Raffaele Iorio

Background: Over the last two decades, an increasing number of late‐ and very‐late onset myasthenia gravis cases (VLOMG) with acetylcholine receptor antibodies (AChR‐MG) have been reported, whereas demographic studies on muscle‐specific tyrosine kinase antibodies MG (MuSK‐MG) are lacking. We investigated whether the proportion of patients with MuSK‐MG with onset ≥ 50 years has increased and whether these patients show distinct clinical characteristics. Methods: We retrospectively enrolled consecutive patients with MuSK‐MG onset ≥ 16 years followed between 1980 and 2025 at our tertiary center. Demographic characteristics and maximum disease severity, classified according to Myasthenia Gravis Foundation of America classification, were analyzed. Patients were stratified into three age‐at‐onset subgroups. Results: Overall, 120 patients were included. A significant increase in the median age at MuSK‐MG onset was observed, from 36 years (IQR, 23–45.75) in the 1980s to 47 years (IQR, 29–69) in the 2013–2025 period ( p = 0.033). Patients with onset ≥ 50 years increased from 2/17 (11.8%) to 19/39 (48.7%) ( p = 0.015), including 12 VLOMG cases. Males increased from 23.5% to 35.9%. Maximum MG severity decreased over time, with a remarkable reduction of respiratory crises ( p = 0.004), with no significant differences across age‐at‐onset groups. Conclusions: Demographic changes observed in AChR‐MG also occur, though less prominently, in MuSK‐MG.

Objectives: Super‐refractory status epilepticus (SRSE) is a neurological emergency with high morbidity and mortality. Cenobamate, a novel antiseizure medication, may be helpful in managing SRSE, but evidence is limited. Methods: This retrospective case series reports the use of cenobamate as add‐on therapy in the management of three cases of SRSE. Results: Median age at status epilepticus (SE) onset was 28 years (range 27–75). The etiologies of SRSE included one case of febrile infection‐related epilepsy syndrome (FIRES), one patient with a probable genetic etiology (SCN7A variant of uncertain significance), and one case of unknown etiology. Cenobamate was introduced at a median of 27 days (range 13–103) after SE onset. Resolution of SRSE was observed after a median of 7 days (range 3–30) once cenobamate was started. Median dose of cenobamate at SRSE cessation was 25 mg/day (range 12.5–50 mg/day), and the median maintenance dose at the time of discharge was 200 mg/day (range 100–400 mg/day). Two patients died and one patient achieved functional independence. No severe medication side effects, specifically drug reaction with eosinophilia and systemic symptoms (DRESS), were observed. Discussion: Cenobamate may have a role in the management of SRSE. Further studies are needed to define the optimal timing of initiation, titration strategy, and target dose of cenobamate in the context of SE.

Myasthenia gravis (MG) is an autoimmune disorder of the neuromuscular junction most commonly associated with acetylcholine receptor (AChR) antibodies (AChR-Abs), detected in up to 80% of patients. The emergence of targeted therapies, such as neonatal Fc receptor (FcRn) inhibitors, highlights the need for standardized functional assays capable of dissecting AChR-Ab pathogenic mechanisms. By selectively reducing circulating IgG through FcRn blockade, these agents differ fundamentally from conventional immunosuppressants, emphasizing the need to characterize antibody-mediated AChR dysfunction and complement activation as potential markers of therapeutic response. However, current functional assays often rely on transiently transfected or heterogeneous cell systems, limiting reproducibility and scalability. A stably transfected human cell line expressing physiologically clustered adult AChRs could fill this methodological gap and enable standardized, quantitative evaluation of antibody effector functions. We generated a stable rhabdomyosarcoma (RD) cell line expressing clustered human adult AChRs (hAChR-RDcl) using the P iggyBac transposon system for genomic integration of AChR subunit genes. The hAChR-RDcl line was applied to functional cell-based assays using serum samples from 30 patients with AChR-MG before and after one treatment cycle with efgartigimod. Clinical efficacy was assessed by Quantitative Myasthenia Gravis (QMG) and MG Activities of Daily Living (MG-ADL) scores. The hAChR-RDcl cell line showed stable transcription and surface expression of adult AChR subunits, confirmed by RT-qPCR, α-bungarotoxin binding, and antibody-specific reactivity (mAb637 and patient serum samples). Baseline functional assays identified blocking antibodies in 15 of 30 (50%), internalizing antibodies in 20 of 30 (66.7%), and complement-activating antibodies in 14 of 30 (46.6%) samples. After efgartigimod treatment, all 3 antibody-mediated mechanisms were significantly reduced. Patients with persistent complement activity after treatment experienced more severe symptoms (higher QMG scores) compared with those showing other antibody-mediated pathogenetic mechanisms or complete suppression of antibody effector functions. The hAChR-RDcl cell line represents a reliable and scalable platform for standardized functional profiling of AChR-Abs. Functional characterization of AChR-Abs provides a translational approach to monitor therapeutic responses and elucidate the mechanisms underlying FcRn inhibitor efficacy in MG.

Background and ObjectivesMyasthenia gravis-inflammatory myopathy (MG-IM) overlap syndrome can occur as an immune-related adverse event (irAE) after immune checkpoint inhibitor (ICI) therapy. Before...

Objectives: To characterize the magnetic resonance imaging (MRI) lesion dynamics, comorbidities, predictors of relapse, and outcomes in anti‐ γ ‐aminobutyric acid type A receptor (GABA _A R) encephalitis, and assess the utility of LIM‐domain‐only‐protein 5 (LMO5) antibodies as tumor markers. Methods: GABA _A R antibodies were confirmed by 2 techniques in serum or cerebrospinal fluid. Long‐term outcomes were defined as good (modified Rankin scale, mRS = 0–1) or poor (mRS 2–5) at ≥12 months. LMO5 antibodies were assessed by cell‐based assays and Western blot. Results: Thirty‐three patients were identified (4 children, 29 adults; median age, 5.5 and 60 years; 61% male). Ten patients (10/32, 31%) had concurrent systemic autoimmunity. Adults presented with seizures and cognitive/behavioral symptoms, often with thymoma, gastrointestinal, or other tumors (18/33, 55%), whereas children frequently had seizures and ataxia with cerebellar MRI lesions. Multifocal T2/fluid‐attenuated inversion recovery hyperintensities were present at onset in 23 of 31 (74%) or developed later in those with absent or single lesions. Lesions showed dynamic changes, suggesting ongoing inflammation even without clinical correlate. Relapses occurred in 17 of 31 (55%, all adults) and were associated with older age ( p = 0.02) and lack of second‐line immunotherapy ( p = 0.02). Four patients (4/33, 12%) died. After a 32.5‐month median follow‐up, 9 of 20 (45%) had persistent cognitive deficits, and 6 of 20 (30%) had a poor outcome, which was associated with relapses ( p = 0.04). LMO5 antibodies were absent in patients and controls. Interpretation: Anti‐GABA _A R encephalitis shows age‐dependent presentations, most commonly seizures. MRI reveals dynamic changes consistent with an ongoing “clinically silent” inflammation. Relapses and cognitive sequelae are common and associate with not receiving second‐line immunotherapy. LMO5 antibodies lack tumor‐predictive value. ANN NEUROL 2026;100:139–150

Background: Paraneoplastic limbic encephalitis (PLE) with anti-Ma2 antibodies is a rare immune-mediated disorder associated with testicular cancer, particularly in young males. While neurological manifestations are well documented, hypothalamic–pituitary dysfunctions remain underreported. We present a case of anti-Ma2 PLE associated with testicular cancer together with a systematic review of PLE associated with testicular cancer, selectively restricted to anti-Ma2 positive cases and focusing on hypothalamic–endocrine involvement. Case presentation: We describe a 21-year-old male diagnosed with anti-Ma2 PLE and intratubular germ cell neoplasia of the right testis. He underwent orchifunicolectomy and immunosuppressive therapy with neurological improvement. Four years later, he developed new-onset temporal seizures, decreased libido, and a polyuria–polydipsia syndrome. Dynamic endocrine testing, including a water deprivation test and copeptin measurement, supported a diagnosis of partial central diabetes insipidus (CDI). Methods: A systematic literature review was performed in accordance with PRISMA guidelines. PubMed was searched using predefined keywords without time restriction. Studies reporting PLE associated with testicular tumors in humans with confirmed anti-Ma2 antibody positivity were included. Results: Eleven studies were included, reporting a total of 38 patients with anti-Ma2-associated PLE and testicular cancer. Hypothalamic or diencephalic involvement was described in 16 patients (42.0%), while endocrine manifestations were explicitly reported in four cases. Only two previous reports mentioned CDI, without detailed diagnostic evaluation. Conclusions: This study highlights the importance of recognizing hypothalamic-endocrine manifestations in PLE. In patients presenting with polydipsia and polyuria, CDI should be carefully differentiated from primary polydipsia using dynamic testing. Hypothalamic involvement may emerge years after tumor treatment, warranting long-term endocrine surveillance.

Background and Purpose: Myasthenia gravis (MG) is a complex autoimmune disorder affecting neuromuscular transmission, often leading to diagnostic and therapeutic challenges. Timely identification of “red flags” in diagnosis, therapeutic reassessment, and myasthenic crisis is crucial to optimizing patient outcomes. This Delphi‐based consensus is aimed at synthesizing expert recommendations for improving clinical practice in Italy. Methods: A scientific board of 19 MG specialists and an extended panel of 47 neuromuscular experts participated in a structured Delphi methodology. Over an 11‐month period, consensus was developed across four areas: diagnostic red flags, confirmatory instrumental examinations, therapeutic reassessment, and the continuum from exacerbation to impending myasthenic crisis or to crisis. The threshold for achieving consensus was set at ≥ 75% agreement. Results: Globally, 68 statements reached consensus. Key findings include the identification of “red flags” for suspecting MG, with fluctuating and fatigable muscle weakness serving as primary diagnostic indicators, often involving ocular, bulbar, and respiratory muscles. Instrumental tests, such as repetitive nerve stimulation and antibody assays, were deemed essential for diagnostic confirmation. Therapeutic reassessment in MG is warranted for unsatisfactory symptom control, clinically significant adverse events, new or worsening comorbidities, planning pregnancy, or neoplastic disease. Persistent fluctuations, exacerbations, or triggers like infections should prompt adjustments, aiming to optimize treatment while minimizing risks. High‐risk factors and triggers for myasthenic crises, including thymoma and infections, were identified, with arterial blood gas analysis highlighted as critical for crisis management. Conclusions: This consensus provides actionable recommendations to enhance the identification and management of MG, addressing diagnostic delays, therapy optimization, and crisis prevention. These findings aim to guide clinical practice and foster a systematic approach to managing this heterogeneous disorder.

Background: The role of thymectomy in ocular myasthenia gravis (OMG) remains controversial, particularly before secondary generalization. Methods: We conducted a multicenter retrospective study on 174 OMG patients who underwent thymectomy (112 OMG, 62 generalized OMG [g-OMG]). The primary endpoint was complete stable remission (CSR; MGFA-PIS criteria). Multivariable analyses identified predictors of CSR and generalization. Results: Mean age at surgery was 42.3 ± 13.0 years; 53.4% were male. Thymoma was present in 29.3%. CSR was achieved in 18.9% overall, significantly higher in OMG (23.2%) compared to g-OMG (11.3%, p = 0.036), with 5-year CSR probabilities of 43% vs. 22% (p = 0.017). In non-thymomatous patients, 5-year CSR remained higher in OMG (41% vs. 17%, p = 0.010). Postoperative myasthenic crisis occurred exclusively in g-OMG (8.1%, p = 0.004). Multivariable analysis identified preoperative cholinesterase inhibitor monotherapy as an independent predictor of CSR (HR = 31.776, 95% CI: 4.188–241.111, p = 0.001; non-thymomatous: HR = 19.746, 95% CI: 2.518–154.849, p = 0.005). Minimally invasive techniques (78.6%) were associated with low morbidity (5.2%). Conclusions: Thymectomy during the purely ocular stage is associated with higher CSR rates and lower perioperative neurological risk than after generalization, particularly in non-thymomatous disease. Use of cholinesterase inhibitors as sole therapy prior to thymectomy independently predicts CSR. These findings support earlier surgical consideration in selected OMG patients and highlight the safety of minimally invasive approaches.