Andrea Calvo

Caregiver burden and patients’ perception of being a burden in ALS

The determinants of ALS caregiver burden and the feeling of the patients as being a burden were assessed using the Caregiver Burden Inventory and the Self-Perceived Burden Scale in 60 caregiver-patient couples. Caregiver burden was correlated to their level of depression and quality of life and, differently from other chronic disorders, increased with the worsening of patients’ disability. ALS patients have a good objective perception of their impact on caregivers.

Prevalence of SOD1 mutations in the Italian ALS population

Background: Five to 10% of amyotrophic lateral sclerosis (ALS) cases are reported to be familial (FALS), and mutations of SOD1 account for 20% of these cases. However, estimates of SOD1 mutation prevalence have been exclusively based on case series and clinic referral cohorts. Objective: To assess the frequency and nature of SOD1 mutations in a large population-based cohort of Italian patients diagnosed with ALS over a 6-year period. Methods: All ALS cases incident in Piemonte and Valle dAosta, Italy, are collected through a prospective epidemiologic register. Almost all patients with ALS resident in the largest province of Piemonte (Turin) have been evaluated for SOD1 mutations in the 6-year period 2000 through 2005. Results: During the study period, 386 residents of Turin province were diagnosed with ALS (mean crude incidence rate of 2.9/100,000/year). Twenty-two patients (5.7%) had a positive family history of ALS. SOD1 analysis was performed in 325 patients (84.2% of the whole cohort), including all FALS cases. Five patients carried a SOD1 coding mutation, three with a family history of ALS (13.6% of FALS) and two in sporadic cases (0.7% of sporadic ALS). Conclusions: In this population-based series, the frequency of familial amyotrophic lateral sclerosis (FALS) was lower than that reported in series from ALS referral centers. While the frequency of SOD1 mutations in FALS was similar to the data reported in the literature, only 0.7% of sporadic ALS cases had a SOD1 mutation. Our data indicate that studies from referral centers may overestimate the frequency of FALS and of SOD1 mutations in sporadic ALS. GLOSSARY: ALS = amyotrophic lateral sclerosis; FALS = familial ALS; SALS = sporadic ALS.

Caregiver time use in ALS

The authors evaluated the caregiver time for 70 patients with ALS. The mean number of caregivers per patient was 2.0 (SD 1.3). Caregiver time increased with worsening of disability (p = 0.0001). The most time-consuming duties were housekeeping, feeding, and toileting. With worsening of patients disability, families relied increasingly on paid caregivers. Caregiver time is a hidden cost of ALS care and is a major burden for caregivers.

Neurobehavioral dysfunction in ALS has a negative effect on outcome and use of PEG and NIV

Objective: To assess the effect of neurobehavioral dysfunction on amyotrophic lateral sclerosis (ALS) survival and on the use of life-prolonging therapies in a population-based setting. Methods: Of the 132 patients diagnosed with ALS in the province of Torino, Italy, between January 1, 2007, and June 30, 2008, 128 participated in the study. Neurobehavioral dysfunction was assessed with the Frontal Systems Behavior Scale (FrSBe), using the Family Rating forms, administered within 4 months from diagnosis. Results: The 128 patients included 71 men and 57 women, with a mean age at onset of 64.7 (SD 11) years. Forty-one patients (32.0%) had a neurobehavioral dysfunction and 9 (7.0%) an isolated dysexecutive behavior. Enteral nutrition (EN) and noninvasive ventilation (NIV) were performed with similar frequencies in patients with and without neurobehavioral dysfunction. Patients with neurobehavioral dysfunction had a significantly shorter survival than those with a normal FrSBe score (median survival, 3.3 vs 4.3 years; p = 0.02). Patients with isolated dysexecutive behavior had a shorter survival than those without neurobehavioral dysfunction (median survival, 2.5 vs 4.5 years; p = 0.03). Patients with neurobehavioral dysfunction had a shorter survival after EN and NIV, while patients with isolated dysexecutive behavior had a shorter survival after NIV but not after EN. The negative effect of comorbid neurobehavioral dysfunction and of isolated dysexecutive behavior on survival persisted under the Cox multivariate model. Conclusions: The presence of neurobehavioral dysfunction or of isolate dysexecutive behavior in ALS at diagnosis is a strong predictor of a poor outcome, partially related to a reduced efficacy of life-prolonging therapies.

ATXN2 polyQ intermediate repeats are a modifier of ALS survival

Objective: To analyze the frequency and clinical characteristics of patients with amyotrophic lateral sclerosis (ALS) with intermediate-length (CAG) expansion (encoding 27–33 glutamines, polyQ) in the ATXN2 gene, in a population-based cohort of Italian patients with ALS (discovery cohort), and to replicate the findings in an independent cohort of consecutive patients from an ALS tertiary center (validation cohort). Methods: PolyQ repeats were assessed in 672 patients with incident ALS in Piemonte and Valle dAosta regions, Italy, in the 2007–2012 period (discovery cohort); controls were 509 neurologically healthy age- and sex-matched subjects resident in the study area. The validation cohort included 661 patients with ALS consecutively seen between 2001 and 2013 in the ALS Clinic Center of the Catholic University in Rome, Italy. Results: In the discovery cohort, the frequency of ≥31 polyQ ATNX2 repeats was significantly more common in ALS cases (19 patients vs 1 control, p = 0.0001; odds ratio 14.8, 95% confidence interval 1.9–110.8). Patients with an increased number of polyQ repeats had a shorter survival than those with <31 repeats (median survival, polyQ ≥31, 1.8 years, interquartile range [IQR] 1.3–2.2; polyQ <31, 2.7 years, IQR 1.6–5.1; p = 0.001). An increased number of polyQ repeats remained independently significant at multivariable analysis. In the validation cohort, patients with ≥31 polyQ repeats had a shorter survival than those with <31 repeats (median survival, polyQ ≥31, 2.0 years, IQR 1.5–3.4; polyQ <31, 3.2 years, IQR 2.0–6.4; p = 0.007). Conclusions: ATXN2 polyQ intermediate-length repeat is a modifier of ALS survival. Disease-modifying therapies targeted to ATXN2 represent a promising therapeutic approach for ALS.

Involvement of immune response in the pathogenesis of amyotrophic lateral sclerosis: a therapeutic opportunity?

The immune system has been found to be involved with positive and negative effects in the nervous system of amyotrophic lateral sclerosis (ALS) patients. In general, T cells, B cells, NK cells, mast cells, macrophages, dendritic cells, microglia, antibodies, complement and cytokines participate in limiting damage. Several mechanisms of action, such as production of neurotrophic growth factors and interaction with neurons and glial cells, have been shown to preserve these latter from injury and stimulate growth and repair. The immune system also participates in proliferation of neural progenitor stem cells and their migration to sites of injury and this activity has been documented in various neurologic disorders including traumatic injury, ischemic and hemorrhagic stroke, multiple sclerosis, infection, and neurodegenerative diseases (Alzheimers disease, Parkinsons disease and ALS). Many therapies have been shown to stimulate the protective and regenerative aspects of the immune system in humans, such as intravenous immunoglobulins, and other experimental interventions such as vaccination, minocycline, antibodies and neural stem cells, have shown promise in animal models of ALS. Consequently, several immunosuppressive and immunomodulatory therapies have been tried in ALS, generally with no success, in particular intravenous immunoglobulins. The multiple aspects of the immune response in ALS are beginning to be appreciated, and their potential as pharmacologic targets in neurologic disease is being explored.

Sclerosi laterale amiotrofica come modello di gestione interdisciplinare

Amyotrophic lateral sclerosis (ALS) is a paradigm of clinical care for its characteristics of progression, reduced life expectancy, loss of autonomy, lack of effective etiological therapies. The interdisciplinary approach proposed for some time in the management of patients with ALS provides an effective model of care, useful also for other pathological conditions. It is focused on the patient and his family, around which revolve all the professionalism, with the same role and importance. In the evolution of these models, research improvements, in particular genetic and neuropsychological discoveries become crucial: therefore the approach to the patient has become increasingly complex. In this work the main areas of interdisciplinary intervention will be considered, reporting different experiences, in particular of the Torino Expert Regional Center for ALS.