Publications by authors named "Gregorio Spagni"

14 Publications

  • Page 1 of 1

Human Leukocyte Antigen Class II associations in late-onset Myasthenia Gravis.

Ann Clin Transl Neurol 2021 03 5;8(3):656-665. Epub 2021 Feb 5.

Dipartimento di Medicina e chirurgia traslazionale, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Sezione di Patologia generale, Rome, Italy.

Objective: Genetic factors predisposing to late-onset myasthenia gravis (LOMG) have not been clearly defined yet. However, genome-wide association studies identified Human Leukocyte Antigen (HLA) Class II alleles as a hotspot in this disease subtype. The aim of this study was to analyze the correlations of HLA Class II alleles with clinical data and titin antibodies in this patient subgroup.

Methods: This study consecutively enrolled anti-acetylcholine receptor antibody-positive, non-thymoma patients with generalized LOMG. All patients were of Italian ancestry. HLA-DRB1 and -DQB1 genotyping and serum titin antibody testing were performed in this population.

Results: A total of 107 patients (females: 28/107, 26.2%; median age of onset: 68 years, range: 50-92) were included. We found a positive association with HLA-DRB1*07 (P = 1.1 × 10 ), HLA-DRB1*14 (P = 0.0251) and HLA-DQB1*02 (P = 0.0095). HLA-DRB1*03, HLA-DRB1*11, and HLA-DQB1*03 were protective alleles (P = 7.9 × 10 , P = 0.0104, and P = 0.0067, respectively). By conditional haplotype analysis, HLA-DRB1*07-DQB1*02 was found to be the major risk haplotype (OR = 4.10; 95% C.I.: 2.80-5.99; P = 6.01 × 10 ). The mean age at onset was 73.4 years in DRB1*07 homozygotes, 69.7 years in heterozygotes, and 66.6 in non-carriers (P = 0.0488). DRB1*07 carriers and non-carriers did not differ in disease severity and response to therapy. Titin antibodies were detected in 61.4% of the cases, having no association with HLA alleles or specific clinical characteristics.

Interpretation: In our study, we identified the HLA DRB1*07-DQB1*02 haplotype as a predisposing factor for the development of generalized LOMG in the Italian population.
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http://dx.doi.org/10.1002/acn3.51309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7951107PMC
March 2021

In sickness and in health: when myasthenia gravis is a conjugal matter.

Neurol Sci 2021 May 7;42(5):2099-2101. Epub 2021 Jan 7.

Institute of Neurology, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, Largo A. Gemelli, 8, 00168, Rome, Italy.

Objective: Genes and environment contribute to the multifactorial etiology of autoimmune diseases. Familial clusters of autoimmune diseases are often observed among first-degree relatives sharing the same genetic background and environmental exposure. Rarer is the occurrence of the same autoimmune diseases in non-consanguineous spouses. We hereinafter report two non-consanguineous spouses who developed one after the other AChR-positive myasthenia gravis.

Methods: This study has been approved by Catholic University Ethic Committee. The wife, previously affected by Graves-Basedow disease, was the first to be diagnosed with myasthenia gravis, basing on a generalized weakness and an anti-AChR-positive assay. The husband, who suffered from ulcerative colitis, 16 years after his wife diagnosis complained of a mild generalized weakness. Repetitive nerve stimulation test and anti-AChR assay were confirmed myasthenia gravis. In these spouses, myasthenia gravis was not associated with thymoma. Human leukocyte antigen (HLA) class II genotyping showed distinct associations, with the wife carrying the DRB1*03:01 DQB1*02:01 and the husband the DRB1*07 DQB102 alleles.

Results: The wife's haplotype is strongly associated with myasthenia gravis and thyroiditis whereas HLA DRB1*07 allele was found to be related both to late-onset myasthenia gravis and ulcerative colitis.

Conclusions: Compared with other autoimmune disorders, myasthenia gravis has a lower prevalence. The surveillance environmental exposure may greatly improve our knowledge of non-genetic drivers of autoimmunity.
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http://dx.doi.org/10.1007/s10072-020-04944-yDOI Listing
May 2021

Acetylcholine receptor antibody positivity rate in ocular myasthenia gravis: a matter of age?

J Neurol 2021 May 2;268(5):1803-1807. Epub 2021 Jan 2.

Istituto di Neurologia, Università Cattolica del Sacro Cuore, Largo Agostino Gemelli, 8, 00168, Rome, Italy.

Background: Anti-acetylcholine receptor antibodies (AChR Abs) are detected in 85% of myasthenia gravis (MG) patients, at higher rates in patients with late-onset disease. AChR Ab frequency is generally thought to be much lower in ocular MG (OMG), although recent studies reported positivity rates higher than 70%. We hypothesized that the improved AChR Ab diagnostic yield in OMG could be related to an increased frequency of late-onset disease, as observed in generalized MG.

Methods: We compared OMG patients, with disease onset before or after 1998, for the age of onset, sex, presence of thymoma, immunosuppressive therapy rate, AChR Ab positivity, and follow-up duration. All patients had a follow-up ≥ 2 years. AChR Abs were tested by radioimmunoassay.

Results: The study included 133 patients. Disease onset occurred before 1998 in 54/133 cases (41%). Age of onset, the proportion of late-onset patients, and AChR Ab positivity rate were significantly increased in the more recent population. Thymoma frequency was similar in the two series. On multivariate analysis, the only variable predicting AChR Ab positivity was the age at onset ≥ 50 years (OR = 6.50, 95% CI = 2.70-15.63, p < 0.0001).

Conclusions: Our results confirm that current AChR Ab positivity in OMG may be higher than generally thought. In our population, this finding was associated with an increased frequency of late-onset cases.
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http://dx.doi.org/10.1007/s00415-020-10342-3DOI Listing
May 2021

Clinical Reasoning: A 71-Year-Old Man Presenting With Acute Onset Dysarthria and Dysphagia.

Neurology 2021 01 11;96(4):180-184. Epub 2020 Sep 11.

From the Institute of Neurology (G.S., L.T., G.D.M.), Università Cattolica del Sacro Cuore; and Unità Operativa Complessa di Neurologia (A.M., M.M., G.D.M., V.B.), Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.

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http://dx.doi.org/10.1212/WNL.0000000000010816DOI Listing
January 2021

Unprotected stroke management in an undiagnosed case of Severe Acute Respiratory Syndrome Coronavirus 2 infection.

J Stroke Cerebrovasc Dis 2020 Sep 23;29(9):104981. Epub 2020 May 23.

Area Neuroscienze, UOC Neurologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy. Electronic address:

Coronavirus disease 19 (COVID-19) is an emerging infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In this scenario, managing acute medical conditions, such as stroke, requires a timely treatment together with proper strategies that minimize the risk of infection spreading to health care workers and other patients. We report the case of a 79-year-old woman, who was admitted for a wake-up stroke due to occlusion of the left middle cerebral artery. She was treated outside the COVID-19-dedicated track of the hospital because she had no concomitant signs or symptoms suggestive of SARS-CoV-2 infection nor recent contact with other infected individuals. Post-mortem nasal and pharyngeal swab was positive for SARS-CoV-2 infection. We propose that hyperacute stroke patients should be tested for SARS-CoV-2 infection at admission and then managed as having COVID-19 until cleared by a negative result. We are aware that such measure results in some delay of the acute treatment of stroke, which could be minimal using well-exercised containment protocols.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2020.104981DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7245230PMC
September 2020

An Italian Neurology Outpatient Clinic Facing SARS-CoV-2 Pandemic: Data From 2,167 Patients.

Front Neurol 2020 29;11:564. Epub 2020 May 29.

Dipartimento Scienze dell'Invecchiamento, Neurologiche, Ortopediche e della Testa-Collo, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.

Neurological sequelae of SARS-CoV-2 infection have already been reported, but there is insufficient data about the impact of the pandemic on the management of the patients with chronic neurological diseases. We aim to analyze the effect of COVID-19 pandemic and social restriction rules on these fragile patients. Patients with chronic neurologic diseases routinely followed at the outpatient clinic of Gemelli University Hospital, Rome, were assessed for symptoms suggestive of SARS-CoV-2 infection in the pandemic period, consequences of social restrictions, and neurological disease features, concomitant medical conditions, current medical and disease-specific treatments. Data source: a dedicated telephone survey designed to encompass questions on COVID-19 symptoms and on pandemic effects in chronic neurologic conditions. Overall, 2,167 individuals were analyzed: 63 patients reported contact with COVID-19 positive cases, 41 performed the swab, and 2 symptomatic patients tested positive for COVID-19 (0.09%). One hundred fifty-eight individuals (7%) needed urgent neurological care, deferred due to the pandemic; 641 patients (30%) suspended hospital treatments, physiotherapy or other support interventions; 405 individuals (19%) reported a subjective worsening of neurological symptoms. In our population, the presence of neurological chronic diseases did not increase the prevalence of COVID-19 infection. Nevertheless, the burden of neurological disorders has been worsened by the lockdown.
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http://dx.doi.org/10.3389/fneur.2020.00564DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7273723PMC
May 2020

Long-Lasting Rituximab-Induced Reduction of Specific-But Not Total-IgG4 in MuSK-Positive Myasthenia Gravis.

Front Immunol 2020 5;11:613. Epub 2020 May 5.

Istituto di Neurologia, Università Cattolica del Sacro Cuore, Rome, Italy.

The use of rituximab (RTX), an anti-CD20 monoclonal antibody (Ab), in refractory myasthenia gravis (MG) is associated with a better response in patients with Abs to the muscle-specific tyrosine kinase (MuSK) than in other MG subgroups. Anti-MuSK Abs are mostly IgG4 with proven pathogenicity and positive correlation with clinical severity. The rapid and sustained response to RTX may be related to MuSK Ab production by short-lived Ab-secreting cells derived from specific CD20 B cells. Here, we investigated the long-term effects of RTX in nine refractory MuSK-MG patients with a follow-up ranging from 17 months to 13 years. In patients' sera, we titrated MuSK-specific IgG (MuSK-IgG) and MuSK-IgG4, along with total IgG and IgG4 levels. Optimal response to RTX was defined as the achievement and maintenance of the status of minimal manifestations (MM)-or-better together with ≥ 50% steroid reduction, withdrawal of immunosuppressants, and no need for plasma-exchange or intravenous immunoglobulin. After a course of RTX, eight patients improved, with optimal response in six, while only one patient did not respond. At baseline, MuSK-IgG and MuSK-IgG4 serum titers were positive in all patients, ranging from 2.15 to 49.5 nmol/L and from 0.33 to 46.2 nmol/L, respectively. MuSK Abs mostly consisted of IgG4 (range 63.80-98.86%). RTX administration was followed by a marked reduction of MuSK Abs at 2-7 months and at 12-30 months ( < 0.02 for MuSK-IgG and < 0.01 for MuSK-IgG4). In patients with a longer follow-up, MuSK Ab titers remained suppressed, paralleling clinical response. In the patient who achieved long-term complete remission, MuSK-IgG4 was no longer detectable within 2 years, while MuSK-IgG remained positive at very low titers up to 10 years after RTX. In the patient who did not respond, MuSK-IgG and MuSK-IgG4 remained unchanged. In this patient series, total IgG and IgG4 transiently decreased ( < 0.05) at 2-7 months after RTX. The different trends of reduction between MuSK-IgG4 and total IgG4 after RTX support the view that short-lived Ab-secreting cells are the main producers of MuSK Abs. The ratio between short-lived Ab-secreting cells and long-lived plasma cells may influence the response to RTX, and B-cell severe depletion may reduce self-maintaining autoimmune reactivity.
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http://dx.doi.org/10.3389/fimmu.2020.00613DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7214629PMC
March 2021

Clinical Reasoning: A 55-year-old woman presenting with ataxia and numbness 1 year after ileum resection.

Neurology 2019 10;93(15):675-679

From the Institute of Neurology (V.C., G.S., R.I.), Università Cattolica del Sacro Cuore; and Fondazione Policlinico Universitario "A. Gemelli" IRCCS (R.I.), Rome, Italy.

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http://dx.doi.org/10.1212/WNL.0000000000008253DOI Listing
October 2019

Immunotherapy improves sleep and cognitive impairment in anti-IgLON5 encephalopathy.

Neurol Neuroimmunol Neuroinflamm 2019 07 21;6(4):e577. Epub 2019 May 21.

Institute of Neurology (V.B., G.D.M., G.S., R.I.), Università Cattolica del Sacro Cuore; and Fondazione Policlinico Universitario "A. Gemelli" IRCCS (G.D.M., R.I.), Roma, Italy.

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http://dx.doi.org/10.1212/NXI.0000000000000577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6624089PMC
July 2019

Paraneoplastic neurological syndromes.

Semin Diagn Pathol 2019 Jul 21;36(4):279-292. Epub 2019 Jun 21.

Università Cattolica del Sacro Cuore, Roma, Italy.

Paraneoplastic neurological syndromes (PNS) constitute a heterogeneous group of cancer-related disorders that can affect any level of the central and peripheral nervous system. There is compelling evidence that PNS are caused by an immune response directed against neural antigens that are abnormally expressed by the tumour. PNS are frequently associated with neural-specific autoantibodies whose characterization has direct implications for diagnostic workup, treatment and outcome. The last decade has seen a dramatic rise in the discovery of novel autoantibodies associated with PNS, which has led to more accurate diagnoses and earlier treatments, potentially resulting in better outcomes. The latest advancements in the field of autoimmune neurology have paved the way to a more comprehensive understanding of PNS; yet, many aspects of their immunopathogenesis remain to be elucidated and patient-tailored treatment strategies still need to be optimized.
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http://dx.doi.org/10.1053/j.semdp.2019.06.005DOI Listing
July 2019

Grading the severity of autoimmune encephalitis: Advances and pitfalls.

Ann Neurol 2019 07 20;86(1):150. Epub 2019 May 20.

Institute of Neurology, Università Cattolica del Sacro Cuore, Rome, Italy.

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http://dx.doi.org/10.1002/ana.25496DOI Listing
July 2019

Teaching NeuroImages: Transient mutism associated with splenium lesion in capecitabine-induced leukoencephalopathy.

Neurology 2019 02;92(9):e1000-e1001

From the Institute of Neurology, Catholic University of the Sacred Heart; and Institute of Neurology, Fondazione Policlinico A. Gemelli IRCSS, Rome.

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http://dx.doi.org/10.1212/WNL.0000000000007012DOI Listing
February 2019

Central vein sign differentiates Multiple Sclerosis from central nervous system inflammatory vasculopathies.

Ann Neurol 2018 02 15;83(2):283-294. Epub 2018 Feb 15.

Department of Neuroscience, Drug and Child Health, University of Florence, Florence, Italy.

Objectives: In multiple sclerosis (MS), magnetic resonance imaging (MRI) is a sensitive tool for detecting white matter lesions, but its diagnostic specificity is still suboptimal; ambiguous cases are frequent in clinical practice. Detection of perivenular lesions in the brain (the "central vein sign") improves the pathological specificity of MS diagnosis, but comprehensive evaluation of this MRI biomarker in MS-mimicking inflammatory and/or autoimmune diseases, such as central nervous system (CNS) inflammatory vasculopathies, is lacking. In a multicenter study, we assessed the frequency of perivenular lesions in MS versus systemic autoimmune diseases with CNS involvement and primary angiitis of the CNS (PACNS).

Methods: In 31 patients with inflammatory CNS vasculopathies and 52 with relapsing-remitting MS, 3-dimensional T2*-weighted and T2-fluid-attenuated inversion recovery images were obtained during a single MRI acquisition after gadolinium injection. For each lesion, the central vein sign was evaluated according to consensus guidelines. For each patient, lesion count, volume, and brain location, as well as fulfillment of dissemination in space MRI criteria, were assessed.

Results: MS showed higher frequency of perivenular lesions (median = 88%) than did inflammatory CNS vasculopathies (14%), without overlap between groups or differences between 3T and 1.5T MRI. Among inflammatory vasculopathies, Behçet disease showed the highest median frequency of perivenular lesions (34%), followed by PACNS (14%), antiphospholipid syndromes (12%), Sjögren syndrome (11%), and systemic lupus erythematosus (0%). When a threshold of 50% perivenular lesions was applied, central vein sign discriminated MS from inflammatory vasculopathies with a diagnostic accuracy of 100%.

Interpretation: The central vein sign differentiates inflammatory CNS vasculopathies from MS at standard clinical magnetic field strengths. Ann Neurol 2018;83:283-294.
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http://dx.doi.org/10.1002/ana.25146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5901412PMC
February 2018

Clinical and immunological characteristics of the spectrum of GFAP autoimmunity: a case series of 22 patients.

J Neurol Neurosurg Psychiatry 2018 02 26;89(2):138-146. Epub 2017 Sep 26.

Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center, Utrecht, The Netherlands.

Objective: To report the clinical and immunological characteristics of 22 new patients with glial fibrillar acidic protein (GFAP) autoantibodies.

Methods: From January 2012 to March 2017, we recruited 451 patients with suspected neurological autoimmune disease at the Catholic University of Rome. Patients' serum and cerebrospinal fluid (CSF) samples were tested for neural autoantibodies by immunohistochemistry on mouse and rat brain sections, by cell-based assays (CBA) and immunoblot. GFAP autoantibodies were detected by immunohistochemistry and their specificity confirmed by CBA using cells expressing human GFAPα and GFAPδ proteins, by immunoblot and immunohistochemistry on GFAP-/- mouse brain sections.

Results: Serum and/or CSF IgG of 22/451 (5%) patients bound to human GFAP, of which 22/22 bound to GFAPα, 14/22 to both GFAPα and GFAPδ and none to the GFAPδ isoform only. The neurological presentation was: meningoencephalomyelitis or encephalitis in 10, movement disorder (choreoathetosis or myoclonus) in 3, anti-epileptic drugs (AED)-resistant epilepsy in 3, cerebellar ataxia in 3, myelitis in 2, optic neuritis in 1 patient. Coexisting neural autoantibodies were detected in five patients. Six patients had other autoimmune diseases. Tumours were found in 3/22 patients (breast carcinoma, 1; ovarian carcinoma, 1; thymoma, 1). Nineteen patients were treated with immunotherapy and 16 patients (84%) improved. Histopathology analysis of the leptomeningeal biopsy specimen from one patient revealed a mononuclear infiltrate with macrophages and CD8+ T cells.

Conclusions: GFAP autoimmunity is not rare. The clinical spectrum encompasses meningoencephalitis, myelitis, movement disorders, epilepsy and cerebellar ataxia. Coexisting neurological and systemic autoimmunity are relatively common. Immunotherapy is beneficial in most cases.
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http://dx.doi.org/10.1136/jnnp-2017-316583DOI Listing
February 2018