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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 β-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. [ABSTRACT FROM AUTHOR]

Objective: To test two hypotheses: (1) partners of ALS patients have higher mortality due to outcomes related to psychological distress, and (2) parents and siblings of ALS patients have higher mortality due to diseases that co-occur with ALS. Methods: We performed a nationwide, register-based cohort study in Sweden. We included ALS-free partners, biological parents and full siblings (N = 11,704) of ALS patients, as well as ALS-free partners, biological parents and full siblings (N = 14,460,150) of ALS-free individuals, and followed them during 1961–2013. Hazard ratios (HRs) and 95% confidence intervals (CIs) of overall and cause-specific mortality were derived from Cox regression. Results: Partners of ALS patients, compared to partners of ALS-free individuals, displayed higher mortality due to external causes (HR 2.14; 95% CI 1.35–3.41), including suicide (HR 2.44; 95% CI 1.09–5.44) and accidents (HR 2.09; 95% CI 1.12–3.90), after diagnosis of the ALS patients. Parents of ALS patients had a slightly higher overall mortality (HR 1.03; 95% CI 1.00–1.07), compared with parents of ALS-free individuals. This was driven by mortality due to dementias and cardiovascular, respiratory, and skin diseases. Parents of ALS patients had, however, lower mortality than parents of ALS-free individuals due to neoplasms. Siblings of ALS patients had higher mortality due to dementias, and digestive and skin diseases. Conclusions: Increased mortality due to suicide and accidents among partners of ALS patients is likely attributable to severe psychological distress following the ALS diagnosis. Increased mortality due to dementias among parents and full siblings of ALS patients suggests shared mechanisms between neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Objective:To determine if inflammation in proximity of the motor unit may contribute to neurodegeneration in amyotrophic lateral sclerosis (ALS). Methods: We identified all patients diagnosed in Sweden with concurrent ALS and multiple sclerosis (MS), myasthenia gravis (MG), inflammatory polyneuropathies (IP), or dermatopolymyositis (DMPM) during 1991–2014 according to the Swedish Patient Register (N = 263). We validated medical records for 92% of these patients (18 records were not retrieved and three did not contain enough information) and compared patients with a confirmed overlap (N = 28) with an independent sample of patients with solely ALS (N = 271). Results: Ninety-one patients were deemed as not having ALS (34.6%). Among the remaining 151 with validated ALS, 12 had also a confirmed MS diagnosis, nine a confirmed MG diagnosis, four a confirmed IP diagnosis, and three a confirmed DMPM diagnosis. Seventeen of the patients were women and 11 were men. Seventy-nine percent of the patients with a confirmed overlap had MS, MG, IP, or DMPM diagnosed prior to ALS. Compared to patients with only ALS, the concurrent patients were significantly older at symptoms onset, had higher prevalence of bulbar onset, but used Riluzole and noninvasive ventilation less frequently. Conclusions: We found that a high concurrence of ALS and MS/MG/IP/DMPM diagnoses is largely due to diagnostic uncertainty. A minority of patients had a true concurrence, where MS, MG, IP, and DMPM preceded the ALS diagnosis, which might be due to chance alone. Four patients were diagnosed with MG shortly after onset of ALS, suggesting that neurodegeneration might trigger autoimmunity. [ABSTRACT FROM AUTHOR]

Background: Depression and use of antidepressants are more common among patients with multiple sclerosis (MS) compared to the general population, but the relation of psychiatric comorbidity to use of different disease-modifying therapies (DMTs) is less clear. Objective: To determine whether risk of incident depression or antidepressant use differed across DMTs, and to assess whether depression and antidepressants affected risk of DMT discontinuation and MS relapses. Methods: We prospectively followed for 8 years a register-based nationwide cohort of 3803 relapsing-remitting MS patients. Results: Patients on rituximab had a lower risk of being diagnosed with depression or initiating antidepressants compared with the reference group treated with interferons (hazard ratio (HR) = 0.72, 95% confidence interval (CI) = 0.54–0.96). Patients diagnosed with depression discontinued interferon treatment to a higher extent than patients without depression (HR = 1.51; 95% CI = 1.15–1.98), as did patients on fingolimod initiating an antidepressant compared to patients who did not initiate an antidepressant (HR = 1.47; 95% CI = 1.04–2.08). Conclusions: Our results indicate that the choice of DMT is associated with subsequent risk of depression in MS, but further studies are needed to establish whether there is a causal link. Overall, depression and use of antidepressants displayed limited associations with DMT discontinuation and MS relapse. [ABSTRACT FROM AUTHOR]

Objective: To assess the associations of 43 autoimmune diseases with the subsequent risk of ALS and further evaluate the contribution of familial confounding to these associations. Methods: We conducted a nationwide register-based nested case-control study including 3561 ALS patients diagnosed during 1990–2013 in Sweden and 35,610 controls that were randomly selected from the general population and individually matched to the cases on age, sex, and county of birth. To evaluate the contribution of familial factors on the studied association, we additionally studied the first-degree relatives (siblings and children) of ALS patients and their controls. Results: Patients with ALS had a 47% higher risk of being previously diagnosed with autoimmune disease (OR 1.47, 95% confidence interval [CI] 1.31–1.64), compared with controls. A positive association was noted for several autoimmune diseases, including myasthenia gravis, polymyositis or dermatomyositis, Guillain-Barre syndrome, type 1 diabetes diagnosed younger than 30 years, multiple sclerosis, and hypothyreosis. The increased risk of any autoimmune disease was greatest during the year before ALS diagnosis, likely due to misdiagnosis. A statistically significantly increased risk was also noted during 2–5 years, but not earlier, before ALS diagnosis. First-degree relatives of ALS patients had however no increased risk of autoimmune diseases compared with first-degree relatives of controls. Conclusions: Although it is difficult to completely remove the potential effects of misdiagnosis, there is likely a positive association between autoimmune disease (such as type 1 diabetes and multiple sclerosis) and ALS, which is not fully explained by shared familial confounding factors. [ABSTRACT FROM AUTHOR]