Quality of life assessment in adult spinal muscular atrophy patients treated with nusinersen.

OBJECTIVE: To retrospectively evaluate quality of life (QoL) in a large multicenter cohort of adult patients affected by spinal muscular atrophy (SMA) during nusinersen treatment. METHODS: We included adult (≥ 18 years) patients clinically and genetically defined as SMA2, SMA3 and SMA4, who started nusinersen treatment in adulthood. QoL was rated by the Individualized Neuromuscular Quality of Life (INQoL) questionnaire. Concurrent motor function evaluation included the Hammersmith Functional Motor Scale Expanded (HFMSE), the Revised Upper Limb Module (RULM), the 6 min walking test (6MWT). RESULTS: 189 completed questionnaires were collected during a 14 months' treatment period. 78 patients were included (7 SMA2 and 69 SMA3 and 2 SMA4) with mean disease duration at first nusinersen administration of 33.2 years (± 12.5 years). All the scores for each INQoL domain (weakness, fatigue, activities, independence, social relationship, emotions, body images) and the derived QoL total score, significantly improved during the observation period, except the muscle locking and pain items. Exploratory analyses suggested that emotions and social relationships were more relevant issues for females compared to males. Social relationships were affected also by a longer disease duration (> 30 years). In SMA3 non-walker patients, activities ameliorate better compared to walkers. The HFMSE and RULM significantly improved from baseline; however, no associations with QoL total score and weakness, activities or independence were demonstrated. CONCLUSION: In our cohort, adult SMA patients showed a global improvement at the INQoL assessment over 14 months of nusinersen treatment. QoL assessment is relevant to SMA multidisciplinary evaluation.

Nusinersen safety and effects on motor function in adult spinal muscular atrophy type 2 and 3.

OBJECTIVE: To retrospectively investigate safety and efficacy of nusinersen in a large cohort of adult Italian patients with spinal muscular atrophy (SMA). METHODS: Inclusion criteria were: (1) clinical and molecular diagnosis of SMA2 or SMA3; (2) nusinersen treatment started in adult age (>18 years); (3) clinical data available at least at baseline (T0-beginning of treatment) and 6 months (T6). RESULTS: We included 116 patients (13 SMA2 and 103 SMA3) with median age at first administration of 34 years (range 18-72). The Hammersmith Functional Rating Scale Expanded (HFMSE) in patients with SMA3 increased significantly from baseline to T6 (median change +1 point, p<0.0001), T10 (+2, p<0.0001) and T14 (+3, p<0.0001). HFMSE changes were independently significant in SMA3 sitter and walker subgroups. The Revised Upper Limb Module (RULM) in SMA3 significantly improved between T0 and T14 (median +0.5, p=0.012), with most of the benefit observed in sitters (+2, p=0.018). Conversely, patients with SMA2 had no significant changes of median HFMSE and RULM between T0 and the following time points, although a trend for improvement of RULM was observed in those with some residual baseline function. The rate of patients showing clinically meaningful improvements (as defined during clinical trials) increased from 53% to 69% from T6 to T14. CONCLUSIONS: Our data provide further evidence of nusinersen safety and efficacy in adult SMA2 and SMA3, with the latter appearing to be cumulative over time. In patients with extremely advanced disease, effects on residual motor function are less clear.

Evaluation of mexiletine effect on conduction delay and bradyarrhythmic complications in patients with myotonic dystrophy type 1 over long-term follow-up.

BACKGROUND: Myotonic dystrophy type 1 (DM1) is a multisystemic disorder characterized by progressive cardiac conduction impairment, arrhythmias, and sudden death. Mexiletine is a sodium channel blocker drug used by patients with DM1 for treatment of myotonia, even though definitive proof of its safety over long-term follow-up is lacking. OBJECTIVE: The purpose of this study was to assess the impact of mexiletine for treatment of neurological symptoms on the composite endpoint of significant electrocardiogram modification (new onset or worsening of atrioventricular [AV] or intraventricular conduction delay) and bradyarrhythmic complications requiring pacemaker (PM) implantation (advanced AV block, symptomatic sinus pause >3 seconds). METHODS: This retrospective longitudinal study included a series of consecutive patients with genetically confirmed DM1 evaluated at our neurology and cardiology clinics from January 1, 2011, to January 1, 2020, who received mexiletine 200 mg twice daily. Patients with a PM, implantable cardioverter-defibrillator, or severe conduction abnormality (PQ interval ≥230 ms, complete bundle branch block, or atrial fibrillation) at enrollment were excluded. RESULTS: The study comprised 18 mexiletine-treated patients and 68 mexiletine-free controls. Over median follow-up of 53 months, the endpoint was reached by 4 (22%) mexiletine-treated patients and 23 (33%) non-mexiletine-treated patients (log-rank P = .45). In 3 non-mexiletine-treated patients, bradyarrhythmic complications requiring PM implantation were observed. At univariable analysis, only the presence of mild conduction delay (first-degree AV block with PQ interval <230 ms or left anterior fascicular block) at baseline predicted the endpoint (hazard ratio 2.22; 95% confidence interval 1.04-4.76). CONCLUSION: Mexiletine 200 mg twice daily is safe in patients with DM1 and no severe conduction abnormality.

Recognition of emotions conveyed by facial expression and body postures in myotonic dystrophy (DM).

INTRODUCTION: Neuromuscular diseases may be of neuropsychological interest insofar as they may affect representations based on embodied cognition theories. Previous studies have shown impaired ability to recognize facial emotions and an association between facial emotion recognition and visuospatial abilities in myotonic dystrophy type 1 (DM1) patients. Here we examined the ability of both DM1 and DM2 patients to recognize emotions expressed by body postures and its relation, and their association with cognitive performance. METHODS: Participants included 34 DM1 patients, 8 DM2 patients, and 24 healthy control subjects. Emotional recognition ability was assessed through two computerized matching tasks (face and bodies). A neuropsychological battery was used to measure cognition in three domains and global cognition. We used univariate and adjusted linear regression models to investigate the association between cognition and emotion recognition performance. RESULTS: DM patients (combined DM1 and DM2) performed worse on emotional facial expression (p = .006) and body posture (p = .004) accuracy measures than healthy controls. In linear regression models, DM patients' facial expression accuracy was associated with executive function (p = .013) and visuospatial (p < .001) z-scores. Body posture accuracy was associated with visuospatial (p = .001) and memory (p = .012) z-scores. There were no associations among controls or between cognition and reaction time. DISCUSSION: These findings suggest that impaired emotional recognition among DM patients is also extended to emotions conveyed by body postures. Consistent with embodied cognition theories, people affected in their body and its movement may have impaired sensorimotor representation in ways that have yet to be fully understood.

The Role of Motor System in Mental Rotation: New Insights from Myotonic Dystrophy Type 1.

OBJECTIVE: This study explored mental rotation (MR) performance in patients with myotonic dystrophy 1 (DM1), an inherited neuromuscular disorder dominated by muscular symptoms, including muscle weakness and myotonia. The aim of the study was twofold: to gain new insights into the neurocognitive mechanisms of MR and to better clarify the cognitive profile of DM1 patients. To address these aims, we used MR tasks involving kinds of stimuli that varied for the extent to which they emphasized motor simulation and activation of body representations (body parts) versus visuospatial imagery (abstract objects). We hypothesized that, if peripheral sensorimotor feedback system plays a pivotal role in modulating MR performance, then DM1 patients would exhibit more difficulties in mentally rotating hand stimuli than abstract objects. METHOD: Twenty-four DM1 patients and twenty-four age- and education-matched control subjects were enrolled in the study and were required to perform two computerized MR tasks involving pictures of hands and abstract objects. RESULTS: The analysis of accuracy showed that patients had impaired MR performance when the angular disparities between the stimuli were higher. Notably, as compared to controls, patients showed slower responses when the stimuli were hands, whereas no significant differences when stimuli were objects. CONCLUSION: The findings are coherent with the embodied cognition view, indicating a tight relation between body- and motor-related processes and MR. They suggest that peripheral, muscular, abnormalities in DM1 lead to alterations in manipulation of motor representations, which in turn affect MR, especially when body parts are to mentally rotate.

Assessing the Role of Anti rh-GAA in Modulating Response to ERT in a Late-Onset Pompe Disease Cohort from the Italian GSDII Study Group.

INTRODUCTION: Patients with late-onset Pompe disease (LOPD) receiving enzyme replacement therapy (ERT) may develop IgG antibodies against alglucosidase alpha (anti-rhGAA) in the first 3 months of treatment. The exact role of these antibodies in modulating efficacy of ERT in this group of patients is still not fully understood. To assess whether anti rh-GAA antibodies interfere with ERT efficacy, we studied a large Italian cohort of LOPD patients. METHODS: We analyzed clinical findings and performed serial measurements of IgG anti rh-GAA antibody titers from 64 LOPD patients treated with ERT. The first examination (T0) was completed on average at 17.56 months after starting ERT, while the follow-up (T1) was collected on average at 38.5 months. Differences in T0-T1 delta of the six-minute walking test (6MWT), MRC sum score (MRC), gait, stairs and chair performance (GSGC) and forced vital capacity (FVC) were considered and then related to the antibody titers. RESULTS: Almost 22% of the patients never developed antibodies against GAA, while 78.1% had a positive titer (31.2% patients developed a low titer, 43.8% a medium titer and 3.1% a high titer). No statistical significance was found in relating the T0-T1 delta differences and antibody titers, except for MRC sum score values in a subgroup of patients treated < 36 months, in which those with a null antibody titer showed a greater clinical improvement than patients with a positive titer. CONCLUSION: Our results confirm that in a large cohort of LOPD patients, anti rh-GAA antibody generation did not significantly affect either clinical outcome or ERT efficacy. However, in the first 36 months of treatment, a possible interference of low-medium antibody titers with the clinical status could be present. Therefore, a careful and regular evaluation of antibody titers, especially in cases with evidence of clinical decline despite ERT, should be performed.

Amyotrophic lateral sclerosis and environmental factors.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder that affects central and peripheral motor neuron cells. Its etiology is unknown, although a relationship between genetic background and environmental factors may play a major role in triggering the neurodegeneration. In this review, we analyze the role of environmental factors in ALS: heavy metals, electromagnetic fields and electric shocks, pesticides, ß-N-methylamino-L-alanine, physical activity and the controversial role of sports. The literature on the single issues is analyzed in an attempt to clarify, as clearly as possible, whether each risk factor significantly contributes to the disease pathogenesis. After summarizing conflicting observations and data, the authors provide a final synthetic statement.