Angela Romano

Background: The F64L variant is among the most frequent TTR mutations in Italy, typically associated with a predominantly neurologic phenotype and limited cardiac involvement. Methods: Data from 181 ATTRv patients in the multicenter Patisiranitaly database treated with Patisiran since 2020 were analyzed. Neurologic impairment scores, Norfolk QoL‐DN, and cardiac parameters were compared between F64L ( n = 56), V30M ( n = 37), and non‐F64L ( n = 125) patients at baseline and during follow‐up. Cluster analysis was applied to identify patient subgroups based on these variables. Results: F64L represented 30.9% of the cohort. Compared to non‐F64L patients, F64L patients had a higher prevalence of neurologic onset and neurologic phenotype, a thinner interventricular septum, and lower NT‐proBNP levels. Cluster analysis segregated patients into two distinct groups, predominantly reflecting F64L vs. non‐F64L status and corresponding neurologic severity. F64L patients showed milder cardiac involvement compared to V30M patients. Longitudinal repeated‐measures ANOVA showed stable clinical and instrumental measures. Conclusions: F64L is characterized by predominant neurologic involvement and milder cardiac involvement in this Patisiran‐treated cohort. Mutation‐specific diagnostic and follow‐up strategies are essential to capture its natural history and treatment response.

We evaluated the feasibility and clinical outcomes of MRIgSBRT for nodal recurrence in the oligometastatic disease (OMD) setting, focusing on per-lesion outcomes and prognostic factors. We collected clinical and dosimetric data from a retrospective single-center cohort of patients treated with a 0.35 T MRIgSBRT for nodal recurrences. Endpoints included the 1-year progression-free survival (PFS), local progression-free survival (LPFS), and 3-year overall survival (OS) rate from recurrence. Per-lesion Kaplan-Meier and Cox regression assessed clinical, dosimetric, and technical predictors. 71 patients received nodal MRIgSBRT, with a total of 115 treated metastatic lesions. Local control was high: LPFS 95.5% at 12 months and 94.0% at 24/36 months. OS was favorable (100% at 12 months, 97.2% at 24 months, 95.3% at 36 months). Systemic progression drove most events: PFS 52.6% at 12 months and 24.4% at 24 months; median 12.4 months. No clinically relevant acute or late toxicity was observed. On multivariable analysis, BED₁₀ ≥ 70 Gy was independently associated with improved OS. Multiple metastases increased the risk of local failure in univariate analysis (UVA) (HR 6.30, p = 0.027). MRIgSBRT represents a safe and viable treatment option in nodal oligometastatic setting. It provides excellent and durable local control with minimal toxicity. As distant progression remains the main challenge, careful selection in low-burden disease, dose escalation to BED₁₀ ≥ 70 Gy, and thoughtful integration with systemic therapy emerge as key levers to optimize outcomes. Further prospective studies are needed to assess OMD long-term survival and quality of life and to evaluate possible further treatment optimization strategies.

Background: Neurofilament light chains (NfL) represent reliable serum biomarkers of neuroaxonal injury. Due to their low serum levels, precise detection methods are critical. This study aimed to scrutinize the comparability of two techniques: Single Molecule Array (SiMoA) and Ella automated immunoassay, analyzing serum NfL levels in ATTRv presymptomatic subjects and polyneuropathy patients.Methods: Blood samples were processed and analyzed using commercial Ella and SiMoA kits. Statistical analysis included the Wilcoxon signed‐rank test, Spearman correlation, Bland–Altman, and Passing‐Bablok regression. ANCOVA models were used to compare NfL levels between cohorts.Results: The study measured serum NfL levels in 55 symptomatic and 55 presymptomatic ATTRv subjects. Median NfL concentrations were significantly higher with Ella (median 27.5 pg/mL) than SiMoA (median 15.9 pg/mL). Both methods showed a strong positive correlation (r = 0.8, p < 0.001), but Ella overestimated NfL by 42%. Bland–Altman analysis revealed a mean bias of 15.4 pg/mL, with limits of agreement between −41.1 and 72.0 pg/mL. The slope of the Passing–Bablok regression line was 0.58, and the intercept was 3.48 pg/mL, suggesting that the Ella platform tends to overestimate NfL concentrations compared to the SiMoA platform, especially at higher concentrations. Both methods effectively distinguished presymptomatic from symptomatic patients (p < 0.001 for both).Conclusions: Our findings underscore that both platforms are effective in measuring serum NfL, with Ella consistently overestimating, especially at higher concentrations. The difference between the two platforms must be taken into account when deeming the concentrations as pathological or normal, as well as when conducting longitudinal studies.

Background/Objectives: Fabry disease (FD) is an inborn error of the glycosphingolipid metabolism with variable kidney, heart, and central nervous system (CNS) involvement. CNS-related FD manifestations include early ischemic stroke and white matter lesions (WMLs) related to cerebral small-vessel disease (CSVD), possibly resulting in cognitive impairment. We studied 40 adult FD patients (17 male) to assess: (i) prevalence of cerebrovascular and cognitive manifestations in FD and their correlation with heart and renal involvement; and (ii) the potential value of serum neurofilament light chain (NfL) levels as an indicator of WMLs in FD. Methods: Patients underwent detailed diagnostic assessment related to FD, also including Mainz Severity Score Index (MSSI), neuropsychological tests, brain MRI to assess WMLs by the modified Fazekas score (mFS), and NfL determination by single-molecule array (SiMoA) (n = 22 FD patients vs. 15 healthy controls). Results: Overall, 4 FD patients had a history of ischemic stroke and 13/32 patients (40.6%) had an mFS ≥ 1. Almost two-thirds of FD patients (27/39, 69.2%) showed impairment on at least one cognitive test. On univariate analysis, only a reduction in estimated glomerular filtration rate was associated with an increased likelihood of having WMLs on brain MRI. Serum NfL levels were higher in FD patients vs. controls, with a trend toward significance (p = 0.08). Conclusions: Mild-to-moderate CSVD is a characteristic brain “signature” in FD patients. Both cardiac and renal involvement correlate with WML load, but only renal involvement appears to be predictive of CNS damage. Brain microvascular damage is associated with mild cognitive impairment in FD, and serum NfL might represent a potential biomarker of CSVD in FD.

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.

Background: Hereditary transthyretin (ATTRv, v for variant) amyloidosis with polyneuropathy is a rare disease caused by mutations in the transthyretin gene. In ATTRv amyloidosis, multisystem extracellular deposits of amyloid cause tissue and organ dysfunction. Patisiran is a small interfering RNA molecule drug that reduces circulating levels of mutant and wild-type TTR proteins. Prior to its regulatory approval, patisiran was available in Italy through a compassionate use programme (CUP). The aim of this study was to analyse the long-term outcomes of patients who entered into the CUP. Methods: This was a multicentre, observational, retrospective study of patients with ATTRv amyloidosis treated with patisiran. The analysis included change from baseline to 12, 24, 36 and 48 months in familial amyloid polyneuropathy (FAP) stage, polyneuropathy disability (PND) class, neuropathy impairment score (NIS), modified body mass index (mBMI), Compound Autonomic Dysfunction Test (CADT), Karnofsky Performance Status (KPS) scale and Norfolk Quality of Life–Diabetic Neuropathy (QoL-DN) questionnaire. Safety data were also analysed. Results: Forty patients from 11 Italian centres were enrolled: 23 in FAP 1 (6 in PND 1 and 17 in PND 2) and 17 in FAP 2 (8 in PND 3a and 9 in PND 3b) stage. In this population, the mean NIS at baseline was 71.4 (± 27.8); mBMI, 917.1 (± 207) kg/m²; KPS, 67.1 (± 14.0); Norfolk QoL-DN, 62.2 (± 25.2); and CADT, 13.2 (± 3.3). Statistical analysis showed few significant differences from baseline denoting disease stability. No new safety signals emerged. Conclusions: Patisiran largely stabilised disease in patients with ATTRv amyloidosis.

Background and purpose: This study aimed to assess the diagnostic criteria, ancillary investigations and treatment response using real‐life data in multifocal motor neuropathy (MMN) patients.Methods: Clinical and laboratory data were collected from 110 patients enrolled in the Italian MMN database through a structured questionnaire. Twenty‐six patients were excluded due to the unavailability of nerve conduction studies or the presence of clinical signs and symptoms and electrodiagnostic abnormalities inconsistent with the MMN diagnosis. Analyses were conducted on 73 patients with a confirmed MMN diagnosis and 11 patients who did not meet the diagnostic criteria.Results: The European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) diagnostic criteria were variably applied. AUTHOR:When applying the American Association of Electrodiagnostic Medicine criteria, an additional 17% of patients fulfilled the criteria for probable/definite diagnosis whilst a further 9.5% missed the diagnosis. In 17% of the patients only compound muscle action potential amplitude, but not area, was measured and subsequently recorded in the database by the treating physician. Additional investigations, including anti‐GM1 immunoglobulin M antibodies, cerebrospinal fluid analysis, nerve ultrasound and magnetic resonance imaging, supported the diagnosis in 46%–83% of the patients. Anti‐GM1 immunoglobulin M antibodies and nerve ultrasound demonstrated the highest sensitivity. Additional tests were frequently performed outside the EFNS/PNS guideline recommendations.Conclusions: This study provides insights into the real‐world diagnostic and management strategies for MMN, highlighting the challenges in applying diagnostic criteria.

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an immune-mediated disorder affecting the peripheral nervous system. Despite the established diagnostic criteria, monitoring disease activity and treatment remains challenging. To address this limitation, we investigated serum neurofilament light chain (sNfL) and serum free light chains (sFLCs) as potential biomarkers. A total of 32 CIDP patients undergoing immunoglobulin therapy and 32 healthy controls enrolled in the present study, and agreed to have their blood plasma sNfL and sFLCs analyzed, while CIDP severity was assessed through the modified Rankin Scale (mRS) and the Overall Neuropathy Limitations Scale (ONLS). In line with the immunoglobulin treatment aimed at limiting neuronal damage administered to the majority of patients, sNfL levels did not exhibit significant differences between the two groups. However, CIDP patients showed significantly elevated sFLC and sFLC ratios, while the marker levels did not correlate with the clinical scores. The study confirms the potential of sFLCs as a sensitive biomarker of inflammatory processes in CIDP. Additionally, the present study results regarding neurofilaments strengthen the role of sNfL in monitoring CIDP treatments, confirming the effectiveness of immunoglobulin therapy. Overall, our results demonstrate how combining these markers can lead to better patient characterization for improved treatment.

Background and purpose: There are different criteria for the diagnosis of different variants of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). The 2021 European Academy of Neurology/Peripheral Nerve Society (EAN/PNS) guidelines provide specific clinical criteria for each CIDP variant even if their therapeutical impact has not been investigated.Methods: We applied the clinical criteria for CIDP variants of the 2021 EAN/PNS guidelines to 369 patients included in the Italian CIDP database who fulfilled the 2021 EAN/PNS electrodiagnostic criteria for CIDP.Results: According to the 2021 EAN/PNS clinical criteria, 245 patients achieved a clinical diagnosis of typical CIDP or CIDP variant (66%). We identified 106 patients with typical CIDP (29%), 62 distal CIDP (17%), 28 multifocal or focal CIDP (7%), four sensory CIDP (1%), 27 sensory‐predominant CIDP (7%), 10 motor CIDP (3%), and eight motor‐predominant CIDP (2%). Patients with multifocal, distal, and sensory CIDP had milder impairment and symptoms. Patients with multifocal CIDP had less frequently reduced conduction velocity and prolonged F‐wave latency and had lower levels of cerebrospinal fluid protein. Patients with distal CIDP more frequently had reduced distal compound muscle action potentials. Patients with motor CIDP did not improve after steroid therapy, whereas those with motor‐predominant CIDP did. None of the patients with sensory CIDP responded to steroids, whereas most of those with sensory‐predominant CIDP did.Conclusions: The 2021 EAN/PNS criteria for CIDP allow a better characterization of CIDP variants, permitting their distinction from typical CIDP and more appropriate treatment for patients.