Raffaele Manni

Bio: Raffaele Manni is an academic researcher from University of Pavia. The author has contributed to research in topics: Epilepsy & Polysomnography. The author has an hindex of 46, co-authored 171 publications receiving 6541 citations. Previous affiliations of Raffaele Manni include University Hospital of Lausanne.

Risk and predictors of dementia and parkinsonism in idiopathic REM sleep behaviour disorder: a multicentre study

Abstract: Idiopathic REM sleep behaviour disorder (iRBD) is a powerful early sign of Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. This provides an unprecedented opportunity to directly observe prodromal neurodegenerative states, and potentially intervene with neuroprotective therapy. For future neuroprotective trials, it is essential to accurately estimate phenoconversion rate and identify potential predictors of phenoconversion. This study assessed the neurodegenerative disease risk and predictors of neurodegeneration in a large multicentre cohort of iRBD. We combined prospective follow-up data from 24 centres of the International RBD Study Group. At baseline, patients with polysomnographically-confirmed iRBD without parkinsonism or dementia underwent sleep, motor, cognitive, autonomic and special sensory testing. Patients were then prospectively followed, during which risk of dementia and parkinsonsim were assessed. The risk of dementia and parkinsonism was estimated with Kaplan-Meier analysis. Predictors of phenoconversion were assessed with Cox proportional hazards analysis, adjusting for age, sex, and centre. Sample size estimates for disease-modifying trials were calculated using a time-to-event analysis. Overall, 1280 patients were recruited. The average age was 66.3 ± 8.4 and 82.5% were male. Average follow-up was 4.6 years (range = 1-19 years). The overall conversion rate from iRBD to an overt neurodegenerative syndrome was 6.3% per year, with 73.5% converting after 12-year follow-up. The rate of phenoconversion was significantly increased with abnormal quantitative motor testing [hazard ratio (HR) = 3.16], objective motor examination (HR = 3.03), olfactory deficit (HR = 2.62), mild cognitive impairment (HR = 1.91-2.37), erectile dysfunction (HR = 2.13), motor symptoms (HR = 2.11), an abnormal DAT scan (HR = 1.98), colour vision abnormalities (HR = 1.69), constipation (HR = 1.67), REM atonia loss (HR = 1.54), and age (HR = 1.54). There was no significant predictive value of sex, daytime somnolence, insomnia, restless legs syndrome, sleep apnoea, urinary dysfunction, orthostatic symptoms, depression, anxiety, or hyperechogenicity on substantia nigra ultrasound. Among predictive markers, only cognitive variables were different at baseline between those converting to primary dementia versus parkinsonism. Sample size estimates for definitive neuroprotective trials ranged from 142 to 366 patients per arm. This large multicentre study documents the high phenoconversion rate from iRBD to an overt neurodegenerative syndrome. Our findings provide estimates of the relative predictive value of prodromal markers, which can be used to stratify patients for neuroprotective trials.

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.

Seizure control and treatment in pregnancy: Observations from the EURAP epilepsy pregnancy registry

Abstract: Objective: To analyze seizure control and treatment in pregnant women with epilepsy. Methods: Seizure control and treatment were recorded prospectively in 1,956 pregnancies of 1,882 women with epilepsy participating in EURAP, an international antiepileptic drugs (AEDs) and pregnancy registry. Results: Of all cases, 58.3% were seizure-free throughout pregnancy. Occurrence of any seizures was associated with localization-related epilepsy (OR: 2.5; 1.7 to 3.9) and polytherapy (OR: 9.0; 5.6 to 14.8) and for tonic-clonic seizures, with oxcarbazepine monotherapy (OR: 5.4; 1.6 to 17.1). Using first trimester as reference, seizure control remained unchanged throughout pregnancy in 63.6%, 92.7% of whom were seizure-free during the entire pregnancy. For those with a change in seizure frequency, 17.3% had an increase and 15.9% a decrease. Seizures occurred during delivery in 60 pregnancies (3.5%), more commonly in women with seizures during pregnancy (OR: 4.8; 2.3 to 10.0). There were 36 cases of status epilepticus (12 convulsive), which resulted in stillbirth in one case but no cases of miscarriage or maternal mortality. AED treatment remained unchanged in 62.7% of the pregnancies. The number or dosage of AEDs were more often increased in pregnancies with seizures (OR: 3.6; 2.8 to 4.7) and with monotherapy with lamotrigine (OR: 3.8; 2.1 to 6.9) or oxcarbazepine (OR: 3.7; 1.1 to 12.9). Conclusions: The majority of patients with epilepsy maintain seizure control during pregnancy. The apparently higher risk of seizures among women treated with oxcarbazepine and the more frequent increases in drug load in the oxcarbazepine and lamotrigine cohorts prompts further studies on relationships with pharmacokinetic changes. Risks associated with status epilepticus appear to be lower than previously reported.

Risk factors for neurodegeneration in idiopathic rapid eye movement sleep behavior disorder: A multicenter study

Abstract: Objective To assess whether risk factors for Parkinson disease and dementia with Lewy bodies increase rate of defined neurodegenerative disease in idiopathic rapid eye movement (REM) sleep behavior disorder (RBD). Methods Twelve centers administered a detailed questionnaire assessing risk factors for neurodegenerative synucleinopathy to patients with idiopathic RBD. Variables included demographics, lifestyle factors, pesticide exposures, occupation, comorbid conditions, medication use, family history, and autonomic/motor symptoms. After 4 years of follow-up, patients were assessed for dementia or parkinsonism. Disease risk was assessed with Kaplan–Meier analysis, and epidemiologic variables were compared between convertors and those still idiopathic using logistic regression. Results Of 305 patients, follow-up information was available for 279, of whom 93 (33.3%) developed defined neurodegenerative disease. Disease risk was 25% at 3 years and 41% after 5 years. Patients who converted were older (difference = 4.5 years, p < 0.001), with similar sex distribution. Neither caffeine, smoking, nor alcohol exposure predicted conversion. Although occupation was similar between groups, those who converted had a lower likelihood of pesticide exposure (occupational insecticide = 2.3% vs 9.0%). Convertors were more likely to report family history of dementia (odds ratio [OR] = 2.09), without significant differences in Parkinson disease or sleep disorders. Medication exposures and medical history were similar between groups. Autonomic and motor symptoms were more common among those who converted. Risk factors for primary dementia and parkinsonism were generally similar, except for a notably higher clonazepam use in dementia convertors (OR = 2.6). Interpretation Patients with idiopathic RBD are at very high risk of neurodegenerative synucleinopathy. Risk factor profiles between convertors and nonconvertors have both important commonalities and differences. Ann Neurol 2015;77:830–839

Relationship between hallucinations, delusions, and rapid eye movement sleep behavior disorder in Parkinson's disease

Abstract: Psychotic symptoms are the main and the most disabling “nonmotor” complications of Parkinson's disease (PD), the pathophysiology of which is poorly recognized. Polysomnographic studies have shown a relationship between visual hallucinations and rapid eye movement (REM) sleep. The objective of this study is to clarify the relationship between psychotic symptoms and REM sleep behavior disorder (RBD) in PD. In a Parkinson's disease outpatient unit, 289 consecutive subjects with idiopathic PD were administered (in the period from January to December 2002) a multiple-choice questionnaire and structured interview on sleep and mental disorders. RBD was diagnosed in accordance with the minimal diagnostic criteria of the International Classification of Sleep Disorders. Hallucinations and delusional disorders were diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders-IV criteria. The presence or absence of psychotic symptoms, of RBD, and of daytime sleepiness, as well as motor status, cognitive status, and mood were assessed. Approximately 32% (n = 92) of the subjects presented with psychotic disorders; 30% (n = 86) had experienced hallucinations; 2% (n = 6) had delusions without hallucinations. Sixty-two (72%) hallucinators reported nocturnal hallucinations. A total of 6.6% (n = 19) of the subjects complained of a delusional disorder. There were 26.6% (n = 77) of subjects who presented with RBD: 28 (36%) with onset before and 49 (63%) with onset after PD diagnosis. The presence of RBD was associated with an increased risk of manifesting hallucinations and delusions (odds ratio [OR], 2.73). Other independent clinical factors found to have an effect on psychotic disorders were cognitive impairment (OR, 3.92), disease duration (OR, 2.46), advanced age (OR, 2.34), and severity of motor symptoms (OR, 2.06). These results suggest that RBD is widely associated with psychosis in PD. © 2005 Movement Disorder Society

ILAE classification of the epilepsies: Position paper of the ILAE Commission for Classification and Terminology.

Abstract: The International League Against Epilepsy (ILAE) Classification of the Epilepsies has been updated to reflect our gain in understanding of the epilepsies and their underlying mechanisms following the major scientific advances that have taken place since the last ratified classification in 1989. As a critical tool for the practicing clinician, epilepsy classification must be relevant and dynamic to changes in thinking, yet robust and translatable to all areas of the globe. Its primary purpose is for diagnosis of patients, but it is also critical for epilepsy research, development of antiepileptic therapies, and communication around the world. The new classification originates from a draft document submitted for public comments in 2013, which was revised to incorporate extensive feedback from the international epilepsy community over several rounds of consultation. It presents three levels, starting with seizure type, where it assumes that the patient is having epileptic seizures as defined by the new 2017 ILAE Seizure Classification. After diagnosis of the seizure type, the next step is diagnosis of epilepsy type, including focal epilepsy, generalized epilepsy, combined generalized, and focal epilepsy, and also an unknown epilepsy group. The third level is that of epilepsy syndrome, where a specific syndromic diagnosis can be made. The new classification incorporates etiology along each stage, emphasizing the need to consider etiology at each step of diagnosis, as it often carries significant treatment implications. Etiology is broken into six subgroups, selected because of their potential therapeutic consequences. New terminology is introduced such as developmental and epileptic encephalopathy. The term benign is replaced by the terms self-limited and pharmacoresponsive, to be used where appropriate. It is hoped that this new framework will assist in improving epilepsy care and research in the 21st century.

Clinical diagnostic criteria for dementia associated with Parkinson's disease.

Abstract: Dementia has been increasingly more recognized to be a common feature in patients with Parkinson's disease (PD), especially in old age. Specific criteria for the clinical diagnosis of dementia associated with PD (PD-D), however, have been lacking. A Task Force, organized by the Movement Disorder Study, was charged with the development of clinical diagnostic criteria for PD-D. The Task Force members were assigned to sub-committees and performed a systematic review of the literature, based on pre-defined selection criteria, in order to identify the epidemiological, clinical, auxillary, and pathological features of PD-D. Clinical diagnostic criteria were then developed based on these findings and group consensus. The incidence of dementia in PD is increased up to six times, point-prevelance is close to 30%, older age and akinetic-rigid form are associated with higher risk. PD-D is characterized by impairment in attention, memory, executive and visuo-spatial functions, behavioral symptoms such as affective changes, hallucinations, and apathy are frequent. There are no specific ancillary investigations for the diagnosis; the main pathological correlate is Lewy body-type degeneration in cerebral cortex and limbic structures. Based on the characteristic features associated with this condition, clinical diagnostic criteria for probable and possible PD-D are proposed.

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