Challenges in diagnosis of motor neuron disease: A case series of ALS mimic syndromes.

Amyotrophic lateral sclerosis (ALS) is most often a sporadic disorder that affects both upper and lower motor neurons. Because the prognosis of ALS is uniformly poor compared to other motor neuron disorders, defining the diagnosis can help guide appropriate clinical management and improve quality of life for patients. However, the diagnosis of ALS is often challenging and there may be overlapping clinical features with other rare diseases. We present four patients who were referred to our center because of the clinical suspicion of ALS, in whom more detailed assessments revealed an alternative diagnosis, and we discuss the limitations of the modified-El Escorial criteria.

Cardiovascular diseases may play a negative role in the prognosis of amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: Only a few studies have considered the role of comorbidities in the prognosis of amyotrophic lateral sclerosis (ALS) and have provided conflicting results. METHODS: Our multicentre, retrospective study included patients diagnosed from 1 January 2009 to 31 December 2013 in 13 referral centres for ALS located in 10 Italian regions. Neurologists at these centres collected a detailed phenotypic profile and follow-up data until death in an electronic database. Comorbidities at diagnosis were recorded by main categories and single medical diagnosis, with the aim of investigating their role in ALS prognosis. RESULTS: A total of 2354 incident cases were collected, with a median survival time from onset to death/tracheostomy of 43 months. According to univariate analysis, together with well-known clinical prognostic factors (age at onset, diagnostic delay, site of onset, phenotype, Revised El Escorial Criteria and body mass index at diagnosis), the presence of dementia, hypertension, heart disease, chronic obstructive pulmonary disease, haematological and psychiatric diseases was associated with worse survival. In multivariate analysis, age at onset, diagnostic delay, phenotypes, body mass index at diagnosis, Revised El Escorial Criteria, dementia, hypertension, heart diseases (atrial fibrillation and heart failure) and haematological diseases (disorders of thrombosis and haemostasis) were independent prognostic factors of survival in ALS. CONCLUSIONS: Our large, multicentre study demonstrated that, together with the known clinical factors that are known to be prognostic for ALS survival, hypertension and heart diseases (i.e. atrial fibrillation and heart failure) as well as haematological diseases are independently associated with a shorter survival. Our findings suggest some mechanisms that are possibly involved in disease progression, giving new interesting clues that may be of value for clinical practice and ALS comorbidity management.

Impact of an early respiratory care programme with non-invasive ventilation adaptation in patients with amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: Forced vital capacity (FVC) <80% is one of the key indications for starting non-invasive ventilation (NIV) in amyotrophic lateral sclerosis (ALS). It was hypothesized that a very early start of NIV could lengthen the free interval before death compared to later-start NIV; as a secondary outcome, the survival rate of patients on NIV without tracheotomy was also evaluated. METHODS: This retrospective study was conducted on 194 ALS patients, divided into a later group (LG) with FVC <80% at NIV prescription (n = 129) and a very early group (VEG) with FVC ≥80% at NIV prescription (n = 65). Clinical and respiratory functional data and time free to death between groups over a 3-year follow-up were compared. RESULT: At 36 months from diagnosis, mortality was 35% for the VEG versus 52.7% for the LG (P = 0.022). Kaplan-Meier survival curves adjusted for tracheotomy showed a lower probability of death (P = 0.001) for the VEG as a whole (P = 0.001) and for the non-bulbar (NB) subgroup (P = 0.007). Very early NIV was protective of survival for all patients [hazard ratio (HR) 0.45; 95% confidence interval (CI) 0.28-0.74; P = 0.001] and for the NB subgroup (HR 0.43; 95% CI 0.23-0.79; P = 0.007), whilst a tracheotomy was protective for all patients (HR 0.27; 95% CI 0.15-0.50; P = 0.000) and both NB (HR 0.26; 95% CI 0.12-0.56; P = 0.001) and bulbar subgroups (HR 0.29; 95% CI 0.11-0.77; P = 0.013). Survival in VEG patients on NIV without tracheotomy was three times that for the LG (43.1% vs. 14.7%). CONCLUSION: Very early NIV prescription prolongs the free time from diagnosis to death in NB ALS patients whilst tracheotomy reduces the mortality risk in all patients.

Inefficient skeletal muscle oxidative function flanks impaired motor neuron recruitment in Amyotrophic Lateral Sclerosis during exercise.

This study aimed to evaluate muscle oxidative function during exercise in amyotrophic lateral sclerosis patients (pALS) with non-invasive methods in order to assess if determinants of reduced exercise tolerance might match ALS clinical heterogeneity. 17 pALS, who were followed for 4 months, were compared with 13 healthy controls (CTRL). Exercise tolerance was assessed by an incremental exercise test on cycle ergometer measuring peak O2 uptake ([Formula: see text]O2peak), vastus lateralis oxidative function by near infrared spectroscopy (NIRS) and breathing pattern ([Formula: see text]E peak). pALS displayed: (1) 44% lower [Formula: see text]O2peak vs. CTRL (p < 0.0001), paralleled by a 43% decreased peak skeletal muscle oxidative function (p < 0.01), with a linear regression between these two variables (r2 = 0.64, p < 0.0001); (2) 46% reduced [Formula: see text]Epeak vs. CTRL (p < 0.0001), achieved by using an inefficient breathing pattern (increasing respiratory frequency) from the onset until the end of exercise. Inefficient skeletal muscle O2 function, when flanking the impaired motor units recruitment, is a major determinant of pALS clinical heterogeneity and working capacity exercise tolerance. CPET and NIRS are useful tools for detecting early stages of oxidative deficiency in skeletal muscles, disclosing individual impairments in the O2 transport and utilization chain.

Meditation training for people with amyotrophic lateral sclerosis: a randomized clinical trial.

BACKGROUND AND PURPOSE: Studies investigating psychological interventions for the promotion of well-being in people with amyotrophic lateral sclerosis (ALS) are lacking. The purpose of the current study was to examine the use of an ALS-specific mindfulness-based intervention for improving quality of life in this population. METHODS: A randomized, open-label and controlled clinical trial was conducted on the efficacy of an ALS-specific meditation programme in promoting quality of life. Adults who received a diagnosis of ALS within 18 months were randomly assigned either to usual care or to an 8-week meditation training based on the original mindfulness-based stress reduction programme and tailored for people with ALS. Quality of life, assessed with the ALS-Specific Quality of Life Revised scale, represented the primary outcome, whilst secondary outcomes included anxiety and depression, assessed with the Hospital Anxiety and Depression Scale, and specific quality of life domains. Participants were assessed at recruitment and after 2, 6 and 12 months. The efficacy of the treatment was assessed on an intention-to-treat basis of a linear mixed model. RESULTS: A hundred participants were recruited between November 2012 and December 2014. Over time, there was a significant difference between the two groups in terms of quality of life (ß = 0.24, P = 0.015, d = 0.89). Significant differences between groups over time were also found for anxiety, depression, negative emotions, and interaction with people and the environment. CONCLUSIONS: An ALS-specific meditation programme is beneficial for the quality of life and psychological well-being of people with ALS.

Novel FUS mutations identified through molecular screening in a large cohort of familial and sporadic amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. Approximately 5%-10% of cases are familial (FALS) and the remaining are sporadic (SALS). To date FUS mutations are responsible for 4%-6% of familial cases as well as 0.7%-1.8% of sporadic cases. METHODS: The frequency of FUS mutations was investigated in an Italian cohort of 500 SALS and 40 FALS patients through direct sequencing of exons 5, 6, 13, 14 and 15. RESULTS: Eight FUS mutation carriers were identified in five SALS (1%) and three FALS (7.5%), five already known and three new mutations: a de novo mutation was identified in a sporadic subject as well as the co-presence of FUS/C9ORF72 mutations in a FALS subject. The molecular and clinical details of the three patients harbouring a novel mutation (G245V, G509D and R491C) are presented here. Moreover the co-presence of the R491C mutation and C9ORF72 pathological expansion was found according to the oligogenic disease model. CONCLUSIONS: In conclusion our results revealed a higher frequency of FUS mutation carriers (7.5%) in FALS compared to literature data together with a higher presence of female gender.

Amyotrophic lateral sclerosis in pregnancy is associated with a vascular endothelial growth factor promoter genotype.

BACKGROUND AND PURPOSE: The occurrence of amyotrophic lateral sclerosis (ALS) during pregnancy is uncommon and the effect of one on the other is not well described. METHODS: The clinical and genetic features of five cases of ALS are reported with an onset during pregnancy or within 1 month from delivery. Charts from 239 women with a diagnosis of ALS attending the neuromuscular clinics at the Neuromuscular Omnicentre (NEMO) and at IRCCS Policlinico San Donato from 2008 to 2011 were reviewed. RESULTS: Of these, 12.8% of the women in child-bearing age had a diagnosis of ALS during pregnancy or immediately after delivery. Genetic screening of the major causative genes revealed two mutations in superoxide dismutase 1 (SOD1) gene; the analysis of vascular endothelial growth factor (VEGF) promoter variation showed a segregation of the haplotype CA/AG (-2578C/A; -1190A/G) in patients developing ALS related to pregnancy. No effects on foetal development or neonatal course were observed. CONCLUSIONS: Pregnancy may unmask ALS but whether this is coincidental is unclear. Hormonal and inflammatory modifications might trigger ALS in subjects with increased susceptibility to oxidative stress related to the toxic function of SOD1 or in subjects with a reduction of neuroprotective molecules such as VEGF.

Exploring motor and visual imagery in Amyotrophic Lateral Sclerosis.

Amyotrophic Lateral Sclerosis (ALS) is a motor neuron disease characterized by the progressive atrophy of both the first and the second motor neurons. Although the cognitive profile of ALS patients has already been defined by the occurrence of language dysfunctions and frontal deficit symptoms, it is less clear whether the degeneration of upper and lower motor neurons affects motor imagery abilities. Here, we directly investigated motor imagery in ALS patients by means of an established task that allows to examine the presence of the effects of the biomechanical constraints. Twenty-three ALS patients and 23 neurologically unimpaired participants have been administered with the (1) hand laterality task (HLT) in which participants were asked to judge the laterality of a rotated hand and the (2) mirror letter discrimination task (MLD) in which participants were asked to judge whether a rotated alphanumeric character was in its canonical or mirror-reversed form (i.e. control task). Results show that patients present the same pattern of performance as unimpaired participants at the MLD, while at the HLT, they present only partially with the effects of biomechanical constraints. Taken together, our findings provide evidences that motor imagery abilities, related to the mental simulation of an action, are affected by this progressive disease.

Trauma and amyotrophic lateral sclerosis: a case-control study from a population-based registry.

BACKGROUND AND PURPOSE: Published reports on the association between amyotrophic lateral sclerosis (ALS) and trauma are controversial suggesting the need for a new case-control study done in a large population. METHODS: A case-control study was undertaken in Italy to assess this association. Cases were patients with newly diagnosed ALS from four population-based registries. For each case, two hospital controls were selected, matched for age, sex, and province of residence, one with a neurological (non-degenerative) disease and one with a non-neurological disease (other than orthopedic or surgical). Traumatic events (defined as accidental events causing injuries requiring medical care) were recorded with details on type, site, timing, severity, and complications. The risks were assessed as odds ratios (ORs) with 95% confidence intervals (CI), crude and adjusted for age, sex, education, interviewee (patient or surrogate), physical activity, smoking, alcohol, and coffee. RESULTS: The study population comprised 377 patients in each of the three groups. One or more traumatic events were reported by 225 cases (59.7%), 191 neurological controls (50.7%), and 179 non-neurological controls (47.5%) (P < 0.01) (OR 1.63; 95% CI 1.25-2.14) (P < 0.01). The ORs were 3.07 (95% CI 1.86-5.05) for patients reporting 3+ traumatic events and 2.44 (95% CI 1.36-4.40) for severe traumatic events. The ORs remained significant when the analysis was limited to events that occurred 5+ and 10+ years before ALS onset, to incident ALS, and direct informant. CONCLUSION: Antecedent trauma, repeated trauma, and severe trauma may be risk factors for ALS.

Free insulin-like growth factor (IGF)-1 and IGF-binding proteins-2 and -3 in serum and cerebrospinal fluid of amyotrophic lateral sclerosis patients.

BACKGROUND: The insulin-like growth factor-1 (IGF-1) signaling system is regulated by many factors which interact in regulating the bioavailability of IGF-I. In this context, little information is available on free IGF-1, the bioactive form of IGF-1, in amyotrophic lateral sclerosis (ALS). METHODS: We investigated the endogenous expression of IGF-1, and two related binding proteins (IGF-binding proteins, IGFBP-2 and BP-3) in serum and cerebrospinal fluid (CSF) of 54 sporadic ALS (sALS) patients. Twenty-five healthy individuals and 25 with other neurological diseases (OND) were used as controls. Total and free IGF-1, and IGFBP-3 levels were detected by immunoradiometric assay (IRMA); IGFBP-2 levels were determined by radioimmunoassay (RIA). RESULTS: Total and free IGF-1, IGFBP-2 and BP-3 serum levels were not significantly different between patients and controls, although in sALS patients free IGF-1 was negatively correlated with ALS-Functional Rating Scale-revised (ALS-FRS-R) score (r = -0.4; P = 0.046) and forced vital capacity (FVC) (r = -0.55; P < 0.04). In CSF, free IGF-1 was significantly increased in sALS patients compared with OND (P < 0.0001). CONCLUSIONS: Though in the serum we did not find significant differences amongst the three groups, IGF-1 bioavailability, represented by the free IGF-1 levels, correlated with disease severity. In the CSF, the significant increment of the free fraction of IGF-1 suggests an up-regulation of the IGF-1 system in the intrathecal compartment of sALS patients. Since IGF-1 is a trophic factor for different tissues, we speculate that high levels of the free IGF-1 in sALS might reflect a physiological defensive mechanism promoted in response to neural degeneration and/or muscle atrophy.

[Towards a multi-step informed consent: considerations and proposals for a good practice]. / Verso un consenso informato a più fasi: considerazioni e proposte per una buona prassi.

Any therapeutic intervention needs consent from the patient, after have received information from the physician. This is often seen as a bureaucratic accomplishment but it could enhance therapeutic alliance. We propose to divide consent from information, offering a place in which doubts and emotions can be explored, with the assistance of a psychological interview. We believe that this new approach can enhance physician-patient relationship, with an improvement in patient satisfaction and a decrease of claims and complaints.