Federico Piccoli

Noninvasive positive-pressure ventilation in ALS: Predictors of tolerance and survival

Objective: To identify factors associated with tolerance and survival after noninvasive positive-pressure ventilation (NIPPV) and to investigate the influence of NIPPV on lung function in patients with ALS. Methods: NIPPV was offered to 71 patients with ALS in accordance with currently published guidelines. Effects of NIPPV on lung function and factors influencing tolerance and survival after NIPPV were studied. Results: Forty-four patients (61.9%; 95% CI: 50.6 to 73.2) tolerated NIPPV (NIPPV use ≥4 h/day) and 27 (38.1%; 95% CI: 26.8 to 49.4) were intolerant (NIPPV use <4 h/day). Patients with mild or moderate bulbar symptoms were more likely to tolerate NIPPV than those with severe impairment (odds ratio = 6.09, 95% CI: 1.18 to 31.52, p = 0.031). After NIPPV introduction, a slower decline in forced vital capacity (FVC) was observed in tolerant vs intolerant patients (p = 0.002). The slope of FVC decline after NIPPV initiation (risk ratio [RR]: 0.78, 95% CI: 0.65 to 0.94, p = 0.01) together with NIPPV tolerance (RR: 0.32, 95% CI: 0.13 to 0.78, p = 0.013) were the only independent predictors of survival in the overall group of patients. In multivariate analysis, body mass index was the most powerful predictor of longer survival after NIPPV in tolerant patients (RR: 0.77, 95% CI: 0.61 to 0.96, p = 0.022). Conclusion: Survival after noninvasive ventilation was independently related to ventilatory use (≥4 h/day) and to the modifications of forced vital capacity decline after treatment initiation. The severity of bulbar impairment and the nutritional status of the ALS patients at the introduction of ventilation may predict tolerance and survival.

Cognitive impairment in patients suffering from relapsing‐remitting multiple sclerosis with EDSS ≤ 3.5

Objectives – Previous papers have mainly demonstrated the presence and the frequency of cognitive impairment in patients suffering from relapsing‐remitting multiple sclerosis. The purpose of this study was to investigate subjects with the relapsing‐remitting form of the disease and mild clinical disability (EDSS ≤ 3.5), so as to quantify this deficit when the illness does not yet interfere with daily living and the ability to work.

Percutaneous endoscopic gastrostomy in amyotrophic lateral sclerosis: Effect on survival

BACKGROUND Percutaneous endoscopic gastrostomy (PEG) is offered to amyotrophic lateral sclerosis (ALS) patients with severe dysphagia. Immediate benefits of PEG are adequate food intake and weight stabilization. However, the impact of PEG on survival is still uncertain. In this work we retrospectively evaluated the effect of PEG on survival in a cohort of ALS patients followed in a tertiary referral centre. METHODS Between 2000 and 2007, 150 dysphagic ALS patients were followed until death or tracheostomy. PEG was placed in 76 patients who accepted the procedure and survival was analysed using the Kaplan-Meier life-table method. RESULTS In ALS patients submitted to PEG, no major complications were observed. Total median survival time from symptom onset was 38 months for PEG users as compared to 32 months for the remaining dysphagic patients who declined the procedure (p=0.05). Among bulbar-onset patients, PEG users showed a median survival time longer than those with no PEG (28 months vs. 25 months), even though the difference was not significant. Conversely, dysphagic spinal-onset patients with PEG lived significantly longer than those who refused this palliative care (44 months vs. 36 months, p=0.046). Survival in patients with PEG was not affected by the severity of the respiratory impairment, as measured by forced vital capacity. CONCLUSIONS This study demonstrates that PEG improves survival in dysphagic ALS patients, with few side effects. The procedure is safe and applicable even to patients with impaired respiratory function. PEG remains a milestone in palliative care in dysphagic ALS patients.

Causes and place of death in Italian patients with amyotrophic lateral sclerosis

Spataro R, Lo Re M, Piccoli T, Piccoli F, La BellaV. Causes and place of death in Italian patients with amyotrophic lateral sclerosis.
Acta Neurol Scand: 122: 217–223.
© 2010 The Authors Journal compilation

Long-term interferon-β treatment for multiple sclerosis

Abstract.The aim of our study was to analyze the dropout rate in patients with relapsing-remitting multiple sclerosis (RRMS) under long-term treatment with the three commercially available interferon beta (IFNβ) preparations. According to the drug taken, we divided 122 RRMS patients into 4 groups: Betaferon group, 56 patients taking INFβ-1b (24 MIU weekly, subcutaneous injections); Avonex group, 38 patients taking IFNβ-1a (6 MIU weekly, intramuscularly); Rebif group, 18 patients taking INFβ-1b (18 MIU subcutaneously). Ten patients who shifted from Betaferon to Avonex were included in a fourth group. Dropouts were registered every trimester with the related cause. Data were evaluated using Kaplan-Meier survival analysis and log-rank test. During the observation period of five years, 48 patients (39.9%) dropped out: 48% of the patients in Betaferon group withdrew at a median of 758 days, 26% of the Avonex group at 356 days; 38% of the Rebif group at 421 days, and 40% of those who shifted from Betaferon to Avonex at 259 days. The differences between groups were not significant on survival analysis. Patients receiving higher dose treatment (Betaferon and Rebif groups) dropped out mainly for clinical adverse events; conversely, patients receiving lower dose therapy (Avonex group) dropped out most often for inefficacy. Patients who shifted to a lower dose treatment (fourth group) had a dropout rate similar to that of the initial treatment. Our data showed that one-third of the patients stopped the therapy, mostly for adverse events and then for inefficacy, while the remaining two-thirds were still on treatment without problems up to 5 years of follow-up. Compliance seems related to the dose of the drug, but further analysis is needed to confirm our data.

γ-Aminobutyric acid type A/benzodiazepine receptors regulate rat retina neurosteroidogenesis

It has been previously shown that retinal ganglion cells have the ability to synthesize steroids including neuroactive steroids such as pregnenolone sulfate. Since ganglion cells possess GABAA/benzodiazepine (BZ) receptors and neurosteroids modulate retinal GABAA receptor function, we investigated the role of these receptors in isolated rat retina neurosteroidogenesis. Ligands for central-type BZ receptors stimulated retinal pregnenolone synthesis. Clonazepam was the most potent ligand examined acting at nanomolar concentrations. Moreover, the effective steroidogenesis stimulatory dose (ED50) for these ligands and the Ki to inhibit [3H]flunitrazepam binding showed a coefficient of correlation of r = 0.87, suggesting the involvement of the central-type BZ receptors in this event. Ro 5-4864, which preferentially binds to peripheral-type BZ receptors, was less efficacious and potent whereas PK 11195 did not affect the basal pregnenolone formation and did not antagonize the Ro 5-4864 stimulated steroid synthesis. The GABAergic agonist muscimol, stimulated neurosteroid synthesis and this effect was reversed by the GABAergic antagonists bicuculline and picrotoxinin. In addition, these antagonists decreased basal pregnenolone formation, suggesting a tonic GABAergic control of the steroidogenic pathway, and reduced clonazepam-stimulated steroidogenesis. These results, together with the reported ability of neurosteroids to modulate GABAA receptor function, suggest a novel regulatory mechanism to control the inhibitory transmission.

Guidelines for the diagnosis of dementia and Alzheimer's disease

SIN DOCUMENT*The Dementia Study Group is co-ordinated by Sandro Sorbi andincludes: Margherita Alberoni, Milan; Pasquale Alfieri, SommaVesuviana (NA); Serena Amici, Perugia; Daniele Antana, Rome;Ildebrando Appollonio, Monza (MI); Stefano Avanzi,Castelgoffredo (MN); Antonella Bartoli, Pescara; BrunoBergamasco, Turin; Laura Bracco, Florence; Amalia Bruni,Lamezia Terme (CZ); Orso Bugiani, Milan; Paolo Caffarra, Parma;Carlo Caltagirone, Rome; Antonio Carolei, L’Aquila; Anna RosaCasini, Rome; Luciana Ciannella, Benevento; Antonietta Citterio,Pavia; Antonio Daniele, Rome; Graziella D’Achille, Isernia;Giuseppe Del Curatolo, Grosseto; Grazia Dell’Agnello, Pisa;Daniele Durante, Parma; Elisabetta Farina, Milan; Patrizia Ferrero,Turin; Paolo Forleo, Florence; Guido Gainotti, Rome; PaoloGabriele, Cassino (FR); Emanuela Galante, Castelgoffredo (MN);Virgilio Gallai, Perugia; Roberto Gallassi, Bologna; MaddalenaGasparini, Milan; Bernardino Ghetti, Indianapolis (USA); GiorgioGiaccone, Milan; Floriano Girotti, Milan; Luigi Grimaldi, Milanand Caltanisetta; Serenella Grioli, Catania; Bianca MariaGuarnieri, Pescara; Stefano Grottoli, Fossombrone (PS); FrancescoIemolo, Ragusa; Stefania Latorraca, Florence; Francesco Le Pira,Catania; Gian Luigi Lenzi, Rome; Sebastiano Lorusso, Rimini;Claudio Mariani, Milan; Gabriella Marcon, Udine; VincenzoMascia, Carbonia (CA); Simonetta Mearelli, L’Aquila; MariaMorante, Senigallia (AN); Michela Morbin, Milan; MassimoMusicco, Segrate (MI); Ettore Nardelli, Verona; Paolo Nichelli,Modena; Alessandro Padovani, Brescia; Marco Paganini, Florence;Roberta Pantieri, Bologna; Pietro Parisen, Vicenza; LucillaParnetti, Perugia; Bruno Passerella, Brindisi; Carla Pettenati, Rho(MI); Silvia Piacentini, Florence; Federico Piccoli, Palermo; CarloPiccolini, Perugia; Gilberto Pizzolato, Padova; LeandroProvinciali, Ancona; Nicola Pugliese, Salerno; Francesco Redi,Arezzo; Rosa Maria Ruggieri, Palermo; Umberto Ruggiero,Naples; Marco Saetta, Siracusa; Rudolf Schoenuber, Bolzano;Maria Caterina Silveri, Rome; Sandro Sorbi, Florence; GiuseppeSorrentino, Naples; Patrizia Sucapane, L’Aquila; Andrea Stracciari,Bologna; Massimo Tabaton, Genova; Fabrizio Tagliavini, Milan;Vito Toso, Vicenza; Francesco Valluzzi, Putignano Noci (BA)S. Sorbi ( )Department of Neurological and Psychiatric SciencesUniversity of FlorenceViale Morgagni 85, I-50131 Florence, Italy

Restless legs syndrome in patients with amyotrophic lateral sclerosis

We aimed to evaluate the frequency and determinants of restless legs syndrome (RLS) in a group of 76 patients with amyotrophic lateral sclerosis (ALS) and 100 control subjects. A diagnosis of RLS was made according to the criteria of the International RLS Study Group, and severity was assessed by the RLS severity scale. RLS was significantly more frequent in patients with ALS (ALS/RLS+) than in control subjects (25% vs. 8%; P = 0.002). Compared with control subjects, patients with ALS/RLS+ showed shorter history of RLS complaints and higher frequency of symptoms occurrence. Moreover, compared with those without RLS, patients with ALS/RLS+ showed increased functional impairment and more often reported sleep complaints. Multivariate logistic regression confirmed the association between RLS and functional impairment. Our findings suggest that RLS should be considered as a possible cause of disrupted sleep in patients with ALS and should be specifically investigated in these patients.

Alpha‐dihydroergocryptine in the treatment of de novo parkinsonian patients: results ofa multicentre, randomized, double‐blind, placebo‐controlled study

Introduction– A multicentre, randomized, double‐blind, placebo‐controlled, parallel group study was carried out in 123 patients suffering from never treated (de novo) idiopathic Parkinsons disease (PD). The aim of the study was to confirm the efficiency and safety of α‐dihydroergocryptine (α‐DHEC) given as monotherapy in the symptomatic treatment of PD. The total score of the Unified Parkinsons Disease Rating Scale (UPDRS) was identified as the efficacy target variable. Patients and methods– Sixty‐two patients (32 males, 30 females, mean age±SD 64±10) were randomized to α‐dihydroergocryptine and 61 (30 males, 31 females, mean age 63.8±9.1) to placebo. According to the experimental design, a 18‐month double‐blind phase vs placebo was followed. Two interim analyses were planned both at the 3rd and 12th month of treatment, in order to avoid continuation on placebo, if clear differences between groups were found (stopping criterium: nominal significance level equal to 0.022 in the analysis of the target variable). Analysis of variance was performed both on the per protocol (PP) and intent‐to‐treat (ITT) sample. Results– The results on the first interim analysis showed significant differences between treatment groups of the UPDRS total score both in the ITT (115 patients, α‐DHEC: No. 56; placebo: No. 59; P=0.019) and PP (96 patients, α‐DHEC: No. 46; placebo: No. 50; P=0.001) sample, why the trial was stopped. At the time of stopping the trial, 73 patients (α‐DHEC: No. 37; placebo: No. 36) had reached the 6‐month observation visit; the analysis carried out on this subset of patients confirmed the efficacy of α‐dihydroergocryptine in early PD and the correctness of the decision to stop. The incidence of adverse drug reactions (ADR) did not differ between α‐dihydroergocryptine and placebo recipients, gastrointestinal complaints being the most frequent. Conclusion– The results indicate that α‐dihydroergocryptine is safe and effective in improving symptoms of de novo parkinsonian patients.

Interaction of uridine with GABA binding sites in cerebellar membranes of the rat.

The effect of uridine, a postulated anticonvulsant agent, on GABA receptors has been investigated. Uridine inhibits [3H]GABA binding to rat cerebellar bufferwashed membranes. Pretreatment of the membranes with Triton X-100 increases the effect of uridine on GABA-binding. The Scatchard analysis reveals that both high and low affinities of GABA for its receptors are affected by 1 mM uridine, while the apparent number of binding sites remains unchanged. The ability of uridine to interact competitively with GABA binding sites, also examined by the Lineweaver-Burk analysis, suggests a possible mechanism of action of this anticonvulsant agent, so including it among those compounds characterized by a GABAergic agonist activity.