Withdrawal of mechanical ventilation in amyotrophic lateral sclerosis patients: a multicenter Italian survey

Background: Law 219/2017 was approved in Italy in December 2017, after a years-long debate on the autonomy of healthcare choices. This Law, for the first time in Italian legislation, guarantees the patient's right to request for withdrawal of life-sustaining treatments, including mechanical ventilation (MV). Objective: To investigate the current status of MV withdrawal in amyotrophic lateral sclerosis (ALS) patients in Italy and to assess the impact of Law 219/2017 on this practice. Methods: We conducted a Web-based survey, addressed to Italian neurologists with expertise in ALS care, and members of the Motor Neuron Disease Study Group of the Italian Society of Neurology. Results: Out of 40 ALS Italian centers, 34 (85.0%) responded to the survey. Law 219/2017 was followed by an increasing trend in MV withdrawals, and a significant increase of neurologists involved in this procedure (p 0.004). However, variations across Italian ALS centers were observed, regarding the inconsistent involvement of community health services and palliative care (PC) services, and the intervention and composition of the multidisciplinary team. Conclusions: Law 219/2017 has had a positive impact on the practice of MV withdrawal in ALS patients in Italy. The recent growing public attention on end-of-life care choices, along with the cultural and social changes in Italy, requires further regulatory frameworks that strengthen tools for self-determination, increased investment of resources in community and PC health services, and practical recommendations and guidelines for health workers involved

Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic Lateral Sclerosis

Importance: Juvenile amyotrophic lateral sclerosis (ALS) is a rare form of ALS characterized by age of symptom onset less than 25 years and a variable presentation.Objective: To identify the genetic variants associated with juvenile ALS.Design, Setting, and Participants: In this multicenter family-based genetic study, trio whole-exome sequencing was performed to identify the disease-associated gene in a case series of unrelated patients diagnosed with juvenile ALS and severe growth retardation. The patients and their family members were enrolled at academic hospitals and a government research facility between March 1, 2016, and March 13, 2020, and were observed until October 1, 2020. Whole-exome sequencing was also performed in a series of patients with juvenile ALS. A total of 66 patients with juvenile ALS and 6258 adult patients with ALS participated in the study. Patients were selected for the study based on their diagnosis, and all eligible participants were enrolled in the study. None of the participants had a family history of neurological disorders, suggesting de novo variants as the underlying genetic mechanism.Main Outcomes and Measures: De novo variants present only in the index case and not in unaffected family members.Results: Trio whole-exome sequencing was performed in 3 patients diagnosed with juvenile ALS and their parents. An additional 63 patients with juvenile ALS and 6258 adult patients with ALS were subsequently screened for variants in the SPTLC1 gene. De novo variants in SPTLC1 (p.Ala20Ser in 2 patients and p.Ser331Tyr in 1 patient) were identified in 3 unrelated patients diagnosed with juvenile ALS and failure to thrive. A fourth variant (p.Leu39del) was identified in a patient with juvenile ALS where parental DNA was unavailable. Variants in this gene have been previously shown to be associated with autosomal-dominant hereditary sensory autonomic neuropathy, type 1A, by disrupting an essential enzyme complex in the sphingolipid synthesis pathway.Conclusions and Relevance: These data broaden the phenotype associated with SPTLC1 and suggest that patients presenting with juvenile ALS should be screened for variants in this gene.</p

Neutrophil-to-lymphocyte ratio improves outcome prediction of acute intracerebral hemorrhage

Background: The inflammatory response plays a role in determining the course of intra-cerebral hemorrhage (ICH) and immune parameters may have prognostic value. The aim of the study was to determine whether the peripheral leukocyte counts and neutrophil-to-lymphocyte ratio (NLR) were associated to 30-day functional status after ICH, and improved the accuracy of outcome prediction when added to the Modified ICH score. Methods: We retrospectively identified consecutive patients with spontaneous ICH who underwent blood sampling and cranial CT neuroimaging within 24 h from onset. Total white blood cells (WBC), absolute neutrophil count (ANC) and absolute lymphocyte count (ALC) were collected, and the NLR computed as the ANC to ALC ratio. The study endpoint was 30-day functional status; poor outcome was defined as death or major disability (modified Rankin Scale score ≥ 3). Results: Two hundred and eight patients were enrolled, of which 111 (53.4%) had a modified Rankin Scale score ≥ 3 at 30 days from ICH. At multivariate analysis, the WBC (adjusted odd ratio [adjOR] for 1000 leukocytes increase 1.20, 95% confidence interval [CI] 1.05–1.38), ANC (adjOR for 1000 neutrophils increase 1.34, 95% CI 1.14–1.57), ALC (adjOR for 1000 lymphocytes increase 0.34, 95% CI 0.20–0.59) and NLR (adjOR for 1-point increase 1.49, 95% CI 1.24–1.79) were independently associated with 30-day poor outcome. Predictive accuracy of the Modified ICH score was enhanced by adding the NLR. Conclusions: The NLR was associated with 30-day mortality and morbidity after ICH, and improved the accuracy of outcome prediction when added to the Modified ICH score

Incidence and long-term functional outcome of neurologic disorders in hospitalized COVID-19 patients infected with pre-omicron variants

Background and objective: A variety of neurological disorders has been reported as presentations or complications of COVID-19 infection. The objective of this study was to determine their incidence dynamics and long-term functional outcome. Methods: The Neuro-COVID Italy study was a multicentre, observational, cohort study with ambispective recruitment and prospective follow-up. Consecutive hospitalized patients presenting new neurological disorders associated with COVID-19 infection (neuro-COVID), independently from respiratory severity, were systematically screened and actively recruited by neurology specialists in 38 centers in Italy and the Republic of San Marino. The primary outcomes were incidence of neuro-COVID cases during the first 70 weeks of the pandemic (March 2020 to June 2021) and long-term functional outcome at 6 months, categorized as full recovery, mild symptoms, disabling symptoms or death. Results: Among 52759 hospitalized COVID patients, 1865 patients presenting 2881 new neurological disorders associated with COVID-19 infection (neuro-COVID) were recruited. Incidence of neuro-COVID cases significantly declined over time, comparing the first three pandemic waves (8.4%, 95% CI [7.9, 8.9]; 5.0%, 95% CI [4.7, 5.3]; 3.3%, 95% CI [3.0, 3.6], respectively; p = 0.027). The most frequent neurological disorders were acute encephalopathy (25.2%), hyposmia-hypogeusia (20.2%), acute ischemic stroke (18.4%) and cognitive impairment (13.7%). The onset of neurological disorders was more common in the prodromic phase (44.3%) or during the acute respiratory illness (40.9%), except for cognitive impairment whose onset prevailed during recovery (48.4%). A good functional outcome was achieved by the majority of neuro-COVID patients (64.6%) during follow-up (median 6.7 months) and the proportion of good outcome increased throughout the study period (r = 0.29, 95% CI [0.05, 0.50]; p = 0.019). Mild residual symptoms were frequently reported (28.1%), while disabling symptoms were common only in stroke survivors (47.6%). Discussion: Incidence of COVID-associated neurologic disorders decreased during the pre-vaccination phase of the pandemic. Long-term functional outcome was favourable in most neuro-COVID disorders, although mild symptoms commonly lasted over 6 months after infection

Association of Variants in the SPTLC1 Gene with Juvenile Amyotrophic Lateral Sclerosis

Importance: Juvenile amyotrophic lateral sclerosis (ALS) is a rare form of ALS characterized by age of symptom onset less than 25 years and a variable presentation. Objective: To identify the genetic variants associated with juvenile ALS. Design, Setting, and Participants: In this multicenter family-based genetic study, trio whole-exome sequencing was performed to identify the disease-associated gene in a case series of unrelated patients diagnosed with juvenile ALS and severe growth retardation. The patients and their family members were enrolled at academic hospitals and a government research facility between March 1, 2016, and March 13, 2020, and were observed until October 1, 2020. Whole-exome sequencing was also performed in a series of patients with juvenile ALS. A total of 66 patients with juvenile ALS and 6258 adult patients with ALS participated in the study. Patients were selected for the study based on their diagnosis, and all eligible participants were enrolled in the study. None of the participants had a family history of neurological disorders, suggesting de novo variants as the underlying genetic mechanism. Main Outcomes and Measures: De novo variants present only in the index case and not in unaffected family members. Results: Trio whole-exome sequencing was performed in 3 patients diagnosed with juvenile ALS and their parents. An additional 63 patients with juvenile ALS and 6258 adult patients with ALS were subsequently screened for variants in the SPTLC1 gene. De novo variants in SPTLC1 (p.Ala20Ser in 2 patients and p.Ser331Tyr in 1 patient) were identified in 3 unrelated patients diagnosed with juvenile ALS and failure to thrive. A fourth variant (p.Leu39del) was identified in a patient with juvenile ALS where parental DNA was unavailable. Variants in this gene have been previously shown to be associated with autosomal-dominant hereditary sensory autonomic neuropathy, type 1A, by disrupting an essential enzyme complex in the sphingolipid synthesis pathway. Conclusions and Relevance: These data broaden the phenotype associated with SPTLC1 and suggest that patients presenting with juvenile ALS should be screened for variants in this gene.