Publications by authors named "Sara Mariotto"

60 Publications

Brain Stimulation as a Therapeutic Tool in Amyotrophic Lateral Sclerosis: Current Status and Interaction With Mechanisms of Altered Cortical Excitability.

Front Neurol 2020 5;11:605335. Epub 2021 Feb 5.

Unit of Neurology, Neurophysiology, Neurobiology, Department of Medicine, Campus Bio-Medico University, Rome, Italy.

In the last 20 years, several modalities of neuromodulation, mainly based on non-invasive brain stimulation (NIBS) techniques, have been tested as a non-pharmacological therapeutic approach to slow disease progression in amyotrophic lateral sclerosis (ALS). In both sporadic and familial ALS cases, neurophysiological studies point to motor cortical hyperexcitability as a possible priming factor in neurodegeneration, likely related to dysfunction of both excitatory and inhibitory mechanisms. A trans-synaptic anterograde mechanism of excitotoxicity is thus postulated, causing upper and lower motor neuron degeneration. Specifically, motor neuron hyperexcitability and hyperactivity are attributed to intrinsic cell abnormalities related to altered ion homeostasis and to impaired glutamate and gamma aminobutyric acid gamma-aminobutyric acid (GABA) signaling. Several neuropathological mechanisms support excitatory and synaptic dysfunction in ALS; additionally, hyperexcitability seems to drive DNA-binding protein 43-kDA (TDP-43) pathology, through the upregulation of unusual isoforms directly contributing to ASL pathophysiology. Corticospinal excitability can be suppressed or enhanced using NIBS techniques, namely, repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS), as well as invasive brain and spinal stimulation. Experimental evidence supports the hypothesis that the after-effects of NIBS are mediated by long-term potentiation (LTP)-/long-term depression (LTD)-like mechanisms of modulation of synaptic activity, with different biological and physiological mechanisms underlying the effects of tDCS and rTMS and, possibly, of different rTMS protocols. This potential has led to several small trials testing different stimulation interventions to antagonize excitotoxicity in ALS. Overall, these studies suggest a possible efficacy of neuromodulation in determining a slight reduction of disease progression, related to the type, duration, and frequency of treatment, but current evidence remains preliminary. Main limitations are the small number and heterogeneity of recruited patients, the limited "dosage" of brain stimulation that can be delivered in the hospital setting, the lack of a sufficient knowledge on the excitatory and inhibitory mechanisms targeted by specific stimulation interventions, and the persistent uncertainty on the key pathophysiological processes leading to motor neuron loss. The present review article provides an update on the state of the art of neuromodulation in ALS and a critical appraisal of the rationale for the application/optimization of brain stimulation interventions, in the light of their interaction with ALS pathophysiological mechanisms.
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http://dx.doi.org/10.3389/fneur.2020.605335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892772PMC
February 2021

Antibodies to MOG in CSF only: pathological findings support the diagnostic value.

Acta Neuropathol 2021 Feb 20. Epub 2021 Feb 20.

Neurology Unit, Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Policlinico GB Rossi, P.le LA Scuro 10, 37134, Verona, Italy.

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http://dx.doi.org/10.1007/s00401-021-02286-3DOI Listing
February 2021

NfL levels predominantly increase at disease onset in MOG-Abs-associated disorders.

Mult Scler Relat Disord 2021 Feb 11;50:102833. Epub 2021 Feb 11.

Section of Neurology, Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy.

The unpredictable course and uncertain impact of relapses make treatment strategies of anti-myelin oligodendrocyte glycoprotein antibodies associated disorders (MOGAD) challenging. We analysed neurofilament light chain levels (NfL) in onset and follow-up sera of 18 patients with MOGAD to clarify the timing of axonal damage. In comparison with disease onset values (median 8.9 pg/mL, range 1.8-97), NfL levels remained stable or decreased in most follow-up measurements (n=52, median 6.7 pg/mL, range 0.2-207), including those measured on relapses. The predominant axonal damage occurs during onset, which could be the main driving factor of final disability, with subsequent relevant clinical and therapeutic implications.
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http://dx.doi.org/10.1016/j.msard.2021.102833DOI Listing
February 2021

Mechanisms of Nerve Damage in Neuropathies Associated with Hematological Diseases: Lesson from Nerve Biopsies.

Brain Sci 2021 Jan 20;11(2). Epub 2021 Jan 20.

Neurology Unit, Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, 37134 Verona, Italy.

Despite the introduction of non-invasive techniques in the study of peripheral neuropathies, sural nerve biopsy remains the gold standard for the diagnosis of several neuropathies, including vasculitic neuropathy and neurolymphomatosis. Besides its diagnostic role, sural nerve biopsy has helped to shed light on the pathogenic mechanisms of different neuropathies. In the present review, we discuss how pathological findings helped understand the mechanisms of polyneuropathies complicating hematological diseases.
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http://dx.doi.org/10.3390/brainsci11020132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7909400PMC
January 2021

Serum Neurofilament to Magnetic Resonance Imaging Lesion Area Ratio Differentiates Spinal Cord Infarction From Acute Myelitis.

Stroke 2021 Jan 11;52(2):645-654. Epub 2021 Jan 11.

Departments of Neurology (E.S., A.M., S.J.P., E.P.F., A.A.R., D.M.N., N.L.Z.), Mayo Clinic, Rochester.

Background And Purpose: The diagnosis of spontaneous spinal cord infarction (SCI) is limited by the lack of diagnostic biomarkers and MRI features that often overlap with those of other myelopathies, especially acute myelitis. We investigated whether the ratio between serum neurofilament light chain levels and MRI T2-lesion area (neurofilament light chain/area ratio-NAR) differentiates SCI from acute myelitis of similar severity.

Methods: We retrospectively identified Mayo Clinic patients (January 1, 2000-December 31, 2019) with (1) SCI, (2) AQP4 (aquaporin 4)-IgG or MOG (myelin oligodendrocyte glycoprotein)-IgG-associated myelitis at disease clinical presentation, or (3) idiopathic transverse myelitis from a previously identified population-based cohort of patients seronegative for AQP4-IgG and MOG-IgG. Serum neurofilament light chain levels (pg/mL) were assessed at the Verona University (SIMOA, Quanterix) in a blinded fashion on available stored samples obtained ≤3 months from myelopathy presentation. For each patient, the largest spinal cord lesion area (mm) was manually outlined by 2 independent raters on sagittal T2-weighted MRI images, and the mean value was used to determine NAR (pg/[mL·mm]).

Results: Forty-eight patients were included SCI, 20 (definite, 11; probable, 6; possible, 3); acute myelitis, 28 (AQP4-IgG-associated, 17; MOG-IgG-associated, 5; idiopathic transverse myelitis, 6). The median expanded disability status scale score (range) at myelopathy nadir were 7.75 (2-8.5) and 5.5 (2-8), respectively. Serum neurofilament light chain levels (median [range] pg/mL) in patients with SCI (188 [14.3-2793.4]) were significantly higher compared with patients with AQP4-IgG-associated myelitis (37 [0.8-6942.9]), MOG-IgG-associated myelitis (45.8 [4-283.8]), and idiopathic transverse myelitis (15.6 [0.9-217.8]); =0.01. NAR showed the highest accuracy for identification of SCI versus acute myelitis with values ≥0.35 pg/(mL·mm) yielding 86% specificity and 95% sensitivity (area under the curve=0.93). The positive and negative likelihood ratios were 6.67 and 0.06, respectively. NAR remained independently associated with SCI after adjusting for age, gender, immunotherapy before sampling, and days from myelopathy symptoms onset to sampling (=0.0007).

Conclusions: NAR is a novel and promising clinical biomarker for differentiation of SCI from acute myelitis.
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http://dx.doi.org/10.1161/STROKEAHA.120.031482DOI Listing
January 2021

SARS-CoV-2 encephalitis is a cytokine release syndrome: evidences from cerebrospinal fluid analyses.

Clin Infect Dis 2021 Jan 4. Epub 2021 Jan 4.

Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Italy.

Background: Recent findings indicated that SARS-CoV-2 related neurological manifestations involve cytokine release syndrome along with endothelial activation, blood brain barrier dysfunction, and immune-mediated mechanisms. Very few studies have fully investigated the CSF correlates of SARS-CoV-2 encephalitis.

Methods: Patients with PCR-confirmed SARS-CoV-2 infection and encephalitis (COV-Enc), encephalitis without SARS-CoV-2 infection (ENC) and healthy controls (HC) underwent an extended panel of CSF neuronal (NfL, T-tau), glial (GFAP, TREM2, YKL-40) and inflammatory biomarkers (IL-1β, IL-6, Il-8, TNF- α, CXCL-13 and β2-microglobulin).

Results: Thirteen COV-Enc, 21 ENC and 18 HC entered the study. In COV-Enc cases, CSF was negative for SARS-CoV-2 real-time PCR but exhibited increased IL-8 levels independently from presence of pleocytosis/hyperproteinorracchia. COV-Enc patients showed increased IL-6, TNF- α, and β2-microglobulin and glial markers (GFAP, sTREM-2, YKL-40) levels similar to ENC but normal CXCL13 levels. Neuronal markers NfL and T-Tau were abnormal only in severe cases.

Conclusions: SARS-CoV-2-related encephalitis were associated with prominent glial activation and neuroinflammatory markers, whereas neuronal markers were increased in severe cases only. The pattern of CSF alterations suggested a cytokine-release syndrome as the main inflammatory mechanism of SARS-CoV-2 related encephalitis.
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http://dx.doi.org/10.1093/cid/ciaa1933DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7799260PMC
January 2021

Scientific productivity in neurology: impact of the socio-economic status.

Neurol Sci 2021 Jan 2. Epub 2021 Jan 2.

Section of Endocrinology, Diabetes and Metabolism, University and Azienda Ospedaliera Universitaria Integrata of Verona, Piazzale Stefani, 1, 37126, Verona, Italy.

Objective: Scientific productivity is relevant to support clinical activity, improve therapeutic strategies, and understand the pathophysiological mechanisms of neurological disorders. We performed an updated bibliometric research to assess the country-specific relationship between neurological scientific production and socio-economic variables of dedicated resources.

Methods: Neurological scientific productivity of 168 countries, from 1996 to 2019, was obtained using the SCImago online website. Data on gross domestic product (GDP), percentage of GDP spent in research and development, and number of researchers per million people were obtained using the World Bank Group website.

Results: The USA was the first country in terms of documents produced (260,030), followed by Germany (69,841), Japan (65,200), the UK (60,914), and Italy (50,017). Except for Japan, all the most productive countries had an increase in scientific productivity in the last 12 years. In 2019, the USA still ranked first in the number of neurological papers published, followed by Germany, the UK, Italy, and Japan. Among the most productive countries, Canada and Japan did not increase the percentage of GDP spent in research over time. Except for Canada and Japan, all the most productive countries increased the number of researchers in the last years.

Conclusions: Our analysis provided novel evidence of the adequacy of the scientific return on country-specific investment of local dedicated resources.
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http://dx.doi.org/10.1007/s10072-020-04893-6DOI Listing
January 2021

Neuronal intermediate filament IgGs in CSF: Autoimmune Axonopathy Biomarkers.

Ann Clin Transl Neurol 2021 02 28;8(2):425-439. Epub 2020 Dec 28.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.

Objectives: To describe CSF-defined neuronal intermediate filament (NIF) autoimmunity.

Methods: NIF-IgG CSF-positive patients (41, 0.03% of 118599 tested, 1996-2019) were included (serum was neither sensitive nor specific). Criteria-based patient NIF-IgG staining of brain and myenteric NIFs was detected by indirect immunofluorescence assay (IFA); NIF-specificity was confirmed by cell-based assays (CBAs, alpha internexin, neurofilament light [NF-L]), heavy-[NF-H] chain).

Results: Sixty-one percent of 41 patients were men, median age, 61 years (range, 21-88). Syndromes were encephalopathy predominant (23), cerebellar ataxia predominant (11), or myeloradiculoneuropathies (7). MRI abnormalities (T2 hyperintensities of brain, spinal cord white matter tracts. and peripheral nerve axons) and neurophysiologic testing (EEG, EMG, evoked potentials) co-localized with clinical neurological phenotypes (multifocal in 29%). Thirty patients (73%) had ≥ 1 immunological perturbation: cancer (paraneoplastic), 22; systemic infection (parainfectious [including ehrlichosis, 3] or HIV), 7; checkpoint-inhibitor cancer immunotherapy, 4; other, 5. Cancers were as follows: neuroendocrine-lineage carcinomas, 12 (small cell, 6; Merkel cell, 5; pancreatic, 1 [11/12 had NF-L-IgG detected, versus 8/29 others, P = 0.0005]) and other, 11. Onset was predominantly subacute (92%) and accompanied by inflammatory CSF (75%), and immunotherapy response (77%). In contrast, CSF controls (15684 total) demonstrated NIF-IgG negativity (100% of test validation controls), and low frequencies of autoimmune diagnoses (20% of consecutively referred clinical specimens) and neuroendocrine-lineage carcinoma diagnosis (3.1% vs. 30% of NIF cases), P < 0.0001. Median NF-L protein concentration was higher in 8 NF-L-IgG-positive patients (median, 6718 ng/L) than 16 controls.

Interpretation: Neurological autoimmunity, defined by CSF-detected NIF-IgGs, represents a continuum of treatable axonopathies, sometimes paraneoplastic or parainfectious.
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http://dx.doi.org/10.1002/acn3.51284DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7886032PMC
February 2021

Hypothalamic-Bulbar MRI Hyperintensity in Anti-IgLON5 Disease with Serum-Restricted Antibodies: A Case Report and Systematic Review of Literature.

J Alzheimers Dis 2021 ;79(2):683-691

Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy.

Background: Anti-IgLON5 disease is a rare neurodegenerative tauopathy that displays heterogeneity in clinical spectrum, disease course, cerebrospinal fluid (CSF) findings, and variable response to immunotherapy. Sleep disorders, bulbar dysfunction, and gait abnormalities are common presenting symptoms, and conventional brain MRI scanning is often unrevealing.

Objective: To provide a comprehensive overview of the literature and to assess the frequency of symptoms, MRI findings, and treatment response in patients with IgLON5 autoimmunity in the serum and CSF or restricted to serum.

Methods: We examined a 65-year-old woman with bulbar-onset IgLON5 disease with serum-restricted antibodies, and we also performed a systematic review of all confirmed cases reported in the English literature.

Results: We identified 93 patients, included our case. Clinical data were obtained in 58 subjects, in whom the most frequent symptoms were sleep-disordered breathing, dysphagia, parasomnias, dysarthria, limb or gait ataxia, stridor or vocal cord paresis, movement disorders, and postural instability. Distinct MRI alterations were identified in 12.5% of cases, as opposed to unspecific or unremarkable changes in the remaining patients. T2-hyperintense non-enhancing signal alterations involving the hypothalamus and the brainstem tegmentum were observed only in the present case. Inflammatory CSF was found in half of the cases and serum-restricted antibodies in 4 patients. Treatment with immunosuppressant or immunomodulatory drugs led to sustained clinical response in 19/52 patients.

Conclusion: Anti-IgLON5 autoimmunity should be considered in patients with sleep disorders, bulbar syndrome, autonomic involvement, and movement disorders, and high-field brain MRI can be of diagnostic help.
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http://dx.doi.org/10.3233/JAD-201105DOI Listing
January 2021

Anti-MOG-associated demyelinating disorders: two sides of the same coin.

Neurol Sci 2020 Nov 14. Epub 2020 Nov 14.

Neurology Unit, Department of Neuroscience, Biomedicine, and Movement Sciences, University of Verona, Verona, Italy.

Background: Anti-myelin oligodendrocyte glycoprotein antibody-associated disorders (MOGAD) are new emerging diseases with heterogeneous course, treatment, response, and prognosis.

Case Report: We herein present 2 cases with antibodies to MOG, one with a cerebellar/brainstem monophasic syndrome which partially improved after treatment, and the other with an optic neuritis onset then relapsed with cortical encephalitis and presented a subsequent complete recovery. We further discuss elements possibly associated with disease heterogeneity and influencing treatment choices.

Conclusions: MOGAD is an extremely variable disease which can relapse and accumulate disability over time. An early diagnosis and correct timely treatment is fundamental to improve clinical outcome.
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http://dx.doi.org/10.1007/s10072-020-04892-7DOI Listing
November 2020

Acute Cervical Longitudinally Extensive Transverse Myelitis in a Child With Lipopolysaccharide-Responsive-Beige-Like-Anchor-Protein (LRBA) Deficiency: A New Complication of a Rare Disease.

Front Pediatr 2020 16;8:580963. Epub 2020 Oct 16.

Pediatric Hematology Oncology, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.

Lipopolysaccharide responsive beige-like anchor protein (LRBA) deficiency is a primary immunodeficiency disorder (PID) that can cause a common variable immunodeficiency (CVID)-like disease. The typical features of the disease are autoimmunity, chronic diarrhea, and hypogammaglobulinemia. Neurological complications are also reported in patients affected by LRBA deficiency. We describe a 7-year old female with an acute cervical longitudinally extensive transverse myelitis (LETM) as a feature of LRBA deficiency. This is the first case of LETM associated with LRBA deficiency described in literature.
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http://dx.doi.org/10.3389/fped.2020.580963DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7596261PMC
October 2020

Clinical Presentation and Outcomes of Severe Acute Respiratory Syndrome Coronavirus 2-Related Encephalitis: The ENCOVID Multicenter Study.

J Infect Dis 2021 01;223(1):28-37

Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.

Background: Several preclinical and clinical investigations have argued for nervous system involvement in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Some sparse case reports have described various forms of encephalitis in coronavirus disease 2019 (COVID-19) disease, but very few data have focused on clinical presentations, clinical course, response to treatment, and outcomes.

Methods: The SARS-CoV-2 related encephalopaties (ENCOVID) multicenter study included patients with encephalitis with full infectious screening, cerebrospinal fluid (CSF), electroencephalography (EEG), and magnetic resonance imaging (MRI) data and confirmed SARS-CoV-2 infection recruited from 13 centers in northern Italy. Clinical presentation and laboratory markers, severity of COVID-19 disease, response to treatment, and outcomes were recorded.

Results: Twenty-five cases of encephalitis positive for SARS-CoV-2 infection were included. CSF showed hyperproteinorrachia and/or pleocytosis in 68% of cases whereas SARS-CoV-2 RNA by reverse-transcription polymerase chain reaction resulted negative. Based on MRI, cases were classified as acute demyelinating encephalomyelitis (ADEM; n = 3), limbic encephalitis (LE; n = 2), encephalitis with normal imaging (n = 13), and encephalitis with MRI alterations (n = 7). ADEM and LE cases showed a delayed onset compared to the other encephalitis cases (P = .001) and were associated with previous, more severe COVID-19 respiratory involvement. Patients with MRI alterations exhibited worse response to treatment and final outcomes compared to those with other encephalitis.

Conclusions: SARS-CoV-2 infection is associated with a wide spectrum of encephalitis characterized by different clinical presentation, response to treatment, and outcomes.
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http://dx.doi.org/10.1093/infdis/jiaa609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7543535PMC
January 2021

Inter-center agreement in the interpretation of oligoclonal bands.

Clin Chem Lab Med 2021 Feb 28;59(3):e91-e94. Epub 2020 Sep 28.

Department of Neurosciences, Biomedicine and Movement Sciences, Neurology Unit, University of Verona, Verona, Italy.

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http://dx.doi.org/10.1515/cclm-2020-1037DOI Listing
February 2021

Epileptic seizures of suspected autoimmune origin: a multicentre retrospective study.

J Neurol Neurosurg Psychiatry 2020 Nov 28;91(11):1145-1153. Epub 2020 Aug 28.

Department of Neuroscience, Biomedicine and Movement Sciences, Section of Neurology, University of Verona, Verona, Italy

Objective: To analyse autoantibody status in a well-defined European multicentre cohort of patients with epilepsy of unknown aetiology and to validate the recently proposed Antibody Prevalence in Epilepsy (APE2) and Response to ImmunoTherapy in Epilepsy (RITE2) scores.

Methods: We retrospectively collected clinical and paraclinical data of 92 patients referred to the Neurology Units of Verona and Salzburg between January 2014 and July 2019 with new-onset epilepsy, status epilepticus or chronic epilepsy of unknown aetiology. Fixed and live cell-based assays, tissue-based assays, immunoblot, and live rat hippocampal cell cultures were performed in paired serum/cerebrospinal fluid (CSF) to detect antineuronal and antiglial antibodies. The APE2 and RITE2 scores were then calculated and compared with clinical and laboratory data.

Results: Autoantibodies were detected in 29/92 patients (31.5%), with multiple positivity observed in 6/29 cases. The APE2 score (median 5, range 1-15) significantly correlated with antibody positivity (p=0.014), especially for the presence of neuropsychiatric symptoms (p<0.01), movement disorders (p<0.01), dysautonomia (p=0.03), faciobrachial dyskinesias (p=0.03) and cancer history (p<0.01). Status epilepticus was significantly more frequent in antibody-negative patients (p<0.01). Among the items of the RITE2 score, early initiation of immunotherapy correlated with a good treatment response (p=0.001), whereas a cancer history was significantly more common among non-responders (p<0.01). Persistence of neuropsychiatric symptoms and seizures correlated with antiepileptic maintenance after at least 1 year.

Conclusions: This is the first study that independently validates the APE2 and RITE2 scores and includes the largest cohort of patients whose paired serum and CSF samples have been tested for autoantibodies possibly associated with autoimmune epilepsy.
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http://dx.doi.org/10.1136/jnnp-2020-323841DOI Listing
November 2020

Gender disparity in editorial boards of journals in neurology.

Neurology 2020 09 4;95(11):489-491. Epub 2020 Aug 4.

From the Neurology Unit (S.M., S.C., S.B.), Department of Neurosciences, Biomedicine, and Movement Sciences, University of Verona; and Section of Endocrinology (G.B., A.M.), Diabetes and Metabolism, University and Azienda Ospedaliera Universitaria Integrata of Verona, Italy.

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http://dx.doi.org/10.1212/WNL.0000000000010500DOI Listing
September 2020

GABA receptor autoimmunity after alemtuzumab treatment for multiple sclerosis.

Neurology 2020 09 10;95(9):399-401. Epub 2020 Jul 10.

From the Department of Neurology and Stroke Unit "A. Cardarelli Hospital" (G.T.M., G.S., V.M., M.N., P.C., C.F.); Multiple Sclerosis Centre "A. Cardarelli Hospital" (G.T.M., C.F.), Naples; Neurology Unit (S.M., S.F., S.B.), Department of Neurosciences, Biomedicine, and Movement Sciences, University of Verona, Italy; Institute of Neurology (R.H.), Medical University of Vienna, Austria; Multiple Sclerosis Center (R.C.), ASST - Spedali Civili of Brescia, Montichiari; Department of Neuroradiology (S.G.), San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan; and Ragon Institute of Massachusetts General Hospital (M.S.), Massachusetts Institute of Technology and Harvard Medical School, Cambridge.

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http://dx.doi.org/10.1212/WNL.0000000000010310DOI Listing
September 2020

Novel decision algorithm to discriminate parkinsonism with combined blood and imaging biomarkers.

Parkinsonism Relat Disord 2020 08 22;77:57-63. Epub 2020 Jun 22.

Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria. Electronic address:

Introduction: To determine an exploratory multimodal approach including serum NFL and MR planimetric measures to discriminate Parkinson's disease (PD), multiple system atrophy (MSA) and progressive supranuclear palsy (PSP).

Methods: MR planimetric measurements and NFL serum levels, with a mean time interval of 60 months relative to symptom onset, were assessed in a retrospective cohort of 11 progressive supranuclear palsy (PSP), 22 Parkinson's disease (PD), 16 multiple system atrophy (MSA) patients and 42 healthy controls (HC). A decision tree model to discriminate PD, PSP, and MSA was constructed using receiver operating characteristic curve analysis and Classification and Regression Trees algorithm.

Results: Our multimodal decision tree provided accurate differentiation of PD versus MSA and PSP patients using a serum NFL cut-off of 14.66 ng/L. The pontine-to-midbrain-diameter-ratio (P/M) discriminated MSA from PSP at a cut-off value of 2.06. The combined overall diagnostic yield was an accuracy of 83.7% (95% CI 69.8-90.8%).

Conclusion: We provide a clinically feasible decision algorithm which combines serum NFL levels and a planimetric MRI marker to differentiate PD, MSA and PSP with high diagnostic accuracy.

Classification Of Evidence: This study provides Class III evidence that the combination of serum NFL levels und MR planimetric measurements discriminates between PD, PSP and MSA.
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http://dx.doi.org/10.1016/j.parkreldis.2020.05.033DOI Listing
August 2020

Serum neurofilament light chain studies in neurological disorders, hints for interpretation.

J Neurol Sci 2020 09 14;416:116986. Epub 2020 Jun 14.

Neurology Unit, Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Policlinco GB Rossi, P.le LA Scuro 10, 37134 Verona, Italy. Electronic address:

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http://dx.doi.org/10.1016/j.jns.2020.116986DOI Listing
September 2020

Sural nerve biopsy: current role and comparison with serum neurofilament light chain levels.

J Neurol 2020 Oct 27;267(10):2881-2887. Epub 2020 May 27.

Neurology Unit, Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Policlinico GB Rossi, P.le LA Scuro 10, 37134, Verona, Italy.

The diagnosis of peripheral neuropathies can be challenging with consequent difficulties in patients' management. The aim of this study was to explore the current diagnostic role of sural nerve biopsy and to compare pathological findings with serum neurofilament light chain levels (NfL) as biomarkers of axonal damage. We collected demographic, clinical, and paraclinical data of patients referred over 1 year to the Neurology Unit, University of Verona, Italy, to perform nerve biopsy for diagnostic purposes, and we analyzed NfL levels in available paired sera using a high sensitive technique (Quanterix, Simoa). Eighty-two patients were identified (37.8% females, median age 65.5 years). Neuropathy onset was frequently insidious (68.3%) with a slowly progressive course (76.8%). Lower limbs were usually involved (81.7%), with a predominance of sensory over motor symptoms (74.4% vs 42.7%). The most common neuropathological findings were a demyelinating pattern (76.8%), clusters of regenerations (58.5%), and unmyelinated fibers involvement on ultrastructural evaluation (52.4%). A definite pathological diagnosis was achieved in 29 cases, and in 20.7% of patients, the referral clinical diagnosis was modified. Coexistent hematological conditions and hepatitis were diagnostic confounding factors (p = 0.012 and 0.034, respectively). In the analyzed paired sera (n = 37), an inverse despite not significant relationship between NfL values and fiber density was observed (Spearman's rho - 0.312, p = 0.056). In addition, we noted increased serum NfL values of patients with active axonal degeneration. Nerve biopsy remains a useful diagnostic investigation to achieve a correct diagnosis and guide patients' management in selected cases of peripheral neuropathy. Serum NfL is an accessible and potential valuable marker of axonal damage in these conditions.
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http://dx.doi.org/10.1007/s00415-020-09949-3DOI Listing
October 2020

Diagnostic features of initial demyelinating events associated with serum MOG-IgG.

J Neuroimmunol 2020 07 7;344:577260. Epub 2020 May 7.

Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona and Neurology Unit B, Azienda Ospedaliera Universitaria Integrata Verona, Verona, Italy.

Background: Myelin oligodendrocyte glycoprotein (MOG)-IgG associated disorders are increasingly recognized as a distinct disease entity. However, diagnostic sensitivity and specificity of serum MOG-IgG as well as recommendations for testing are still debated.

Materials And Methods: Between October 2015 and July 2017 we tested serum MOG-IgG in 91 adult patients (49 females) with a demyelinating event (DE) not fulfilling 2010 McDonald criteria for MS at sampling, negative for neuromyelitis optica (NMO)-IgG and followed-up for at least 12 months. We assessed the sensitivity and specificity of a live-cell MOG-IgG assay for each final diagnosis at last follow-up, for the 2018 international recommendations for MOG-IgG testing, and for other combinations of clinical and laboratory characteristics.

Results: Clinical presentations included acute myelitis (n = 48), optic neuritis (n = 36), multifocal encephalomyelitis (n = 4), and brainstem syndrome (n = 3). Twenty-four patients were MOG-IgG positive. Sensitivity and specificity of MOG-IgG test applied to the 2018 international recommendations were 28.4% and 86.7%, while they were 42.1% and 88.6% when applied to DE of unclear aetiology as defined above with two or more among: 1_no periventricular and juxtacortical MS-like lesions on brain MRI; 2_longitudinally extensive MRI optic nerve lesion; 3_no CSF-restricted oligoclonal bands; 4_CSF protein > 50 mg/dl.

Conclusions: Simplified requirements compared to those currently proposed for MOG-IgG testing could facilitate the applicability of the assay in the diagnosis of adults with DEs of unclear aetiology.
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http://dx.doi.org/10.1016/j.jneuroim.2020.577260DOI Listing
July 2020

Antibodies to neurofascin, contactin-1, and contactin-associated protein 1 in CIDP: Clinical relevance of IgG isotype.

Neurol Neuroimmunol Neuroinflamm 2020 01 21;7(1). Epub 2019 Nov 21.

From the Department of Brain and Behavioral Sciences (A.C., I.C., G.C., R.C., E.V.), University of Pavia, Pavia, Italy; Department of Neuromuscular Disease (A.C.), UCL Queen Square Institute of Neurology, London, United Kingdom; Neuroalgology Unit (R.L., P.D., L.P., G.L.), IRCCS Fondazione Istituto Neurologico "Carlo Besta," Milan, Italy; Department of Neurosciences (C.B., M.R., A.S.), University of Padova, Padova, Italy; IRCCS Mondino Foundation (I.C., G.C., E.Z., R.C., M.G., E.V., E.A., A.B., D.F.), Pavia, Italy; Department of Neuroscience (L.B., C.D.M., A.S.), Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genova, Genova, Italy; IRCCS Ospedale Policlinico San Martino (L.B., C.D.M., A.S.), Genova, Italy; Department of Neurosciences (F.M., E.S., A.T.), Odontostomatological and Reproductive Sciences, University of Naples "Federico II," Naples, Italy; Fondazione Policlinico Universitario Agostino Gemelli-IRCCS. UOC Neurologia (M.L., A.R., M.S.), Rome, Italy; Università Cattolica del Sacro Cuore (M.L., A.R., M.S.), Rome, Italy; Section of Neurology (S.F., S.M.), Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy; Department of Neurology and Stroke Unit (A.M.C.), Ospedale di Circolo/Fondazione Macchi, Varese, Italy; Department of Systems Medicine (G.A.M., G.M.), University of Rome Tor Vergata, Rome, Italy; Neurological Department (A.R.), ASST Lecco; Ospedale Treviglio ASST Bergamo Ovest (M.C.), Italy; Department of Neurology (R.F., F.C.), San Raffaele Scientific Institute, Milan, Italy; Department of Neurorehabilitation Sciences (M.C.), Casa Cura Policlinico (CCP), Milan, Italy; Department of Clinical and Experimental Medicine (A.M.), University of Messina, Messina, Italy; Department of Medicine, Surgery and Neurosciences (F.G.), University of Siena, Italy; Referral Center for Neuromuscular Diseases and ALS (L.K., E.M.), AP-HM, Timone University Hospital, Marseille, France; Université de Bordeaux (C.M.), Interdisciplinary Institute for Neuroscience, Bordeaux, France; Humanitas Clinical and Research Center (C.G., P.D., E.N.-O.), Milan University, Milan, Italy; IRCCS Centro Neurolesi "Bonino Pulejo" (C.S.), Messina, Italy; Department of Biomedical and Clinical Sciences "Luigi Sacco" (G.B., G.L.), University of Milan, Milan, Italy; and Institute for Neurosciences of Montpellier (J.D.), INSERM U1051, Montpellier University, Hopital Saint Eloi, Montpellier, France.

Objective: To assess the prevalence and isotypes of anti-nodal/paranodal antibodies to nodal/paranodal proteins in a large chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) cohort, compare clinical features in seronegative vs seropositive patients, and gather evidence of their isotype-specific pathogenic role.

Methods: Antibodies to neurofascin-155 (Nfasc155), neurofascin-140/186 (Nfasc140/186), contactin-1 (CNTN1), and contactin-associated protein 1 (Caspr1) were detected with ELISA and/or cell-based assay. Antibody pathogenicity was tested by immunohistochemistry on skin biopsy, intraneural injection, and cell aggregation assay.

Results: Of 342 patients with CIDP, 19 (5.5%) had antibodies against Nfasc155 (n = 9), Nfasc140/186 and Nfasc155 (n = 1), CNTN1 (n = 3), and Caspr1 (n = 6). Antibodies were absent from healthy and disease controls, including neuropathies of different causes, and were mostly detected in patients with European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) definite CIDP (n = 18). Predominant antibody isotypes were immunoglobulin G (IgG)4 (n = 13), IgG3 (n = 2), IgG1 (n = 2), or undetectable (n = 2). IgG4 antibody-associated phenotypes included onset before 30 years, severe neuropathy, subacute onset, tremor, sensory ataxia, and poor response to intravenous immunoglobulin (IVIG). Immunosuppressive treatments, including rituximab, cyclophosphamide, and methotrexate, proved effective if started early in IVIG-resistant IgG4-seropositive cases. Five patients with an IgG1, IgG3, or undetectable isotype showed clinical features indistinguishable from seronegative patients, including good response to IVIG. IgG4 autoantibodies were associated with morphological changes at paranodes in patients' skin biopsies. We also provided preliminary evidence from a single patient about the pathogenicity of anti-Caspr1 IgG4, showing their ability to penetrate paranodal regions and disrupt the integrity of the Nfasc155/CNTN1/Caspr1 complex.

Conclusions: Our findings confirm previous data on the tight clinico-serological correlation between antibodies to nodal/paranodal proteins and CIDP. Despite the low prevalence, testing for their presence and isotype could ultimately be part of the diagnostic workup in suspected inflammatory demyelinating neuropathy to improve diagnostic accuracy and guide treatment.

Classification Of Evidence: This study provides Class III evidence that antibodies to nodal/paranodal proteins identify patients with CIDP (sensitivity 6%, specificity 100%).
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http://dx.doi.org/10.1212/NXI.0000000000000639DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6935837PMC
January 2020

Antibody response against HERV-W in patients with MOG-IgG associated disorders, multiple sclerosis and NMOSD.

J Neuroimmunol 2020 01 6;338:577110. Epub 2019 Nov 6.

Section of Neurology, Department of Clinical, Surgery and Experimental Sciences, University of Sassari, Italy. Electronic address:

Increased expression of the retroviruses of HERV-W family has been linked to multiple sclerosis (MS) pathophysiology; nothing is known at the moment about MOG-IgG associated disorders. We compared antibody response against HERV-W peptides among patients with MOG-IgG associated disorders, multiple sclerosis (MS) and aquaporin-4 (AQP4)-IgG positive neuromyelitis optica spectrum disorder (NMOSD). A total of 102 serum samples were retrospectively analyzed. Antibody reactivity against HERV-W env peptides was similar in MOG-IgG associated disorders and MS, but different from AQP4-IgG positive NMOSD. Our findings expand the diagnostic role of HERV-W antibodies to the spectrum of demyelinating disorders associated with MOG-IgG.
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http://dx.doi.org/10.1016/j.jneuroim.2019.577110DOI Listing
January 2020

Relevance of antibodies to myelin oligodendrocyte glycoprotein in CSF of seronegative cases.

Neurology 2019 11 23;93(20):e1867-e1872. Epub 2019 Oct 23.

From the Section of Neurology (S.M., A.G., M.Z., D.A., S.M., S.F.), Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona; Neurology Unit (L.B., R.D., G.S., S.L., M.I.P.), Department of Medical, Surgical, and Experimental Sciences, University of Sassari; Neurology Unit (B.B.), AOUI Verona, Italy; and Clinical Department of Neurology (K.S., M.R.), Medical University of Innsbruck, Austria.

Objective: To determine the diagnostic relevance of myelin oligodendrocyte glycoprotein antibodies (MOG-Abs) in CSF of seronegative cases by retrospectively analyzing consecutive time-matched CSF of 80 MOG-Ab-seronegative patients with demyelinating disease.

Methods: The cohort included 44 patients with NMOSD and related disorders and 36 patients with multiple sclerosis (MS). Two independent neurologists blinded to diagnosis analyzed MOG-Abs by live cell-based immunofluorescence assay with goat anti-human immunoglobulin (Ig) G (whole molecule) antibody. Sera were tested at dilutions of 1:20 and 1:40, and a cutoff of 1:160 was considered for serum positivity. CSF specimens were tested undiluted and at 1:2 dilution with further titrations in case of positivity. Anti-IgG-Fc and anti-IgM-µ secondary antibodies were used to confirm the exclusive presence of MOG-IgG in positive cases. CSF of 13 MOG-Abs seropositive cases and 36 patients with neurodegenerative conditions was analyzed as controls.

Results: Three seronegative cases had CSF MOG-Abs (4% of the whole cohort or 7% of cases excluding patients with MS, in which MOG-Abs seem to lack diagnostic relevance). In particular, 2 patients with neuromyelitis optica spectrum disorder (NMOSD) and 1 with acute disseminated encephalomyelitis had MOG-Abs in CSF. Analysis with anti-IgG-Fc and anti-IgM confirmed the exclusive presence of MOG-IgG in the CSF of these patients. Among the control group, MOG-Abs were detectable in the CSF of 8 of 13 MOG-Ab-seropositive cases and in none of the patients with neurodegenerative disorders.

Conclusion: Although serum is the optimal specimen for MOG-Ab testing, analyzing CSF could improve diagnostic sensitivity in seronegative patients. This observation has relevant diagnostic impact and might provide novel insight into the biological mechanisms of MOG-Ab synthesis.
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http://dx.doi.org/10.1212/WNL.0000000000008479DOI Listing
November 2019

Distinct serum and cerebrospinal fluid cytokine and chemokine profiles in autoantibody-associated demyelinating diseases.

Mult Scler J Exp Transl Clin 2019 Apr-Jun;5(2):2055217319848463. Epub 2019 May 15.

Clinical Department of Neurology, Medical University of Innsbruck, Austria.

Background: Demyelinating diseases of the central nervous system associated with autoantibodies against aquaporin-4 and myelin-oligodendrocyte-glycoprotein are mediated by different immunopathological mechanisms compared to multiple sclerosis.

Objective: The purpose of this study was to evaluate serum and cerebrospinal fluid cytokine/chemokine profiles in patients with autoantibodies against aquaporin-4 or autoantibodies against myelin-oligodendrocyte-glycoprotein-associated demyelination compared to multiple sclerosis and autoimmune encephalitis.

Methods: Serum and cerebrospinal fluid cytokine/chemokine levels were analysed using Procartaplex Multiplex Immunoassays. First, we analysed a panel of 32 cytokines/chemokines in a discovery group (nine aquaporin-4-antibody seropositive, nine myelin oligodendrocyte glycoprotein-antibody seropositive, eight encephalitis, 10 multiple sclerosis). Significantly dysregulated cytokines/chemokines were validated in a second cohort (11 aquaporin-4-antibody seropositive, 18 myelin oligodendrocyte glycoprotein-antibody seropositive, 18 encephalitis, 33 multiple sclerosis).

Results: We found 11 significantly altered cytokines/chemokines in cerebrospinal fluid and serum samples in the discovery group (a proliferation-inducing ligand, fractalkine=CX3CL1, growth-regulated oncogene-α, interleukin-1 receptor antagonist, interleukin-6, interleukin-8=CXCL8, interleukin-10, interleukin-21, interferon-ɣ-induced protein-10=CXCL10, monokine induced by interferon-ɣ=CXCL9, macrophage inflammatory protein-1ß=CCL4). Most of these cytokines/chemokines were up-regulated in autoantibodies against aquaporin-4 or autoantibodies against myelin-oligodendrocyte-glycoprotein positive patients compared to multiple sclerosis. We confirmed these results for cerebrospinal fluid interleukin-6 and serum interleukin-8, growth-regulated oncogene-α, a proliferation-inducing ligand and macrophage inflammatory protein-1β in the validation set. Receiver-operating characteristic analysis revealed increased levels of cerebrospinal fluid interleukin-6, serum interleukin-8 and growth-regulated oncogene-α in most patients with autoantibody-associated neurological diseases.

Conclusion: This study suggests that distinctive cerebrospinal fluid and serum cytokine/chemokine profiles are associated with autoantibody-mediated demyelination, but not with multiple sclerosis.
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http://dx.doi.org/10.1177/2055217319848463DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6537078PMC
May 2019

Management of antibody-mediated autoimmune encephalitis in adults and children: literature review and consensus-based practical recommendations.

Neurol Sci 2019 Oct 3;40(10):2017-2030. Epub 2019 Jun 3.

Department of Neurology, Ospedale Santa Chiara, Trento, Italy.

Autoimmune encephalitis associated with antibodies against neuronal surface targets (NSAE) are rare but still underrecognized conditions that affect adult and pediatric patients. Clinical guidelines have recently been published with the aim of providing diagnostic clues regardless of antibody status. These syndromes are potentially treatable but the choice of treatment and its timing, as well as differential diagnoses, long-term management, and clinical and paraclinical follow-up, remain major challenges. In the absence of evidence-based guidelines, management of these conditions is commonly based on single-center expertise.Taking into account different published expert recommendations in addition to the multicenter experience of the Italian Working Group on Autoimmune Encephalitis, both widely accepted and critical aspects of diagnosis, management and particularly of immunotherapy for NSAE have been reviewed and are discussed.Finally, we provide consensus-based practical advice for managing hospitalization and follow-up of patients with NSAE.
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http://dx.doi.org/10.1007/s10072-019-03930-3DOI Listing
October 2019

Clinical and neurophysiological serial assessments of brentuximab vedotin-associated peripheral neuropathy.

Leuk Lymphoma 2019 11 6;60(11):2806-2809. Epub 2019 May 6.

Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy.

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http://dx.doi.org/10.1080/10428194.2019.1605068DOI Listing
November 2019

Conventional brain MRI features distinguishing limbic encephalitis from mesial temporal glioma.

Neuroradiology 2019 Aug 26;61(8):853-860. Epub 2019 Apr 26.

Neuroradiology, Department of Medicine and Surgery, Sezione di Neuroscienze, University of Salerno, Salerno, Italy.

Purpose: Radiological hallmark of autoimmune limbic encephalitis (LE) is a hyperintense signal in MRI T2-weighted images of mesial temporal structures. We aimed to identify conventional magnetic resonance imaging (MRI) features that can help distinguish LE from temporal glioma.

Methods: Brain MRIs of 25 patients affected by antibody-positive autoimmune LE, 24 patients affected by temporal glioma (tumor group), and 5 negative controls were retrospectively blindly evaluated in random order.

Results: Ten brain MRIs from the LE group were correctly recognized; one additional patient with mesial temporal hyperintensity with anti-AK5 abs LE was wrongly diagnosed as having a tumor. The brain MRIs of the remaining 14 of the 25 patients with LE were judged negative or, in three cases, showed features not typical for LE. In the tumor group, all MRIs showed pathological alterations diagnosed as tumors in 22/24 cases and as LE in two (2/22, 9%). Unilateral lesions were more common in tumors than in neuroradiologically abnormal LE (96% vs. 18%, p < 0.001). T2/FLAIR hyperintensity of the parahippocampal gyrus was associated more with tumor than with LE (71% vs. 18%) (p = 0,009), as T2/FLAIR hyperintensity of extralimbic structures (p = 0.015), edema (p = 0.041), and mass effect (p = 0.015). Maintenance of gray/white matter distinction was strongly associated with LE (91% vs. 17%, p < 0.001).

Conclusion: Conventional brain MRI is a fundamental tool in the differential diagnosis between LE and glioma. Bilateral involvement and maintenance of gray/white matter distinction at the cortical/subcortical interface are highly suggestive of LE.
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http://dx.doi.org/10.1007/s00234-019-02212-1DOI Listing
August 2019