Amyotrophic lateral sclersosis: epidemiology, risk factors and treatment

Abstract

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease of motor neurons leading to progressive weakness of the limbs, the bulbar muscles and the respiratory muscles. Fifty percent of patients die within 3 years after onset of symptoms, mainly due to respiratory failure. In a large, prospective, population-based study we calculated the incidence and prevalence of ALS in the Netherlands using the capture-recapture methodology. The annual incidence rate was 2.77 per 100,000 person years. ALS is considered to be a multifactorial disease. Several molecular mechanisms have been described to mediate motor neuron death. We investigated several possible risk factors in ALS, studied in a large prospective, population-based case-control study in the Netherlands between 2006 and 2010. Cigarette smoke could increase the risk of developing ALS through several mechanisms, including inflammation, oxidative stress, and neurotoxicity caused by heavy metals and other chemical compounds present in cigarette smoke. Our study showed that cigarette smoking is, indeed, independently associated with an increased risk of ALS and alcohol consumption is independently associated with a reduced risk of ALS. Current smoking is also associated with a worse prognosis. ALS is more prevalent in men. This suggests a possible neuroprotective effect of female reproductive hormones. We concluded that a longer reproductive time-span, which may be a proxy for longer exposure to female productive hormones, was found to be independently associated with a decreased risk of ALS and with a prolonged survival of ALS patients. An association with increased parental age might suggest there is a role for specific (epi)genetic changes, however in our large study, parental age was not associated with an increased risk of ALS. Familial aggregation of ALS with neurodegenerative diseases such as Parkinson’s disease or dementia, could suggest shared genetic or environmental risk factors.However, in our study no familial aggregation of ALS with other neurodegenerative diseases could be established. On the other hand, the lowered risk of vascular diseases in relatives of ALS patients supports the hypothesis that a beneficial vascular risk profile is associated with increased susceptibility for ALS. Supportive of this hypothesis, a higher level of leisure time physical activity was found in our study . Diagnosing ALS remains difficult because of the lack of a reference test with a high positive predictive value. The aim of the revisions of the different sets of diagnostic criteria was to enhance clinical research, therapeutic trials and molecular genetic studies. Our study showed that the revised El Escorial criteria as well as the Awaji algorithm, still exclude a large percentage of the patients for clinical trials at time of diagnosis. A higher copy number of the SMN2 gene is associated with a more favorable disease course in ALS patients. Increasing the survival motor neuron (SMN) protein expression by enhancing SMN2 transcription by valproic acid could therefore modify the disease course in ALS patients. In our randomized, placebo-controlled, double-blind, clinical trial, valproic acid, at a dose used in epilepsy, as an adjunct to riluzole, did not improve survival in ALS