NEURO-COVAX: An Italian Population-Based Study of Neurological Complications after COVID-19 Vaccinations.

OBJECTIVE: In this Italian population-based study, we aimed to evaluate the neurological complications after the first and/or second dose of COVID-19 vaccines and factors potentially associated with these adverse effects. METHODS: Our study included adults aged 18 years and older who received two vaccine doses in the vaccination hub of Novegro (Milan, Lombardy) between 7 and 16 July 2021. The NEURO-COVAX questionnaire was able to capture the neurological events, onset and duration. That data that were digitized centrally by the Lombardy region were used to match the demographic/clinical characteristics and identify a vulnerability profile. Associations between vaccine lines and the development of complications were assessed. Digital healthcare system matching was also performed to evaluate severe neurological complications (Guillain-Barrè syndrome, Bell's palsy, transverse myelitis, encephalitis) and the incidence of hospital admissions and/or the mortality rate after two doses of the vaccines. RESULTS: The NEURO-COVAX-cohort included 19.108 vaccinated people: 15.368 with BNT162b2, 2077 with mRNA-1273, 1651 with ChAdOx1nCov-19, and 12 with Ad26.COV2.S who were subsequently excluded. Approximately 31.2% of our sample developed post-vaccination neurological complications, particularly with ChAdOx1nCov-19. A vulnerable clinical profile emerged, where over 40% of the symptomatic people showed comorbidities in their clinical histories. Defining the neurological risk profile, we found an increased risk for ChAdOx1nCov-19 of tremors (vs. BNT162b2, OR: 5.12, 95% CI: 3.51-7.48); insomnia (vs. mRNA-1273, OR: 1.87, 95% CI: 1.02-3.39); muscle spasms (vs. BNT162b2, OR: 1.62, 95% CI: 1.08-2.46); and headaches (vs. BNT162b2, OR: 1.49, 95% CI: 0.96-1.57). For mRNA-1273, there were increased risks of parethesia (vs. ChAdOx1nCov-19, OR: 2.37, 95% CI: 1.48-3.79); vertigo (vs. ChAdOx1nCov-19, OR: 1.68, 95% CI: 1.20-2.35); diplopia (vs. ChAdOx1nCov-19, OR: 1.55, 95% CI: 0.67-3.57); and sleepiness (vs. ChAdOx1nCov-19, OR: 1.28, 95% CI: 0.98-1.67). In the period that ranged from March to August 2021, no one was hospitalized and/or died of severe complications related to COVID-19 vaccinations. DISCUSSION: This study estimates the prevalence and risk for neurological complications potentially associated with COVID-19 vaccines, thus improving the vaccination guidelines and loading in future personalized preventive medicine.

In Situ Equilibrium Polyethylene Passive Sampling of Soil Gas VOC Concentrations: Modeling, Parameter Determinations, and Laboratory Testing.

The use of low-density polyethylene (PE) sheets as equilibrium passive soil gas samplers to quantify volatile organic compounds (VOCs) such as benzene, toluene, ethylbenzene, and xylenes, and chlorinated solvents (e.g., trichloroethene and tetrachloroethene) in unsaturated subsurface environments was evaluated via modeling and benchtop testing. Two methods were devised to quantify such VOCs in PE. Key chemical properties, including PE-water (KPEw) and PE-air (KPEa) partition coefficients and diffusivities in the PE (Dpe), were determined. These KPEw, KPEa, and Dpe values were consistent with extrapolations of data based on larger compounds. Using these parameter values, field equilibration times of less than 1 day were estimated for such VOCs when using 70-100 µm thick PE sheets. Further, benchtop batch tests carried out in jars filled with VOC-contaminated soils, after 1 or 2 days, showed concentrations in soil air deduced from PE that were consistent with concentrations deduced by analyzing either water or headspace gases recovered from the same tests. Thus, PE-based measurements may overcome inaccuracies from using total soil concentrations and equilibrium partitioning models that may overestimate vapor phase concentrations up to 2 orders of magnitude.

National validation and proposed revision of REM sleep behavior disorder screening questionnaire (RBDSQ).

We validated the Italian version of the rapid eye movement sleep behavior disorder (RBD) screening questionnaire (RBDSQ) and calculated its cut-off value for discriminating RBD group from other sleep disorders and healthy controls (HC). 380 patients with sleep disorders and 101 HC were enrolled. RBDSQ achieved an acceptable Cronbach's α value of 0.787 and item 10 was the only one with a very low item-total biserial correlation (0.141). At ROC analysis, we obtained an AUC of 0.888, denoting a good performance of the RBDSQ total score for predicting the RBD status. The optimal cut-off value was 8 and it achieved good values of both sensitivity and specificity (0.842 and 0.780, respectively). Due to the poor performance of item 10 in our sample, we analyzed the RBDSQ without this item (called "revised RBDSQ"). We obtained a good Cronbach's α of 0.802. When evaluating the performance of the revised score in predicting the RBD status, we obtained an increased value of AUC (0.899). The optimal cut-off value was still 8 (sensitivity = 0.829; specificity = 0.820). The Italian version of RBDSQ is a sensitive tool for the identification of RBD patients. An improvement of the instrument could be obtained by removing item 10 and define a higher cut-off value of 8. The "revised RBDSQ" represents a reliable screening questionnaire for primary care physicians and neurologists and its employment may facilitate the choice of subjects that should undergo a PSG that confirms the diagnosis of RBD, thus avoiding polysomnographic exams when not needed.

Relevance of the bioavailable fraction of DDT and its metabolites in freshwater sediment toxicity: New insight into the mode of action of these chemicals on Dictyostelium discoideum.

In this work, the toxicity of lake sediments contaminated with DDT and its metabolites DDD and DDE (collectively, DDX) was evaluated with widely used toxicity tests (i.e., Vibrio fischeri, Daphnia magna, Pseudokirchneriella subcapitata, and Lumbriculus variegatus) and with the social amoeba Dictyostelium discoideum, a model organism that is also suitable for studying pollutant-induced alterations at the molecular and cellular levels. Although the DDX concentration in the sediments was high (732.5 ppb), the results suggested a minimal environmental risk; in fact, no evidence of harmful effects was found using the different bioassays or when we considered the results of more sensitive sublethal biomarkers in D. discoideum amoebae. In line with the biological results, the chemical data showed that the concentration of DDX in the pore water (in general a highly bioavailable phase) showed a minimal value (0.0071ppb). To confirm the importance of the bioavailability of the toxic chemicals in determining their biological effects and to investigate the mechanisms of DDX toxicity, we exposed D. discoideum amoebae to 732.5ppb DDX in water solution. DDX had no effect on cell viability; however, a strong reduction in amoebae replication rate was observed, which depended mainly on a reduction in endocytosis rate and on lysosomal and mitochondrial alterations. In the presence of a moderate and transient increase in reactive oxygen species, the glutathione level in DDX-exposed amoebae drastically decreased. These results highlight that studies of the bioavailability of pollutants in environmental matrices and their biological effects are essential for site-specific ecological risk assessment. Moreover, glutathione depletion in DDX-exposed organisms is a new finding that could open the possibility of developing new pesticide mixtures that are more effective against DDT-resistant malaria vectors.

Defining the phenotype of restless legs syndrome/Willis-Ekbom disease (RLS/WED): a clinical and polysomnographic study.

Clinical features variability between familial and sporadic restless legs syndrome/Willis-Ekbom disease (RLS/WED) has been previously reported. With this retrospective cohort study, we aimed to determine the clinical and polysomnographic characteristics of 400 RLS/WED patients. Patients with familial RLS/WED were significantly younger than sporadic RLS/WED, while clinical and polysomnographic characteristics were similar in both groups. No difference was found for the age-at-onset between idiopathic and secondary RLS/WED. Periodic limb movements (PLM) index and REM sleep time were higher in idiopathic RLS/WED. Time of onset of symptoms was in the evening or at bedtime in 28.04 and 37.80% of patients, respectively, while in 21.34% of patients onset was more than 1 h after sleep onset. Impulse control and compulsive behaviours (ICBs) were found in 13.29% patients on dopamine agonist therapy. Our analyses support the hypothesis that patients with a familial history of RLS/WED may have a genetic component. Nevertheless, the dichotomy between early and late onset disease seems to be less sharp than previously reported. A large proportion of RLS/WED patients can have atypical features, therefore making the diagnosis challenging. Some cases can be missed even when the patient refers to a sleep specialist, as revealed by the partial absence of daytime symptoms, the high comorbidity with insomnia and other sleep complaints and the high percentage of symptoms beginning after sleep onset. This draws attention on the importance of a careful evaluation of the patient, to recognize potentially treatable secondary forms of RLS/WED.

New data on psychological traits and sleep profiles of patients affected by nocturnal eating.

OBJECTIVE: Nocturnal eating behavior is shared by patients affected by a parasomnia, sleep-related eating disorder (SRED), and several eating disorders such as night eating syndrome (NES) and binge-eating disorder (BED); however, the differential clinical features of these patients have been poorly studied, with persisting difficulties in defining the borders between these pathologies. The aim of this study was to evaluate polysomnographic and personality characteristics of nocturnal eaters to further differentiate the syndromes. METHODS: During a period of six months, consecutive patients complaining of nocturnal eating were asked to participate to the study. Twenty-four patients who were found to eat during the polysomnographic recording (PSG) study, and gender-matched control subjects were included. All subjects underwent a full-night video-PSG study and a psychometric assessment including the Eating Disorder Inventory (EDI-2), the self-rating Bulimic Investigatory Test-Edinburgh (BITE), the Temperament and Character Inventory (TCI), and the Barratt Impulsivity Scale (BIS). RESULTS: Nocturnal eaters showed a mild reduction in sleep efficiency and duration due to a moderate sleep fragmentation, whereas the percentage of each sleep stage was not significantly affected. Nocturnal eaters scored higher at many subscales of the EDI-2, at the BITE symptoms subscale, and at the BIS attentional impulsivity subscale. CONCLUSION: The psychological characteristics found in our patients with NES seem to be typical for patients affected by eating disorders, and support the hypothesis that the nocturnal behavior of these individuals is due to an eating disorder; however, specific traits also allow differentiation of NES from BED.

Restless legs syndrome/Willis Ekbom disease: new diagnostic criteria according to different nosology.

Restless Legs Syndrome/Willis Ekbom Disease (RLS/WED) is a common neurological disorder characterized by uncomfortable and unpleasant sensations in the legs, with an urge to move. The symptoms typically begin or worsen during periods of rest, in particular during the evening and at night, while the activity may typically relieve them. The majority of patients complains of poor sleep. Recent studies reported the prevalence is ranging from 5 to 10%. RLS/WED can be divided into primary (patients without associated conditions that may explain the symptoms) and secondary forms (mostly iron deficiency). RLS/WED is typically a chronic condition. The clinical course varies according to the age of onset. A great load of accumulating research and clinical data have led to an extended consensus for a need to enhance the diagnostic criteria. The aim of this paper is to provide a critical comparison among different diagnostic criteria, taking into account respectively the International Classification of Sleep Disorders (ICSD), the International RLS Study Group (IRLSSG) and the Diagnostic and Statistical Manual of Mental Disorders (DSM). There are several remarkable distinctions between the IRLSSG revised criteria, ICSD-3 and DSM-V. Contrary to the DSM-V criteria, ICSD-3 diagnostic criteria are more aligned to the IRLSSG ones. In fact, the five essential criteria of the IRLSSG are also required for the diagnosis of RLS/WED according to ICSD-3. The new IRLSSG criteria provide a more rigorous approach to case ascertainment and a better characterization of patients by specifying clinical significance and course. Future ascertainment of correct diagnosis should include documentation that all five diagnostic criteria are considered.

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.

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.

Pramipexole versus ropinirole: polysomnographic acute effects in restless legs syndrome.

BACKGROUND: Pramipexole and ropinirole have become the first-line treatment for restless legs syndrome. The aim of this study was to perform the first direct comparison between these two molecules in restless legs syndrome. METHODS: A double-blind, placebo-controlled, double-night and prospective investigation was carried out in 45 consecutive naïve patients with idiopathic restless legs syndrome. Each patient underwent two consecutive full-night polysomnographies: the first baseline recording was performed without premedication and, before the second recording, first group received a single oral dose of 0.25 mg pramipexole, second group a single oral dose of 0.5 mg ropinirole, and the remaining patients received placebo. RESULTS AND DISCUSSION: Both dopamine agonists improved restless legs syndrome symptoms and markedly suppressed periodic leg movements during sleep compared to placebo, without significant differences between pramipexole and ropinirole. No significant side effects, except for mild morning nausea (2 patients treated with ropinirole, 3 with pramipexole, and 1 with placebo), were reported.

Effects of acute dopamine-agonist treatment in restless legs syndrome on heart rate variability during sleep.

OBJECTIVE: To compare heart rate variability (HRV) changes in patients with restless legs syndrome (RLS) and in healthy subjects, and to evaluate HRV before and after treatment with pramipexole in RLS patients. METHODS: A prospective, polysomnographic, single-blind, placebo-controlled study was performed in 23 patients with RLS and 10 healthy subjects. Basal spectral analysis of HRV and phasic heart rate (HR) changes during PLMS were compared between the two groups and, within the RLS group, before and after treatment with placebo or pramipexole. RESULTS: No differences were found in the basal sympathovagal balance outside of PLMS between RLS and controls and, in the RLS group, before and after treatment. The amplitude of PLMS-related HR changes was higher in patients than in controls. Treatment with pramipexole decreased the number of PLMS and normalized the increased PLMS-related HR response in RLS subjects. CONCLUSIONS: The repetitive abnormal autonomic response to PLMS might play a role in the increased cardiovascular risk proposed for RLS patients. Pramipexole reduced the number of PLMS and the amplitude of the autonomic response to residual PLMS, without effects on the tonic sympathovagal regulation. D3 receptors in the sympathetic pre-ganglionic neurons of the spinal intermediolateral columns might be a target of pramipexole. The normalization of the HR response could be relevant in reducing the risk of cardiovascular diseases and associated autonomic dysfunctions in patients with RLS.

Improved computation of the atonia index in normal controls and patients with REM sleep behavior disorder.

OBJECTIVE: The aim of this study was to evaluate the effects of a simple method of noise reduction before the calculation of the REM sleep atonia index (AI) on a large number of recordings from different normal controls and patient groups. SUBJECTS AND METHODS: Eighty-nine subjects were included: 25 young controls, 10 aged controls, 31 untreated patients with idiopathic REM sleep behavior disorder (iRBD), 8 treated patients with iRBD, 10 patients with multiple system atrophy (MSA) and 5 patients with obstructive sleep apnea syndrome (OSAS). The average amplitude of the rectified submentalis muscle EMG signal was then obtained for all 1-s mini epochs of REM sleep. The new correction method was implemented by subtracting from each mini epoch the minimum value found in a moving window including the 60 mini epochs surrounding it. RESULTS: Two arbitrary thresholds were established at AI<0.8 and 0.80.9; this was not true for aged controls, 3 of whom presented 0.80.9. All MSA patients showed AI<0.8. CONCLUSIONS: After the introduction of this new method for noise reduction, REM sleep AI index values lower than 0.8 were strongly indicative of altered (reduced) chin EMG atonia during REM sleep; values of AI between 0.8 and 0.9 indicated a less evident involvement of atonia, and values above 0.9 characterized the majority of normal recordings.

Acute dopamine-agonist treatment in restless legs syndrome: effects on sleep architecture and NREM sleep instability.

STUDY OBJECTIVES: To analyze cyclic alternating pattern (CAP) in restless legs syndrome (RLS) and the eventual changes induced by the acute administration of pramipexole. SETTING: Sleep clinic in a scientific research institute. INTERVENTIONS: Placebo or pramipexole 0.25 mg. METHODS: Thirty-four patients were included: 19 patients received 0.25 mg of pramipexole and 15 were given placebo. The control group included 13 normal subjects. Nocturnal polysomnography was carried out in all subjects, and a second night was recorded after pramipexole or placebo was administered to patients with RLS. Sleep stages, CAP, and leg movement activity were scored following standard criteria. MEASUREMENTS AND RESULTS: At baseline, rapid eye movement sleep latency was significantly longer in patients with RLS than in normal control subjects, and the periodic leg movement during sleep index (PLMS) was also significantly higher. On the contrary, many CAP parameters appeared to be significantly different, with a general increase in CAP rate in patients with RLS. Acute administration of pramipexole induced moderate changes in sleep architecture (increased number of stage shifts/h, sleep efficiency, and percentage of stage 2 sleep; decreased wakefulness after sleep onset; and a lower PLMS index. No effects of treatment on CAP were observed. CONCLUSION: Patients with RLS show significant abnormalities in sleep microstructure, represented by an excessive sleep instability/discontinuity. Acute pramipexole administration seems to exert no action on these abnormalities; the moderate effects seen on sleep architecture might be interpreted as the beneficial consequence of the removal of presleep RLS symptoms and PLMS.

Measuring the error in sleep estimation in normal subjects and in patients with insomnia.

The aims of this study were to measure the error in sleep estimation in normal controls and subjects with primary insomnia to establish the minimum amount of sleep needed for reliable subjective estimation and to depict the distribution of the error in sleep estimation in both groups. A two-step retrospective (study 1) and prospective (study 2) validation study was carried out. Study 1 included 288 normal subjects [176 females and 112 males, mean age 58.5 years, standard deviation (SD) 7.23]. Study 2 included 159 patients (98 females and 61 males; mean age 49.1 years, SD 12.71) with primary insomnia. Participants underwent a full-night polysomnographic study, followed by a morning assessment of subjective sleep parameters. A misperception index (MI) was computed using the following formula: MI = [objective total sleep time (oTST)-subjective total sleep time (sTST)]/oTST. The statistical properties of this index were analysed in detail in both groups. In controls, the Bland-Altman test demonstrated the reliability of this index for values of oTST >120 min. Healthy subjects estimated their sleep time correctly, while insomniacs largely underestimated their sleep time. Statistical analysis of the distribution of MI in insomnia patients disclosed the presence of two subgroups, one with moderate sleep misperception (132 patients) and the other with high sleep misperception (27 patients). The latter presented MI values >or=0.9, exhibiting statistical properties different from those with MI <0.9 and from normal subjects. The MI gives a reliable and immediate description of sleep misperception in healthy and insomnia subjects. Its application supports the existence of the high misperception of insomnia as a separate pathological entity.

Association between bruxism and nocturnal groaning.

Bruxism is a well-known sleep-related movement disorder, usually associated with teeth damage and morning temporo-mandibular discomfort. Nocturnal groaning (NG) is a less common entity consisting of a nocturnal monotonous sound, which occurs during the expiratory phase, especially during REM sleep, recently classified among parasomnias. We describe the first case of an association between bruxism and NG. According to the polysomnographic findings, bruxism and NG episodes were closely related to each other and seemed to be organized in stereotyped sequences. Both phenomena always occurred during NREM sleep and were synchronous with cortical arousals, leg movements, and sympathetic activations. The hypothesis of a common trigger mechanism for NG and bruxism, through an arousal-induced activation, is discussed.

First night efficacy of pramipexole in restless legs syndrome and periodic leg movements.

OBJECTIVE: Restless legs syndrome (RLS) seems to improve immediately after a single dose of dopamine-agonists (DA). The aim of the present study was to investigate the acute effects of a low standard dose of pramipexole in RLS drug-naïve patients. METHODS: A single-blind placebo-controlled study in 32 consecutive idiopathic RLS de-novo patients was carried out. Patients who met the standard criteria for RLS, with a PLMS index greater than 10 as well as an RLS rating scale score greater than 20 underwent clinical and neurophysiological evaluation, hematological screening and two consecutive full-night polysomnographies. On the second night, all patients received 0.25mg of pramipexole or placebo at 9:00 p.m. Acute symptom response was assessed by a visual analogical scale (VAS). RESULTS: Eighteen patients received pramipexole and 14 patients received placebo. Compared to placebo, the single low dose (0.25mg) of pramipexole significantly improved RLS symptoms (VAS: from 7.4+/-1.68 to 1.3+/-1.62, p<0.00001) and strongly reduced PLMS index (from 45.8+/-33.56 to 9.4+/-11.40, p<0.0002). A significant increase in the percentage of stage 2 non-rapid eye movement (NREM) sleep was also observed in the pramipexole group (from 38.7+/-10.50 to 50.6+/-12.13, p<0.02). CONCLUSIONS: A low dose of pramipexole was effective in treatment-naïve patients with RLS from the first night of administration. These results support a direct involvement of the dopaminergic system in RLS pathogenesis and might have important implications for a possible future pramipexole administration on-demand, as well as for a pharmacological test to confirm diagnosis in clinically complex cases.

Topiramate treatment for nocturnal frontal lobe epilepsy.

PURPOSE: Aim of this study was to evaluate the efficacy and tolerability of the antiepileptic drug topiramate (TPM) in a sample of patients with nocturnal frontal lobe epilepsy (NFLE). METHODS: A 24 patients with video-polysomnographically confirmed NFLE received topiramate as single or add-on therapy. They all completed diaries concerning the seizures frequency and complexity and underwent to periodic follow-up visits. We classified the patients as: seizure-free, responders or non-responders. RESULTS: 15 M; 9 F; mean age 29.3+/-10.4 years. The video-polysomnographic recordings showed a wide spectrum of seizures, ranging from repeated stereotypic brief motor attacks to prolonged attacks, with complex and bizarre behaviour; the recorded episodes occurred during non-REM sleep, both stage 2 and stage 3-4. The EEG during wakefulness was normal in all the patients, while seven of them showed epileptiform abnormalities during polysomnography. TPM was administered as single or add-on therapy from 50 to 300mg daily at bedtime. The follow-up duration ranged from 6 months to 6 years. The patients were classified as: seizure-free=6 (25%); responders (reduction of at least 50% of seizures)=15 (62.5%); non-responders=3 (12.5%). The adverse events were: weight loss (6 pts, 25%); paresthesias (3 pts, 12.5%); speech dysfunction (2 pts, 8.3%). All the adverse events disappeared within 3 months. CONCLUSIONS: In our experience, TPM seems to be effective in about 90% of patients with NFLE. Few of them experienced transitory adverse events. TPM could be included in the options for patients with this form of epilepsy.

Evidence for a fourth locus for autosomal dominant nocturnal frontal lobe epilepsy.

Mutations responsible for autosomal dominant nocturnal frontal lobe epilepsy have been identified in two members of the neuronal nicotinic acetylcholine receptor gene family: CHRNA4(ENFL1 locus) and CHRNB2 (ENFL3 locus) coding for alpha4 and beta2 subunit, respectively. However, mutations in these genes account for only a minority (less than 10%) of cases. For a third ADNFLE locus (ENFL2) on chromosome 15q24 the gene was not identified. The involvement of the three loci in the pathogenesis of ADNFLE was investigated in 12 unrelated Italian families, selected on the basis of anamnestic and video-polysomnographic data. Compliant family members were typed for polymorphic markers spanning the analyzed chromosome regions. Linkage analyses excluded association of all chromosome regions with ADNFLE in 72% of cases. In two, four and one families it was impossible to ascertain or exclude association with ENFL1, ENFL2, or ENFL3, respectively, however, no mutations have been detected in the nicotinic receptor genes located in these regions. These data strongly suggest that ENFL1, ENFL2 and ENFL3 are minor loci for the disease and point to the existence of at least a fourth locus for ADNFLE.

Genetics in restless legs syndrome.

Several studies on Restless legs syndrome (RLS) have suggested a substantial genetic contribution in the etiology of this sleep disorder. Clinical surveys of idiopathic RLS patients have shown that up to 60% report a positive family history. Investigations of single families with RLS have suggested an autosomal dominant mode of inheritance with variable expressivity, and some families show possible anticipation. At present, only one twin study is available, showing a high concordance rate (83.3%) between identical twins. Despite several reports suggesting a genetic contribution to the etiology of idiopathic RLS, few molecular genetic studies have been carried out attempting to identify genes that can predispose to this disorder. In particular, genes encoding for the GABA A receptor subunits, the gene for the alpha1 subunit of the glycine receptor, and genes involved in dopaminergic transmission and metabolism have been analyzed, but no significant findings have been reported. Genome-wide studies have been conducted to map genes that play a role in vulnerability to RLS. In a single French-Canadian family significant linkage was established on chromosome 12q. The susceptibility locus on chromosome 12q was not confirmed in two South Tyrolean families, or in our two Italian families. However, the efforts toward the identification of RLS genes must continue in order to obtain a better characterization of the syndrome and to identify new therapeutic strategies.

Cabergoline is an effective single-drug treatment for restless legs syndrome: clinical and actigraphic evaluation.

STUDY OBJECTIVES: To evaluate the efficacy and the safety of cabergoline, a dopamine-receptor agonist with a long half-life, in restless legs syndrome (RLS). DESIGN: A 2 month, single blind, open labeled clinical trial. Patients were evaluated with polysomnography at baseline (B), following 1 week of placebo (T0), and after 1 week (T1) and 2 months (T2) of cabergoline treatment. The clinical global impression was assessed using International RLS Study Group Rating Scale and nocturnal actigraphy. SETTING: Sleep Disorders Center. PATIENTS: Twelve patients with moderate to severe RLS (mean age 56.6 years) who were naive to treatment with dopaminergic agents. INTERVENTIONS: Upward titration of cabergoline (from 0.5 mg to 2 mg) in a single evening dose. MEASUREMENTS AND RESULTS: Ten patients completed the study (mean dose, 1.1 mg), and all showed an improvement of RLS symptoms. The results from the International RLS Study Group Rating Scale showed similarities between B (24.3+/-2.9) and T0 (23.1+/-5.9; P=0.6), with significant improvement at T1 (12.5+/-6.0; P=0.01 vs B and T0) and T2 (9.8+/-6.9; P=0.001 vs B and P=0.005 vs T0). The mean nocturnal activity value measured by actigraphy during week 1 decreased from T0 (19.8+/-9.3) to T1 (13.6+/-6.4) and dropped significantly at T2 (8.5+/-5.3; P=0.05). Nine patients continued the treatment up to 12 months with consistent efficacy, few side effects, and no augmentation. CONCLUSIONS: Low doses of cabergoline showed effectiveness and safety in patients with moderate to severe RLS, with no appearance of augmentation phenomenon. Double blind, crossover, polysomnographic studies are necessary to confirm this preliminary data.