Giancarlo Logroscino

Prognostic factors in ALS: A critical review

We have performed a systematic review to summarize current knowledge concerning factors related to survival in ALS and to evaluate the implications of these data for clinical trials design. The median survival time from onset to death ranges from 20 to 48 ;months, but 10–20% of ALS patients have a survival longer than 10 ;years. Older age and bulbar onset are consistently reported to have a worse outcome. There are conflicting data on gender, diagnostic delay and El Escorial criteria. The rate of symptom progression was revealed to be an independent prognostic factor. Psychosocial factors, FTD, nutritional status, and respiratory function are also related to ALS outcome. The effect of enteral nutrition on survival is still unclear, while NIPPV has been found to improve survival. There are no well established biological markers of progression, although some are likely to emerge in the near future. These findings have relevant implications for the design of future trials. Randomization, besides the type of onset, should take into account age, respiratory status at entry, and a measure of disease progression pre-entry. Alternative trial designs can include the use of natural history controls, the so-called minimization method for treatment allocation, and the futility approach.

Descriptive epidemiology of amyotrophic lateral sclerosis: new evidence and unsolved issues

Amyotrophic lateral sclerosis (ALS) is a relatively rare disease with a reported population incidence of between 1.5 and 2.5 per 100u2009000 per year. Over the past 10 years, the design of ALS epidemiological studies has evolved to focus on a prospective, population based methodology, employing the El Escorial criteria and multiple sources of data to ensure complete case ascertainment. Five such studies, based in Europe and North America, have been published and show remarkably consistent incidence figures among their respective Caucasian populations. Population based studies have been useful in defining clinical characteristics and prognostic indicators in ALS. However, many epidemiological questions remain that cannot be resolved by any of the existing population based datasets. The working hypotheses is that ALS, like other chronic diseases, is a complex genetic condition, and the relative contributions of individual environmental and genetic factors are likely to be relatively small. Larger studies are required to characterise risks and identify subpopulations that might be suitable for further study. This current paper outlines the contribution of the various population based registers, identifies the limitations of the existing datasets and proposes a mechanism to improve the future design and output of descriptive epidemiological studies.

Primary Prevention of Stroke by Healthy Lifestyle

Background— The combination of healthy lifestyle factors is associated with lower risk of coronary heart disease, diabetes, and total cardiovascular disease. Little is known about the impact of multiple lifestyle factors on the risk of stroke. Methods and Results— We conducted a prospective cohort study among 43 685 men from the Health Professionals Follow-up Study and 71 243 women from the Nurses’ Health Study. Diet and other lifestyle factors were updated from self-reported questionnaires. We defined a low-risk lifestyle as not smoking, a body mass index <25 kg/m2, ≥30 min/d of moderate activity, modest alcohol consumption (men, 5 to 30 g/d; women, 5 to 15 g/d), and scoring within the top 40% of a healthy diet score. We documented 1559 strokes (853 ischemic, 278 hemorrhagic) among women and 994 strokes (600 ischemic, 161 hemorrhagic) among men during follow-up. Women with all 5 low-risk factors had a relative risk of 0.21 (95% confidence interval [CI], 0.12, 0.36) for total and 0.19 (95% CI, 0.09, 0.40) for ischemic stroke compared with women who had none of these factors. Among men, the relative risks were 0.31 (95% CI, 0.19, 0.53) for total and 0.20 (95% CI, 0.10, 0.42) for ischemic stroke for the same comparison. Among the women, 47% (95% CI, 18 to 69) of total and 54% (95% CI, 15 to 78%) of ischemic stroke cases were attributable to lack of adherence to a low-risk lifestyle; among the men, 35% (95% CI, 7 to 58) of total and 52% (95% CI, 19 to 75) of ischemic stroke may have been prevented. Conclusion— A low-risk lifestyle that is associated with a reduced risk of multiple chronic diseases also may be beneficial in the prevention of stroke, especially ischemic stroke.

Global Epidemiology of Amyotrophic Lateral Sclerosis: a Systematic Review of the Published Literature

Background: Amyotrophic lateral sclerosis (ALS) is relatively rare, yet the economic and social burden is substantial. Having accurate incidence and prevalence estimates would facilitate efficient allocation of healthcare resources. Objective: To provide a comprehensive and critical review of the epidemiological literature on ALS. Methods: MEDLINE and EMBASE (1995-2011) databases of population-based studies on ALS incidence and prevalence reporting quantitative data were analyzed. Data extracted included study location and time, design and data sources, case ascertainment methods and incidence and/or prevalence rates. Medians and interquartile ranges (IQRs) were calculated, and ALS case estimates were derived using 2010 population estimates. Results: In all, 37 articles met the inclusion criteria. In Europe, the median incidence rate (/100,000 population) was 2.08 (IQR 1.47-2.43), corresponding to an estimated 15,355 (10,852-17,938) cases. Median prevalence (/100,000 population) was 5.40 (IQR 4.06-7.89), or 39,863 (29,971-58,244) prevalent cases. Conclusions: Disparity in rates among ALS incidence and prevalence studies may be due to differences in study design or true variations in population demographics such as age and geography, including environmental factors and genetic predisposition. Additional large-scale studies that use standardized case ascertainment methods are needed to more accurately assess the true global burden of ALS.

Prognosis of status epilepticus: role of aetiology, age, and consciousness impairment at presentation.

Background: Identification of outcome-predictive factors could lower risk of under- or over-treatment in status epilepticus (SE). Older age and acute symptomatic aetiology have been shown to predict mortality, but other variables are controversial and level of consciousness has received relatively little attention. The objective of this study was to assess variables predictive of mortality, particularly those available at presentation. Methods: The discharge database (1997–2004) of two university hospitals was screened for adult patients with EEG confirmed SE, excluding cerebral anoxia. Outcome at discharge (mortality, return to baseline clinical conditions) was analysed in relation to demographics, clinical features, and aetiology. Aetiologies were also classified based on whether or not they were potentially fatal independently of SE. Results: Mortality was 15.6% among 96 patients with a first SE episode, 10 of whom also experienced recurrent SE during the study period. Eleven other patients had only recurrent SE. Mortality was 4.8% among these 21 patients with recurrent SE. Return to baseline condition was more frequent after recurrent than incident SE (pu200a=u200a0.02). For the first SE episode, death was associated with potentially fatal aetiology (pu200a=u200a0.01), age ⩾65 (pu200a=u200a0.02), and stupor or coma at presentation (pu200a=u200a0.04), but not with gender, history of epilepsy, SE type, or time to treatment ⩾1 h. Conclusions: At initial evaluation, older age and marked impairment of consciousness are predictive of death. Surviving a first SE episode could lower the mortality and morbidity of subsequent episodes, suggesting that underlying aetiology, rather than SE per se, is the major determinant of outcome.

Status Epilepticus Severity Score (STESS)

BackgroundStatus epilepticus (SE) treatment ranges from small benzodiazepine doses to coma induction. For some SE subgroups, it is unclear how the risk of an aggressive therapeutic approach balances with outcome improvement. We recently developed a prognostic score (Status Epilepticus Severity Score, STESS), relying on four outcome predictors (age, history of seizures, seizure type and extent of consciousness impairment), determined before treatment institution. Our aim was to assess whether the score might have a role in the treatment strategy choice.MethodsThis cohort study involved adult patients in three centers. For each patient, the STESS was calculated before primary outcome assessment: survival vs. death at discharge. Its ability to predict survival was estimated through the negative predictive value for mortality (NPV). Stratified odds ratios (OR) for mortality were calculated considering coma induction as exposure; strata were defined by the STESS level.ResultsIn the observed 154 patients, the STESS had an excellent negative predictive value (0.97). A favorable STESS was highly related to survival (P < 0.001), and to return to baseline clinical condition in survivors (P < 0.001). The combined Mantel-Haenszel OR for mortality in patients stratified after coma induction and their STESS was 1.5 (95 % CI: 0.59–3.83).ConclusionThe STESS reliably identifies SE patients who will survive. Early aggressive treatment could not be routinely warranted in patients with a favorable STESS, who will almost certainly survive their SE episode. A randomized trial using this score would be needed to confirm this hypothesis.

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)u200a=u200a2.1 (1.7 to 2.7) than for women (IRu200a=u200a1.2 (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.

Mortality after a first episode of status epilepticus in the United States and Europe

Summary:u2002 Objective: In the last decade several studies have been published on incidence, etiology, and prognosis of status epilepticus (SE) with population‐based data from the United States and Europe. The aim of this review is to summarize the available information on the epidemiology of SE and to outline the sources of the variability in reported mortality after SE.

Parkinson disease and risk of mortality: a prospective comorbidity-matched cohort study.

Objective: To evaluate the association between Parkinson disease (PD) and mortality after adjustment for comorbidities. Methods: We conducted a matched cohort analysis among 22,071 participants in the Physicians’ Health Study. Five hundred sixty incident PD cases were identified by self-report. We used a modified Charlson Comorbidity Index to calculate a comorbidity score. Each PD case was matched by age to a comparator who was alive and had an identical comorbidity score at the time of PD diagnosis of the case. Both cohorts were followed for all-cause mortality. We used proportional hazards models to calculate hazard ratios (HRs) for mortality. Results: A total of 330 participants died over a median follow-up of 5.8 years, 200 (35.7%) in the PD group and 130 (23.2%) in the reference group. After adjustment for smoking and age at PD onset, the HR for mortality was 2.32 (95% CI 1.85–2.92). The mortality risk remained significant with increasing age at onset, even in those aged ≥80 years (HR = 2.10; 95% CI 1.44–3.00). The increased risk was apparent for short PD duration (<2 years) and remained stable with increasing duration. We found no different risk of mortality associated with PD according to smoking status. Conclusions: In this large prospective cohort of men and after matching on comorbidities, we found that Parkinson disease patients had an increased risk of all-cause mortality. Mortality was increased regardless of disease duration, did not diminish with increasing age at onset, and was not influenced by smoking status. GLOSSARY: BMI = body mass index; COPD = chronic obstructive pulmonary disease; HR = hazard ratio; ICD-9 = International Classification of Diseases, 9th Revision; PD = Parkinson disease; PHS = Physicians’ Health Study; RR = relative risk; WHO = World Health Organization.

A Prospective Cohort Study of Cancer Incidence Following the Diagnosis of Parkinson's Disease

Background: Prior studies suggest a decreased risk of cancer among patients with Parkinsons disease (PD). Methods: Matched cohort analysis among the 22,071 participants in the Physicians Health Study. A total of 487 incident cases of PD without preceding cancer were identified by self-report. Each PD case was matched by age to a reference participant who was alive and cancer free at the time of PD diagnosis. Both cohorts were followed for incident cancer. We used proportional hazards models to calculate adjusted relative risks (RR) for cancer. Results: A total of 121 cancers were confirmed during a median follow-up of 5.2 years (PD) and 5.9 years (reference). Those with PD developed less cancer (11.0% versus 14.0%), with an adjusted RR of 0.85 [95% confidence interval (95% CI), 0.59-1.22]. Reduced risk was present for smoking-related cancers such as lung (RR, 0.32), colorectal (RR, 0.54), and bladder (RR, 0.68), as well as for most non–smoking-related cancers such as prostate cancer (RR, 0.74). In contrast, PD patients were at significantly increased risk (RR, 6.15; 95% CI, 1.77-21.37) for melanoma. PD patients who smoked were at reduced risk for smoking-related cancer (RR, 0.33; 95% CI, 0.12-0.92), whereas nonsmokers with PD were at increased risk (RR, 1.80; 95% CI, 0.60-5.39). This interaction was statistically significant (Pinteraction = 0.02). Conclusions: Our results suggest a decreased incidence of most cancers in patients with PD. PD patients had a significantly increased risk of malignant melanoma, a finding consistent with prior studies. We confirmed an interaction between smoking and the relationship of PD to smoking-related cancer that may fit the pattern of a gene-environment interaction. (Cancer Epidemiol Biomarkers Prev 2007;16(6):1260–5)