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.

Parkinsonism may aggravate dysphagia in myotonic dystrophy type 1: two case reports.

Introduction: Weakness of trunk muscles, fatigue and reduced mobility are features of myotonic dystrophy type 1 (DM1) and may also characterize patients with extrapyramidal disorders.Dysphagia is common in DM1 and parkinsonism and can be predominant compared to other symptom, often requiring surgical tratment. Methods: We describe two cases of patients with DM1 and parkinsonism who arrived at our Center for worsening dysphagia and who showed very similar and peculiar clinical features. Case reports: The first patient presented initially at the outpatient clinic reporting a 7 year history of progressive difficulties in swallowing and movement slowness. Neurologic examination showed a general bradykinesia, plastic rigidity of upper limbs, diffuse hypotrophy and deep tendon reflexes weakness. MRI scan of brain and spine was unremarkable, but neurophysiological evaluation revealed diffuse myotonic discharges on distal limb muscles. Genetic testing confirmed DM1 diagnosis (CTG range E1).The second patient, presented with an initial diagnosis of parkinsonism due to a 10 years history of gait impairment, generalized weakness and dysphagia. Due to low back pain a neurophysiological study was performed after 5 years from diagnosis of parkinsonism detecting diffuse myotonic discharges and genetic testing confirmed diagnosis of DM1 (CTG range E2).Percutaneous endoscopic gastrostomy (PEG) was severe and burdensome for both patients.To date, only one case of molecularly confirmed DM1 along with parkinsonism has been described. We have described two cases of DM1 and parkinsonism in which swallowing function has been affected by a synergic effect triggered by both muscle condition and extrapyramidal disease.

Epidemiological, Clinical and Genetic Features of ALS in the Last Decade: A Prospective Population-Based Study in the Emilia Romagna Region of Italy.

Increased incidence rates of amyotrophic lateral sclerosis (ALS) have been recently reported across various Western countries, although geographic and temporal variations in terms of incidence, clinical features and genetics are not fully elucidated. This study aimed to describe demographic, clinical feature and genotype-phenotype correlations of ALS cases over the last decade in the Emilia Romagna Region (ERR). From 2009 to 2019, our prospective population-based registry of ALS in the ERR of Northern Italy recorded 1613 patients receiving a diagnosis of ALS. The age- and sex-adjusted incidence rate was 3.13/100,000 population (M/F ratio: 1.21). The mean age at onset was 67.01 years; women, bulbar and respiratory phenotypes were associated with an older age, while C9orf72-mutated patients were generally younger. After peaking at 70-75 years, incidence rates, among women only, showed a bimodal distribution with a second slight increase after reaching 90 years of age. Familial cases comprised 12%, of which one quarter could be attributed to an ALS-related mutation. More than 70% of C9orf72-expanded patients had a family history of ALS/fronto-temporal dementia (FTD); 22.58% of patients with FTD at diagnosis had C9orf72 expansion (OR 6.34, p = 0.004). In addition to a high ALS incidence suggesting exhaustiveness of case ascertainment, this study highlights interesting phenotype-genotype correlations in the ALS population of ERR.