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.

Trauma and amyotrophic lateral sclerosis: a european population-based case-control study from the EURALS consortium.

OBJECTIVES: To assess the association between amyotrophic lateral sclerosis (ALS) and previous traumatic events, age of trauma, and site of injury. METHODS: A population-based case-control study was performed in five European countries (Italy, Ireland, France, United Kingdom, Serbia). Newly diagnosed ALS patients and matched controls were interviewed to collect relevant demographic factors and exposures. Key clinical features at diagnosis were collected in ALS patients. Trauma was any accidental event causing an injury. Injuries were dated and classified according to cause, severity, type, site, and complications. All exposures were censored five years before symptoms onset. Risks were computed as odds ratios (OR) with 95% confidence intervals (CI) using univariate and multivariate conditional logistic regression models. RESULTS: Five hundred and seventy-five ALS patients and 1150 controls were interviewed. Disabling traumatic events predominated in the cases (OR 1.54 (95% CI 1.24-1.92)) and maintained significance after adjustment, with a significant gradient. A history of 2 + head injuries was associated with an almost three-fold increased risk of ALS. The risk was almost two-fold when trauma occurred at age 35-54 years. Site of injury was uneventful. CONCLUSIONS: Traumatic events leading to functional disability or confined to the head are risk factors for ALS. Traumatic events experienced at age 35-54 years carry the highest risk.

Amyotrophic Lateral Sclerosis, a Multisystem Pathology: Insights into the Role of TNFα.

Amyotrophic lateral sclerosis (ALS) is considered a multifactorial, multisystem disease in which inflammation and the immune system play important roles in development and progression. The pleiotropic cytokine TNFα is one of the major players governing the inflammation in the central nervous system and peripheral districts such as the neuromuscular and immune system. Changes in TNFα levels are reported in blood, cerebrospinal fluid, and nerve tissues of ALS patients and animal models. However, whether they play a detrimental or protective role on the disease progression is still not clear. Our group and others have recently reported opposite involvements of TNFR1 and TNFR2 in motor neuron death. TNFR2 mediates TNFα toxic effects on these neurons presumably through the activation of MAP kinase-related pathways. On the other hand, TNFR2 regulates the function and proliferation of regulatory T cells (Treg) whose expression is inversely correlated with the disease progression rate in ALS patients. In addition, TNFα is considered a procachectic factor with a direct catabolic effect on skeletal muscles, causing wasting. We review and discuss the role of TNFα in ALS in the light of its multisystem nature.

Is firstly diagnosed ALS really ALS? Results of a population-based study with long-term follow-up.

OBJECTIVE: To revise the first diagnosis of amyotrophic lateral sclerosis (ALS) in patients from a well-defined population. METHODS: Patients diagnosed with ALS in the years 1998-2002 and resident of Lombardy Region, Northern Italy were followed until death or April 30 2016 to assess long-term survival. During follow-up, the caring neurologists were asked to confirm the first diagnosis. Revised diagnoses were classified as confirmed and unconfirmed motor neuron disease (MND) with further specification where available. The two groups were compared for age, sex, disease duration at diagnosis, site of onset, and El Escorial category. Survival with predictors were also compared. RESULTS: Included were 280 men and 203 women aged 18-93 years. During follow-up, 25 cases (5.2%) received a diagnosis different from MND. Diseases of spinal roots and peripheral nerves and vascular encephalopathy predominated. Patients with definite (OR 0.15; 95%CI 0.04-0.52) and probable (OR 0.15; 95%CI 0.04-0.62) ALS were least likely to have an unconfirmed MND diagnosis. At end of follow-up, 2.2% of patients with confirmed MND and 44.0% of patients with unconfirmed MND were reported alive (HR 0.14; 95%CI 0.08-0.25). CONCLUSIONS: At the time of a first diagnosis of ALS, the possibility still exists that another, less severe clinical condition, is present.

Angiotensin-converting enzyme inhibitors and motor neuron disease: An unconfirmed association.

OBJECTIVE: To investigate the association between angiotensin converting enzyme inhibitors (ACEIs), angiotensin II receptors blockers (ARBs) and motor neuron disease (MND). METHODS: This is a population-based nested case-control study. Data were obtained from a population registry and the administrative database of the Lombardy Region (Northern Italy) from 2000 through 2010. Included were 1,200 patients with newly diagnosed MND/ALS and 120,000 controls, randomly selected from the same population and matched for gender, age and area of residence. Exposure to ACEIs or ARBs was quantified using defined daily doses (DDDs). Cumulative DDD (cDDD) was estimated as the sum of dispensed DDDs in the preceding 5 years, excluding 1 year before the MND/ALS diagnosis. Overall exposure, levels of exposure, and individual drugs were all assessed. Subgroup analyses were performed according to age, sex, ALS and ACEI-ARB association. RESULTS: There was no significant association between MND/ALS and antecedent use of ACEIs or ARBs. Data were confirmed in multivariable models and in subgroups. CONCLUSIONS: A protective role of ACEIs and ARBs in MND was not confirmed. Differences with a previous report (showing an inverse association between ACEIs and ALS) can be explained by different genetic background, dietary habits and susceptibility to environmental exposures, including drugs.

Migraine improves after ischemic stroke.

OBJECTIVE: To assess if migraine frequency spontaneously changes after stroke. BACKGROUND: Patent foramen ovale (PFO) closure has been reported to decrease migraine attacks. Because many closures are carried out after an ischemic stroke, it is possible that migraine spontaneously improves after stroke. METHODS: We have prospectively collected all patients with ischemic stroke and active migraine admitted to our stroke unit and have compared their migraine frequency before and 6, 12, and 24 months after stroke. RESULTS: We studied 43 patients. Mean follow-up was 1.3±.5 years. The mean number of migraine attacks per month decreased from 2.9±2.2 before stroke to .7±1.4 six months after stroke (P<.0001), and to .6±.6 one year after stroke (P<.0001). Migraine attacks completely disappeared in 23 of 43 patients at 6 months after stroke (53.5%) and in 22 of 40 at 1 year (55.0%). Improvement of 50% or more or total disappearance of attacks occurred in 34 of 43 patients at 6 months after stroke (79.1%) and in 33 of 40 at 1 year (82.5%). CONCLUSIONS: Ischemic stroke is very often followed by a marked and persistent improvement of prestroke migraine. The causes of improvement are unclear and may involve changes in lifestyle and psychological status, drugs, platelet activation, or modifications of vasoreactivity after stroke. These data suggest that studies reporting the efficacy of PFO closure for migraine in stroke patients are probably biased by the lack of a control group.

Common carotid artery duplex for the bubble test to detect right-to-left shunt.

We prospectively compared the bubble test with agitated saline for right-to-left shunt using transcranial Doppler (TCD) of the right middle cerebral artery and second harmonic imaging duplex of the right common carotid artery (CCA) in 100 consecutive patients. Microembolic signals (MES) were counted offline. MES were classified into 6 classes: absent (class 0), 1-10 MES (class 1), 11-20 MES (class 2), 21-30 MES (class 3), 31-50 MES (class 4) and >50 MES or "curtain effect" (class 5). For TCD, classes 2-5 combined (i.e., "large" shunts), the sensitivity of duplex with the Valsalva maneuver was 95.3%, the specificity was 100%, the positive predictive 100%, the negative predictive value 96.6% and accuracy 98.0%. Second harmonic imaging duplex of the CCA may substitute TCD for the bubble test when an adequate cranial bone window is not available. This technique may also greatly increase the number of facilities where the bubble test can be carried out. However, tests with few or no MES need to be confirmed by TCD or transesophageal echocardiography.

E-selectin A561C and G98T polymorphisms influence susceptibility and course of multiple sclerosis.

Three hundred seven patients with MS and 300 controls were genotyped for G98T and A561C SNPs in the E-selectin gene, and genetic data were correlated with the course of the disease. The frequency of the T/T genotype of the G98T SNP was significantly increased in RR-MS patients compared with controls, while was absent in PP-MS. The frequency of the A561C SNP was significantly decreased in SP-MS compared with benign RR-MS. The T/T genotype of the G98T SNP is likely to confer an increased risk to develop MS. The A561C polymorphism seems to act as protective factor towards the progression to SP-MS.

Reliability of the El Escorial diagnostic criteria for amyotrophic lateral sclerosis.

BACKGROUND: The El Escorial diagnostic criteria are the most commonly used in clinical studies and therapeutic trials in patients with amyotrophic lateral sclerosis (ALS). The accuracy of the El Escorial criteria was tested in clinical practice, but the reliability is unknown when the diagnosis of ALS must be assessed on the basis of medical records. OBJECTIVE: To assess the reliability of the El Escorial criteria for the diagnosis of ALS in different settings. DESIGN AND METHODS: Semistructured forms were used to include the main diagnostic information on 20 patients with definite (n = 6), probable (n = 6), possible (n = 6), and suspected ALS (n = 2) and 19 patients with clinical conditions considered in the differential diagnosis. Agreement was tested by comparing the diagnosis made by the attending physician (the 'gold standard') with that of 4 raters with different backgrounds: a teaching neurologist with research and practical experience in the field of motor neuron disorders, a neurologist with specific interest in motor neuron disorders and neurophysiological background, a neurophysiologist, and a general neurologist with only occasional ALS patients. Sources of disagreement were discussed and the agreement was tested further on the medical records of 98 additional cases taken from an ongoing ALS registry. Eight additional cases (ALS: 4; other conditions: 4) were examined directly by the 4 raters. RESULTS: The interrater agreement on the medical records was poor (overall kappa 0.05-0.29). When the differential diagnosis was made between ALS (all diagnostic levels) and other conditions, interrater agreement was at best modest, with moderate variations when raters were compared in pairs (kappa 0.03-0.58) and when each rater was compared with the physician (kappa 0.27-0.51). Agreement was higher after direct examination of the patients (kappa 0.33-1) and increased significantly on the medical records after training (overall kappa 0.52-0.79). However, concordance was low (overall kappa 0.08-0.36), even after training, at the lowest diagnostic level (definite to suspected ALS vs. other conditions). CONCLUSIONS: The El Escorial criteria are a poor diagnostic indicator when patients' records are examined. Although medical education significantly improves the reliability of the criteria, concordance is still modest when the diagnosis includes suspected ALS.