Luigi Serlenga

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.

Freezing Gait in Parkinson's Disease

Freezing is a well-known problem in Parkinsons disease (PD) and is characterized by an abrupt difficulty in starting or continuing rhythmic and repetitive movements. We utilized a questionnaire in order to assess the occurrence of the freezing gait phenomenon (FG) in a population of 100 consecutive PD patients. Our PD population included 70 males and 30 females, with a mean age of 61.1 +/- 9.1 years. Mean duration of PD was 6.5 +/- 4.0 years. 92/100 patients were under L-Dopa treatment. The FG phenomenon occurred in 60% of patients. It appeared on average 4.8 years after the beginning of PD; in 16% of the cases it was evident before starting L-Dopa treatment. FG was more frequent among female patients. There was no significant correlation between the occurrence of FG and the age of the patients; on the other hand, a significant correlation was found with the duration of the disease (p < 0.001). FG occurred more frequently in the subgroup of patients with the akinetic form (odds ratio: 3.05); whilst an opposite tendency was evident in the subgroup with the tremor predominant form (odds ratio: 0.29).

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.

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.

Elevated plasma homocysteine levels in patients with amyotrophic lateral sclerosis.

Background: Both in vitro and in vivo studies indicate that homocysteine (Hcy) may be directly involved in the damage of motor neurons and in several pathways implicated in amyotrophic lateral sclerosis (ALS) pathogenesis. Objective: To determine whether plasma Hcy levels were higher in ALS patients than healthy controls and to examine the relationship between Hcy levels and clinical ALS phenotypes. Methods: In a cross-sectional study, we compared Hcy, B12, and folate levels in 62 patients with ALS and 88 age- and sex-matched controls recruited as outpatients in a tertiary clinical center. Results: Patients with ALS had higher median plasma Hcy levels (11.2 [range 5.8 to 46] vs 9.7 [range 4.5 to 15.9] μmol/L; p = 0.0004) and lower folate levels (4.4 [range 1.7 to 22.1] vs 5.8 [range 2.3 to 21.1] ng/mL; p = 0.0003), compared with controls. Multivariate logistic regression revealed a strong direct association between plasma Hcy levels and presence of ALS (odds ratios adjusted for age, sex, and B-vitamin levels comparing the top tertile [Hcy levels ≥ 11.6 μmol/L] with the bottom tertile [Hcy levels < 9.2 μmol/L]: 6.4; 95% CI 2.2 to 19.1; p for trend = 0.0008). We also found a trend for higher Hcy levels in patients with shorter interval from symptom onset to diagnosis (ODI; <14 months), compared with patients with longer ODI (>14 months; median Hcy levels 11.8 [range 5.8 to 46] vs 10.1 [range 7.2 to 17.6] μmol/L; p = 0.09). In a multivariate model, Hcy levels strongly correlated with shorter interval onset diagnosis (r2 = 0.18; p = 0.01). Conclusions: Plasma homocysteine (Hcy) levels were significantly increased in patients with amyotrophic lateral sclerosis (ALS) compared with healthy controls. ALS cases with shorter time to diagnosis presented higher Hcy levels, suggesting that higher Hcy may be linked to faster progression of the disease.

ALS multidisciplinary clinic and survival. Results from a population-based study in Southern Italy.

BackgroundAmyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting motorneurons, for which there is no effective cure. Because of the multifactorial nature of impairment and disablity in ALS, multidisciplinary clinics (MDC) have been recently introduced in the management of ALS patients; their effects on survival remain, however, largely debated.ObjectiveTo compare survival of ALS patients who received their care at MDC with that of patients followed by general neurology clinics.MethodsSource of the study was a prospective population-based registry of ALS established in Puglia, Southern Italy, in 1997. We examined survival of 126 out of 130 incident ALS cases that were diagnosed during the period 1998–99.Results84 patients (67%) were enrolled and followed by MDC and the remaining 42 (33%) by general neurological clinics. No difference in median survival time from the diagnosis was observed between patients followed by ALS multidisciplinary (17.6 months) and general clinics (18 months). No beneficial effect was present among bulbar onset ALS (11.7 versus 23 months). In multivariate analysis management by ALS MDC was associated with only a 10% increase in survival probability at 12 months (HR: 0.91; 95%CI: 0.44–1.89; p = 0.9).ConclusionsIn this population-based series, we found that in Southern Italy management of ALS by multidisciplinary clinics does not improve survival, regardless of site of symptoms onset.

Spinocerebellar ataxia type 2 in southern Italy : a clinical and molecular study of 30 families

Abstract Autosomal dominant cerebellar ataxia type I is the most common form of dominant ataxia. A genetic heterogeneity has been identified with five different loci (SCA1, 2, 3, 4, and 6). A pathological expansion of a CAG sequence has been identified in SCA1, 2, 3, and 6. We performed molecular analysis in 51 families with autosomal dominant cerebellar ataxia type I, mainly originating from southern Italy and Sicily. Thirty families carry an expanded CAG sequence within SCA2 gene. The mean number of repeats was 39.9 ± 3.3 in 85 expanded alleles, with a range of 34–52. The number of triplets was inversely correlated with age at onset and explained 76% of the variance. The best fit was obtained with an exponential relationship between variables. Expanded alleles were unstable when transmitted from parents to offspring. Expansions were more common than contractions, accounting for 59% of the total meioses and for 80% of the father-child transmissions. The mean intergenerational variation was 1.9 repeats (range –3 to +15) with higher values for male transmissions. Bulbar and autonomic signs were related to disease duration, pyramidal signs to CAG size, cerebellar features and peripheral neuropathy to both. Among the remaining 21 families, three carried the SCA1 and one the SCA6 mutation. This study suggests that SCA2 is the prevalent mutation in southern Italy.

Signs and symptoms at diagnosis of amyotrophic lateral sclerosis: a population-based study in southern Italy

Amyotrophic lateral sclerosis (ALS) diagnostic criteria are used to select patients for clinical trials based on different levels of diagnostic certainty, according to the spread of upper (UMN) and lower motoneuron (LMN) signs in different anatomic regions. However, the clinical presentation of ALS patients is extremely variable and this can delay the time to diagnosis and decrease the likelihood for trial entry. The aims of the study were to describe the signs and symptoms of diagnosis in a population‐based incident cohort of ALS cases, using the El Escorial (EEC) and the Revised Airlie Diagnostic Criteria (AHC). The source of the study was a prospective population‐based registry established in Puglia, southern Italy, in 1997. The diagnosis and the classification of the cases were based on EEC and AHC. All incident ALS cases during the period 1998–1999 were enrolled and followed up. During the surveillance period, we identified 130 ALS incident cases, and bulbar‐ALS represented 20% of our cohort. The highest risk for bulbar onset was among subjects aged >75 years [RR: 20.1, 95% confidence interval (CI) 3.4–118.0] compared with subjects aged <55 years and among females compared with males (Relative risk (RR): 2.75, 95% CI: 1–7.3). The vast majority of patients (72%) referred progressive muscle weakness in the limbs as the presenting symptom. Eighty percent of cases presented contemporary bulbar or spinal involvement; UMN signs in the bulbar region were present in 24% of cases and any motoneuronal sign in thoracic region in only 15% of the cases. In this population‐based series, progressive muscle weakness was the most common presenting sign; bulbar onset was associated with advanced age and female sex. UMN signs in the bulbar region and any motoneuronal sign in the thoracic region were observed in 20% of our case series. This may represent the main limitation to show the spread of signs during diagnostic assessment for inclusion in epidemiological studies and clinical trials.