Effect of RNS60 in amyotrophic lateral sclerosis: a phase II multicentre, randomized, double-blind, placebo-controlled trial.

BACKGROUND AND PURPOSE: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with limited treatment options. RNS60 is an immunomodulatory and neuroprotective investigational product that has shown efficacy in animal models of ALS and other neurodegenerative diseases. Its administration has been safe and well tolerated in ALS subjects in previous early phase trials. METHODS: This was a phase II, multicentre, randomized, double-blind, placebo-controlled, parallel-group trial. Participants diagnosed with definite, probable or probable laboratory-supported ALS were assigned to receive RNS60 or placebo administered for 24 weeks intravenously (375 ml) once a week and via nebulization (4 ml/day) on non-infusion days, followed by an additional 24 weeks off-treatment. The primary objective was to measure the effects of RNS60 treatment on selected biomarkers of inflammation and neurodegeneration in peripheral blood. Secondary objectives were to measure the effect of RNS60 on functional impairment (ALS Functional Rating Scale-Revised), a measure of self-sufficiency, respiratory function (forced vital capacity, FVC), quality of life (ALS Assessment Questionnaire-40, ALSAQ-40) and survival. Tolerability and safety were assessed. RESULTS: Seventy-four participants were assigned to RNS60 and 73 to placebo. Assessed biomarkers did not differ between arms. The mean rate of decline in FVC and the eating and drinking domain of ALSAQ-40 was slower in the RNS60 arm (FVC, difference 0.41 per week, standard error 0.16, p = 0.0101; ALSAQ-40, difference -0.19 per week, standard error 0.10, p = 0.0319). Adverse events were similar in the two arms. In a post hoc analysis, neurofilament light chain increased over time in bulbar onset placebo participants whilst remaining stable in those treated with RNS60. CONCLUSIONS: The positive effects of RNS60 on selected measures of respiratory and bulbar function warrant further investigation.

Rapid versus slow withdrawal of antiepileptic monotherapy in two-year seizure-free adults patients with epilepsy (RASLOW) study: A pragmatic multicentre, prospective, randomized, controlled study.

PURPOSE: To establish whether a slow or a rapid withdrawal of antiepileptic monotherapy influences relapse rate in seizure-free adults with epilepsy and calculates compliance and differences in the severity of relapses, based on the occurrence of status epilepticus, seizure-related injuries, and death. METHODS: This is a multicentre, prospective, randomized, open label, non-inferiority trial in people aged 16 + years who were seizure-free for more than 2 years. Patients were randomized to slow withdrawal (160 days) or rapid withdrawal (60 days) and were followed for 12 months. The primary outcome was the probability of a first seizure relapse within the 12-months follow-up. The secondary outcomes included the cumulative probability of relapse at 3, 6, 9, and 12 months. A non-inferiority analysis was performed with non-inferiority margin of - 0.15 for the difference between the probabilities of seizure recurrence in slow versus rapid withdrawal. RESULTS: The sample comprised 48 patients, 25 randomized to slow withdrawal and 23 to rapid withdrawal. Median follow-up was 11.9 months. In the intention-to-treat population, 3 patients in the slow-withdrawal group and 1 in the rapid withdrawal group experienced seizure relapses. The corresponding probabilities of seizure recurrence were 0.12 for slow withdrawal and 0.04 for rapid withdrawal, giving a difference of 0.08 (95% CI - 0.12; 0.27), which is entirely above the non-inferiority margin. No patients developed status epilepticus and seizure-related injuries or died. Risks were similar in the Per-Protocol population. CONCLUSIONS: Seizure-relapse rate after drug discontinuation is lower than in other reports, without complications and unrelated to the duration of tapering.

Effect modification of the association between total cigarette smoking and ALS risk by intensity, duration and time-since-quitting: Euro-MOTOR.

BACKGROUND: We investigated the association between cigarette smoking and risk of amyotrophic lateral sclerosis (ALS) in a pooled analysis of population-based case-control studies and explored the independent effects of intensity, duration and time-since-quitting. METHODS: ALS cases and controls, matched by age, sex and region, were recruited in the Netherlands, Italy and Ireland (*Euro-MOTOR project). Demographics and detailed lifetime smoking histories were collected through questionnaires. Effects of smoking status, intensity (cigarettes/day), duration (years), pack-years and time-since-quitting (years) on ALS risk were estimated using logistic regression models, adjusting for age, sex, alcohol, education and centre. We further investigated effect modification of the linear effects of pack-years by intensity, duration and time-since-quitting using excess OR (eOR) models. RESULTS: Analyses were performed on 1410 cases and 2616 controls. Pack-years were positively associated with ALS risk; OR=1.26 (95% CI: 1.03 to 1.54) for the highest quartile compared with never smokers. This association appeared to be predominantly driven by smoking duration (ptrend=0.001) rather than intensity (ptrend=0.86), although the trend for duration disappeared after adjustment for time-since-quitting. Time-since-quitting was inversely related to ALS (ptrend<0.0001). The eOR decreased with time-since-quitting smoking, until about 10 years prior to disease onset. High intensity smoking with shorter duration appeared more deleterious than lower intensity for a longer duration. CONCLUSIONS: Our findings provide further support for the association between smoking and ALS. Pack-years alone may be insufficient to capture effects of different smoking patterns. Time-since-quitting appeared to be an important factor, suggesting that smoking may be an early disease trigger.

Prediction of Falls in Subjects Suffering From Parkinson Disease, Multiple Sclerosis, and Stroke.

OBJECTIVE: To compare the risk of falls and fall predictors in patients with Parkinson disease (PD), multiple sclerosis (MS), and stroke using the same study design. DESIGN: Multicenter prospective cohort study. SETTING: Institutions for physical therapy and rehabilitation. PARTICIPANTS: Patients (N=299) with PD (n=94), MS (n=111), and stroke (n=94) seen for rehabilitation. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Functional scales were applied to investigate balance, disability, daily performance, self-confidence with balance, and social integration. Patients were followed for 6 months. Telephone interviews were organized at 2, 4, and 6 months to record falls and fall-related injuries. Incidence ratios, Kaplan-Meier survival curves, and Cox proportional hazards models were used. RESULTS: Of the 299 patients enrolled, 259 had complete follow-up. One hundred and twenty-two patients (47.1%) fell at least once; 82 (31.7%) were recurrent fallers and 44 (17.0%) suffered injuries; and 16%, 32%, and 40% fell at 2, 4, and 6 months. Risk of falls was associated with disease type (PD, MS, and stroke in decreasing order) and confidence with balance (Activities-specific Balance Confidence [ABC] scale). Recurrent fallers were 7%, 15%, and 24% at 2, 4, and 6 months. The risk of recurrent falls was associated with disease type, high educational level, and ABC score. Injured fallers were 3%, 8%, and 12% at 2, 4, and 6 months. The only predictor of falls with injuries was disease type (PD). CONCLUSIONS: PD, MS, and stroke carry a high risk of falls. Other predictors include perceived balance confidence and high educational level.

Epidemiology of Parkinson's Disease: A Population-Based Study in Primary Care in Italy.

BACKGROUND: There are no studies on prevalence, incidence and comorbidities of Parkinson's disease (PD) in the Italian population. METHODS: The database of 700 Italian general practitioners (population, 923,356) was investigated. All patients with International Classification of Diseases Ninth Revision - Clinical Modification (ICD-9-CM) diagnosis of PD during the period 2002-2012 were included. Parkinsonisms were excluded. Clinical conditions preceding PD were identified through ICD-9-CM codes. The Charlson Comorbidity Index was used. PD crude and standardized prevalence and annual incidence were calculated. Crude and adjusted hazard ratios were calculated for comorbidities. RESULTS: A total of 2,204 patients (1,140 men, 1,064 women, age 22-95 years) were included. The crude prevalence of PD was 239/100,000. Prevalence increased exponentially with age. Standardized prevalence was 233 (95% CI 232-235). One hundred ninety-four patients were newly diagnosed, giving a crude incidence of 22/100,000 and a standardized incidence of 23.1/100,000 (95% CI 22.9-23.2). Incidence increased steadily until age 75-84 years and then decreased. Older age, cardiovascular and gastrointestinal disorders, diabetes, and restless-legs syndrome were associated with increased PD risk and smoking and hypersomnia with decreased PD risk. The Charlson Comorbidity Index was associated with PD risk with a documented gradient. CONCLUSIONS: Prevalence and incidence of PD in Italy are in line with studies with the highest case ascertainment. PD risk varies with the number and type of comorbidities.

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.

Physical activity and amyotrophic lateral sclerosis: a European population-based case-control study.

OBJECTIVE: To assess whether physical activity is a risk factor for amyotrophic lateral sclerosis (ALS). METHODS: From February 2008 to April 2012, 652 patients with ALS from European population-based registries (France, Ireland, Italy, United Kingdom, Serbia) and 1,166 population controls (matched for age, sex, and residency) were assessed. Upon direct interview, data were collected on occupation and history of sport and leisure activities, physical activity, and accidental injuries. Physical exercise was defined as having spent time doing activities that caused an individual to breath hard at least once per month and was coded as none, job-related, and/or sport-related. Sport-related and work-related physical exercise were quantified using metabolic equivalents (METs). Risks were calculated using conditional logistic regression models (adjusting for age, country, trauma, and job-related physical activity) and expressed as odds ratios (ORs) and adjusted ORs (Adj ORs) with 95% confidence intervals (CIs). RESULTS: Overall physical activity was associated with reduced odds of having ALS (Adj OR=0.65, 95% CI=0.48-0.89) as were work-related physical activity (Adj OR=0.56, 95% CI=0.36-0.87) and organized sports (Adj OR=0.49, 95% CI=0.32-0.75). An inverse correlation was observed between ALS, the duration of physical activity (p=0.0041), and the cumulative MET scores, which became significant for the highest exposure (Adj OR=0.34, 95% CI=0.21-0.54). An inverse correlation between ALS and sport was found in women but not in men, and in subjects with repeated traumatic events. INTERPRETATION: Physical activity is not a risk factor for ALS and may eventually be protective against the disease.

Tolerability and efficacy of erythropoietin (EPO) treatment in traumatic spinal cord injury: a preliminary randomized comparative trial vs. methylprednisolone (MP).

The only available treatment of traumatic spinal cord injury (TSCI) is high-dose methylprednisolone (MP) administered acutely after injury. However, as the efficacy of MP is controversial, we assessed the superiority of erythropoietin (EPO) versus MP in improving clinical outcome of acute TSCI. Patients aged 18 to 65 years after C5-T12 injury, and grade A or B of the ASIA Impairment Scale (AIS), admitted within 8 h, hemodynamically stable, were randomized to MP according to the NASCIS III protocol or EPO iv (500 UI/kg, repeated at 24 and 48 h). Patients were assessed by an investigator blind to treatment assignment at baseline and at day 3, 7, 14, 30, 60 and 90. Primary end point: number of responders (reduction of at least one AIS grade). Secondary end points: treatment safety and the effects of drugs on a number of disability measures. Frequentistic and post hoc Bayesian analyses were performed. Eight patients were randomized to MP and 11 to EPO. Three patients (27.3 %) on EPO and no patients on MP reached the primary end point (p = 0.17). No significant differences were found for the other disability measures. No adverse events or serious adverse events were reported in both groups. The Bayesian analysis detected a 91.8 % chance of achieving higher success rates on the primary end point with EPO in the intention-to-treat population with a 95 % chance the difference between EPO and MP falling in the range (-0.10, 0.51) and a median value of 0.2. The results of Bayesian analysis favored the experimental treatment.

Knowledge and attitudes towards epilepsy in Zambia: a questionnaire survey.

Misconception and stigma towards epilepsy have a profound impact on this disease in Africa. An unselected sample of Zambian people was interviewed to investigate their knowledge and attitudes towards epilepsy. Proper/improper answers were scored, and a composite score was developed with negative values for unsatisfactory awareness and high stigma levels. The sample comprised 231 people residing in urban (107) or in rural (124) areas. The median and interquartile range of scores for epilepsy awareness and stigma were, respectively, -1 (-3; +1) and +1 (-1; +6). Poor education was the only significant predictor of unsatisfactory awareness (p=0.0131), while education and residency were significantly associated with stigma (p<0.0001 and p=0.0004). Rural people were mostly in the highest stigma level (44.2%) and urban people in the lowest stigma level (60.4%). Misconception and negative attitudes towards epilepsy among Zambian people reflect poor education and rural residency.

Methodological Quality of Clinical Trials in Amyotrophic Lateral Sclerosis: A Systematic Review.

Background: More than 200 clinical trials have been performed worldwide in ALS so far, but no agents with substantial efficacy on disease progression have been found. Objective: To describe the methodological quality of all clinical trials performed in ALS and published before December 31, 2022. Methods: We conducted a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta Analyses. Results: 213 trials were included. 47.4% manuscripts described preclinical study evaluation, with a positive effect in all. 67.6% of trials were conducted with a parallel-arm design, while 12.7% were cross-over studies; 77% were randomized, while in 5.6% historical-controls were used for comparison. 70% of trials were double blind. Participant inclusion allowed forced vital capacity (or corresponding slow vital capacity)<50% in 15% cases, between 55-65% in 21.6%, between 70-80% in 14.1% reports, and 49.3% of the evaluated manuscripts did not provide a minimum value for respiratory capacity at inclusion. Disease duration was < 6-months in 6 studies, 7-36 months in 68, 37-60 months in 24, 8 trials requested more than 1-month of disease duration, while in 107 reports a disease duration was not described. Dropout rate was ≥20% in 30.5% trials, while it was not reported for 8.5%. Conclusion: The methodological quality of the included studies was highly variable. Major issues to be addressed in future ALS clinical trials include: the requirement for standard animal toxicology and phase I studies, the resource-intensive nature of phase II-III studies, adequate study methodology and design, a good results reporting.

Temporal and spatial patterns in the prescriptions of disease-modifying therapies for multiple sclerosis. Results from the Italian Multiple Sclerosis and Related Disorders Register.

BACKGROUND: The therapeutic scenario in multiple sclerosis (MS) has evolved over recent years with the progressive introduction of new drugs focused to better balance efficacy, safety and management requirements. The objective of this study was to examine the prescribing patterns of disease-modifying therapies (DMT) over time and across different geographic areas, and the latency between disease onset, first Register center visit, disease diagnosis, and the start of treatment in a large cohort of persons with MS from the Italian Multiple Sclerosis and Related Disorders Register. METHODS: Up to 2022, the Register collected data from 124 centers on more than 78,000 persons, of whom 56,872 received at least one DMT prescription. Beside baseline demographic and clinical characteristics, we focused on DMT according to their efficacy distinguishing between moderate-efficacy (ME), or high-efficacy (HE). RESULTS: There was a higher probability of prescribing HE-DMT for increasing calendar years (multivariable odds ratio, OR=11.51 in 2021 or thereafter vs before 2000), in males (OR=1.08 vs females), patients with primary progressive with or without relapse (OR=3.00 vs clinically isolated syndrome), those with a higher Expanded Disability Status Scale score (OR=3.85 for >4 versus 0-1), and those from larger referral centers (OR=1.89 vs smaller ones). Conversely, higher age at onset was associated to a lower probability of prescribing HE-DMT (OR=0.74 at 40 or more vs <20 years). A trend to shorter times was observed in subsequent calendar years for disease onset, first center visit, diagnosis and first DMT prescription. No trend was detected based on the location of the geographic referral centers. The times between disease onset, first center visit, and diagnosis and the first DMT prescription showed significant decreases according to the year, while differences were less evident for the geographic areas. CONCLUSION: This study highlights some factors influencing the choice of HE-DMT, including aspects of both healthcare and clinical phenotype. The absence of a geographic pattern may indicate some homogeneity in DMT prescriptions across different Italian MS centers.

Acceptance of epilepsy surgery in the pediatric age - what the parents think and what the doctors can do.

Epilepsy surgery (ES) in pediatrics is safe and effective but can be underutilized. Possible barriers could be parental resistance and doctor inertia. We surveyed 138 parents of pediatric patients with epilepsy and found that 25.2% were opposed to this treatment. However, upon completing the questionnaire that contained factual information about ES, 50.4% of the responders stated that they had become more favorable vs. 3.3% more contrary and 46.3% unchanged. Parents of prepubescent patients were most receptive (p=0.0343) and more likely to shift to a more favorable attitude. Thus, pediatric neurologists should not hesitate to discuss ES as soon as indicated, providing all necessary information to increase acceptance. However, among 60 child neurologists surveyed, 60% did not fully comply with guidelines or follow accepted standards of practice, indicating that they may not be apt to provide proper parental guidance. We conclude that education of both practicing neurologists and parents is needed to facilitate the process.

Retrospective observational study on the use of acetyl-L-carnitine in ALS.

ALCAR (Acetyl-L-carnitine) is a donor of acetyl groups and increases the intracellular levels of carnitine, the primary transporter of fatty acids across the mitochondrial membranes. In vivo studies showed that ALCAR decrease oxidative stress markers and pro-inflammatory cytokines. In a previous double-blind placebo-controlled phase II trial showed positive effects on self-sufficiency (defined as a score of 3+ on the ALSFRS-R items for swallowing, cutting food and handling utensils, and walking) ALSFRS-R total score and FVC. We conducted an observational, retrospective, multicentre, case-control study to provide additional data on the effects of ALCAR in subjects with ALS in Italy. Subjects treated with ALCAR 1.5 g/day or 3 g/day were included and matched with not treated subjects by sex, age at diagnosis, site of onset, and time from diagnosis to baseline, (45 subjects per group). ALCAR 3 g/day vs not treated: 22 not treated subjects (48.9%) were still alive at 24 months after baseline, compared to 23 (51.1%) treated subjects (adj. OR 1.18, 95% CI 0.46-3.02). No statistically significant differences were detected in ALSFRS nor FVC nor self-sufficiency. ALCAR 1.5 g/day vs not treated: 22 not treated subjects (48.9%) were still alive at 24 months after baseline, compared to 32 (71.1%) treated subjects (adj. OR 0.27, 95% CI 0.10-0.71). For ALSFRS-R, a mean slope of - 1.0 was observed in treated subjects compared to - 1.4 in those not treated (p = 0.0575). No statistically significant difference was detected in the FVC nor self-sufficiency. Additional evidence should be provided to confirm the efficacy of the drug and provide a rationale for the dosage.

Barriers toward epilepsy surgery. A survey among practicing neurologists.

PURPOSE: Guidelines for refractory epilepsy recommend timely referral of potential surgical candidates to an epilepsy center for evaluation. However, this approach is seldom a priority for treating neurologists, possibly because of inertia of previous practice and personal attitudes, leading to a buildup of psychosocial disabilities and increased risk of morbidity and mortality. The aim of this study was to assess knowledge and attitudes toward epilepsy surgery among practicing neurologists and identify the barriers that delay the treatment. METHODS: We surveyed 183 Italian adult and child neurologists with an ad hoc questionnaire exploring physicians' willingness to refer patients for epilepsy surgery when such treatment may be indicated. Thirteen of 14 questions had graded answers ranging from 1 (unfavorable to surgery) to 10 (favorable). We compared the overall scores and per-question scores of the neurologists versus a group of academic and clinical leaders in the field. KEY FINDINGS: The neurologists gave responses characterized by extreme variability (i.e., wide response interquartile range) around intermediate scores. Experts had higher and less variable scores favoring surgery. The two groups differed significantly on issues such as how long to pursue pharmacologic treatment and information about indications and outcome of surgery. Multivariate analysis indicated that neurologists' attitudes correlated with the number of patients referred for surgery (p < 0.01) and the geographical region where specialty was attained (p < 0.01). Other variables such as years in practice, number of patients treated for epilepsy, or type of specialty had no predictive value on physicians' behavior. SIGNIFICANCE: The majority of Italian neurologists have highly variable attitudes toward epilepsy surgery, reflecting ambivalence and uncertainty toward this type of treatment. About two thirds of responders are nonaligned with the opinion leaders, mainly due to differences in handling pharmacologic treatment and information regarding epilepsy surgery, which affect their attitudes and ultimately patient management. Strategies that may solve the lack of agreement include reinforcing the concept of pharmacoresistance and associated risks, as opposed to the safety and potential benefits of surgery, the use of epilepsy quality measures during follow-up, and the adoption of structured referral sheets and greater involvement of patients in decision making. These measures should facilitate the referral of potential candidates for surgical evaluation and improve overall quality of care.

Acceptance of epilepsy surgery among adults with epilepsy--what do patients think?

Physician inertia is usually blamed for the underutilization of epilepsy surgery (ES) at the cost of increased patient disability and risk of mortality. Investigations on selected groups of patients with intractable TLE and minorities suggested that patient beliefs may also limit access to ES. To assess acceptance of ES among "mainstream" patients, we distributed an ad hoc questionnaire to 228 adults attending epilepsy clinics and found widespread fears and misconceptions leading to unfavorable perception of ES, irrespective of diagnosis, seizure type, and degree of intractability. Moreover, while a group firmly rejected ES, the majority became more favorable when given further information about modality, rationale, and expected outcome of ES. Attitude changes correlated with patient's social profile. Neurologists are responsible for providing all pertinent information to potential surgical candidates as soon as indicated. Therefore, an untimely or inadequate intervention of the treating physician constitutes an additional barrier to optimal utilization of ES.

ALS incidence and population aging in Northern Italy.

Objective: Data on and increase of the incidence of amyotrophic lateral sclerosis (ALS) are conflicting and reflect the use of differing populations and designs. We investigated the incidence of ALS using data from a large population-based registry (SLALOM) in two three-year periods using the same diagnostic criteria and equal methods of case ascertainment. Methods: The registry is based in Lombardy, a 10 million population area of Northern Italy. Using different sources of cases (hospital discharge and ambulatory records, regional claims and prescription records) from nine Lombardy provinces (population, 5,485,163), all patients with newly diagnosed ALS during the periods 1998-2000 and 2008-2010 were included. Results: A total of 235 and 440 newly diagnosed patients were traced during the two study periods. The corresponding incidence rates were, respectively, 1.61 and 2.72 per 100,000 person-years. Data varied with age, sex and province by a significant increase was found only in men aged 65 through 74 years. Conclusions: Based on our findings, the increased incidence of ALS with time is real and can be largely interpreted as a reflection of the advancing age of the general population.

Geographical clusters of amyotrophic lateral sclerosis and the Bradford Hill criteria.

With the aim of shedding further light on the role of environmental factors in amyotrophic lateral sclerosis (ALS) etiology, we hereby conducted a historical narrative review to critically appraise the published reports on ALS geographical clusters using the modern interpretation of the Bradford Hill criteria for causation. Our research hypothesis was that the more criteria were met, the greater was the evidence supporting a causal association. We found that cluster studies that met the greatest number of Bradford's Hill criteria regarded the non-protein amino acid ß-N-methylamino-L-alanine (L-BMAA) and exposure to metals and minerals, but the evidence for causation was at best moderate and was poor for other environmental factors. This defective picture might be attributed not only to the methodological approach adopted by published studies, but also to the inherent difficulties in the application of Bradford Hill criteria, due to the complexity of the disease phenotype and the underlying pathogenic mechanisms.

Trends in survival of ALS from a population-based registry.

Objective: To assess survival of ALS patients in general and in selected demographic and clinical subgroups comparing two periods (1998-2000 vs. 2008-2010). Methods: Newly diagnosed adults resident of Lombardy, Northern Italy from a population-based registry were included. Data were collected on age at diagnosis, sex, site of onset, diagnostic delay, and El-Escorial diagnostic category. Patients were followed until death or last observation. Survival was evaluated using Kaplan-Meier curves and Cox's proportional hazards models. Results: In 2008-2010 (267 patients), median survival was 2.4 years and 1-year, 2-year, 3-year and 5-year survival rates were 79%, 56%, 41% and 24%. Longer survival was associated with male sex, younger age, spinal onset, and longer diagnostic delay. Multivariable analysis confirmed higher death in 65-69yr (HR 2.8; 95% CI 1.4-5.6), 70-74yr (HR 3.2; 95% CI 1.6-6.3) and 75 + yr (HR 6.9; 95% CI 3.5-13.8) categories, compared to ≤49yr, in females (HR 1.4; 95% CI 1.02-1.8), compared to males, and in patients diagnosed after 6-12 months (HR 1.9; 95% CI 1.4-2.7), compared with longer diagnostic delay. In 1998-2000 (235 patients), median survival was 2.2 years. The 1-year, 2-year, 3-year and 5-year survival rates were 77%, 53%, 38% and 20%. When adjusting for demographic and clinical variables, the HR for death in 2008-2010 versus 1998-2000 was 0.80 (95% CI 0.66-0.98). A significant increase of survival in 2008-2010 was found only in patients aged 50-59yr and 70-74yr at diagnosis. Conclusions: Survival of ALS has increased over time in the last decades, especially in middle aged and elderly patients. The benefits of comprehensive care in selected age groups might explain our findings.

Drug treatments and interactions, disease progression and quality of life in ALS patients.

Background: Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disease that causes a wide range of symptoms demanding treatment, but the evidence base for their effectiveness is limited. Affected individuals may present several comorbidities. Polypharmacy exposes ALS patients to the adverse effects of drugs and to drug-drug interactions. At present, no data on drug-drug and drug-disease interactions are available in patients with ALS. Methods: Multicenter, case-series, observational study aimed to provide a picture of the therapeutic habits of patients with ALS, and identify drug-drug interactions (DDIs) and their effects on the outcome of the disease (measured by ALSFRS-R) and quality of life (ALSAQ-40). Results: 440 patients were included, 50 of them with follow-up data. The maximum number of DDIs at baseline was 2 for minor, 9 for moderate, 3 for major, and 3 for contraindicated interactions. At least one minor, moderate, major, or contraindicated DDI was present in 18 (4.1%), 127 (28.9%), 46 (10.5%) and 37 (8.4%) patients. Patients with DDIs were older. In those with major/contraindicated DDIs, the scores on the emotional domain of the ALSAQ-40 and the ALSFRS-R total score were worse than the scores of patients without DDIs or with minor/moderate DDIs. At the 48-week visit, patients with DDIs showed lower ALSFRS-R scores, and higher scores on all domains of ALSAQ-40, as compared to patients without DDIs. Conclusions: Symptomatic treatment aims to improve quality of life of patients. The higher the number of drugs, the higher the risk to incurring (relevant) interactions.