Risk stratification for phenoconversion in patients with isolated REM sleep behavior disorder. A follow-up study from Turkey. / Estratificación del riesgo de fenoconversión al parkinsonismo en pacientes con trastorno de conducta del sueño REM aislado. Estudio de seguimiento en un centro de Turquía.

INTRODUCTION: Isolated rapid eye movement (REM) sleep behavior disorder (iRBD) is one of the strongest prodromal markers of alpha-synucleinopathies. We aimed to investigate non-invasive clinical and quantitative predictors of phenoconversion from iRBD to parkinsonism. PATIENTS AND METHODS: We prospectively followed-up a total of 45 patients (57.8% men) for eight years. Clinical assessments, Sniffin' Sticks Odor Identification Test, Farnsworth-Munsell 100 Hue Color Vision test, Beck Depression Inventory and Rome III Criteria for constipation were performed. Polysomnographic parameters, sleep spindles, electroencephalographic (EEG) spectral analysis, heart rate variability (HRV) were analyzed. RESULTS: Eight patients (17.8%) showed phenoconversion to parkinsonism after a mean duration of 3.2 ± 1 years. Odds ratio for predicting phenoconversion was highest for patients =60 years of age with anosmia and constipation -44.8 (4.5-445.7); kappa = 4.291-. Duration, frequency or density of sleep spindles failed to demonstrate significant correlations. In EEG spectral analysis, lower alpha power in occipital region during wakefulness and REM sleep was significantly correlated with phenoconversion. Slowing in EEG spectrum power, together with age =60 years, anosmia and constipation, resulted in the highest odds ratio -122.5 (9.7-1543.8); kappa = 3.051-. CONCLUSIONS: It is of great importance to have a world-wide perspective of phenoconversion rates from iRBD to overt neurodegeneration, since racial and geographical factors may play important modifying roles. Relatively younger age and shorter disease duration may also be confounding factors for lower rate in our study. Neurophysiological biomarkers seem to be important predictors of phenoconversion, though more research is needed to establish subtypes of iRBD with different probabilities of evolution to overt synucleinopathy.

TITLE: Estratificación del riesgo de fenoconversión al parkinsonismo en pacientes con trastorno de conducta del sueño REM aislado. Estudio de seguimiento en un centro de Turquía.Introducción. El trastorno aislado de la conducta del sueño con movimientos oculares rápidos (iRBD) es uno de los marcadores prodrómicos más potentes de las alfa-sinucleinopatías. Nuestro objetivo fue investigar los predictores clínicos y cuan­titativos no invasivos de la fenoconversión de iRBD a parkinsonismo. Pacientes y métodos. Se siguió prospectivamente a un total de 45 pacientes (57,8% hombres) durante ocho años del período de estudio. Se realizaron evaluaciones clínicas, la prueba de identificación de olores Sniffin' Sticks, la prueba Farnsworth-Munsell 100 Hue Color Vision, el inventario de depresión de Beck y los criterios de Roma III para el estreñimiento. Se analizaron parámetros polisomnográficos, husos del sueño, análisis espectral electroencefalográfico (EEG) y variabilidad de la frecuencia cardíaca. Resultados. Ocho pacientes (17,8%) mostraron fenoconversión a parkinsonismo después de una duración media de seguimiento de 3,2 ± 1 año. La odds ratio para predecir la fenoconversión fue más alta para los pacientes =60 años con anosmia y estreñimiento ­44,8 (4,5-445,7); kappa = 4,291­. La disminución de la potencia del espectro EEG, junto con la edad =60 años, la anosmia y el estreñimiento, dio como resultado el índice de odds más alto ­122,5 (9,7-1543,8); kappa = 3,051­. Conclusiones. Es de gran importancia tener una perspectiva mundial de las tasas de fenoconversión de iRBD a neurodegeneración manifiesta, ya que los factores raciales y geográficos pueden desempeñar importantes papeles modificadores. Los biomarcadores neurofisiológicos parecen ser predictores importantes de la fenoconversión, aunque se necesita más investigación para establecer subtipos de iRBD con diferentes probabilidades de evolución hacia una sinucleinopatía manifiesta.

The relations of circulating agouti-related peptide and leptin with altered sleep architecture in patients with active Cushing's disease: a pilot study.

AIM: To evaluate sleep architecture of patients with Cushing's disease (CD) and to explore whether agouti-related peptide (AgRP) and/or leptin play a permissive role in sleep alterations in patients with active CD. METHODS: We performed polysomnography on 26 patients with active CD and age 26 age- and sex-matched control subjects. Blood samples were obtained from all participants for the analyzes of AgRP and leptin. The laboratory and sleep-related parameters were compared. RESULTS: The groups were similar in age, gender, and body mass index. The CD group had reduced sleep efficiency (71.6 ± 12.1% vs. 78.8 ± 12.6%, p = 0.042) and increased wake after sleep onset (WASO%) (24.7 ± 13.1% vs. 17.4 ± 11.6%, p = 0.040) as compared to control group. Seventeen patients with CD (65.4%) and 18 control subjects (69.2%) had obstructive sleep apnea. Serum AgRP (13.2 ± 7.4 pg/ml vs. 9 ± 3.1, p = 0.029), leptin (59.5 mcg/l, [IQR] 32.6-94.6 vs. 25.3 mcg/l, [IQR] 12.9-57.5, p = 0.007) were higher in CD group. AgRP and leptin correlated negatively with total sleep time, sleep efficiency, stage N2 sleep (%), and positively with WASO%. In multiple regression analyses, serum cortisol (ß = - 0.359, p = 0.042) and AgRP (ß = - 0.481, p = 0.01) were significant predictor of sleep efficiency. AgRP was also significant predictor of WASO% (ß = 0.452 and p < 0.05). CONCLUSIONS: Active CD carries an increased risk of impaired sleep efficiency and continuity which may worsen health-related quality of life. Elevated circulating AgRP and, to a lesser extent, leptin may be associated with decreased sleep efficiency and continuity in patients with CD. Patients with CD who have subjective sleep symptoms should be screened with polysomnography.

The Comparison of the Sleep Structure and Sleep Spindle Activity in Children With Primary Snoring and Sleep-Disordered Breathing.

Obstructive sleep apnea syndrome (OSAS) in children is associated with changes in the structure of sleep. The possible effects of snoring on spindle activity have not been established. We analyzed the polysomnography recordings and sleep spindle activity in children with primary snoring and/or OSAS compared with healthy children. Fifty-one children were included; 8 had primary snoring, 16 had OSAS and snoring, 11 had OSAS without snoring, and 16 were healthy controls. The density (P = .034) and duration (P = .019) of sleep spindles were decreased in children with OSAS compared with controls. The sleep spindle activity did not show significant changes between children with primary snoring and healthy controls, or between OSAS with/without snoring. We conclude that it is not snoring per se but OSAS that affects sleep spindle activity. Obstructive sleep apnea syndrome with/without snoring deserves greater attention because it has different phenotypes of the disease with different pathophysiologies.

Sleep parameters associated with long-term outcome following subthalamic deep brain stimulation in Parkinson's disease.

INTRODUCTION: We aimed to investigate the effects of changes in sleep architecture on long-term clinical outcome in patients with Parkinson's disease (PD) who underwent deep brain stimulation of subthalamic nuclei (STN DBS). METHODS: We followed up eight PD patients before and three years after STN DBS surgery. In addition to clinical assessments, polysomnography (PSG) followed by multiple sleep latency tests was performed before and after STN DBS, while stimulator was ON and OFF. RESULTS: Subjective sleep latency was significantly decreased (P=0.033) and sleep duration was increased (P=0.041), as measured by Pittsburgh sleep quality index. Latency to REM sleep stage was shortened after surgery with STN DBS ON (P=0.002). Index of central type of abnormal respiratory events was significantly increased while stimulator was ON (P=0.034). Total number of major body movements was found to be increased when stimulator was turned OFF (P=0.012). Among PSG data obtained during STN DBS ON, it was observed that duration of N3 sleep was negatively correlated with UPDRS scores at 1st (P=0.038) and 3rd (P=0.045) post-operative years. Among PSG variables during STN DBS OFF, durations of N3 sleep (P=0.017) and REM sleep (P=0.041) were negatively correlated with UPDRS scores at post-operative 1st year. CONCLUSION: Disturbances in sleep architecture are associated with higher UPDRS scores and worse prognosis at 1st and 3rd post-operative years. Similar results obtained while stimulator was OFF at the end of 1st year support the presence of microlesion effect after STN DBS, which is probably not long lasting.

Morning headache in sleep apnoea: clinical and polysomnographic evaluation and response to nasal continuous positive airway pressure.

Morning headache is accepted as part of clinical findings of obstructive sleep apnoea syndrome (OSAS). The prevalence of morning headache is at variable levels from 18% to 74% in patients with OSAS. However, there is controversy over the association of morning headache and OSAS. We studied morning headache prevalence and characteristics in 101 controls with apnoea-hypnoea index (AHI) < 5 and 462 OSAS patients with AHI > or = 5. Morning headache was reported by only nine (8.9%) subjects in a control group compared with 156 (33.6%) of OSAS patients (P < 0.01). Morning headache prevalence was significantly higher in severe and moderate OSAS groups. AHI was significantly higher in OSAS patients with morning headache compared with patients without morning headaches. Oxygen saturation nadir during rapid eye movement and non-rapid eye movement sleep as well as mean oxygen saturation value during total sleep time were also found to be significantly lower in morning headache group. However, none of the sleep parameters was found to be determinants of morning headache. Morning headache was more frequently reported by patients of female gender and with primary headache history. Morning headache was totally resolved in 90% of patients treated with nasal continuous positive airway pressure. The history of OSAS should be considered in the differential diagnosis of morning headache.

The role of mean inspiratory effort on daytime sleepiness.

This study has investigated the role of average maximum inspiratory effort in excessive daytime sleepiness in patients with obstructive sleep apnoea syndrome (OSAS) and upper airway resistance syndrome (UARS). Fifteen patients diagnosed with UARS and 32 patients with OSAS, with >5.5 h total sleep time (TST) during 8 h of nocturnal polygraphic recordings, were included in the study. Demographical data, polysomnographical data and data about daytime sleepiness, including Epworth sleepiness scale (ESS) and multiple sleep latency test (MSLT), were evaluated. In order to compute the average maximum inspiratory effort from oesophageal pressure (Poes) measurements, maximum Poes was obtained from 20 representative obstructive respiratory events (obstructive apnoeas, hypopnoeas or flow limitations) for each sleep stage in both supine and side positions. From Poes measurements during sleep, the increase in Poes (deltaPoes) during respiratory events was also calculated. The average maximum Poes, deltaPoes, respiratory disturbance index (RDI) and arousal index were significantly correlated with ESS in OSAS patients. In patients with UARS, the only significant correlation was obtained between average maximum Poes and ESS. The MSLT score did not show any significant correlation with arousal index, number of stage variations, RDI, average Poes, deltaPoes, minimum oxygen saturation (Sa,O2) and percentage of TST with an Sa,O2 <90% in both UARS and OSAS patients. The results of multiple regression analysis showed that average maximum Poes correlates best with the variance in ESS for OSAS patients. In conclusion, the data from this study indicate the possible important role of average inspiratory effort in determining subjective sleepiness in both obstructive sleep apnoea syndrome and upper airway resistance syndrome patients.

EEG arousals and awakenings in relation with periodic leg movements during sleep.

It is known that periodic leg movements are frequently accompanied by full awakenings or by signs of EEG arousals. The time relationship of these EEG arousals with leg movements varies from patient to patient. They may precede or follow leg movements or occur simultaneously. It is not clear whether these arousals trigger leg movements or, alternatively, whether both EEG arousals and leg movements are separate expressions of a common pathophysiological mechanism. We investigated the temporal relationship of five EEG arousals, such as alpha activity, K-complexes, spindles, K-alpha, K-spindle activities and awakenings, with leg movements in 10 periodic leg movement patients. These EEG arousals were considered to be associated with leg movements if they occurred 10 s before/after or simultaneously with the onset of right or left tibialis muscle EMG potentials. It was found that 49.19% of EEG arousals occurred before leg movements, 30.61% occurred simultaneously and 23.18% occurred just after leg movements. The number of EEG arousals was significantly higher in the 10 s preceding leg movement than simultaneously or in the 10 s following. Alpha activity was the phenomenon associated most frequently with leg movements, irrespective of its temporal organization and was significantly higher during the 10 s preceding movement. Spindle and K-spindle activities were significantly higher before leg movement, whereas K-complex activity was significantly more frequent during leg movements. The number of awakenings was significantly higher after leg movements than simultaneously. These results indicated that leg movements are not primary, but rather are a phenomenon associated with an underlying arousal disorder.

Problems associated with switch to modafinil - a novel alerting agent in narcolepsy.

Modafinil is a novel medication recently approved for the treatment of narcolepsy and idiopathic hypersomnia. Commonly, patients had already been prescribed medications for their syndrome. This report outlines difficulties encountered in the clinical practice of switching patients to modafinil. Naïve subjects accepted modafinil best. Subjects withdrawn from amphetamine had the most problems and failure to withdraw. Venlafaxine hydrochloride combined well with modafinil to control cataplectic attacks. Usage of a progressive withdrawal protocol may ease the difficulties observed.

Are periodic leg movements during sleep (PLMS) responsible for sleep disruption in insomnia patients?

On the basis of polygraphic findings, it has been suggested that periodic leg movements during sleep are not responsible for sleep impairment (Lugaresi et al., 1972). However, for some authors it is an important cause of insomnia (Guilleminault et al., 1975; Coleman, 1982). Thus, the relationship between periodic leg movements during sleep, sleep disruption and the complaint of patients is particularly complex. We investigated the macro- and micro-structure of sleep with and without leg movements in 10 PLMS patients complaining of insomnia to clarify whether periodic leg movements are responsible for sleep disruption. The total sleep time without periodic leg movements was significantly longer than sleep time with leg movements. Sleep time without leg movements was longer than sleep time with leg movements in stage 2, slow wave sleep (SWS) and rapid eye movement (REM) sleep. Short lasting awakenings were significantly more frequent during periodic leg movements associated sleep whilst long lasting awakenings were equally frequent during sleep with and without periodic leg movements. The percentage of the four electroencephalogram (EEG) activities (delta, theta, alpha and spindles) did not show any significant difference between periodic leg movements associated and not associated with sleep stages and total sleep time. The lack of significant differences in both the macro- and micro-structure of sleep and EEG activity content regarding the association with movements confirm the hypothesis that periodic leg movements did not primarily cause sleep disturbance.

Hypersomnia after head-neck trauma: a medicolegal dilemma.

OBJECTIVES: To evaluate the severity of daytime sleepiness in patients with a history of head trauma who complain of daytime somnolence, to investigate polygraphic abnormalities during nocturnal sleep, and to determine whether daytime sleepiness was the cause or consequence of the head trauma. METHODS: The authors performed a systematic evaluation of 184 patients comprised of clinical interviews, sleep disorders questionnaires, sleepiness and depression scales, medical and neurologic evaluations, sleep logs with actigraphy, nocturnal polysomnography, and the Multiple Sleep Latency Test (MSLT). Assessments of sleepiness before the accident were based on bed partner interviews, coworker and employer reports, health reports, driving records, and employment history that included absenteeism. RESULTS: Post-traumatic complaint of somnolence was associated with variable degrees of impaired daytime functioning in more than 98% of patients. Patients who were in a coma for 24 hours, who had a head fracture, or who had immediate neurosurgical interventions were likely to have scores > 16 points on the Epworth Sleepiness Scale (ESS) and < or = 5 minutes on the MSLT. Pain at night was an important factor in nocturnal sleep disruption and daytime sleepiness. Sleep-disordered breathing was a common finding and was the only finding in whiplash patients with daytime sleepiness. Extensive evaluation of pretrauma behavior supported the conclusion that the onset of symptomatic sleep-disordered breathing was associated with the trauma. The patients who showed a "compulsive presleep behavior" were severely impaired in performing their daily activities. CONCLUSIONS: A systematic approach is required when dealing with patients complaining of hypersomnia following a head-neck trauma.

Effects of 48 hours sleep deprivation on human immune profile.

It is a common belief that sleep deprivation increases the susceptibility to diseases. In order to evaluate the effects of sleep deprivation on immune profile in humans, peripheral venous blood was obtained from sixteen healthy young male volunteers. Ten of the volunteers underwent 48 hours of sleep deprivation and the other six maintained their regular sleep schedule and acted as controls. The first blood samples were taken at the end of the first polysomnographic recording at 8:00 a.m. After this sampling, ten subjects were sleep deprived for 48 hours in sedentary conditions. The second and third blood samples were taken at the 24th and 48th hours. The subjects were recorded again to verify rebound effects of sleep deprivation after the third blood sampling. In this second polysomnographic recording, all sleep-deprived subjects showed slow wave and REM sleep rebound. The last blood samples were taken at the 72nd hour of study at 8:00 a.m. CD4, CD8, CD5, CD16, CD19 surface antigen positive lymphocyte subsets, serum IgG, IgM, and cortisol levels were assessed in all samples. Our results showed that the proportion of NK cells were decreased during sleep deprivation and returned to normal values after recovery sleep. In the control group, we did not observe any changes in the same direction as the sleep-deprived group.