Stefano Zoccolella

Incidence of amyotrophic lateral sclerosis in southern Italy: a population based study

Background: While the incidence of amyotrophic lateral sclerosis (ALS) is similar across the world (range, 1.0 to 2.5/100 000), a latitude gradient from north to south has been observed. Objective: To determine the incidence of ALS in Puglia, a region of south eastern Italy, and to test the latitude gradient hypothesis comparing the present study with findings in studies conducted with the same design in a northern latitude. Methods: Puglia (4 086 613 residents in 2001) is the site of a multicentre-multisource prospective population based registry established in 1997. All incident ALS cases during the period 1998–99 were enrolled and followed up. Cases were classified using the first and the revised El Escorial criteria. Results: During the study period 130 cases were enrolled. The annual crude incidence for ALS in Puglia for the two year period 1998–99 was 1.6/100 000 (95% confidence interval, 1.3 to 1.9). The incidence was higher for men (incidence rate (IR) = 2.1 (1.7 to 2.7) than for women (IR = 1.2 (0.9 to 1.5)) in all age groups, with a male to female ratio of 1.6. For both men and women, the incidence increased through age 75 and declined rapidly afterwards. The mean annual incidence adjusted by age and sex to the 2001 Italian population was 1.7/100 000 (1.4 to 2.0). Conclusions: ALS incidence is within a narrow range across countries, with a peak between 65 and 75 years and a higher incidence in men. A north to south latitude gradient of ALS incidence is not supported by the results of cohort studies.

Analysis of survival and prognostic factors in amyotrophic lateral sclerosis: a population based study.

Objective: To measure survivorship and predictors of prognosis of amyotrophic lateral sclerosis (ALS). Methods: Incident cases, diagnosed in the 1998–1999 period and classified according to the El Escorial criteria, were enrolled from a prospective population based registry established in Puglia, Southern Italy, with a reference population of 4 025 329. Cases were followed up until death or 30 June 2004. Results: We identified 130 incident cases of ALS while four were lost to follow-up. Median survival was 28 months from first symptoms and 16 months from diagnosis, while cumulative survivorship at 4 years was approximately 30%. Advanced age (>75 years: hazard ratio (HR) 7.5; 95% CI 1.9 to 29.6; p = 0.004) and bulbar or generalised (HR 1.8; 95% CI 1.1 to 3.0; p = 0.01) onset of symptoms were independent predictors of adverse survival. After stratifying patients according to site of first symptoms, age was a predictor of death among spinal (HR for patients aged >75 years compared with patients aged 45 years or less: HR 11; 95% CI 1.5 to 78.5; p = 0.01) but not among bulbar ALS (HR 4.5; 95% CI 0.4 to 46.5; p = 0.2). Among spinal onset cases, cases with predominant upper motoneuronal (UMN) involvement presented with a borderline significant better survivorship (HR 0.5; 95% CI 0.2 to 1.3; p = 0.1) Conclusions: Bulbar signs and advanced age among subjects with spinal onset were indicators of poor prognosis while El Escorial category at entry did not predict survival. Among subjects with spinal onset of the disease, a trend for a better survivorship of subjects with UMN signs was noted.

The epidemiology and treatment of ALS : focus on the heterogeneity of the disease and critical appraisal of therapeutic trials

Abstract Effective treatments for amyotrophic lateral sclerosis (ALS) have remained elusive. Only riluzole, a drug thought to affect glutamate metabolism, improves survival albeit to modest extent. Explanations for the negative results of therapeutic trials include a likely heterogeneity, both in disease susceptibility and pathogenic mechanisms, and faulty methodology of clinical trials. Further understanding of these factors will lead to improvements in patient stratification, and in the design of future clinical trials.

Elevated cerebrospinal fluid neurofilament light levels in patients with amyotrophic lateral sclerosis: a possible marker of disease severity and progression

To date there are no biomarkers with proven reliability as a measure of disease burden in amyotrophic lateral sclerosis (ALS). The aim of our study is to assess the neurofilament light chain (NFL) in cerebrospinal fluid (CSF) samples as a measure of disease activity and progression in ALS.

Effects of levodopa and COMT inhibitors on plasma homocysteine in Parkinson's disease patients

Homocysteine (Hcy) is a risk factor for vascular diseases, cognitive impairment, and dementia. Elevated plasma concentrations of Hcy have been found recently in Parkinsons disease (PD) patients treated with levodopa, suggesting that levodopa is a cause of hyperhomocysteinemia (HHcy). The mechanism underlying HHcy in PD is the O‐methylation of levodopa catalyzed by catechol‐O‐methyltransferase (COMT) that produces S‐adenosylhomocysteine, which is hydrolyzed rapidly to Hcy. COMT inhibitors (COMT‐I) are used currently in the treatment of PD; however, no study has assessed the effects of COMT‐I administration on Hcy concentrations in PD patients. We compared plasma levels of Hcy, B12, and folate in 26 PD patients treated with levodopa, 20 PD patients treated with levodopa + COMT‐I, and 32 controls. No significant differences were found in vitamin B12 levels, whereas folate concentrations were significantly lower in the levodopa‐treated group. Plasma Hcy was increased significantly in the two groups of PD patients and was significantly lower in the group treated with levodopa + COMT‐I. Statistical analysis showed that the difference in mean Hcy levels observed among PD patients was related to the addition of COMT‐I, rather than to folate concentrations. We conclude that levodopa treatment increases plasma Hcy and the addition of COMT‐I effectively reduces HHcy.

Riluzole and amyotrophic lateral sclerosis survival: a population-based study in southern Italy

Riluzole is to date the only treatment that prolongs amyotrophic lateral sclerosis (ALS) survival. However, results on the efficacy of riluzole in observational population‐based studies with a longer follow‐up are conflicting and it is still unclear if the effect of the drug is limited to an early stage of the disease and to some specific subgroups of patients. The objective is: (i) to evaluate the effect of riluzole on ALS survival in a cohort of incident cases; (ii) to examine whether bulbar‐ALS benefits from the medication to a greater extent and (iii) to assess the efficacy of the drug in elderly patients. Source of the study was a prospective population‐based registry of ALS established in Puglia, Southern Italy. We examined survival of 126/130 incident ALS cases diagnosed during the period 1998–1999. Seventy‐three patients were prescribed riluzole and the remaining 53 were not. Riluzole therapy increased survival rates at 12 months by approximately 10% and prolonged survival by 6 months (18.2 months vs. 12.4; peto‐test: 2.78; P = 0.09). This beneficial effect was present amongst bulbar‐onset ALS (peto‐test: 4.11; P = 0.042), but not in subjects with limb‐onset (peto‐test: 0.48; P = 0.4). In patients aged >70 years riluzole treatment was associated with an 8 months longer median survival time [15.4 months vs. 7.1] and a reduction in mortality rate at 12 months by 27%, regardless of site of symptoms onset. In multivariate analysis, riluzole use was an independent predictor of survival at 12 months from the diagnosis with borderline significance (P = 0.06). Riluzole was effective amongst cases with bulbar‐onset ALS (P = 0.04), whereas in subjects with limb‐onset there was no effect on survival at 12 months (P = 0.5). In each model riluzole did not influence survival at 24 months. Conversely, riluzole use was associated with an improvement in survival amongst elderly patients both at 12 (P = 0.07), at 24 months (P = 0.03) and in the entire follow‐up period (P < 0.04). In this population‐based series, we found that riluzole therapy improves ALS survival. The efficacy of the drug was present amongst bulbar‐onset ALS and older patients, but not in subjects with limb‐onset. The favourable effect of the drug was transient, as it was lost in prolonged follow‐up. Our observations support the use of riluzole at an early stage of ALS in bulbar and elderly patients. However, the appropriate duration of riluzole treatment remains to be established.

Predictors of delay in the diagnosis and clinical trial entry of amyotrophic lateral sclerosis patients: A population-based study

BACKGROUND The El Escorial and the revised Airlie House diagnostic criteria for amyotrophic lateral sclerosis (ALS) were introduced to select patients for clinical trials. Heterogeneity of clinical presentation at onset and delay in diagnosis may decrease the likelihood for trial entry. OBJECTIVE Identify risk factors for delay in the diagnosis and trial exclusion. METHODS ALS incident cases were identified with El Escorial (EEC) and Airlie House criteria (AHC) through a population-based registry established in Puglia, Southern Italy, in the years 1998-99. RESULTS 130 ALS incident cases were diagnosed with a median interval between onset of symptoms and diagnosis of 9.3 months and not different across both EEC and AHC categories. Twenty percent of cases were not eligible for clinical trials according to the AHC. About 5% of subjects in this series died with only lower motor neuron signs. Predictors for delay in the diagnosis were age between 65 and 75 years and spinal onset while fasciculations and cramps as first symptoms were predictors of exclusion from trials. CONCLUSIONS In this population-based series, diagnostic delay was longer in subjects with spinal onset and age between 65 and 75 and fasciculation as first symptoms. About 80% of incident cases were trial eligible with AHC criteria. However, a significant number of subjects with ALS, characterized by a limited spread of signs, were not trial eligible while alive.

Predictors of long survival in amyotrophic lateral sclerosis: A population-based study

BACKGROUND Although amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disorder, some ALS cases can survive beyond 10 years. However, the predictors of long survival in ALS patients remain uncertain. OBJECTIVE To define clinical predictors of long survival in a cohort of ALS incident cases. METHODS One hundred-thirty incidents cases, diagnosed in 1998--1999 and classified according to the El Escorial criteria (EEC), were enrolled from a prospective population-based registry established in Puglia, Italy. All but two cases were followed-up until death or November 30, 2006. RESULTS Thirteen patients (high 10% of the survivors) were classified as long survivors (LS), 13 as short survivors (SS) (low 10%), and 102 as average survivors (AS). LS presented a lower frequency of bulbar onset (8% versus 29% of AS and 39% of SS; p=0.1) and a significantly longer time between symptom onset to diagnosis [(ODI): 13 months versus 10 and 6; p=0.0005]. In multivariate analysis, predictors of long survival were younger age at diagnosis (>65 compared to < or =45 years: odds ratio (OR):18.9; 95%CI: 1.8-194.7; p=0.04), longer interval onset-diagnosis (< or =9 months compared to >9 months, OR: 7.9; 95%CI: 1.3-47; p=0.02) and clinical features with predominant upper motor neuron signs (OR: 8.5; 95%CI: 1.1-64.2; p=0.04). CONCLUSIONS In this population-based study, younger age, longer interval onset to diagnosis, and clinical features with predominance of upper motor signs predicted long survival, while EEC category at diagnosis did not.

Sleep disorders and the natural history of Parkinson's disease: the contribution of epidemiological studies.

BACKGROUND Sleep disorders (SD) are one of the most frequent non-motor manifestations of Parkinsons disease (PD). Recent studies showed that SD may precede the onset of PD. OBJECTIVES We reviewed current literature concerning 1) the incidence of PD among subjects with SD; and 2) the occurrence and possible clinical correlations of SD during the course of PD. METHODS A Medline search found 17 longitudinal studies. RESULTS The incidence of PD among patients with rapid eye-movement sleep behavioural disorders ranged from 20% to 65% of cases, within a wide interval of time (range: 2.2-13.3). The incidence of SD during PD progressively increased with disease duration in population-based studies but presented marked fluctuations in clinical based studies. Older age, male gender, dopaminergic treatment with higher dosage, cognitive impairment and hallucinations were associated with the onset of SD during PD. In the only population-based study among Japanese men excessive daytime sleepiness was associated with a threefold increased risk of developing PD. CONCLUSIONS Available data suggest that SD could be the heralding clinical manifestation or a risk factor for PD onset. The prevalence of SD increases during the course of the PD and may be related to specific phenotype and rapid progression of PD. However, the current data are limited because of limited sample size and poor study design; prospective studies with larger sample size are warranted.

Trauma and amyotrophic lateral sclerosis: a case-control study from a population-based registry.

Published reports on the association between amyotrophic lateral sclerosis (ALS) and trauma are controversial suggesting the need for a new case–control study done in a large population.