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Background and purpose: Tauroursodeoxycholic acid (TUDCA) is a hydrophilic bile acid that is produced in the liver and used for treatment of chronic cholestatic liver diseases. Experimental studies suggest that TUDCA may have cytoprotective and anti-apoptotic action, with potential neuroprotective activity. A proof of principle approach was adopted to provide preliminary data regarding the efficacy and tolerability of TUDCA in a series of patients with amyotrophic lateral sclerosis (ALS). Methods: As a proof of principle, using a double-blind placebo controlled design, 34 ALS patients under treatment with riluzole who were randomized to placebo or TUDCA (1 g twice daily for 54 weeks) were evaluated after a lead-in period of 3 months. The patients were examined every 6 weeks. The primary outcome was the proportion of responders [those subjects with improvement of at least 15% in the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R) slope during the treatment period compared to the lead-in phase]. Secondary outcomes included between-treatment comparison of ALSFRS-R at study end, comparison of the linear regression slopes for ALSFFRS-R mean scores and the occurrence of adverse events. Results: Tauroursodeoxycholic acid was well tolerated; there were no between-group differences for adverse events. The proportion of responders was higher under TUDCA (87%) than under placebo (P = 0.021; 43%). At study end baseline-adjusted ALSFRS-R was significantly higher (P = 0.007) in TUDCA than in placebo groups. Comparison of the slopes of regression analysis showed slower progression in the TUDCA than in the placebo group (P < 0.01). Conclusions: This pilot study provides preliminary clinical data indicating that TUDCA is safe and may be effective in ALS.

Objective To explore the effectiveness of communication and the variables affecting the eye-tracking computer system (ETCS) utilization in patients with late-stage amyotrophic lateral sclerosis (ALS). Methods We performed a telephone survey on 30 patients with advanced non-demented ALS that were provisioned an ECTS device. Median age at interview was 55 years (IQR = 48–62), with a relatively high education (13 years, IQR = 8–13). A one-off interview was made and answers were later provided with the help of the caregiver. The interview included items about demographic and clinical variables affecting the daily ETCS utilization. Results The median time of ETCS device possession was 15 months (IQR = 9–20). The actual daily utilization was 300 min (IQR = 100–720), mainly for the communication with relatives/caregiver, internet surfing, e-mailing, and social networking. 23.3% of patients with ALS (n = 7) had a low daily ETCS utilization; most reported causes were eye-gaze tiredness and oculomotor dysfunction. Conclusions Eye-tracking computer system is a valuable device for AAC in patients with ALS, and it can be operated with a good performance. The development of oculomotor impairment may limit its functional use.

Objective To assess sleep characteristics and the occurrence of abnormal muscle activity during sleep, such as REM sleep without atonia (RSWA), REM sleep behavior disorder (RBD), and periodic leg movements during sleep (PLMS), in patients with amyotrophic lateral sclerosis (ALS). Methods A total of 41 patients with ALS and 26 healthy subjects were submitted to clinical interview and overnight video-polysomnography. Results A total of 22 patients with ALS (53.6%) reported poor sleep quality. Polysomnographic studies showed that patients with ALS had reduced total sleep time, increased wakefulness after sleep onset, shortened REM and slow-wave sleep, and decreased sleep efficiency, compared to controls. Polysomnographic abnormalities were not different in patients reporting good or poor sleep and were not correlated to clinical and demographic variables. The PLMS index was significantly higher in patients with ALS than in healthy subjects, and 22 patients (53.6%) showed a PLMS index > 15/h, vs 4 (15.4%) controls (P < 0.001). Finally, two patients with ALS (4.9%) had RBD, and two more patients presented RSWA (4.9%), whereas no controls showed abnormalities of REM sleep. Conclusion Patients with ALS frequently present abnormalities of sleep that can be documented both at the clinical interview and at the polysomnographic evaluation, including insomnia, fragmented sleep, and increased PLMS. Moreover, abnormalities of REM sleep can be found in some of these patients.

Background and objectives Several variables have been linked to a shorter survival in patients with amyotrophic lateral sclerosis (ALS), for example, female sex, older age, site of disease onset, rapid disease progression, and a relatively short diagnostic delay. With regard to marital status, previous studies suggested that living with a partner might be associated to a longer survival and a higher likelihood to proceed to tracheostomy. Therefore, to further strengthen this hypothesis, we investigated the role of marital status as a prognostic variable in a cohort of ALS patients. Methods We performed a retrospective analysis on 501 consecutive ALS patients for which a complete disease's natural history and clinical/demographic data were available. At diagnosis, 409 patients (81.6%) were married or lived with a stable partner, whereas 92 patients (18.4%) were single/widowed/divorced. Results In our ALS cohort, being married was associated with a median longer survival (married, 35 months [24-50] vs unmarried, 27 months [18-42]; P

Background and purpose: Fatigue is a common symptom in amyotrophic lateral sclerosis (ALS). Although sleep disturbances are a candidate factor that may interfere with fatigue in patients with ALS, the role of sleep-related abnormalities in determining fatigue in ALS is unknown. Objective: To evaluate the frequency and determinants of fatigue in a group of 91 consecutive patients with ALS, with special attention to the relationship between fatigue and sleep problems. Methods: Measures included the Fatigue Severity Scale (FSS), Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS), ALS Functional Rating ScaleRevised (ALSFRS-R), and Beck Depression Inventory (BDI). Results: The mean FSS score was 4.35 ± 1.1, and 48 patients with ALS (52.75%) reported clinical significant fatigue. FSS score correlated with ALSFRS-R score, forced vital capacity, ESS, BDI, and global PSQI score. Patients with fatigue were significantly more disabled and more frequently reported difficulties staying asleep and nocturnal complaints, such as nocturia and disturbing muscle cramps. After multivariate analysis, patients disability and nocturnal complaints were significantly associated with fatigue. Conclusion: In this study, we demonstrated that fatigue, a troublesome and disabling symptom in ALS, is associated with physical impairment and night-time complaints (such as nocturia and muscle cramps), suggesting that treating sleep problems might be useful in alleviating fatigue in these patients.

Objectives - To determine the causes and place of death in a cohort of Italian patients with amyotrophic lateral sclerosis (ALS). A better understanding of the likely causes of death in ALS might improve the palliative care at the end-of-life, whereas knowing the place of death will help to verify the need for highly specialized care services, e.g. hospice and nursing home. Patients and methods - Between 2000 and 2008, 182 ALS patients (onset: spinal, 127; bulbar, 55; M/F: 1.6) were followed in a single ALS Tertiary Centre in Palermo, Sicily, Italy until death. Medical data for each individual patient were recorded in a large database throughout the disease course. Information concerning causes and place of death were obtained by consultation with relatives or the family physician. Results - Respiratory failure (terminal respiratory insufficiency, pneumonia) was the most frequent cause of death (81.3%), which included six cases (3.3%) who requested a terminal sedation. Sudden death and death during sleep accounted for by 6.0% and 6.6% of all deaths, respectively. Heart-related causes of death were relatively infrequent in our cohort, accounting for by 7.1 % of all deaths (i.e. sudden death: 6.0% and myocardial infarct: 1.1%). Patients (85.2%) died at home. Conclusions - The leading cause of death in ALS remains the respiratory failure, followed by the sudden death and death during sleep. Most patients in our cohort died at home, a choice that might be only partially driven by cultural factors. These findings might have a great impact on the development of the advanced and end-of-life palliative care and in the planning of specialized care services, as hospice and nursing home.

Background: High cerebrospinal fluid (CSF) and plasma levels of homocysteine (HC) have been reported in certain neurodegenerative disorders, such as Alzheimer’s, Parkinson’s diseases and, recently, amyotrophic lateral sclerosis (ALS). Objectives: To assay the CSF and plasma levels of HC in ALS patients and controls, and to evaluate the relationship between HC levels and clinical variables of the disease. Methods: Cerebrospinal fluid from sixty-nine (M/F 1.87) and plasma from sixty-five ALS patients (M/F 1.83) were taken and stored at −80°C until use. Controls (CSF = 55; plasma = 67) were patients admitted to our hospital for neurological disorders with no known relationship to HC changes. CSF and plasma from ALS patients and controls were obtained as a necessary step of the diagnostic workup. HC levels in CSF and plasma were assayed using a high performance liquid chromatograph (HPLC) and a fluorimeter detector. Results: The median level of total HC in the CSF of ALS patients was 0.46 μM, significantly higher than that of the controls (0.24 μM, +91.6%, P

Mutations in the Angiogenin gene (ANG) linked to 14q11.2 have been recently discovered to be associated with Amyotrophic Lateral Sclerosis (ALS) in Irish and Scottish populations. In our study we investigated the role of ANG gene in ALS patients from southern Italy. We found a novel mutation in the signal peptide of the ANG gene in a sporadic patient with ALS (SALS). The molecular analysis of the ANG gene also demonstrated an allelic association with the rs11701 single nucleotide polymorphism (SNP) in familial ALS (FALS) but not in SALS patients. Our finding supports the evidence that the ANG gene is involved in ALS.

Background and purpose Vesicle-associated membrane-protein-associated protein B (VAPB) is an endoplasmic reticulum (ER) resident protein participating in ER function, vesicle trafficking, calcium homeostasis and lipid transport. Its N-terminal domain, named MSP, is cleaved and secreted, serving as an extracellular ligand. VAPB mutations are linked to autosomal-dominant motor neuron diseases, including amyotrophic lateral sclerosis (ALS) type 8. An altered VAPB function is also suspected in sporadic ALS (SALS). Methods The expression pattern of VAPB cleavage and secreted products in the peripheral blood leukocytes (PBL) and cerebrospinal fluid (CSF) of SALS patients and neurological controls was assessed. PBL from healthy controls were also analyzed. Assays were carried out through western blotting, using an anti-VAPB (N-terminal) antibody. Results Two VAPB fragments containing the MSP domain (17 kDa and 14 kDa molecular sizes) were identified in PBL of SALS and controls, with no significant differences amongst groups. In CSF, only the 14 kDa VAPB MSP fragment was expressed and a corresponding VAPA fragment was not detected. The CSF VAPB fragment was absent in 58.7% of SALS patients, of whom 79.2% were bulbar onset (P = 0.001, bulbar versus spinal). Conclusions The absence of the CSF VAPB MSP fragment from most bulbar-onset SALS patients suggests a specific alteration of brain-derived VAPB cleavage and secretion in this group of patients, and hints at a role of VAPB in the pathophysiology of this motor neuron disease.

We report on a patient with bulbar-onset, clinically defined, sporadic amyotrophic lateral sclerosis (ALS) who also showed a Chiari I malformation. This malformation, otherwise asymptomatic, was detected during the diagnostic work-up for ALS. To our knowledge this is the first report of an association between these two relatively uncommon disorders. Since our patient worked for many years as a bus-driver and because the ALS symptoms began in the brainstem region, we suggest that his hindbrain anomaly, along with the mechanical stress on the spine and cranio-vertebral junction due to the daily driving, might have played a role in the region-specific onset of ALS. Language: en

Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder leading to progressive motor neuron cell death. Etiopathogenesis is still imperfectly known and much effort have been undertaken to find a biological marker that could help in the early diagnosis and in the monitoring of disease progression. Cerebrospinal fluid (CSF) concentrations of tau, an axonal microtubule-associated protein, have been measured in ALS with levels found increased in some studies and unchanged in others. Methods: Total CSF tau level was assayed in a population of ALS patients (n = 57) and controls (n = 110) using a specific ELISA method. Results: No significant differences in the median CSF tau levels between ALS cases and controls were found [ALS: 126 pg/ml (78–222); controls: 112 pg/ml (71–188), P = ns]. In the ALS group, the bulbar-onset patients showed increased CSF tau levels as compared with the spinal-onset cases. These differences might be related to the higher age of the bulbar-onset patients. Further, no correlations were found between CSF tau concentrations and the rate of progression of the disease. Conclusions: These results do not support the hypothesis that total CSF tau protein is a reliable biological marker for ALS.

The relentless evolution of amyotrophic lateral sclerosis (ALS), a severe neurodegenerative disorder of the upper and lower motoneurons, leads to an increasing level of disability. Most patients, during the course of the disease, become unable to attend the tertiary clinical care center and are thus prevented from enrolling in clinical trials or benefiting from specialized care and management. The main objective of this study was to verify whether the ALS functional rating scale (ALSFRS) could be reliably administered by telephone to patients, when unable to attend the ALS clinic, or to their caregivers. ALSFRS is a validated instrument that assesses the functional status and the disease progression in ALS. We first administered the functional rating scale directly in the clinic to 30 patients, with definite or probable ALS, and to their respective caregivers, and found a very high agreement between the two groups for the total score and the majority of the rating items. Next, we showed, in both patients and caregivers, a high degree of correlation between the total score of the ALSFRS measured by telephone and that reported in the clinic. This indicates that ALSFRS is a reliable instrument for monitoring the disease progression in homebound patients, even when the person contacted by telephone is the caregiver. We also performed a telephone clinic, based on an unstructured interview, with 16 ALS patients at an advanced stage of the disease and unable to attend the ALS clinic. On some occasions, the person interviewed was the caregiver. The symptoms most frequently reported were a worsening of muscle strength, swallowing and breathing problems, constipation, and inability to clear lung secretions. Several patients asked for assistive and adaptive equipment. All patients and caregivers found the telephone clinic very useful and considered it a good complement to the management and care programme.

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