Long-term treatment of SOD1 ALS with tofersen: a multicentre experience in 17 patients.

BACKGROUND: In Amyotrophic Lateral Sclerosis (ALS) patients with SOD1 mutation the intrathecal administration of tofersen slowed down the progression of disease in a controlled clinical study, but results were not statistically significant. METHODS: In this multicentre, observational study, we evaluated a cohort of 27 ALS-SOD1 patients who were treated with tofersen, focussing on 17 patients who were followed for at least 48 weeks (median period of 84 weeks, range 48-108). We compared the clinical slopes, as measured by ALSFRS-R, MRC scale and Forced Vital Capacity, during tofersen treatment with retrospective data at 1 year prior to therapy. Cerebrospinal fluid (CSF) and serum neurofilament light chains (NFL) were measured in all patients. RESULTS: Cumulative evaluation of the ALSFRS-R and MRC progression rates showed a statistically significant change during treatment with respect to the period prior to therapy (p = 0.023 and p = 0.007, respectively). The analysis of individual patients showed that nine of the seventeen patients substantially stabilized or slightly improved. Four patients deteriorated during treatment, while in the remaining patients the very slow course did not allow to identify significant changes. CSF and serum NFL concentration markedly decreased in the near totality of patients. Increased levels of white blood cells and proteins in the CSF were found in 60% of patients. Such alterations were clinically asymptomatic in all but two patients who showed an acute pure motor radiculitis, which responded to steroid therapy. CONCLUSIONS: Clinical findings and NFL analysis strongly suggest that tofersen may have a disease-modifying effect in a subset of SOD1-ALS patients.

Dog-assisted physiotherapy in amyotrophic lateral sclerosis: a randomized controlled pilot study.

BACKGROUND: Animal-assisted therapy (AAT) is an intervention in which the animal acts as a co-therapist. It has been mainly used in the context of patients with dementia, showing positive effects on psychological symptoms, but its potential as a physiotherapy treatment for patients with neuromuscular disorders, amyotrophic lateral sclerosis (ALS) in particular, has not yet been investigated. AIM: The aim of the study was to evaluate the impact of AAT, specifically of dog-assisted therapy, on motor functions and psychological status in patients with ALS. DESIGN: This study was a randomized controlled pilot study. SETTING: The study was carried out at the Rehabilitation Unit NEuroMuscular Omnicenter (NEMO) of Arenzano, Genoa. POPULATION: Sixty hospitalized ALS patients were enrolled. METHODS: All patients ran a regular two-weeks neurorehabilitation program twice a day. For three days a week, in place of the morning traditional treatment, the AAT group performed a rehabilitation session with a simultaneous interaction with the therapy-dog, while the control group performed a traditional rehabilitation session. The outcome measures were the Timed Up and Go Test, the Short Physical Performance Battery (SPPB), the Six Minutes Walk Test, the Ten Meters walking Test and the Hospital Anxiety and Depression Scale. RESULTS: Both groups showed an amelioration in motor scales. However, SPPB subscales as well as HADS scores showed a statistically significant improvement only in the AAT group (P values from <0.0001 to 0.0004). Additionally, across almost all motor and psychological measures, post-treatments values were significantly better for the AAT group (P values from <0.0001 to 0.01). CONCLUSIONS: The obtained results not only suggest that AAT is comparable to traditional physiotherapy treatments, but also evidence that this type of treatment has greater beneficial effects on motor and psychological symptoms in patients with ALS. CLINICAL REHABILITATION IMPACT: This study provides first evidence that AAT is a powerful rehabilitation strategy in patients with ALS, improving both motor and psychological symptoms, and therefore possibly ameliorating quality of life.

The upper extremity functional index (UEFI): Italian validation in patients with Facioscapulohumeral muscular dystrophy.

PURPOSE: The aim of this study was to adapt the Upper Extremity Functional Index (UEFI) to an Italian population affected by Facioscapulohumeral muscular dystrophy (FSHD) by translating and validating this instrument in an Italian cohort. MATERIALS AND METHODS: Five Italian FSHD patients were interviewed regarding the form and content of the translated instrument. Subsequently, fifty-two patients were recruited for the validation purpose by serially completing the UEFI-IT and a battery of clinical assessments and questionnaires. Finally, a subset of thirty-nine patients underwent test-retest reliability. RESULTS: The Italian translation of the UEFI was highly relevant to patients, had a level of test-retest reliability from "good" to "excellent" (ICC = 0.90 with 95% confidence interval between 0.82 and 0.95), and a satisfactory internal consistency (Cronbach's alpha = 0.96). Participants confirmed the usefulness and clearness of the tool in cultural validity. In known group validity, the UEFI-IT was significantly lower in patients unable to walk (24.10 ± 11.33 vs 55.71 ± 13.98, p < .0001; AUC = 0.9631) and in patients with longer disease duration (43.43 ± 17.16 vs 58.14 ± 13.71, p = 0.0034; AUC = 0.7359). Finally, the concurrent validity showed strong associations between the UEFI-IT and motor assessments, pain perception, and quality-of-life evaluations. CONCLUSIONS: Overall, the UEFI-IT is an appropriate, valid, and reliable outcome measure for Italian-speaking FSHD patients.

It is important for the clinical community to have a valid instrument that can serially offer an accurate assessment of disability that involves questionnaires of the upper extremity functions.The Upper Extremity Functional Index (UEFI) is a deeply used region-specific patient-reported outcome measure (PROM) that investigates the patients' current upper extremity functional status.The Italian validation of UEFI (UEFI-IT) is a valid instrument that allows patients to report on the functional status of their upper limbs.The UEFI-IT provides clinicians with a valid and reliable outcome measure that is easy to use and applicable to a large number of clinical presentations and for both clinical practice and research.

Assessing Prevalence and Characteristics of Oro-bulbar Involvement in Children and Adults with SMA Type 2 and 3 Using a Multimodal Approach.

Bulbar and jaw muscles are impaired in patients with Spinal Muscular Atrophy (SMA) but the assessment of their severity and progression are limited by the lack of age-appropriate and disease-specific measures. We investigated mastication and swallowing in children and adults with SMA, sitters and walkers. In a 2-year multicentre cross-sectional prospective study, lip and tongue strength (Iowa Oral Performance Instrument), chewing and swallowing (Test of Masticating and Swallowing Solids), active mouth opening (aMMO) were compared to age-appropriate normative data. The perceived burden of oro-bulbar involvement (SMA-Health Index) was recorded. 78 patients were included, 45 children (median age 7.4 years),22 adults (median age 26.8 years) on nusinersen and 11 untreated (median age 32.7 years). Forty-three percent children had reduced mouth opening, 50% had prolonged total time to eat. These issues were more prominent in sitters than in walkers (p = 0.019, p = 0.014). Sixty-six percent needed increased swallows for bolus clearance. Nusinersen treated adults had median aMMO, tongue strength and total time at TOMASS values within normal range (z score: -1.40, -1.22, -1.32, respectively) whereas untreated adults had reduced aMMO (z score: -2.68) and tongue strength (z score: -2.20). Only a minority of children (2/17) and treated adults (5/21) reported burden in swallowing or mastication compared to all untreated adults (5/5). After 16 months, mastication and swallowing were stable in treated children and adults, whether sitters or walkers. The reported multimodal approach to assess oro-bulbar functions demonstrate that swallowing and mastication are impaired in SMA despite patients' perception. These results suggest a trend towards stabilization of oro-bulbar function in patients on long-term treatment with nusinersen.

The facioscapulohumeral muscular dystrophy - health index: Italian validation of a disease-specific measure of symptomatic burden.

PURPOSE: The aim of this study was to adapt the Facioscapulohumeral Muscular Dystrophy - Health Index (FSHD-HI) to an Italian population affected by FSHD by translating, validating, and testing this instrument in an Italian cohort. MATERIALS AND METHODS: Italian FSHD patients were interviewed regarding the form and content of the translated instrument. Subsequently, forty FSHD patients were recruited to test the reliability (Intraclass Correlation Coefficient, ICC for test-retest; and Cronbach's Alpha for Internal consistency), known groups (Mann-Whitney U test and Area Under the Curve, AUC) and concurrent validity (Pearson's and Spearman's Rank Correlation Coefficient) of the instrument by serially completing the FSHD-HI and an extensive set of tests measuring the neuromotor, psychological and cognitive functions, and perceived quality of life (QoL) aspects. RESULTS: The Italian translation of the FSHD-HI and its subscales were highly relevant to patients, had a high internal consistency (Cronbach's Alpha = 0.90), optimal test-retest reliability (ICC= 0.95), and was significantly associated with motor function, respiratory function, and QoL assessments. CONCLUSIONS: Overall, the Italian FSHD-HI is a valid and well-suited measurement of the multi-dimensional aspects of disease burden in FSHD patients.

Facioscapulohumeral muscular dystrophy (FSHD) negatively impacts the quality of life and increases the disease burden.It is important for the clinical community to have a valid instrument that can serially measure a patient's perception of their multifactorial disease burden in FSHD.The Facioscapulohumeral Muscular Dystrophy ­ Health Index (FSHD-HI) is a valid instrument that allows patients to provide their perspective regarding their current health state.FSHD-HI-IT provides a valid option for measuring multifactorial disease burden in Italian patients with FSHD during clinical trials.

Equating norms between the ALS Cognitive Behavioral Screen (ALS-CBS™) and the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) in non-demented ALS patients.

BACKGROUND: The present study aimed at deriving equating norms to estimate scores on the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) based on those on the ALS Cognitive Behavioral Screen (ALS-CBS™) in an Italian cohort of non-demented ALS patients. METHODS: ALS-CBS™ and ECAS scores of 293 ALS patients without frontotemporal dementia were retrospectively retrieved. Concurrent validity of the ALS-CBS™ towards the ECAS was tested by covarying for demographics, disease duration and severity, presence of C9orf72 hexanucleotide repeat expansion and behavioural features. A linear-smoothing equipercentile equating (LSEE) model was employed to derive ALS-CBS™-to-ECAS cross-walks. Gaps in LSEE-based estimation were managed via a linear regression-based equating approach. Equivalence between empirical and derived ECAS scores was tested via a two-one-sided test (TOST) procedure for the dependent sample. RESULTS: The ALS-CBS™ predicted the ECAS (ß = 0.75), accounting for the vast majority of its variance (60% out of an R2 = 0.71). Consistently, a strong, one-to-one linear association between ALS-CBS™ and ECAS scores was detected (r = 0.84; R2 = 0.73). The LSEE was able to estimate conversions for the full range of the ALS-CBS™, except for raw scores equal to 1 and 6 - for whom a linear equating-based equation was derived. Empirical ECAS scores were equivalent to those derived with both methods. DISCUSSION: Italian practitioners and researchers have been herewith provided with valid, straightforward cross-walks to estimate the ECAS based on ALS-CBS™ scores in non-demented ALS patients. Conversions herewith provided will help avoid cross-sectional/longitudinal inconsistencies in test adoption within research, and possibly clinical, settings.

Facial nerve vulnerability in spinal muscular atrophy and motor unit number index of the orbicularis oculi muscle.

INTRODUCTION/AIMS: Measures for assessing cranial nerve vulnerability in spinal muscular atrophy (SMA) have not yet been determined. Motor unit number index (MUNIX) studies have shown correlations with disease severity but have been used only in limb muscles. In the present study, we explore facial nerve response, MUNIX, and motor unit size index (MUSIX) of the orbicularis oculi muscle in a cohort of patients with SMA. METHODS: Facial nerve response (measured as compound muscle action potential, CMAP), MUNIX, and MUSIX of the orbicularis oculi muscle were cross-sectionally recorded in patients with SMA and compared to healthy control subjects (HCs). Active maximum mouth opening (aMMO) was also measured at baseline in our SMA cohort. RESULTS: Thirty-seven patients with SMA (21 SMA II; 16 SMA III) and 27 HCs were recruited. CMAP of the facial nerve and MUNIX of orbicularis oculi proved to be feasible and well tolerated techniques. CMAP amplitude and MUNIX scores were significantly lower in patients with SMA compared to HCs (p < .0001). Both MUNIX and CMAP amplitude were significantly higher in patients with SMA III compared to SMA II. No significant difference emerged comparing CMAP amplitude, MUNIX and MUSIX scores between those with different functional status or nusinersen treatment. DISCUSSION: Our results provide neurophysiological evidence of facial nerve and muscle involvement in patients with SMA. CMAP of the facial nerve and MUNIX of orbicularis oculi showed high accuracy in discriminating between the various subtypes of SMA and in quantifying the motor unit loss of the facial nerve.

Development of prediction models based on respiratory assessments to determine the need for non-invasive ventilation in patients with myotonic dystrophy type 1.

INTRODUCTION: Myotonic dystrophy type 1 is a slowly progressive, multisystem, autosomal dominant disorder, in which the impairments of respiratory systems represent one of the main causes of death. OBJECTIVE: The aim of our study is to develop prediction models to identify the most appropriate test(s) providing indication for NIV. METHODS: DM1 patients attending the NEMO Clinical Center (Milan) between January 2008 and July 2020, who had been subjected to a complete battery of respiratory tests, were retrospectively recruited. Demographic, clinical, and anthropometric characteristics were collected, as well as arterial blood gas (ABG) analysis, spirometry, respiratory muscle strength, cough efficacy, and nocturnal oximetry as respiratory assessments. Patients were stratified in those requiring NIV and those with normal respiratory function. RESULTS: Out of 151 DM1 patients (median age: 44 years [35.00-53.00]; male/female ratio: 0.80 (67/84)), 76 had an indication for NIV initiation (50.33%). ABG, spirometry, and nocturnal oximetry prediction models resulted in an excellent discriminatory ability in distinguishing patients who needed NIV from those who did not (AUC of 0.818, 0.808, and 0.935, respectively). An easy-to-use calculator was developed to automatically determine a score of NIV necessity based on the prediction equations generated from each aforementioned prediction model. CONCLUSIONS: The proposed prediction models may help to identify which patients are at a higher risk of requiring ventilator support and therefore help in defining individual management plans and criteria for specific interventions early in the disease course.

Clinimetrics of the cognitive section of the Italian ALS Cognitive Behavioral Screen (ALS-CBS™).

BACKGROUND: The present study aimed at (1) providing further validity and reliability evidence for the Italian version of the cognitive section of the ALS Cognitive Behavioral Screen (ALS-CBS™) and (2) testing its diagnostics within an Italian ALS cohort, as well as at (3) exploring its capability to discriminate patients from healthy controls (HCs). METHODS: N = 293 non-demented ALS patients were administered the cognitive sections of the ALS-CBS™ and Edinburgh Cognitive and Behavioural ALS Screen (ECAS). N = 96 HCs demographically matched with N = 96 patients were also administered the cognitive section of the ALS-CBS™. In patients, factorial and construct validity, internal reliability, and diagnostics against a defective score on the cognitive section of the ECAS were tested. Case-control discrimination was assessed via a logistic regression. RESULTS: ALS-CBS™ cognitive subscales were underpinned by a simple, unidimensional structure, internally reliable (McDonald's ω = 0.74), and mostly related with ECAS executive and fluency scores (rs = 0.54-0.71). Both raw and age- and education-adjusted scores on the cognitive section of the ALS-CBS™ accurately detected ECAS-defined cognitive impairment (AUC = 0.80 and .88, respectively), yielding optimal error-based, information-based and unitary diagnostics. A cut-off of < 15.374 was identified on adjusted scores. The test was able to discriminate patients from HCs (p < 0.001). DISCUSSION: The cognitive section of the Italian ALS-CBS™ is a valid, reliable, and diagnostically sound ALS-specific screener for detecting frontotemporal, executive-/attentive-based cognitive inefficiency in non-demented ALS patients, being also able to discriminate them from normotypical individuals.

Emotional exhaustion and fear of COVID-19 in geriatric facilities during the COVID-19 pandemic.

OBJECTIVE: Since the onset of the COVID-19 pandemic, healthcare workers, especially those employed in hospital settings, have been exposed to a variety of stressors in the workplace. The aim of this study was to explore the Emotional Exhaustion (EE) of workers in geriatric facilities during the COVID-19 crisis. We accordingly sought to investigate the short-term impact of the COVID-19 pandemic in terms of the EE experienced by workers in geriatric facilities, and to examine the manner in which psychosocial conditions and fear of COVID-19 in the workplace have affected EE. METHODS: Surveys were administered in the midst of the COVID-19 crisis (October to December 2020). The study included 118 French healthcare workers with a mean age of 35.61 ± 0.73 recruited in geriatric facilities. We assessed EE, psychosocial conditions (e.g., demands at work, health and well-being, etc.) and fear of COVID-19 in the workplace. RESULTS: The analysis yielded two main outcomes. First, 34.75% workers (41) reported severe levels of EE. Second, demands at work and the fear of COVD-19 increased EE. Health and well-being were, however, demonstrated to protect against EE. DISCUSSION: Furthermore, fear of COVID-19 was shown to contribute significantly to EE healthcare workers in geriatric facilities. It is likely that Covid-19 indirectly contributes to EE by influencing demands at work.

Fear of COVID-19, emotional exhaustion, and care quality experience in nursing home staff during the COVID-19 pandemic.

BACKGROUND: Nursing home staff have been adversely impacted throughout the COVID-19 pandemic, facing difficulties in providing patient care. The aim of this study was to explore health workers' perception regarding their own care quality experience in nursing homes during the COVID-19 pandemic. Amidst the second wave of the pandemic, we investigated the relationships between fear of COVID-19 and care quality experiences in nursing homes with emotional exhaustion (EE) as a mediating role. We hypothesized that EE is associated with fear of COVID-19 and care quality experience among nursing home staff. Furthermore, we predicted that EE would mediate the relationships between fear of COVID-19 and care quality experience. METHODS: During the second wave of COVID-19 (October to December 2020), we administered surveys to a large sample of 129 French nursing home staff with a mean age of 38.47 ± 10.31 who were directly and repeatedly exposed to COVID-19. We assessed their emotional exhaustion (EE) and care quality experience in the workplace via subjective indicators using self-reported scales. RESULTS: In the context of COVID-19, low to severe emotional exhaustion levels were found among nursing home staff, and these levels were associated with care quality experience as well as fear of COVID-19. The groups with low and severe levels of EE reported the highest levels of fear of COVID-19. The groups with moderate and severe levels of EE reported the lowest levels of care quality experience. Lastly, the relationships between fear of COVID-19 and care quality experience were mediated by EE. CONCLUSIONS: The findings made by the present study focused on the role of emotional coping responses to COVID-19. EE was associated positively with fear of COVID-19 and negatively with care quality experience. Furthermore, EE was found to mediate the relationship between fear of COVID-19 and care quality experience. We discuss these findings as they relate to palliative care issues in nursing homes and the manner in which emotional exhaustion ought to be addressed among nursing home staff.

Assessment of Respiratory Function and Need for Noninvasive Ventilation in a Cohort of Patients with Myotonic Dystrophy Type 1 Followed at One Single Expert Center.

Introduction: Respiratory insufficiency is one of the main causes of death in myotonic dystrophy type 1 (DM1). Although there is general consensus that these patients have a restrictive ventilatory pattern, hypoventilation, chronic hypercapnia, and sleep disturbances, the prevalence of respiratory disease and indication for the effects of noninvasive ventilation (NIV) need to be further explored. Objectives: To describe respiratory function and need for NIV at baseline and over time in a cohort of adult patients with DM1. Methods: A total of 151 adult patients with DM1 were subjected to arterial blood gas analysis, sitting and supine forced vital capacity (FVC), peak cough expiratory flow (PCEF), nocturnal oximetry, and maximal inspiratory pressure and expiratory pressure (MIP/PEP). Results: On first assessment, 84 of 151 had normal respiratory function (median age: 38 years, median BMI: 23.9, and median disease duration: 11 years); 67 received an indication to use NIV (median age: 49 years, median BMI: 25,8, and median disease duration: 14 years). After a median time of 3.85 years, 43 patients were lost to follow-up; 9 of 84 required NIV; only 17 of 67 with the new NIV prescription were adherent. Conclusions: We provide additional data on the natural history of respiratory function decline and treatment adherence in a relatively large cohort of well-characterized patients with DM1. A high proportion (28%) was lost to follow-up. A minority (11%) required NIV, and only 25% were treatment adherent, irrespective of specific demographics and respiratory features. Our results also confirm previous findings, showing that age, disease duration, and higher BMIs are predisposing factors for respiratory impairment.

A phase I/IIa clinical trial of autologous hematopoietic stem cell transplantation in amyotrophic lateral sclerosis.

OBJECTIVE: To verify the safety and potential effect on ALS progression of a low-intensity immunosuppressive regimen followed by autologous hematopoietic stem cell transplantation (aHSCT) in amyotrophic lateral sclerosis (ALS) patients. METHODS: ALS eligible patients underwent a set of clinical and laboratory evaluations at T-4 (screening), T-1 (pre-treatment visit), and for the 12 consecutive months after treatment (T3, T6, T9, T12). We evaluated the tolerability of the procedure, its efficacy on clinical course and quality of life (QoL). RESULTS: Eight of the 11 ALS patients enrolled received the established immunoablative protocol. The procedure was well tolerated and side effects were those expected. One patient died 4 months after the conditioning regimen and another patient underwent tracheotomy just before T3 for a sudden respiratory failure, but he is still alive 4 years after the procedure without being ventilated any more. A third patient died 10 months after conditioning. In the other cases, there was no statistical difference in all functional measures and QoL pre- and post-treatment; however, a transitory slopes' reduction of ALSFRS-R and seated SVC% after the conditioning procedures was reported. Moreover, although not statistically significant, trends of reduction of CD4 + and increment of CD8 + were found. CONCLUSIONS: aHSCT was overall well tolerated, but it was not followed by any significant modification in disease progression. Considering the negative results of this small trial, further studies aimed to evaluate the possible efficacy of the aHSCT using a higher-intensity regimen should be carefully and with caution evaluated.

Body composition and myokines in a cohort of patients with Becker muscular dystrophy.

INTRODUCTION/AIMS: Becker muscular dystrophy (BMD) is an X-linked disease leading to muscle wasting and weakness. The decrease in lean body mass (LBM) in Duchenne muscular dystrophy, has shown correlation with loss of muscle function and bone density (BD). Myokines (including irisin) are hormones secreted by skeletal muscle that allow crosstalk between muscle and bone. The present study analyzed body composition and circulating myokine levels in a cohort of BMD patients; moreover, the association between dual energy X-ray absorptiometry (DXA) parameters, functional motor assessments, and myokine levels was investigated. METHODS: All patients underwent DXA, blood samples for myokine assays, and functional motor assessments. A group of healthy controls (HCs) was also included. RESULTS: Thirty BMD patients, median age at evaluation 36.0 y [26.0-41.0], were included. Twenty-nine patients underwent whole-body DXA. Median value of total body Z-score was -0.70. The prevalence of low skeletal muscle mass defined as appendicular skeletal muscle mass index (ASMMI) < 7.59 kg/m2 was 83%. Irisin levels were significantly lower in BMD compared to HCs (p = .03). All DXA parameters showed significant correlation with the functional motor assessments, in particular the h2 -standardized lean mass lower limb index (p = .0006); h2 -standardized total fat mass showed negative correlations with North Star Ambulatory Assessment and 6 min walk test (p = .03). DISCUSSION: DXA is a useful tool to evaluate body composition in BMD patients; the decrease in BD and LBM is associated with a reduction of motor function in BMD.

A preliminary comparison between ECAS and ALS-CBS in classifying cognitive-behavioural phenotypes in a cohort of non-demented amyotrophic lateral sclerosis patients.

To define the presence and type of frontotemporal dysfunction in amyotrophic lateral sclerosis (ALS), different screening tools have been created. Currently, the most used screening tests are the Edinburgh cognitive and behavioural ALS screen (ECAS) and the ALS cognitive behavioural screen (ALS-CBS). The objective of this study was to compare the ability of ECAS and ALS-CBS in classifying non-demented ALS patients according to Strong criteria. One-hundred and fifty-four in- and out-patients with an age > 18 and a definite or probable ALS diagnosis were recruited between September 2019 and February 2020 at NeMO Clinical Centre and at Istituto Auxologico Italiano in Milan and underwent the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) and the ALS Cognitive Behavioural Screen (ALS-CBS). Exclusion criteria involved patients with a diagnosis of FTD, with a severe cognitive deterioration and/or an important behavioural impairment, with a significant psychiatric disorder or with the co-presence of another significant illness. The distribution of patients according to Strong criteria was different for ECAS and ALS-CBS and the degree of agreement between the two tests in terms of Cohen's Kappa coefficient resulted equal to 0.2047 with a 95% confidence limits interval between 0.1122 and 0.2973. This study for the first time compares the ability of ECAS and ALS-CBS in stratifying ALS patients. Further studies will be conducted to better understand the reasons underlying the differences between these two tests in classifying the different subtypes of fronto-temporal dysfunction in ALS.

The hypometabolic state: a good predictor of a better prognosis in amyotrophic lateral sclerosis.

BACKGROUND: Malnutrition and weight loss are negative prognostic factors for survival in patients with amyotrophic lateral sclerosis (ALS). However, energy expenditure at rest (REE) is still not included in clinical practice, and no data are available concerning hypometabolic state in ALS. OBJECTIVE: To evaluate in a referral cohort of patients with ALS the prevalence of hypometabolic state as compared with normometabolic and hypermetabolic states, and to correlate it with clinical phenotype, rate of progression and survival. DESIGN: We conducted a retrospective study examining REE measured by indirect calorimetry in patients with ALS referred to Milan, Limoges and Tours referral centres between January 2011 and December 2017. Hypometabolism and hypermetabolism states were defined when REE difference between measured and predictive values was ≤-10% and ≥10%, respectively. We evaluated the relationship between these metabolic alterations and measures of body composition, clinical characteristics and survival. RESULTS: Eight hundred forty-seven patients with ALS were recruited. The median age at onset was 63.79 years (IQR 55.00-71.17). The male/female ratio was 1.26 (M/F: 472/375). Ten per cent of patients with ALS were hypometabolic whereas 40% were hypermetabolic. Hypometabolism was significantly associated with later need for gastrostomy, non-invasive ventilation and tracheostomy placement. Furthermore, hypometabolic patients with ALS significantly outlived normometabolic (HR=1.901 (95% CI 1.080 to 3.345), p=0.0259) and hypermetabolic (HR=2.138 (95% CI 1.154 to 3.958), p=0.0157) patients. CONCLUSION: Hypometabolism in ALS is not uncommon and is associated with slower disease progression and better survival than normometabolic and hypermetabolic subjects. Indirect calorimetry should be performed at least at time of diagnosis because alterations in metabolism are correlated with prognosis.

Wheelchair hockey improves quality of life in people with neuromuscular disease.

BACKGROUND: Participation in sports is known to have positive effects on people's health and psychosocial well-being. Recently, physical activity implications for people with disabilities have been explored, showing promising results on quality of life and self-concept. However, few studies have specifically investigated the effects of participation in adaptive sports on quality of life in patients with neuromuscular disease. OBJECTIVE: To evaluate differences in psychosocial well-being between people affected by a neuromuscular disease who play wheelchair hockey and those who do not. Individuals playing an adaptive sport would report better quality of life, higher physical self-efficacy scores, and more effective coping strategies, as assessed by self-reported measures. DESIGN: Cross-sectional study. SETTING: Data were collected during clinical follow-ups at the NEMO Clinical Center in Milan (Italy). PARTICIPANTS: A total of 25 patients affected by neuromuscular diseases, ages 18 to 40 years, participated in the study. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The primary outcome was to compare quality of life between groups. Secondary outcomes were the comparisons of physical self-efficacy and coping strategies through self-reported measures. RESULTS: Wheelchair hockey players scored significantly higher on the Quality of Life Index (specifically on the health/functioning and psychological/spiritual sub-scales) and reported better physical self-efficacy and perceived physical ability compared to the control group (i.e., patients who do not participate in any adaptive sport), controlling for age and pathology. On the contrary, no difference was found in coping strategies between the two groups. CONCLUSIONS: This study identified a significant association between participation in wheelchair hockey and improved physical and psychological well-being of people affected by neuromuscular diseases compared to those who are not involved in adaptive sports.

Standardization of the Italian ALS-CBS™ Caregiver Behavioral Questionnaire.

Background: The present investigation aimed at testing the psychometrics and diagnostics of the Italian version of the Caregiver Behavioral Questionnaire (CBQ) from the ALS Cognitive Behavioral Screen (ALS-CBS™), as well as its case-control discrimination, in a cohort of non-demented patients with ALS. Methods: The caregivers of N = 265 non-demented patients with ALS and N = 99 healthy controls (HCs) were administered the CBQ and the Edinburgh Cognitive and Behavioural ALS Screen-Carer Interview (ECAS-CI). For N = 98 patients, an in-depth behavioural/psychopathological assessment via the Frontal Behavioural Inventory (FBI), the Dimensional Apathy Scale (DAS), the State and Trait Anxiety Inventory-Form Y (STAI-Y), and the Beck Depression Inventory (BDI) was also available. Factorial and construct validity, internal reliability, and diagnostics against an abnormal ECAS-CI score were tested in patients. Case-control discrimination was explored through logistic regression. Results: The CBQ was internally reliable (McDonald's ω = 0.90) and underpinned by a simple, unidimensional structure; it converged with ECAS-CI, FBI, and DAS scores and diverged from STAI-Y and BDI ones. A cutoff of ≤ 33 accurately detected abnormal ECAS-CI scores (AUC = 0.85), yielding optimal error- and information-based diagnostics. The CBQ was independent of demographic and disease-related variables and discriminated patients from HCs (p < 0.001). Discussion: The Italian version of the CBQ from the ALS-CBS™ is a valid, reliable, diagnostically sound, and feasible screener for detecting frontotemporal-like behavioural changes in non-demented patients with ALS. Its adoption is thus recommended within clinical practice and research in the view of providing preliminary information on whether the administration of more extensive behavioural instruments is needed.

Association of Clinically Evident Eye Movement Abnormalities With Motor and Cognitive Features in Patients With Motor Neuron Disorders.

BACKGROUND AND OBJECTIVES: Although oculomotor abnormalities (OMAs) are not usually considered prominent features of amyotrophic lateral sclerosis (ALS), they may represent potential clinical markers of neurodegeneration, especially when investigated together with cognitive and behavioral alterations. The aim of our study was to identify patterns of clinically evident OMAs in patients with ALS and to correlate such findings with cognitive-behavioral data. METHODS: Three consecutive inpatient cohorts of Italian patients with ALS and controls were retrospectively evaluated to assess the frequency of OMAs and cognitive-behavioral alterations. The ALS population was divided into a discovery cohort and a replication cohort. Controls included a cohort of cognitively impaired individuals and patients with Alzheimer disease (AD). Participants underwent bedside eye movement evaluation to determine the presence and pattern of OMAs. Cognitive assessment was performed with a standard neuropsychological battery (discovery ALS cohort and AD cohort) and the Italian Edinburgh Cognitive and Behavioural ALS Screen (ECAS) (replication ALS cohort). RESULTS: We recruited 864 individuals with ALS (635 discovery, 229 replication), 798 who were cognitively unimpaired and 171 with AD. OMAs were detected in 10.5% of our ALS cohort vs 1.6% of cognitively unimpaired controls (p = 1.2 × 10-14) and 11.4% of patients with AD (p = NS). The most frequent deficits were smooth pursuit and saccadic abnormalities. OMA frequency was higher in patients with bulbar onset, prominent upper motor neuron signs, and advanced disease stages. Cognitive dysfunction was significantly more frequent in patients with OMAs in both ALS cohorts (p = 1.1 × 10-25). Furthermore, OMAs significantly correlated with the severity of cognitive impairment and with pathologic scores at the ECAS ALS-specific domains. Last, OMAs could be observed in 35.0% of cognitively impaired patients with ALS vs 11.4% of patients with AD (p = 6.4 × 10-7), suggesting a possible involvement of frontal oculomotor areas in ALS. CONCLUSION: Patients with ALS showed a range of clinically evident OMAs, and these alterations were significantly correlated with cognitive, but not behavioral, changes. OMAs may be a marker of neurodegeneration, and bedside assessment represents a rapid, highly specific tool for detecting cognitive impairment in ALS.

Neurophysiological indices in amyotrophic lateral sclerosis correlate with functional outcome measures, staging and disease progression.

OBJECTIVE: This study examined neurophysiological (NI), split-hand (SI) and split-leg (SLI) index in patients with amyotrophic lateral sclerosis (ALS), and their correlation with functional status, disease duration, staging and survival. METHODS: Eighty-two patients underwent nerve conduction study to analyze NI, SI and SLI. Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R), disease progression rate (ΔFS), Milano-Torino (MiToS) and King's staging systems, Forced Vital Capacity (FVC), and survival data were collected. RESULTS: Both NI and SI indices were significantly associated with ALSFRS-R, MiToS, King's and FVC. Slow progressor patients (ΔFS < 0.5) reported a significantly higher NI and SI values compared to both normal (0.5 ≤ ΔFS < 1.00) and fast progressors (ΔFS ≥ 1.0). After dichotomizing patients in slow progressors (ΔFS < 0.5) and not-slow progressors (ΔFS ≥ 0.5), a combination of SI index and disease duration revealed to be the best prediction model to discriminate patients in accordance with their disease progression (c-index: 0.92), leading to a new prognostic index: the 'Split-Hand prognostic index' (SHpi). CONCLUSION: SI and NI are correlated with functional status and FVC. SHpi index could represent an useful tool to discriminate patients in accordance with their disease progression. SIGNIFICANCE: These data provide novel evidence of neurophysiological indices as promising biomarkers in ALS.