Luigi Ferini-Strambi

Restless legs syndrome and pregnancy

Objective: To perform a large and detailed epidemiologic study on restless legs syndrome (RLS) during pregnancy and the puerperium. Methods: A structured clinical interview, assessing symptoms since the beginning of pregnancy, was performed to a population of 642 pregnant women at the time of delivery and at follow-up evaluation (1, 3, and 6 months after delivery). Main hematologic tests were also evaluated. A woman was considered affected if she met the International RLS Study Group criteria for RLS diagnosis. Results: Twenty-six percent of women were affected by RLS during their pregnancy. The disease was strongly related to the third trimester of pregnancy and tended to disappear reaching the time of delivery. Affected women presented lower values of hemoglobin and mean corpuscular volume compared with healthy subjects (both groups received the same supplemental iron and folate therapy). Conclusions: Pregnancy is associated with transient restless legs syndrome.

Cognitive dysfunction in patients with obstructive sleep apnea (OSA): partial reversibility after continuous positive airway pressure (CPAP).

The aims of this study were to assess cognitive function in obstructive sleep apnea (OSA) patients and to evaluate the effect of short- and long-term treatment with continuous positive airway pressure treatment (CPAP). A battery of neuropsychological tests, the Epworth Sleepiness Scale (ESS), and the Beck Inventory Scale were administered to 23 patients with severe OSA (age: 56.5+/-6.13; AHI: 54.9+/-13.37) and to 23 age- and education-matched controls. The OSA patients were evaluated in a baseline condition and in two follow-up treatment sessions (after 15 days and 4 months of CPAP, respectively). At baseline, OSA patients had a significant impairment, compared to controls, in tests of sustained attention, visuospatial learning, executive function, motor performance, and constructional abilities. The longitudinal evaluation showed that after a 15-days CPAP treatment attentive, visuospatial learning, and motor performances returned to normal levels. A 4-months CPAP treatment did not result in any further improvement in cognitive tests. Performance on tests evaluating executive functions and constructional abilities was not affected by short- and long-term treatment with CPAP. The findings of this study confirm the hypothesis of partial reversibility of cognitive dysfunction in OSA patients after CPAP.

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.

Restless legs syndrome: prevalence and impact in children and adolescents--the Peds REST study.

OBJECTIVES. Restless legs syndrome, a common neurologic sleep disorder, occurs in 5% to 10% of adults in the United States and Western Europe. Although ∼25% of adults with restless legs syndrome report onset of symptoms between the ages of 10 and 20 years, there is very little literature looking directly at the prevalence in children and adolescents. In this first population-based study to use specific pediatric diagnostic criteria, we examined the prevalence and impact of restless legs syndrome in 2 age groups: 8 to 11 and 12 to 17 years. METHODS. Initially blinded to survey topic, families were recruited from a large, volunteer research panel in the United Kingdom and United States. Administration was via the Internet, and results were stratified by age and gender. National Institutes of Health pediatric restless legs syndrome diagnostic criteria (2003) were used, and questions were specifically constructed to exclude positional discomfort, leg cramps, arthralgias, and sore muscles being counted as restless legs syndrome. RESULTS. Data were collected from 10523 families. Criteria for definite restless legs syndrome were met by 1.9% of 8- to 11-year-olds and 2.0% of 12- to 17-year-olds. Moderately or severely distressing restless legs syndrome symptoms were reported to occur ≥2 times per week in 0.5% and 1.0% of children, respectively. Convincing descriptions of restless legs syndrome symptoms were provided. No significant gender differences were found. At least 1 biological parent reported having restless legs syndrome symptoms in >70% of the families, with both parents affected in 16% of the families. Sleep disturbance was significantly more common in children and adolescents with restless legs syndrome than in controls (69.4% vs 39.6%), as was a history of “growing pains” (80.6% vs 63.2%). Various consequences were attributed to restless legs syndrome, including 49.5% endorsing a “negative effect on mood.” Data were also collected on comorbid conditions and restless legs diagnosis rates. CONCLUSIONS. These population-based data suggest that restless legs syndrome is prevalent and troublesome in children and adolescents, occurring more commonly than epilepsy or diabetes.

Autosomal dominant nocturnal frontal lobe epilepsy - A critical overview

Abstract.Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is an idiopathic epilepsy, with a spectrum of clinical manifestations, ranging from brief, stereotyped, sudden arousals to more complex dystonic–dyskinetic seizures. Video–polysomnography allows a correct differential diagnosis. There is no difference between sporadic nocturnal frontal lobe epilepsy (NFLE) and ADNFLE in the clinical and neurophysiological findings. ADNFLE is the first idiopathic epilepsy for which a genetic basis has been identified. Mutations have been found in two genes (CHRNA4 and CHRNB2) coding for neuronal nicotinic receptor subunits (α4 and β2, respectively). Contrasting data have been reported on the effect of these mutations on the functionality of the receptor.Moreover, the incomplete data on the neuronal network/s in which this receptor is involved, make difficult the understanding of the genotype–phenotype correlation. This is an overview on the clinical and genetic aspects of ADNFLE including a discussion of some open questions on the role of the neuronal nicotinic receptor subunit mutations in the pathogenesis of this form of epilepsy.

Efficacy of rotigotine for treatment of moderate-to-severe restless legs syndrome: a randomised, double-blind, placebo-controlled trial

BACKGROUND Continuous administration of a dopamine agonist could be used to treat patients with restless legs syndrome. Our aim was to investigate the efficacy of transdermal rotigotine in the treatment of idiopathic restless legs syndrome. METHODS In this randomised, double-blind, placebo-controlled trial, 458 patients with moderate-to-severe idiopathic restless legs syndrome (average baseline International Restless Legs Syndrome Study Group severity rating scale [IRLS] sum score of 28.1) were randomly assigned to receive transdermal rotigotine 1 mg over 24 h (n=115), 2 mg over 24 h (n=112), or 3 mg over 24 h (n=114), or to receive placebo (n=117). Study medication was delivered via patches, applied once a day for 6 months. Randomisation was done with a computer-generated randomisation list, stratified by centre. Primary efficacy outcomes were absolute change from baseline to end of maintenance in IRLS sum score and in the clinical global impressions (CGI) item 1 score, assessed by analysis of covariance in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT00136045. FINDINGS Efficacy analyses were done on 112 patients in the 1 mg group, 109 in the 2 mg group, 112 in the 3 mg group, and 114 in the placebo group. Mean change in IRLS sum score from baseline at the end of the maintenance phase was -13.7 (SE 0.9) in the 1 mg group, -16.2 (0.9) in the 2 mg group, -16.8 (0.9) in the 3 mg group, and -8.6 (0.9) in the placebo group (p<0.0001 for treatment difference vs placebo with each dose). Mean change in CGI item 1 score from baseline at the end of the maintenance phase was -2.09 (0.14) in the 1 mg group, -2.41 (0.14) in the 2 mg group, -2.55 (0.14) in the 3 mg group, and -1.34 (0.14) in the placebo group (p<0.0001 for treatment difference vs placebo with each dose). Skin reactions, mostly mild or moderate, were seen in 145 (43%) of 341 patients who received rotigotine and in two (2%) of 117 who received placebo. Ten patients had serious adverse event that were deemed to be related to rotigotine: elevation of liver enzymes (one patient), worsening of tinnitus (one patient), non-response to anticoagulation (one patient), electrocardiogram changes (one patient), and application-site reactions (six patients). No admissions to hospital were needed for the application-site reactions, and they all resolved within a short time of patch removal without any other therapeutic intervention. The rate of typical dopaminergic side-effects in patients who received rotigotine was low; no signs of augmentation were noted. INTERPRETATION 24 h transdermal delivery of low-dose rotigotine could be used to relieve the night-time and daytime symptoms of restless legs syndrome. FUNDING Schwarz Biosciences.

Neuropsychological assessment in idiopathic REM sleep behavior disorder (RBD): Does the idiopathic form of RBD really exist?

Objective: To evaluate the cognitive performance of patients with idiopathic REM sleep behavior disorder (RBD). Methods: The authors studied 17 consecutive patients with idiopathic RBD vs 17 age- and education-matched control subjects. Tests given to each patient and control included Mini-Mental State Examination, verbal and spatial short-term memory, visual selective attention, verbal fluency, prose memory, visuoconstructional abilities, spatial learning, and executive function tests. A self-administered depression rating scale was also used. Results: RBD patients had significantly lower scores than control subjects in two tests: copy of Rey–Osterrieth Figure and Corsi Supraspan Learning. No correlation was found between the results of neuropsychological tests and RBD duration or with polysomnographic findings. Conclusions: Visuospatial constructional dysfunction and altered visuospatial learning may be present in idiopathic RBD. A neuropsychological assessment may be indicated in RBD patients.

Italian version of the Epworth sleepiness scale: external validity

Abstract. We assessed the validity of an Italian language version of the Epworth sleepiness scale (ESS). The translated ESS was compared to the multiple sleep latency test (MSLT), considered the gold standard for the diagnosis of excessive daytime sleepiness (EDS). Within the context of a multicentric national study on narcolepsy (Gruppo Italiano Narcolessia Studio Epidemiologico Nazionale, GINSEN) involving 17 Italian sleep centres, we compared the two diagnostic tests on 91 prospectively recruited subjects with suspected EDS (34 with narcolepsy, 16 with obstructive sleep apnea syndrome, 19 with idiopathic hypersomnia, and 22 with other sleep, neurologic or psychiatric disorders). ESS scores were inversely correlated with mean sleep latency values, as measured with MSLT (rho = −0.31, p<0.01). ESS cut-off scores with best sensitivity and specificity were 12 and 17. For the 5-min MSLT cut-off, sensitivity was 87% and 47% respectively; specificity 39% and 74%. For the 8-min MSLT cut-off, sensitivity was 84% and 49%; specificity 50% and 88%. The Italian version of the ESS is an easy-to-use form useful for preliminary screening of daytime sleepiness level in specialist settings.

Nocturnal sleep study in multiple sclerosis: Correlations with clinical and brain magnetic resonance imaging findings

It has been suggested that sleep disturbances in multiple sclerosis (MS) may be related to periodic leg movements (PLM) during sleep, but to date polysomnographic studies were conducted only on small and unselected patient groups. Aim of this study was to evaluate 8-hour polysomnography in MS patients and to correlate sleep results with clinical and brain magnetic resonance imaging (MRI) data. Twenty-five clinically definite MS patients, without mood disorders and drug-free, entered the study. The patients were compared to 25 age- and sex-matched subjects. MS patients had significantly reduced sleep efficiency and experienced more awakenings during sleep. No difference was found in sleep architecture parameters between MS patients and controls. PLM was found in 9 patients (36%) and 2 controls (8%; p = 0.02). Of the six patients who complained of insomnia two had PLM and 2 others presented with PLM and central sleep apnea. In patients with PLM greater MRI lesion loads were detected in the infratentorial regions, particularly in cerebellum and brainstem. Larger studies in neurological diseases that produce focal lesions in these brain areas could provide useful information on the PLM pathogenesis.

Aggressive dream content without daytime aggressiveness in REM sleep behavior disorder

Background: REM sleep behavior disorder (RBD) is characterized by vigorous sleep motor activity associated with dream mentation. Patients with RBD frequently report action-filled and violent dreams. Objective: To systematically assess dream characteristics and daytime aggressiveness in patients with RBD and controls. Methods: Forty-nine patients with polysomnographic-confirmed RBD diagnosis and 71 age- and sex-matched controls were asked to recall the most recent dreams and to complete the Aggression Questionnaire (AQ). Forty-one patients with RBD (81.6%; 36 men, 5 women; mean age: 67.5 ± 7.5 years) and 35 controls (49.3%; 30 men, 5 women; mean age: 69.1 ± 5.9 years) were able to remember their dreams and a total of 98 (RBD) and 69 (controls) dreams were collected in the two groups. Verbatim dream descriptions were scored and analyzed according to the Hall and Van De Castle method. Results: Patients with RBD showed a higher percentage of dream with at least one aggressive episode (DWA) than controls (66% vs 15%; p < 0.00001), a higher aggression/friendliness interaction ratio (86% vs 44%; p < 0.0001), and a greater frequency of animal characters (19% vs 4%; p = 0.0001). In contrast to controls, no patient with RBD had dreams with elements of sexuality (0% vs 9%; p < 0.0001). The two groups did not differ in total AQ scores, except for a lower score on the physical aggressiveness subscale in patients with RBD compared to control subjects (16.5 ± 6.4 vs 20.4 ± 8.3; p = 0.034). No correlation was observed between dream aggressiveness and age, duration, or frequency of RBD symptoms. Conclusions: Dreams in patients with REM sleep behavior disorder were characterized by an elevated proportion of aggressive contents, despite normal levels of daytime aggressiveness. Dreams with aggressiveness and the known excessive phasic muscle activity during REM sleep may be related to the hyperactivity of a common neuronal generator.