Efgartigimod in generalized myasthenia gravis: A real-life experience at a national reference center.

BACKGROUND AND PURPOSE: Inhibition of the neonatal Fc receptor (FcRn) for IgG is a promising new therapeutic strategy for antibody-mediated disorders. We report our real-life experience with efgartigimod (EFG) in 19 patients with generalized myasthenia gravis (gMG) along a clinical follow-up of 14 months. METHODS: EFG was administered according to the GENERATIVE protocol (consisting of a Fixed period of two treatment cycles [given 1 month apart] of four infusions at weekly intervals, followed by a Flexible period of re-cycling in case of worsening). Eight patients were positive for acetylcholine receptor antibody, four for muscle-specific tyrosine kinase antibody, and two for lipoprotein-related protein 4 antibody, and five were classified as triple negative. Efficacy of EFG was assessed by the Myasthenia Gravis Activities of Daily Living, Myasthenia Gravis Composite, and Quantitative Myasthenia Gravis scales. RESULTS: Fifty-three percent of patients needed three treatment cycles, 26% needed four, and 21% needed five along the 14-month clinical follow-up. Meaningful improvement was observed at the end of each cycle with the clinical scores adopted. EFG had a dramatic effect on disease course, as during the year before treatment eight of 19 patients (42%) were hospitalized, and 15 of 19 (79%) needed treatment with plasma exchange or immunoglobulins; three of 19 (16%) were admitted to the intensive care unit. During EFG, none of the patients was hospitalized and only one patient required plasma exchange and intravenous immunoglobulins. No major side effects or infusion-related reactions occurred. CONCLUSIONS: We observed that EFG was safe and modified significantly the course of the disease along a 14-month follow-up. Our experience strengthens the role of FcRn inhibition as an effective new tool for long-term treatment of gMG.

Sporadic Inclusion Body Myositis at the Crossroads between Muscle Degeneration, Inflammation, and Aging.

Sporadic inclusion body myositis (sIBM) is the most common muscle disease of older people and is clinically characterized by slowly progressive asymmetrical muscle weakness, predominantly affecting the quadriceps, deep finger flexors, and foot extensors. At present, there are no enduring treatments for this relentless disease that eventually leads to severe disability and wheelchair dependency. Although sIBM is considered a rare muscle disorder, its prevalence is certainly higher as the disease is often undiagnosed or misdiagnosed. The histopathological phenotype of sIBM muscle biopsy includes muscle fiber degeneration and endomysial lymphocytic infiltrates that mainly consist of cytotoxic CD8+ T cells surrounding nonnecrotic muscle fibers expressing MHCI. Muscle fiber degeneration is characterized by vacuolization and the accumulation of congophilic misfolded multi-protein aggregates, mainly in their non-vacuolated cytoplasm. Many players have been identified in sIBM pathogenesis, including environmental factors, autoimmunity, abnormalities of protein transcription and processing, the accumulation of several toxic proteins, the impairment of autophagy and the ubiquitin-proteasome system, oxidative and nitrative stress, endoplasmic reticulum stress, myonuclear degeneration, and mitochondrial dysfunction. Aging has also been proposed as a contributor to the disease. However, the interplay between these processes and the primary event that leads to the coexistence of autoimmune and degenerative changes is still under debate. Here, we outline our current understanding of disease pathogenesis, focusing on degenerative mechanisms, and discuss the possible involvement of aging.

Facial nerve vulnerability in spinal muscular atrophy and motor unit number index of the orbicularis oculi muscle.

INTRODUCTION/AIMS: Measures for assessing cranial nerve vulnerability in spinal muscular atrophy (SMA) have not yet been determined. Motor unit number index (MUNIX) studies have shown correlations with disease severity but have been used only in limb muscles. In the present study, we explore facial nerve response, MUNIX, and motor unit size index (MUSIX) of the orbicularis oculi muscle in a cohort of patients with SMA. METHODS: Facial nerve response (measured as compound muscle action potential, CMAP), MUNIX, and MUSIX of the orbicularis oculi muscle were cross-sectionally recorded in patients with SMA and compared to healthy control subjects (HCs). Active maximum mouth opening (aMMO) was also measured at baseline in our SMA cohort. RESULTS: Thirty-seven patients with SMA (21 SMA II; 16 SMA III) and 27 HCs were recruited. CMAP of the facial nerve and MUNIX of orbicularis oculi proved to be feasible and well tolerated techniques. CMAP amplitude and MUNIX scores were significantly lower in patients with SMA compared to HCs (p < .0001). Both MUNIX and CMAP amplitude were significantly higher in patients with SMA III compared to SMA II. No significant difference emerged comparing CMAP amplitude, MUNIX and MUSIX scores between those with different functional status or nusinersen treatment. DISCUSSION: Our results provide neurophysiological evidence of facial nerve and muscle involvement in patients with SMA. CMAP of the facial nerve and MUNIX of orbicularis oculi showed high accuracy in discriminating between the various subtypes of SMA and in quantifying the motor unit loss of the facial nerve.

Protein Aggregates and Aggrephagy in Myopathies.

A number of muscular disorders are hallmarked by the aggregation of misfolded proteins within muscle fibers. A specialized form of macroautophagy, termed aggrephagy, is designated to remove and degrade protein aggregates. This review aims to summarize what has been studied so far about the direct involvement of aggrephagy and the activation of the key players, among others, p62, NBR1, Alfy, Tollip, Optineurin, TAX1BP1 and CCT2 in muscular diseases. In the first part of the review, we describe the aggrephagy pathway with the involved proteins; then, we illustrate the muscular disorder histologically characterized by protein aggregates, highlighting the role of aggrephagy pathway abnormalities in these muscular disorders.

Paraneoplastic neurological syndromes associated with non-Hodgkin lymphoma: a case series.

BACKGROUND: Paraneoplastic neurological syndromes (PNS) associated with lymphoma are rare diseases that usually have different peculiar features when compared to PNS associated with solid neoplasms. METHODS: We retrospectively identified patients with NHL-associated PNS. Clinical and demographic data are reported. RESULTS: We report two cases of NHL-associated PNS: a 72-years old female that presented with rapidly progressive cerebellar syndrome (RCPS) and a 65-years old male that presented with encephalomyelitis (confusion, sensory neuropathy, lower motor neuron involvement). Both PNS were associated with a NHL, small lymphocytic lymphoma and nodal marginal zone lymphoma respectively, and onconeural antibodies tested negative. All patients received first-line immunotherapy with absent or minimal benefit and died of intercurrent infection before cancer or immunosuppressive treatment. DISCUSSION: RCPS and encephalomyelitis rarely present in association with NHL. In our cases, those syndromes took place in the setting of non-aggressive advanced hematological disorders, had an unfavorable prognosis with minimal benefit from immunotherapy, and were seronegative for onconeural antibodies. Our patients fulfilled the criteria for "definite PNS" in the 2004 PNS criteria, but they would be classified as "probable", in the new 2021 PNS criteria. The newest criteria rely on onconeural antibodies testing and on the evidence of antigen expression in cancer cells, features that are usually absent in NHL-associated PNS. New antibodies are being discovered but are still not available to promptly test yet. CONCLUSION: NHL-associated PNS are rare and bear unfavorable prognosis. The diagnosis should not be overlooked even in seronegative patients.

Persistent chemosensory dysfunction in a young patient with mild COVID-19 with partial recovery 15 months after the onset.

OBJECTIVE: It is reported that recovery from COVID-19 chemosensory deficit generally occurs in a few weeks, although olfactory dysfunction may persist longer. Here, we provide a detailed follow-up clinical investigation in a very young female patient (17-year-old) with a long-lasting anosmia after a mild infection, with partial recovery 15 months after the onset. METHODS: Neuroimaging and neurophysiologic assessments as well as olfactory mucosa swabbing for microbiological and immunocytochemical analyses were performed. Olfactory and gustatory evaluations were conducted through validated tests. RESULTS: Chemosensory evaluations were consistent with anosmia associated with parosmia phenomena and gustatory impairment, the latter less persistent. Brain MRI (3.0 T) showed no microvascular injury in olfactory bulbs and brain albeit we cannot rule out slight structural abnormalities during the acute phase, and a high-density EEG was negative. Immunocytochemistry of olfactory mucosa swabs showed high expression of ACE2 in sustentacular cells and lower dot-like cytoplasmic positivity in neuronal-shaped cells. DISCUSSION: The occurrence of long-term persistent olfactory deficit in spite of the absence of structural brain and olfactory bulb involvement supports the view of a possible persistent dysfunction of both sustentacular cells and olfactory neurons. The gustatory dysfunction even if less persisting for the described features could be related to a primary gustatory system involvement. Future longitudinal studies are needed to investigate the persistence of chemosensory impairment, which could have a relevant impact on the daily life.

ASL MRI and 18F-FDG-PET in autoimmune limbic encephalitis: clues from two paradigmatic cases.

BACKGROUND: Autoimmune limbic encephalitis (LE) is a neurological condition characterized by seizures and cognitive dysfunction. Fluorine-18 fluorodeoxyglucose (18F-FDG-PET) has recently proved to be an important diagnostic tool in this condition since it may highlight brain metabolism abnormalities in a very early stage of the disease. Two main 18F-FDG-PET patterns have been described: the mixed hypermetabolic/hypometabolic and the neurodegenerative one. Arterial spin labeling (ASL) is an MRI technique showing brain perfusion, rarely used in autoimmune neurological conditions. The aim of the present study was to study patients with LE with both techniques, in order to compare their results. METHODS: Two patients with LE underwent to 18F-FDG-PET and ASL MRI scans using the pseudo-continuous arterial spin labeling (PCASL) technique. Areas of altered perfusion and metabolism were analyzed by visual inspection, and findings were compared between the two techniques. RESULTS: In the first patient, a relapsing LGI-1 LE, right hippocampal hypermetabolism was detected by 18F-FDG-PET (mixed hypermetabolic/hypometabolic pattern), while ASL MRI showed right hippocampal increased perfusion. In the second patient, a seronegative LE, 18F-FDG-PET scan detected a left hemispheric hypoperfusion (neurodegenerative pattern) and ASL MRI yielded similar results. The two 18F-FDG-PET patterns of altered metabolism were similarly detected by ASL imaging. CONCLUSION: ASL and 18F-FDG-PET findings are strongly concordant in LE. ASL imaging was able to detect the two main 18F-FDG-PET patterns previously described in patients with LE.

Epilepsia partialis continua following a Western variant tick-borne encephalitis.

Epilepsia partialis continua (EPC) is a rare entity, first described in 1894 by Kozevnikov, as a variant of simple focal motor status epilepticus. EPC is most frequently characterized by motor symptoms, but as recently described, non-motor manifestations may occur, such as somatosensory symptoms or aura continua. EPC in adults has been attributed to various etiologies: infectious, vascular, neoplastic, and metabolic. According to the recent definition, we reported a case of EPC with behavioral symptoms, following a tick-borne encephalitis (TBE) contracted in an endemic area (North Eastern Italy). Patient's symptom was a poorly localized "whole body sensation", which is reported as a condition occurring only in frontal lobe epilepsy. Patient's EEG showed a left frontal predominance of epileptiform discharges. Literature highlighted the importance of the Far-eastern TBE variant as a cause of EPC, since no Western variant TBE cases are reported. In contrast to what was claimed so far, our case demonstrates that not only the Far-eastern TBE variant, but also Western variant TBE is a cause of EPC. Prognosis of EPC depends largely on the underlying etiology, and it is frequently drug-resistant. Our patient was treated with intravenous levetiracetam, with a subsequent clinical recovery and a disappearance of epileptiform discharges. The rapid clinic and electroencephalographic response to levetiracetam confirm that it can be a promising therapeutic option for treatment of EPC.

Novel DPAGT1 Gene Mutation in Two Twins with Congenital Myasthenic Syndrome and a Review of the Literature.

Congenital myasthenic syndromes (CMS) are rare diseases caused by mutation in genes coding for proteins involved in neuromuscular junction structure and function. DPAGT1 gene mutations are a rare cause of CMS whose clinical evolution and pathophysiological mechanisms have not been clarified completely. We present the case of two twins displaying an infancy-onset predominant limb-girdle phenotype and carrying a novel DPAGT1 mutation associated with unusual histological and clinical findings. CMS can mimic paediatric and adult limb-girdle phenotype, hence neurophysiology plays a fundamental role in the differential diagnosis.

VCP-related myopathy: a case series and a review of literature.

The valosin-containing protein (VCP), a widely expressed protein, controls the ubiquitin-proteasome system, endolysosomal sorting, and autophagy to maintain cellular proteostasis. Frontotemporal dementia (FTD), inclusion body myopathy, and Paget's disease of the bone (PDB) are all caused by dominant missense mutations in the VCP gene, which interfere with these mechanisms and cause a multisystem proteinopathy. We describe phenotypic and genetic findings of five patients with four different mutations in VCP gene (NM_007126): c.278G > A (p.R93H), c.463C > T (p.R155C), c.410C > T (p.P137L), c.464G > A (p.R155H), c.410C > T (p.P137L). We analysed the patient' biopsies, all characterized by a muscular phenotype, and we executed immunofluorescence staining to evaluate the presence of proteins: p62, VCP, desmin, myotilin, TDP-43. Eventually we performed a brief literature review to compare our cases with those already reported. Our report strongly suggest that VCP gene mutations can be related with a predominant skeletal muscle phenotype without any central nervous system involvement, as occasionally reported in the literature. Particularly, our patient with R93H shows only myopathic involvement while this mutation has been described once associated only to Hereditary Spastic Paraplegia. Further study will be necessary to understand such a broad and different clinical spectrum.

Admission neutrophil-to-lymphocyte ratio predicts length of hospitalization and need for ICU admission in adults with Status Epilepticus.

BACKGROUND AND OBJECTIVES: Status epilepticus (SE) is a time-dependent neurological emergency. The current study evaluated the prognostic value of admission neutrophil-to-lymphocyte ratio (NLR) in patients with status epilepticus. METHODS: In this retrospective observational cohort study we included all consecutive patients discharged from our neurology unit with the clinical or EEG diagnosis of SE from 2012 to 2022. Stepwise multivariate analysis was conducted to test the association of NLR with length of hospitalization, need for Intensive Care Unit (ICU) admission and 30 days mortality. Receiver operating characteristic (ROC) analysis was performed to identify the best cutoff for NLR to identify patients who will need ICU admission. RESULTS: A total of 116 patients were enrolled in our study. NLR was correlated with length of hospitalization (p = 0.020) and need for ICU admission ( p = 0.046). In addition, the risk of ICU admission increased in patients with intracranial hemorrhage and length of hospitalization was correlated with C-reactive protein-to-albumin ratio (CRP/ALB). ROC analysis identified a NLR of 3.6 as best cutoff value to discriminate need of ICU admission (area under the curve [AUC]=0.678; p = 0.011; Youden's index=0.358; sensitivity, 90.5%, specificity, 45.3%). DISCUSSION: In patients with SE admission NLR could be a predictor of length of hospitalization and need for ICU admission.

Lymphopenia during treatment with dimethyl fumarate in patients with multiple sclerosis: Prevalence, predicting factors and clinical outcomes.

BACKGROUND: Lymphopenia is a common side effect of treatment with dimethyl fumarate (DMF) in patients with multiple sclerosis (PwMS). Prevalence and predictive factors of this side effect are still uncertain, because literature has provided discrepant results and it is still a matter of debate if lymphopenia is associated with a better treatment outcome. METHODS: We retrospectively recruited PwMS treated for at least one month with DMF and collected clinical, demographic data and absolute lymphocyte count (ALC) during follow-up. Lymphopenia was graded according to CTCAE. Patients according to the grade in lymphopenia (all grades) and severe lymphopenia (grade II-IV). To evaluate predictors of lymphopenia, we compared characteristics of patients with/without lymphopenia and patients with/without severe lymphopenia. A logistic binary regression was performed to elucidate any predictive factor of lymphopenia and severe lymphopenia. Area under the curve (AUC) was calculated to evaluate sensibility and specificity of predictors. We analyzed treatment outcome with NEDA-3 status at 1- and 2-years. RESULTS: 98 of 105 patients treated with DMF were included. 46.9% developed lymphopenia, 27.6% severe lymphopenia. Lymphopenia was associated with basal ALC (p<0.001, AUC=0.786), treatment duration (p = 0.01, AUC=0.685),% of reduction at third month (p = 0.001, AUC=0.616) Severe lymphopenia was associated with basal ALC (p = 0.003, AUC=0.750).NEDA-3 status at 1-year (n = 66) and at 2-year (n = 44) did not differ in patients with/without lymphopenia (p = 0.059; p = 0.583) or with/without severe lymphopenia (p = 1.02; p = 0.169). CONCLUSION: Lymphopenia is a common side effect of DMF and basal ALC predicts its development. Lymphopenia is not associated with the achievement of NEDA-3 status.

Bortezomib in anti-N-Methyl-d-Aspartate-Receptor (NMDA-R) encephalitis: A systematic review.

N-methyl-d-aspartate receptor (NMDAR) encephalitis is a potentially treatable condition, although a small proportion of patients remains refractory to immunotherapy. Bortezomib is a proteasome inhibitor that has a promising role in autoimmune conditions. We performed an independent PubMed search employing "Anti-N-Methyl­D-Aspartate encephalitis AND bortezomib", including papers published between January 1st, 2007 to April 15th, 2021. Fourteen articles were included, with 29 patients. 16 patients (55,2%) had a favorable outcome after bortezomib and 11 (37,9%) patients developed side effects. Quality of studies was overall poor and future trials should aim to include more homogeneous and larger cohorts.

Hiccups, severe vomiting and longitudinally extensive transverse myelitis in a patient with prostatic adenocarcinoma and Aquaporin-4 antibodies.

Neuromyelitis optica spectrum disorder (NMOSD) is not defined as a classical paraneoplastic neurological syndrome, however there are growing evidences that NMOSD may be rarely associated with cancer. Older (>45 years old) male patients with longitudinally extensive transverse myelitis (LETM) or patients with "area postrema" syndrome (intractable vomiting and hiccups) at onset are at higher risk for neoplasm-associated NMOSD. We report the case of 79-years old man who developed, a month after radiotherapy for prostatic adenocarcinoma, an area postrema syndrome rapidly followed by a LETM involving the whole spinal cord (from C2 to the conus). Aquaporin-4-IgG antibodies were positive in serum.

Efficacy of rituximab on seizure control and cognitive symptoms in leucine-rich, glioma-inactivated 1 (LGI1) limbic encephalitis: a high-density electroencephalography case study.

LGI1 encephalitis is an autoimmune disorder characterized by cognitive symptoms and seizures, which rarely respond to common antiepileptic drugs (AEDs). Rituximab (RTX) is a CD-20-depleting monoclonal antibody which has been used for the treatment of LGI1 encephalitis, however, its efficacy remains controversial. A 54-year-old woman came to our attention due to memory loss and gambling. Brain MRI revealed areas of bilateral hippocampal hyperintensity and LGI1 antibodies were found in both serum and cerebrospinal fluid. Immunotherapy with steroids was started, followed by intravenous immunoglobulins with partial improvement. The patient developed multiple generalized tonic-clonic seizures. She was then administered intravenous rituximab with significant improvement for both cognitive symptoms and seizure control. High-density EEG was recorded before treatment, seven days after the first dose and seven days after the second dose. Topoplot and power spectrum analysis were performed for each recording. Interictal epileptiform discharges, as well as theta power bands, were significantly reduced after each dose, while topoplot analysis showed reduced spreading over posterior and frontal electrodes for interictal epileptiform discharges of temporal origin. Our experience indicates that rituximab is a valid treatment for LGI1 encephalitis, demonstrating efficacy for both cognitive symptoms and seizure control. High-density EEG could represent a novel, safe and reproducible method to study epileptogenesis in autoimmune limbic encephalitis.

SARS-CoV-2 pandemic and epilepsy: The impact on emergency department attendances for seizures.

INTRODUCTION: The risk of acquiring SARS-CoV-2 in a hospital setting and the need of reorganizing the Emergency Departments (EDs) to cope with infected patients have led to a reduction of ED attendances for non-infectious acute conditions and to a different management of chronic disorders. METHODS: We performed a retrospective study evaluating the frequency and features of ED attendances for seizures during the lockdown period (March 10th-April 30th 2020) in the University Hospital of Trieste, Italy. We studied the possible pandemic impact on the way patients with seizures sought for medical assistance by comparing the lockdown period to a matched period in 2019 and to a period of identical length preceding the lockdown (January 18th-March 9th 2020). RESULTS: A striking decrease in total ED attendances was observed during lockdown (4664) compared to the matched control (10424) and to the pre-lockdown (9522) periods. A similar reduction, although to a lesser extent, was detected for seizure attendances to the ED: there were 37 during lockdown and 63 and 44 respectively during the two other periods. Intriguingly, during the lockdown a higher number of patients attended the ED with first seizures (p = 0.013), and more EEGs (p = 0.008) and CT brain scans (p = 0.018) were performed; there was a trend towards more frequent transport to the ED by ambulance (p = 0.061) in the lockdown period. CONCLUSIONS: Our data suggest that the pandemic has affected the way patients with seizures access the Health Care System.