the involvement of specific hippocampal subfields in HS. Neuronal loss is greatest in CA1, intermediate in CA3 and CA4, and least in CA2. Further studies are required to determine if this pattern can be detected using in vivo MRI.     

Predictors and patterns of insomnia symptoms in OSA before and after PAP therapy

ObjectiveIdentify factors that predict improvement versus persistence of insomnia symptoms following treatment of obstructive sleep apnea (OSA) with positive airway pressure (PAP) therapy.MethodsArchival data from 68 PAP-treated sleep apnea patients aged 25–83 were analyzed using nonparametric tests and stepwise regression to assess the relationships between insomnia symptoms, multiple OSA variables, and PAP use over time.ResultsPretreatment insomnia symptom severity (ISS; b = −0.72, p < 0.001), PAP average use (b = −0.01, p = 0.01) and respiratory disturbance index (RDI; b = −0.02, p = 0.03) predict change in insomnia following PAP therapy. Forty-five percent (24/53) of the subjects with moderate to severe insomnia at pretreatment reported no/mild symptoms after PAP therapy and were considered improved. Improved subjects had lower pretreatment ISS (p < 0.001), higher RDI (p = 0.01), and higher average PAP use (p < 0.035) than subjects with persistent insomnia. Number of medications and comorbidities were similar between improved and persistent groups. New onset of insomnia symptoms occurred in 13% (2/15) of the patients with no/mild pretreatment insomnia.ConclusionsAlthough ISS declines following PAP treatment, 55% of OSA patients have persistent moderate to severe symptoms despite treatment. More severe OSA is linked to higher likelihood of insomnia improvement and the effect of PAP therapy on insomnia may be mediated by OSA severity. Persistent insomnia is unrelated to medication use or comorbidities and may represent an independent, self-sustaining disorder requiring targeted intervention.     

Predicting outcome in childhood diffuse midline gliomas using magnetic resonance imaging based texture analysis

BackgroundDiffuse midline gliomas (DMG) are aggressive brain tumours, previously known as diffuse intrinsic pontine gliomas (DIPG), with 10% overall survival (OS) at 18 months. Predicting OS will help refine treatment strategy in this patient group. MRI based texture analysis (MRTA) is novel image analysis technique that provides objective information about spatial arrangement of MRI signal intensity (heterogeneity) and has potential to be imaging biomarker.ObjectivesTo investigate MRTA in predicting OS in childhood DMG.MethodsRetrospective study of patients diagnosed with DMG, based on radiological features, treated at our institution 2007–2017. MRIs were acquired at diagnosis and 6 weeks after radiotherapy (54 Gy in 30 fractions). MRTA was performed using commercial available TexRAD research software on T2 W sequence and Apparent Diffusion Coefficient (ADC) maps encapsulating tumour in the largest single axial plane. MRTA comprised filtration-histogram technique using statistical and histogram metrics for quantification of texture. Kaplan-Meier survival analysis determined association of MRI texture parameters with OS.ResultsIn all, 32 children 2–14 years (median 7 years) were included. MRTA was undertaken on T2W (n = 32) and ADC (n = 22). T2W-MRTA parameters were better at prognosticating than ADC-MRTA. Children with homogenous tumour texture, at medium scale on diagnostic T2W MRI, had worse prognosis (Mean of Positive Pixels (MPP): P = 0.005, mean: P = 0.009, SD: P = 0.011, kurtosis: P = 0.037, entropy: P = 0.042). Best predictor MPP was able to stratify patients into poor and good prognostic groups with median survival of 7.5 months versus 17.5 months, respectively.ConclusionsDMG with more homogeneous texture on diagnostic MRI is associated with worse prognosis. Texture parameter MPP is the most predictive marker of OS in childhood DMG.     

Auditory event-related potentials at preschool age in children born very preterm

ObjectiveTo assess auditory event-related potentials at preschool age in children born very preterm (VP, 27.4 ± 1.9 gestational weeks, n = 70) with a high risk of cognitive dysfunction.MethodsWe used an oddball paradigm consisting of a standard tone randomly replaced by one of three infrequent deviants (differing in frequency, sound direction or duration).ResultsThe P1 and N2 latencies were inversely correlated to age (50–63 months) both in VP (r = −0.451, p < 0.001, and r = −0.305, p = 0.01, respectively) and term born controls (TC; n = 15). VP children had smaller P1 than near-term (n = 12) or TC (1.70 ± 0.17 μV vs 2.68 ± 0.41 and 2.92 ± 0.43, respectively; p < 0.05). Mismatch negativity response did not differ between groups.ConclusionsOur data suggest a fast maturation of P1 and N2 responses with fast decrease in P1 and N2 latencies around the age of 5 years. Mismatch negativity response does not seem to be a robust measure for defining abnormalities in VP children.SignificanceIn ERP studies in preschool children, even small, non-significant group differences in age at recording should be corrected for. Very preterm born children at preschool age have aERP patterns as earlier described in full-term born children with cognitive deficits.     

Time structure of leg movement activity during sleep in attention-deficit/hyperactivity disorder and effects of levodopa

ObjectivesTo evaluate the leg movement (LM) time structure (periodicity and night distribution) during sleep in children with attention-deficit/hyperactivity disorder (ADHD) and their eventual changes after treatment with levodopa (L-DOPA).Subjects and methodsOne group of ADHD patients (n = 18) and another group of normal controls (n = 17) were recruited; those with ADHD were randomized to L-DOPA or placebo therapy. At baseline (both groups) and after therapy (only patients) subjects underwent full-night polysomnography (PSG) and the leg motor pattern was evaluated with advanced tools of analysis particularly able to detect and describe LM time structure (periodicity and distribution).ResultsWith respect to controls ADHD children showed prolonged sleep latency, increased number of stage shifts, awakenings, and percentage of sleep stage 1. Arousal index was higher in ADHD and also their PLMS index was slightly but considerably higher than controls; however, their periodicity was low and not different from controls. Only sleep latency was significantly reduced by L-DOPA treatment with all the other parameters (sleep scoring and LM activity) remaining substantially unmodified.ConclusionsLMs during sleep in children with ADHD do not show a highly periodic character and are not considerably modified by L-DOPA treatment; this finding has potential implications for drug treatment that might target the most prominent changes observed in our study including arousals and sleep structure disruption.