Long-term survival in amyotrophic lateral sclerosis: a population-based study

OBJECTIVE: To determine the long-term survival in amyotrophic lateral sclerosis (ALS) and identify predictors of prolonged survival in a population-based cohort of newly diagnosed patients. METHODS: An incident cohort from a population-based registry during the years 1998 through 2002 in Lombardy, Italy was followed until death or to February 28, 2013. Age, sex, date of onset of symptoms, site of onset, date of diagnosis, and El Escorial diagnostic category were collected. Survival was assessed using Kaplan-Meier curves. Cox proportional hazards function was used to identify independent prognostic predictors. Standardized mortality ratios (SMRs) were used to assess the 5-year and 10-year excess mortality of ALS patients. RESULTS: Included were 280 men and 203 women aged 18 to 93 years. Spinal onset ALS was present in 312 cases (64.6%). Definite ALS was diagnosed in 213 cases (44.1%), probable ALS in 130 (26.9%), possible ALS in 93 (19.3%), and suspected ALS in 47 (9.7%). The cumulative time-dependent survival at 1, 5, and 10 years from diagnosis was 76.2%, 23.4%, and 11.8%, respectively. Independent predictors included younger age, the diagnosis of possible/suspected ALS, spinal onset, and symptoms having started >12 months previously at diagnosis. SMR was 9.4 at 5 years and 5.4 at 10 years. SMR at 10 years was higher until age 75 year, predominating in women, and became nonsignificant for males thereafter. INTERPRETATION: The outcome in ALS varies with phenotype. Longer survival is predicted by younger age, spinal onset, male gender, and suspected ALS. After age 75 years, 10-year survival in men with ALS is similar to the general population

Incidence of ALS in Lombardy, Italy

Objective: To assess the incidence and trends of ALS in a large population at risk. Methods: This study was performed in nine provinces of Lombardy in Northern Italy (population 4,947,554). Patients with newly diagnosed ALS were enrolled during the period 1998 to 2002 through a prospective regional register. For each patient, the main demographic and clinical information was collected by the caring physicians and reviewed by a panel of experts according to the original and revised El Escorial diagnostic criteria. Overall, age- and sex-specific and standardized annual incidence rates were calculated for the entire population and for each year and province separately. Results: We studied 517 patients (M:F ratio 1.3) aged 18 to 92 years (mean 63.6). Onset of symptoms was bulbar in 29% of cases. ALS was definite in 45%, probable in 27%, probable laboratory supported in 3.5%, possible in 15%, and suspected in 10%. Mean disease duration at diagnosis was 10.6 months. The standardized incidence rate was 2.09 per 100,000/year (95% CI: 1.17 to 3.18). The rate, which was 2.43 in men and 1.76 in women, tended to increase up to ages 65 to 74 and to decrease thereafter. The rate was unchanged over time and presented moderate variations across provinces. The incidence rate of definite ALS was 0.93 (spinal-onset ALS 1.35; bulbar-onset ALS 0.74) and was consistently higher in men with spinal-onset ALS vs men with bulbar-onset ALS and women. Conclusions: The incidence of ALS varied according to age, sex, and site of onset. No temporal and geographic clusters were detected over a 5-year period

Outcome measures and prognostic indicators in patients with amyotrophic lateral sclerosis

The purpose of the study was to assess frequency and predictors of disability measures in ALS. One hundred and fourteen newly diagnosed patients resident in eight administrative districts of Lombardy, Italy (population 4,947,554), included in a population-based registry, were followed for 2570 person-months (mean 22.5 months). The cumulative time-dependent risk of wheelchair, percutaneous endoscopic gastrostomy, and assisted ventilation was estimated according to the Kaplan-Meier method. Predictors of disability (age, sex, disease duration at diagnosis, type of onset, El-Escorial diagnosis) were assessed with the Cox proportional hazard function. During follow-up, 29 patients (25.4%) became wheelchair bound, 51 (44.7%) received gastrostomy, and 47 (41.2%) received assisted ventilation. The median time to loss of ambulation was 46.7 months (95% CI 36.5-56.8). The median time to gastrostomy and assisted ventilation was 31.1 months (95% CI 26.8-35.4) and 34.6 months (95% CI 29.6-39.6), respectively. Spinal onset ALS was the only predictor of loss of ambulation. Predictors of gastrostomy were older age, definite ALS, and shorter disease duration. Shorter disease duration was the only predictor of assisted ventilation. In conclusion, patients with ALS differ in terms of measures and predictors of disability. These factors are sources of bias and confounding in randomized clinical trials

Long-term survival in amyotrophic lateral sclerosis: A population-based study

Objective To determine the long-term survival in amyotrophic lateral sclerosis (ALS) and identify predictors of prolonged survival in a population-based cohort of newly diagnosed patients. Methods An incident cohort from a population-based registry during the years 1998 through 2002 in Lombardy, Italy was followed until death or to February 28, 2013. Age, sex, date of onset of symptoms, site of onset, date of diagnosis, and El Escorial diagnostic category were collected. Survival was assessed using Kaplan-Meier curves. Cox proportional hazards function was used to identify independent prognostic predictors. Standardized mortality ratios (SMRs) were used to assess the 5-year and 10-year excess mortality of ALS patients. Results Included were 280 men and 203 women aged 18 to 93 years. Spinal onset ALS was present in 312 cases (64.6%). Definite ALS was diagnosed in 213 cases (44.1%), probable ALS in 130 (26.9%), possible ALS in 93 (19.3%), and suspected ALS in 47 (9.7%). The cumulative time-dependent survival at 1, 5, and 10 years from diagnosis was 76.2%, 23.4%, and 11.8%, respectively. Independent predictors included younger age, the diagnosis of possible/suspected ALS, spinal onset, and symptoms having started >12 months previously at diagnosis. SMR was 9.4 at 5 years and 5.4 at 10 years. SMR at 10 years was higher until age 75 year, predominating in women, and became nonsignificant for males thereafter. Interpretation The outcome in ALS varies with phenotype. Longer survival is predicted by younger age, spinal onset, male gender, and suspected ALS. After age 75 years, 10-year survival in men with ALS is similar to the general population

Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis

To elucidate the genetic architecture of amyotrophic lateral sclerosis (ALS) and find associated loci, we assembled a custom imputation reference panel from whole-genome-sequenced patients with ALS and matched controls (n = 1,861). Through imputation and mixed-model association analysis in 12,577 cases and 23,475 controls, combined with 2,579 cases and 2,767 controls in an independent replication cohort, we fine-mapped a new risk locus on chromosome 21 and identified C21orf2 as a gene associated with ALS risk. In addition, we identified MOBP and SCFD1 as new associated risk loci. We established evidence of ALS being a complex genetic trait with a polygenic architecture. Furthermore, we estimated the SNP-based heritability at 8.5%, with a distinct and important role for low-frequency variants (frequency 1-10%). This study motivates the interrogation of larger samples with full genome coverage to identify rare causal variants that underpin ALS risk