Sara Marelli

Obstructive Sleep Apnea: Brain Structural Changes and Neurocognitive Function before and after Treatment

RATIONALE Obstructive sleep apnea (OSA) is commonly associated with neurocognitive impairments that have not been consistently related to specific brain structure abnormalities. Knowledge of the brain structures involved in OSA and the corresponding functional implications could provide clues to the pathogenesis of cognitive impairment and its reversibility in this disorder. OBJECTIVES To investigate the cognitive deficits and the corresponding brain morphology changes in OSA, and the modifications after treatment, using combined neuropsychologic testing and voxel-based morphometry. METHODS A total of 17 patients treatment-naive to sleep apnea and 15 age-matched healthy control subjects underwent a sleep study, cognitive tests, and magnetic resonance imaging. After 3 months of treatment, cognitive and imaging data were collected to assess therapy efficacy. MEASUREMENTS AND MAIN RESULTS Neuropsychologic results in pretreatment OSA showed impairments in most cognitive areas, and in mood and sleepiness. These impairments were associated with focal reductions of gray-matter volume in the left hippocampus (entorhinal cortex), left posterior parietal cortex, and right superior frontal gyrus. After treatment, we observed significant improvements involving memory, attention, and executive-functioning that paralleled gray-matter volume increases in hippocampal and frontal structures. CONCLUSIONS The cognitive and structural deficits in OSA may be secondary to sleep deprivation and repetitive nocturnal intermittent hypoxemia. These negative effects may be recovered by consistent and thorough treatment. Our findings highlight the importance of early diagnosis and successful treatment of this disorder.

A single question for the rapid screening of restless legs syndrome in the neurological clinical practice

The purposes of this study were to validate the use of a single standard question for the rapid screening of restless legs syndrome (RLS) and to analyze the eventual effects of the presence of RLS on self‐assessed daytime sleepiness, global clinical severity and cognitive functioning. We evaluated a group of 521 consecutive patients who accessed our neurology clinic for different reasons. Beside the answer to the single question and age, sex, and clinical diagnosis, the following items were collected from all patients and normal controls: the four criteria for RLS, the Epworth Sleepiness Scale (ESS), the Clinical Global Impression of Severity (CGI‐S), and the Mini‐Mental State evaluation. RLS was found in 112 patients (70 idiopathic). The single question had 100% sensitivity and 96.8% specificity for the diagnosis of RLS. ESS and CGI‐S were significantly higher in both RLS patient groups than in normal controls. RLS severity was significantly higher in idiopathic than in associated/symptomatic RLS patients. RLS can be screened with high sensitivity and good reliability in large patient groups by means of the single question; however, the final diagnosis should always be confirmed by the diagnostic features of RLS and accompanied by a careful search for comorbid conditions.

Autonomic symptoms in idiopathic REM behavior disorder: a multicentre case-control study

Patients with idiopathic REM sleep behavior disorder (iRBD) are at very high risk of developing neurodegenerative synucleinopathies, which are disorders with prominent autonomic dysfunction. Several studies have documented autonomic dysfunction in iRBD, but large-scale assessment of autonomic symptoms has never been systematically performed. Patients with polysomnography-confirmed iRBD (318 cases) and controls (137 healthy volunteers and 181 sleep center controls with sleep diagnoses other than RBD) were recruited from 13 neurological centers in 10 countries from 2008 to 2011. A validated scale to study the disorders of the autonomic nervous system in Parkinsons disease (PD) patients, the SCOPA-AUT, was administered to all the patients and controls. The SCOPA-AUT consists of 25 items assessing the following domains: gastrointestinal, urinary, cardiovascular, thermoregulatory, pupillomotor, and sexual dysfunction. Our results show that compared to control subjects with a similar overall age and sex distribution, patients with iRBD experience significantly more problems with gastrointestinal, urinary, and cardiovascular functioning. The most prominent differences in severity of autonomic symptoms between our iRBD patients and controls emerged in the gastrointestinal domain. Interestingly, it has been reported that an altered gastrointestinal motility can predate the motor phase of PD. The cardiovascular domain SCOPA-AUT score in our study in iRBD patients was intermediate with respect to the scores reported in PD patients by other authors. Our findings underline the importance of collecting data on autonomic symptoms in iRBD. These data may be used in prospective studies for evaluating the risk of developing neurodegenerative disorders.

REM sleep behaviour disorder.

REM sleep behaviour disorder (RBD) is a parasomnia characterised by nocturnal complex motor activity associated with dream mentation. RBD, which affects mainly older men, may be idiopathic or associated with other neurological disorders. A strong association between RBD and alpha-synucleinopathies has been recently observed, with the parasomnia often heralding the clinical onset of the neurodegenerative disease. The idiopathic form accounts for up to 60% of the cases reported in the three largest series of RBD patients. Follow-up studies in small samples revealed that a proportion of RBD patients will eventually develop Parkinson’s disease and/or a dementia of Lewy bodies type in the years following the RBD diagnosis. Recently, neurophysiological and neuropsychological studies in idiopathic RBD have found evidence of central nervous system dysfunction. An impairment of cortical activity, specific neuropsychological deficits, signs of autonomic dysfunction and olfactory impairment have been observed in these patients, challenging the concept of idiopathic RBD. The detection of early markers of neurodegenerative disorders in idiopathic RBD, and the evaluation of their value by the combined application in prospective studies may be crucial for developing early intervention strategies.

Restless Legs Syndrome is a Common Feature of Adult Celiac Disease

Restless legs syndrome (RLS) is a common neurological condition, frequently idiopathic, sometimes associated with specific disorders such as iron deficiency. We investigated RLS prevalence in celiac disease (CD), an autoimmune disease characterized by several features such as malabsorption‐related iron deficiency anemia and peripheral neuropathy. We screened a population of 100 adult CD patients for CD features, iron metabolism, clinical and neurological conditions, and enrolled 100 age‐ and sex‐matched controls in the general population. RLS was ascertained in CD patients and controls by both the presence of the four essential International RLS Study Group diagnostic criteria and neurological examination. The International RLS Study Group rating scale was used to measure RLS severity. We found a 31% prevalence of RLS in the CD population that was significantly higher than the prevalence in the control population (4%; P < 0.001). The average severity of RLS in CD population was moderate (17 ± 6.5). In the CD population, no significant correlation was found between RLS and either gluten‐free diet or iron metabolism, despite hemoglobin levels were significantly lower in CD patients with RLS than without RLS (P = 0.003). We found no correlation between RLS and other possible causes of secondary RLS, including signs of peripheral neuropathy, pregnancy, end‐stage renal disease, and pharmacological treatments.Our study broadens the spectrum of neurological disorders associated with CD and indicates that RLS should be sought for in all patients with CD.

Effects of continuous positive airway pressure on cognitition and neuroimaging data in sleep apnea

Obstructive sleep apnea (OSA) has been associated with a broad range of neurocognitive difficulties. The current view is that the neurocognitive impairment in OSA is due to the adverse effects of sleep fragmentation and/or intermittent hypoxia. The overall picture of cognitive deficits in OSA is complex. On balance, there appears to be negative effects of OSA on cognition, most likely in the domains of attention/vigilance, verbal and visual delayed long-term memory, visuospatial/constructional abilities, and executive dysfunction. Continuous positive airway pressure (CPAP) is the most effective and widely used treatment of OSA. In the majority of studies of OSA patients treated with CPAP, attention/vigilance improved, but changes in global functioning, executive functioning, and memory improved in about half of the studies. This may be due, in part, to variability in study design and sampling methodology across studies. Structural volume changes have been demonstrated in brain regions of OSA patients including areas that regulate memory and executive function (e.g., frontal cortex, anterior cingulate, and hippocampus). Growing evidence suggests that the OSA-related changes in brain morphology may improve with CPAP treatment. Neuroimaging studies performed during cognitive testing have provided insight into CPAPs effect on function of neuroanatomical circuits in the brain. Although neuroimaging can provide important insights into the structural and functional differences associated with OSA, one of the challenges is to interpret the findings in light of comorbid conditions that also cause neural injury. The purpose of this article is to provide a narrative review of the publications on cognition and neuroimaging in OSA before and after CPAP treatment.

An observational clinical and video-polysomnographic study of the effects of clonazepam in REM sleep behavior disorder

OBJECTIVE To analyze the differences in sleep structure and nocturnal motor activity between drug-free REM sleep behavior disorder (RBD) patients and those under therapy with clonazepam, and to evaluate the long-term longitudinal changes under continued therapy with clonazepam. METHODS Fifty-seven consecutive iRBD patients were recruited (52 men and 5 women, mean age 68.8±6.03years). Forty-two patients were not taking any medication at the time of the evaluation (iRBD-Clo) while 15 were taking clonazepam (0.5-1mg) at bedtime (iRBD+Clo). The Clinical Global Impression-Severity (CGI-S) scale was obtained. Sleep was video-polysomnographically recorded and the RBD severity scale (RBDSS) obtained. The chin EMG amplitude was quantitatively assessed and the Atonia Index computed. RESULTS Disease duration was significantly longer in iRBD+Clo patients who also showed a lower rate of stage shifts, higher sleep efficiency and lower percentage of wakefulness after sleep onset and of sleep stage 1, and an increased percentage of sleep stage 2. The longitudinal long-term follow up study in a subgroup of 13 patients showed moderately increased total sleep time, sleep efficiency, sleep stage 2, slow-wave sleep and decreased wakefulness after sleep onset and sleep stage 1, under clonazepam treatment. The CGI scale clearly tended to improve after treatment, but no common trend was evident for RBDSS or Atonia Index. CONCLUSIONS This study provides evidence of important objective effects of clonazepam on NREM sleep in RBD; this data might be very important for the development of new and effective treatments for this condition.

Polysomnographic record and successful management of augmentation in restless legs syndrome/Willis-Ekbom disease.

BACKGROUND Dopamine agonists (DAs) represent the first-line treatment in restless legs syndrome (RLS); however, in the long term, a substantial proportion of patients will develop augmentation, which is a severe drug-related exacerbation of symptoms and the main reason for late DA withdrawal. Polysomnographic features and mechanisms underlining augmentation are unknown. No practice guidelines for management of augmentation are available. METHODS A clinical case series of 24 consecutive outpatients affected by RLS with clinically significant augmentation during treatment with immediate-release DA was performed. All patients underwent a full-night polysomnographic recording during augmentation. A switchover from immediate-release DAs (l-dopa, pramipexole, ropinirole, rotigotine) to the long-acting, extended-release formula of pramipexole was performed. RESULTS Fifty percent of patients presented more than 15 periodic limb movements per hour of sleep during augmentation, showing longer sleep latency and shorter total sleep time than subjects without periodic limb movements. In all patients, resolution of augmentation was observed within two to four weeks during which immediate-release dopamine agonists could be completely withdrawn. Treatment efficacy of extended-release pramipexole has persisted, thus far, over a mean follow-up interval of 13 months. CONCLUSIONS Pramipexole extended release could be an easy, safe, and fast pharmacological option to treat augmentation in patients with restless legs syndrome. As such it warrants further prospective and controlled investigations. This observation supports the hypothesis that the duration of action of the drug plays a key role in the mechanism of augmentation.

Night-to-Night Variability of Automatic Quantitative Parameters of the Chin EMG Amplitude (Atonia Index) in REM Sleep Behavior Disorder

STUDY OBJECTIVES To analyze the night-to-night variability of REM sleep electromyographic (EMG) features of REM sleep behavior disorder (RBD) by using the automatic quantitative method known as atonia index (AI), and to evaluate the improvement in sensitivity and specificity of AI for the diagnosis of RBD when a second recording night is available. SETTING Sleep research center. INTERVENTIONS N/A. METHODS A group of 17 idiopathic RBD patients was recruited for whom 2 all-night polysomnographic (PSG) recordings were available. Thirty normal controls were also recruited and subgrouped into Young (< 45 years of age) or Aged (> 45 years). Chin EMG analysis was run on all recordings; night-to-night variability of both AI and number of chin EMG activations/h during REM sleep was additionally quantified as the absolute difference between the 2 nights standardized as the percentage of their mean. MEASUREMENTS AND RESULTS Night-to-night variability of AI was higher in RBD patients (19.7%) than in the 2 groups of controls (Young 1.8% and Aged 2.8%). The values of variability of chin EMG activations were much higher than those of AI, especially in the Aged controls. Sensitivity of AI ≤ 0.9 for RBD was always higher than 82% and reached 88.9% for the combined-night analysis; specificity was also high, with a value of 92.3% for the combined-value analysis. CONCLUSION The night-to-night variability of AI seems to be very low in normal controls and remains under 20% in RBD patients; that of the number of EMG activations is higher. However, even a single PSG recording provides high values of sensitivity and specificity when a threshold value of AI ≤ 0.9 is used to define abnormal chin EMG levels during REM sleep that increase only moderately when a second night recording is available.

Pharmacotherapy for restless legs syndrome

Introduction: Restless legs syndrome (RLS) is a common condition characterized by paresthesia and an urge to move. Predominantly, symptoms occur at rest in the evening or at night, and they are alleviated by moving the affected extremity. RLS prevalence in the general population has been estimated to be approximately 5%. Areas covered: This review presents all options for the treatment of RLS. Expert opinion: Pharmacological treatment should be limited to those patients who suffer from clinically relevant RLS, that is, when symptoms impair the patients quality of life, daytime functioning, social functioning or sleep. Treatment on demand is a clinical need in some RLS patients, and medications include carbidopa/levodopa, pramipexole, ropinirole, oxycodone, methadone, codeine and tramadol. Chronic RLS should be treated with either a nonergot dopamine agonist or an α-2-δ calcium channel ligand. A dopamine agonist is a more appropriate choice in the presence of depression and overweight. As α-2-δ ligands can alleviate chronic pain and may be helpful in treating anxiety and insomnia, the presence of any of these comorbidities may favor their use. For RLS present through much of the day and night, the use of long-acting agents, such as the rotigotine patch or gabapentin enacarbil should be considered. In refractory RLS, oral prolonged release oxycodone–naloxone should be considered.