Neuralgic amyotrophy, also called Parsonage–Turner syndrome, in its classic presentation is a brachial plexopathy or a multifocal neuropathy, involving mainly motor nerves of the upper limb with a monophasic course. Recently, a new radiological entity was described, the hourglass constriction, which is characterized by a very focal constriction of a nerve, or part of it, usually associated with nerve thickening proximally and distally to the constriction. Another condition, which is similar from a radiological point of view to hourglass constriction, is nerve torsion. The pathophysiology of neuralgic amyotrophy, hourglass constriction and nerve torsion is still poorly understood, and a generic role of inflammation is proposed for all these conditions. It is now widely accepted that nerve imaging is necessary in identifying hourglass constrictions/nerve torsion pre-surgically in patients with an acute mononeuropathy/plexopathy. Ultrasound and MRI are useful tools for diagnosis, and they are consistent with intraoperative findings. The prognosis is generally favorable after surgery, with a high rate of good motor recovery.

Background: Hereditary transthyretin amyloidosis with polyneuropathy (ATTRv) is an adult-onset multisystemic disease, affecting the peripheral nerves, heart, gastrointestinal tract, eyes, and kidneys. Nowadays, several treatment options are available; thus, avoiding misdiagnosis is crucial to starting therapy in early disease stages. However, clinical diagnosis may be difficult, as the disease may present with unspecific symptoms and signs. We hypothesize that the diagnostic process may benefit from the use of machine learning (ML). Methods: 397 patients referring to neuromuscular clinics in 4 centers from the south of Italy with neuropathy and at least 1 more red flag, as well as undergoing genetic testing for ATTRv, were considered. Then, only probands were considered for analysis. Hence, a cohort of 184 patients, 93 with positive and 91 (age- and sex-matched) with negative genetics, was considered for the classification task. The XGBoost (XGB) algorithm was trained to classify positive and negative TTR mutation patients. The SHAP method was used as an explainable artificial intelligence algorithm to interpret the model findings. Results: diabetes, gender, unexplained weight loss, cardiomyopathy, bilateral carpal tunnel syndrome (CTS), ocular symptoms, autonomic symptoms, ataxia, renal dysfunction, lumbar canal stenosis, and history of autoimmunity were used for the model training. The XGB model showed an accuracy of 0.707 ± 0.101, a sensitivity of 0.712 ± 0.147, a specificity of 0.704 ± 0.150, and an AUC-ROC of 0.752 ± 0.107. Using the SHAP explanation, it was confirmed that unexplained weight loss, gastrointestinal symptoms, and cardiomyopathy showed a significant association with the genetic diagnosis of ATTRv, while bilateral CTS, diabetes, autoimmunity, and ocular and renal involvement were associated with a negative genetic test. Conclusions: Our data show that ML might potentially be a useful instrument to identify patients with neuropathy that should undergo genetic testing for ATTRv. Unexplained weight loss and cardiomyopathy are relevant red flags in ATTRv in the south of Italy. Further studies are needed to confirm these findings.

Background/Objectives: Anti-MAG polyneuropathy is a demyelinating peripheral neuropathy associated with IgM monoclonal gammopathies, particularly MGUS (monoclonal gammopathy of undetermined significance) and Waldenström macroglobulinemia. It is characterized by a subacute onset of distal sensory symptoms, with distal motor dysfunction typically appearing only in the later stages of the disease. The condition is caused by the presence of autoantibodies directed against myelin-associated glycoprotein, a structural protein of myelin. This leads to abnormalities in electrophysiological studies, such as markedly delayed distal latencies without conduction blocks or temporal dispersion of potentials. While rituximab (RTX) is the primary treatment, its efficacy is limited, with improvement seen in only 30–50% of patients. Recently, acute worsening of symptoms after RTX treatment has been increasingly reported. Methods: This systematic review compiles case reports and series from inception to June 2024 published on Scopus, PubMed or Cochrane, documenting acute exacerbations after RTX treatment in patients with anti-MAG polyneuropathy. Additionally, we present a case report from our institution that highlights this phenomenon. Results: We identified 13 clinical cases of acute deterioration in patients with anti-MAG polyneuropathy. Among these, eight patients (62%) achieved full recovery following additional treatment, while five patients (38%) did not return to their previous level of function. Plasmapheresis led to complete recovery in all four patients who received this intervention. Interestingly, many patients also experienced recovery after discontinuation of rituximab (RTX) treatment without the need for further therapeutic intervention. Conclusions: Acute clinical deterioration following RTX treatment in anti-MAG polyneuropathy is a possible occurrence. However, to date, no studies have assessed the true prevalence of this phenomenon. Further research is warranted to identify potential predictors of worsening following RTX treatment in this patient population.

Hereditary transthyretin amyloidosis is the most common form of hereditary amyloidosis, with an autosomal dominant inheritance and a variable penetrance. ATTRv amyloidosis can present as a progressive, axonal sensory autonomic and motor neuropathy or as an infiltrative cardiomyopathy. The definition of biomarkers for the early diagnosis of ATTRv is particularly important in the current era of emerging treatments. In this sense, metabolomics could be an instrument able to provide metabolic profiles with their related metabolic pathways, and we would propose them as possible fluid biomarkers. The aim of this study is to identify altered metabolites (free fatty acids and amino acids) in subjects with a confirmed pathogenic TTR variant. Out of the studied total free fatty acids and amino acids, the serum values of palmitic acid are significantly lower in the ATTRv patients compared to the recruited healthy subjects. The metabolic remodeling identified in this neurogenetic disorder could be the manifestation of pathophysiological processes of the disease, such as mitochondrial dysfunction and neuroinflammation, and contribute to explaining some of its clinical manifestations.

Hereditary transthyretin amyloidosis (ATTRv; v for “variant”) is the most common form of hereditary amyloidosis, with an autosomal dominant inheritance and a variable penetrance. This disease has a significant variability in clinical presentation and multiorgan involvement. While kidney involvement in early-onset ATTRv has been reported in one-third of patients, in late-onset ATTRv it has generally been considered rare. In the present study, we describe trajectories of kidney function over time before and after treatment with gene silencing therapies in a cohort of 17 ATTRv patients with different mutations, coming from Italy (nine subjects treated with inotersen and eight patients treated with patisiran). The analysis of estimated glomerular filtration rate (eGFR) slopes revealed that the average change in eGFR was 0.01 mL/min/1.73 m² per month before initiation and −0.23 mL/min/1.73 m² per month during follow-up for inotersen and −0.62 mL/min/1.73 m² per month before initiation and −0.20 mL/min/1.73 m² per month during follow-up for patisiran. In conclusion, we did not observe any significant difference either between the two groups of treatment or within-group before and after therapy, so gene-silencing therapies may be considered safe for renal function in ATTRv and are not associated with a worsening of eGFR slope.

Hereditary transthyretin (ATTRv) amyloidosis is a severe, progressive, and heterogeneous multisystemic condition due to mutations in the TTR gene. Although multiple aspects of its molecular pathophysiological mechanisms have been elucidated over the years, it is possible to hypothesize different pathogenetic pathways. Indeed, we extensively investigated the serum levels of several molecules involved in the immune response, in a cohort of ATTRv patients and healthy controls (HCs). Sixteen ATTRv patients and twenty-five HCs were included in the study. IFN-alpha levels were higher in ATTRv patients than in HCs, as well as IFN-gamma levels. By contrast, IL-7 levels were lower in ATTRv patients than in HCs. No significant difference between groups was found regarding IL-1Ra, IL-6, IL-2, IL-4, and IL-33 levels. Correlation analysis did not reveal any significant correlation between IFN-α, IFN-γ, IL-7, and demographic and clinical data. Larger and longitudinal studies using ultrasensitive methods to perform a full cytokine profiling are needed to better elucidate the role of inflammation in ATTRv pathogenesis and to test the reliability of these molecules as possible biomarkers in monitoring patients’ progression.