Andrea Galbiati

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.

Behavioural and Cognitive-Behavioural Treatments of Parasomnias.

Parasomnias are unpleasant or undesirable behaviours or experiences that occur predominantly during or within close proximity to sleep. Pharmacological treatments of parasomnias are available, but their efficacy is established only for few disorders. Furthermore, most of these disorders tend spontaneously to remit with development. Nonpharmacological treatments therefore represent valid therapeutic choices. This paper reviews behavioural and cognitive-behavioural managements employed for parasomnias. Referring to the ICSD-3 nosology we consider, respectively, NREM parasomnias, REM parasomnias, and other parasomnias. Although the efficacy of some of these treatments is proved, in other cases their clinical evidence cannot be provided because of the small size of the samples. Due to the rarity of some parasomnias, further multicentric researches are needed in order to offer a more complete account of behavioural and cognitive-behavioural treatments efficacy.

Neurocognitive function in patients with idiopathic Restless Legs Syndrome before and after treatment with dopamine-agonist.

Although a huge amount of clinical evidence for Restless Legs Syndrome (RLS) is present in literature, an exhaustive account of cognitive profile in RLS patients is still lacking. In this study we evaluated the neurocognitive function in RLS patients and the effects of a three-month treatment with a dopamine agonist (pramipexole) at low doses. Clinical and polysomnographic characteristics, cognitive abilities, quality of life and psychological clinical indices were assessed in 20 RLS patients and 15 age-matched controls. The neurocognitive results, obtained by untreated RLS patients (baseline), were firstly compared to those of controls and then to those of the same RLS group after treatment (follow-up). Increased Total Sleep Time, Slow Wave Sleep, Sleep Efficiency and decreased Sleep Latency, Wake After Sleep Onset and periodic leg movement index were found by polysomnographic recording after a three-month treatment. Results showed that cognitive functions, impaired at baseline when compared to control subjects, improved after the pharmacological treatment, reaching the scores of healthy subjects. Decision making, problem solving and categorizing abilities, investigated by the Iowa Gambling Task (IGT) and the Wisconsin Card Sorting Test (WCST), resulted lower in RLS patients at baseline than in controls. All these functions improved after pharmacological treatment, as well as quality of life, depressive and anxiety symptoms, and daytime sleepiness.

Validation study of the Italian version of the Insomnia Severity Index (ISI).

To test the factorial structure of the Italian version of the Insomnia Severity Index (ISI) using a confirmatory approach and to assess its psychometric properties. ISI questionnaire was completed by 272 patients (average age 41.28, range 18–73) with insomnia diagnosis performed by a sleep medicine physician and retrospectively enrolled in the study. All patients underwent Cognitive Behavioral Treatment for Insomnia (CBT-I) and completed sleep diaries before starting the treatment. Data from sleep diaries were analyzed for assessing concurrent validity of the ISI. Confirmatory factor analysis (CFA) for ordinal Likert-type items was applied to compare four competing models proposed in the literature. 244 patients, out of the 272, completed the ISI at the end of CBT-I. A comparison of ISI score before and after treatment was performed. The CFA analysis confirmed the presence of three main factors conceptualized as severity and impact of the disease along with sleep satisfaction. Significant correlations of the first three items of the questionnaire, investigating three different subtypes of insomnia, and the subjective measures from the sleep diaries were found, thus supporting the concurrent validity of the test. Sleep efficiency (SE) had a significant inverse correlation with the severity and satisfaction factors and with ISI’s total score. After CBT-I treatment, a significant reduction of ISI’s scores was observed, thus confirming the effectiveness of the CBT-I treatment. The internal reliability coefficient was 0.75. The ISI questionnaire maintains good psychometric properties in the Italian version, thus confirming that this instrument is reliable for detecting insomnia severity and identifying patients’ symptoms.

Sleep microstructure and memory function

Several studies investigated the effect of sleep on memory. In humans, arguably the first experimental description of a ben-eficial role of sleep for memory stabiliza-tion was provided in 1924 (1), indicating a protective benefit of sleep in prevent-ing the normal decay-curve of forgetting that develops across time spent awake. Specific stages of sleep appear to be criti-cal for memory consolidation. Memory is commonly divided into a declarative and a non-declarative memory system (2). Declarative memory is defined by memo-ries accessible to conscious recollection, i.e., memories for events in a spatio-tem-poral context (episodic memory) and fact-based information (semantic memory). Procedural memory for skills is the type of non-declarative memory most thoroughly studied with regard to the effects of sleep. Sleep is characterized by the cyclic occur-rence of REM and NREM sleep comprising SWS (sleep stages 3 and 4) and lighter sleep stages 1 and 2. Two hypotheses were pro-posed regarding sleep stages and memory consolidation (3). The dual process the-ory assumes that the specific sleep stages support consolidation of different types of memories. SWS supports declarative memory consolidation whereas REM sleep does so for procedural memories ( 4). The sequential hypothesis, on the other hand, proposes that sleep benefits memory opti-mally through the cyclic succession of both SWS and REM sleep. The original version of this hypothesis assumed that SWS func-tions to weaken non-adaptive memory traces whereas REM sleep re-stores the remaining traces (5). The dual process hypothesis received support mainly based on the early late sleep comparison, i.e., an approach comparing effects of retention intervals covering the first (SWS-rich) or the second (REM sleep-rich) half of nocturnal sleep. SWS-rich early sleep con-sistently found to support consolidation of hippocampus-dependent declarative memories, whereas REM sleep benefited non-declarative types of memory like priming, and memories for visuo-motor skills ( 6, 7). However, this dichotomy does not fit all results. Several non-declarative tasks, like visual texture discrimination, are also supported by SWS whereas REM sleep in some instances seems to benefit aspects of declarative memory (8).More recently, Genzel and colleagues (9) tried to clarify the link between spe-cific sleep stages and different types of memory consolidation by suppressing sleep stages. They deprived subjects once each of REM sleep and SWS, and once let them sleep undisturbed through the night. After each night, the authors tested declarative and procedural memory con-solidation. Although REM sleep and SWS awakenings led to a significant reduction of the respective sleep stages, memory con-solidation remained unaffected. According to the authors, there are two possible explanations for REM deprivation and SWS deprivation not influencing sleep-dependent consolidation of motor tasks: (1) the diminished amount of REM sleep in the REM deprivation condition was still sufficient for sleep-dependent memory consolidation or (2) the memory con-solidation is dependent on stage 2 sleep. Another explanation of the results is that sleep-associated processes contributing to memory consolidation requires analyses of polysomnographic phenomena, like sleep spindles and slow-wave activity (SWA). This aspect is very important also for the implications for the cognitive decline by increasing age (10, 11). Other factors that change with age, such as hormones and neurotransmitters, or hypoxia related to sleep-disordered breathing (12, 13), may also play an important role.

Clinical pharmacology and efficacy of rotigotine (Neupro® patch) in the treatment of restless leg syndrome.

ABSTRACT Introduction: Restless legs syndrome/Willis Ekbom disease (RLS/WED) is a sensorimotor disorder characterized by unpleasant sensations in the legs accompanied by an urge to move them, that typically occurs and tend to worsen in the evening/night or during period of inactivity. Standard medications for RLS/WED are dopamine agonists and calcium channel α-2-δ ligands. The clinical spectrum of RLS/WED is very broad, ranging from individuals suffering from the disease during limited periods up to those severely affected, with daily symptoms. In such cases a long-acting drug like rotigotine should be considered. Areas covered: The clinical pharmacology and efficacy of rotigotine was examined to evaluate the evidence supporting its use in RLS/WED. Expert opinion: The rotigotine transdermal patch provides constant delivery of the drug, maintaining a stable plasma concentration over 24 hours by means of a single daily application. Several randomized, double-blind, placebo-controlled trials have demonstrated the efficacy of rotigotine in improving moderate-to-severe RLS/WED symptoms. Rotigotine is generally well tolerated. The most common adverse effects were application-site reactions, dose-dependent, more frequently reported in the first period of treatment. Incidence of augmentation in RLS/WED patients treated with oral dopamine agonists is higher when compared with the use of transdermal rotigotine.

REM sleep behaviour disorder

Rapid Eye Movement (REM) sleep Behaviour Disorder (RBD) is a REM sleep parasomnia characterized by loss of the muscle atonia that typically occurs during REM sleep, therefore allowing patients to act out their dreams. RBD manifests itself clinically as a violent behaviour occurring during the night, and is detected at the polysomnography by phasic and/or tonic muscle activity on the electromyography channel. In absence of neurological signs or central nervous system lesions, RBD is defined as idiopathic. Nevertheless, in a large number of cases the development of neurodegenerative diseases in RBD patients has been described, with the duration of the follow-up representing a fundamental aspect. A growing number of clinical, neurophysiologic and neuropsychological studies aimed to detect early markers of neurodegenerative dysfunction in RBD patients. Anyway, the evidence of impaired cortical activity, subtle neurocognitive dysfunction, olfactory and autonomic impairment and neuroimaging brain changes in RBD patients is challenging the concept of an idiopathic form of RBD, supporting the idea of RBD as an early manifestation of a more complex neurodegenerative process.

Treatment Options in Intractable Restless Legs Syndrome/Willis-Ekbom Disease (RLS/WED)

Opinion statementRestless Legs Syndrome/Willis-Ekbom Disease (RLS/WED) is a common condition characterized by an irresistible urge to move the legs, concomitant with an unpleasant sensation in the lower limbs, which is typically relieved by movement. Symptoms occur predominantly at rest and prevail in the afternoon or evening. Treatment of patients with RLS/WED is indicated for those patients who suffer from clinically relevant symptoms. The management of mild forms of RLS/WED is mainly based on dopamine agonists (DA) therapy (including pramipexole and ropinirole) and α-2-δ calcium-channel ligand. Nevertheless, with passing of time, symptoms tend to become more severe and the patient can eventually develop pharmacoresistance. Furthermore, long-term treatment with dopaminergic agents may be complicated by the development of augmentation, which is defined by an increase in the severity and frequency of RLS/WED symptoms despite adequate treatment. Here, we discuss which are the best therapeutic options when RLS/WED becomes intractable, with a focus on advantages and side effects of the available medications. Prevention strategies include managing lifestyle changes and a good sleep hygiene. Different drug options are available. Switching to longer-acting dopaminergic agents may be a possibility if the patient is well-tolerating DA treatment. An association with α-2-δ calcium-channel ligand is another first-line approach. In refractory RLS/WED, opioids such as oxycodone–naloxone have demonstrated good efficacy. Other pharmacological approaches include IV iron, benzodiazepines such as clonazepam, and antiepileptic drugs, with different level of evidence of efficacy. Therefore, the final decision regarding the agent to use in treating severe RLS/WED symptoms should be tailored to the patient, taking into account the symptomatology, comorbidities, the availability of treatment and the history of the disease.

Neurological Deficits in Obstructive Sleep Apnea

Opinion statementObstructive sleep apnea (OSA) is the most common sleep-related breathing disorder characterized by repetitive episodes of complete or partial obstruction of the upper airway. The prevalence of this disorder is strictly dependent on its gravity. At ≥15 events/h apnea–hypopnea index (AHI), it ranges from 6 to 17% in the general population, with higher rates in men and increasing with age. The hypoxia induced by OSA severely affects the structure and function of blood vessels, culminating in mortality and morbidity. Its negative impact influences also cognitive functioning. Recent papers showed the relationship between OSA and some neurological disorders, such as neurodegenerative diseases, stroke, epilepsy, and headache. OSA may accelerate the onset of mild cognitive impairment and Alzheimer’s disease (AD) and might also represent an independent risk factor for Parkinson’s disease (PD). OSA is also frequent in multisystem atrophy. In the early stages of AD, continuous positive airway pressure (CPAP) treatment might slow down the progression of the disease, thus highlighting the potential importance of OSA screening and a timely intervention in these patients. Moreover, CPAP is effective in reducing daytime sleepiness in PD. OSA may induce seizures by means of sleep disruption and deprivation, as well as cerebral hypoxemia with consequent oxidative stress. It has been demonstrated that CPAP treatment is efficacious in controlling epileptic seizures. OSA can represent a risk factor for stroke and death, mainly related to the endothelial dysfunction, with the formation of atherosclerosis caused by hypoxia through oxidative stress. CPAP treatment in patients with OSA and stroke, if delivered in the early stages, is able to increase the magnitude of neurologic improvement after the vascular accident. There is a strong association between OSA and headache. In particular, there is a “sleep apnea headache” described as a recurrent morning headache, with resolution after effective treatment of sleep apnea. This review clearly shows the importance of taking a sleep history in neurological patients and considering the diagnosis and specific treatment of OSA in these patients.

Impaired visual processing in patients with insomnia disorder revealed by a dissociation in visual search

Insomnia disorder is associated with both subjective and objective daytime impairments. In particular, cognitive impairments are frequently reported. However, little is known about the effects of this pathology on perceptual processes. In this study we aim at evaluating the effect of insomnia disorder on visual processing by employing a visual search paradigm. Twenty‐three patients with insomnia disorder and 20 healthy age‐ and sex‐matched control subjects participated in the study. After a polysomnographic recording night patients performed a visual search task in which they had to respond to the presence/absence of a target (letter T) embedded into a set of distractors (letters Os, Xs or Ls). Targets salience and distractors’ numerosity were manipulated, while accuracy and reaction times were recorded as dependent variables. The results mainly confirmed the typical effects of a visual search task. An overall delay in performing the task was observed for patients with insomnia disorder. However, distinguishing the reaction times to stimuli containing the target from reaction times to stimuli in which the target was absent, the clinical group differed from controls solely in the condition of target absent. The performance (reaction times) of the subjects correlated with the age in the control group, whereas no correlation between reaction times and age, disease duration and quality of sleep was found in patients with insomnia disorder. These results experimentally demonstrate the presence of a daytime impairment in patients with insomnia disorder revealed by a dissociation in visual search, and are discussed in the light of the hyperarousal concept of insomnia.