Publications by authors named "Luigi Zuliani"

28 Publications

  • Page 1 of 1

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

Efficacy of different rituximab therapeutic strategies in patients with neuromyelitis optica spectrum disorders.

Mult Scler Relat Disord 2019 Nov 4;36:101430. Epub 2019 Oct 4.

Ospedale Policlinico San Martino - IRCCS, Genoa, Italy; Department of Health Sciences (DISSAL), Section of Biostatistics, University of Genova, Genova, Italy. Electronic address:

Objective: To evaluate disease activity according to rituximab (RTX) induction and maintenance regimens in a multicenter real-life dataset of NMOSD patients.

Methods: This is an observational-retrospective multicentre study including patients with NMOSD treated with RTX in 21 Italian and 1 Swiss centers. Demographics, relapse rate and adverse events over the follow-up were summarized taking into account induction strategy (two-1 g infusions at a 15-day interval (IND-A) vs. 375 mg/m2/week infusions for one month (IND-B)) and maintenance therapy (regimen A (M-A) with fixed time-points infusions vs. regimen B (M-B) based on cytofluorimetric driven reinfusion regimens, the least further subdivided according to CD19+ B cells (M-B1) or CD27+ memory B cells (M-B2) monitoring).

Results: 131 subjects were enrolled, 127 patients completed the induction regimen and 119 patients had at least one follow-up visit and were included in the outcome analysis. Median follow-up was 1.7 years (range 0.1-11.6). Annualized relapse rate (ARR) was 1.7 in the year before RTX start and decreased to 0.19 during the follow-up. Both ARR and Time to first relapse (TTFR) analysis showed a trend toward an increased disease activity for IND-B and M-A. No patients with MT-B2 experienced relapses during the follow-up. Number of relapses in the year before RTX initiation and having received a previous treatment were significantly associated with higher ARR and reduced TTFR in the multivariate analysis.

Interpretation: We confirm RTX efficacy in NMOSD patients. Use of specific induction and maintenance protocols is warranted in order to foster RTX efficacy and to reduce costs and side effects.
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http://dx.doi.org/10.1016/j.msard.2019.101430DOI Listing
November 2019

LGI1 and CASPR2 autoimmunity in children: Systematic literature review and report of a young girl with Morvan syndrome.

J Neuroimmunol 2019 10 18;335:577008. Epub 2019 Jul 18.

Paediatric Neurology and Neurophysiology Unit, Department of Women's and Children's Health, University Hospital of Padua, Italy; Neuroimmunology Group, Paediatric Research Institute "Città della Speranza", Padova, Italy.

Leucine-rich glioma-inactivated protein 1 (LGI1) and contactin-associated protein-like 2 (CASPR2) neurological autoimmunity in adults has been associated with various clinical syndromes involving central, peripheral and autonomic nervous system, while data in children is limited. We perform the first systematic literature review on paediatric LGI1 and CASPR2 autoimmunity, with focus on clinical data, in order to contribute to the definition of clinical features of LGI1 and CASPR2 autoimmunity in paediatric age and favour early diagnosis. Additionally, we report the youngest-to-date case of Morvan syndrome. We identified 37 published paediatric cases of LGI1 and/or CASPR2 autoimmunity. Most frequent syndromes were encephalitis in LGI1-positive and isolated epilepsy in CASPR2-positive children, while syndromes with predominant peripheral symptoms were most frequent in double-positive children. With the limitations imposed by the low number of cases, differences to published adult cohorts included: absence of faciobrachial dystonic seizures and hyponatremia in patients with LGI1-positive encephalitis; slightly higher proportion of isolated epilepsy syndromes in CASPR2-positive patients; absence of tumour in the whole cohort.
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http://dx.doi.org/10.1016/j.jneuroim.2019.577008DOI Listing
October 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

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

Serum and CSF neurofilament light chain levels in antibody-mediated encephalitis.

J Neurol 2019 Jul 3;266(7):1643-1648. Epub 2019 Apr 3.

Neurology Unit, Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Policlinico GB Rossi, P.le LA Scuro 10, 37135, Verona, Italy.

Circulating and cerebrospinal fluid (CSF) neurofilament light chain (NfL) levels represent a reliable indicator of disease activity and axonal damage in different neuroinflammatory conditions. Recently, high CSF NfL levels have been detected in active autoimmune encephalitis, as opposed to significant lower levels after clinical improvement. The aim of the present study was to evaluate serum and CSF NfL concentration in patients with autoimmune encephalitis and to analyse the association between NfL levels and clinical, MRI, and CSF data. We retrospectively included 25 patients with neurological syndromes associated with autoantibodies to neuronal cell surface antigens and we collected clinical, MRI, CSF, and follow-up data. Using an ultrasensitive method (Simoa, Quanterix), we measured NfL levels in serum and CSF samples of all patients and in 25 sera of healthy controls. Serum NfL levels were higher in all cases, including 20 patients with inflammatory MRI/CSF features and 5 non-inflammatory cases (median 16.9 pg/ml, range 4.5-90) than in controls (median 6.9 pg/ml, range 2.7-12.8; p < 0.001). A correlation between serum and CSF NfL levels was found (r = 0.461, p = 0.023), whereas no significant association was observed between NfL levels and clinical, MRI/CSF inflammatory burden, and antibody type. In the 13 available follow-up samples, correlation between disease activity and NfL values was also observed. In conclusion, NfL levels are significantly increased in the serum of patients with antibody-mediated encephalitis, independently of the MRI/CSF inflammatory profile. These findings support the presence of ongoing axonal damage and suggest the co-occurrence of different mechanisms for neuronal/axonal involvement in antibody-associated CNS syndromes.
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http://dx.doi.org/10.1007/s00415-019-09306-zDOI Listing
July 2019

Clinical spectrum and IgG subclass analysis of anti-myelin oligodendrocyte glycoprotein antibody-associated syndromes: a multicenter study.

J Neurol 2017 Dec 23;264(12):2420-2430. Epub 2017 Oct 23.

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

Anti-myelin oligodendrocyte glycoprotein antibodies (MOG-Ab) recently emerged as a potential biomarker in patients with inflammatory demyelinating diseases of the central nervous system. We here compare the clinical and laboratory findings observed in a cohort of MOG-Ab seropositive and seronegative cases and describe IgG subclass analysis results. Consecutive serum samples referred to Verona University Neuropathology Laboratory for aquaporin-4 (AQP4)-Ab and/or MOG-Ab testing were analysed between March 2014 and May 2017. The presence of AQP4-Ab was determined using a cell-based assay. A live cell immunofluorescence assay was used for the detection of MOG-IgG and IgG subclass analysis. Among 454 analysed samples, 29 were excluded due to AQP4-Ab positivity or to the final demonstration of a disorder not compatible with MOG-Ab. We obtained clinical data in 154 out of 425 cases. Of these, 22 subjects resulted MOG-Ab positive. MOG-Ab positive patients were mainly characterised by the involvement of the optic nerve and/or spinal cord. Half of the cases presented relapses and the recovery was usually partial. Brain MRI was heterogeneous while short lesions were the prevalent observation on spinal cord MRI. MOG-Ab titre usually decreased in non-relapsing cases. In all MOG-IgG positive cases, we observed IgG1 antibodies, which were predominant in most subjects. IgG2 (5/22), IgG3 (9/22) and IgG4 (3/22) antibodies were also detectable. We confirm that MOG-Ab-related syndromes have distinct features in the spectrum of demyelinating conditions, and we describe the possible role of the different IgG subclasses in this condition.
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http://dx.doi.org/10.1007/s00415-017-8635-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5688213PMC
December 2017

Diagnostics of the neuromyelitis optica spectrum disorders (NMOSD).

Neurol Sci 2017 Oct;38(Suppl 2):231-236

AUO S. Luigi, Orbassano, Italy.

This document presents the guidelines for anti-aquaporin-4 (AQP4) antibody testing that has been developed following a consensus process built on questionnaire-based surveys, internet contacts, and discussions at workshops of the sponsoring Italian Association of Neuroimmunology (AINI) congresses. Essential clinical information on neuromyelitis optica spectrum disorders, indications and limits of anti-AQP4 antibody testing, instructions for result interpretation, and an agreed laboratory protocol (Appendix) are reported for the communicative community of neurologists and clinical pathologists.
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http://dx.doi.org/10.1007/s10072-017-3027-1DOI Listing
October 2017

Diagnostics of autoimmune encephalitis associated with antibodies against neuronal surface antigens.

Neurol Sci 2017 Oct;38(Suppl 2):225-229

Ospedale S.Antonio AULSS Euganea, Padua, Italy.

This document presents the guidelines for testing antibodies against neuronal surface antigens that have been developed following a consensus process built on questionnaire-based surveys, internet contacts, and discussions at workshops of the sponsoring Italian Association of Neuroimmunology (AINI) congresses. Essential clinical information on autoimmune encephalitis associated with antibodies against neuronal surface antigens, indications and limits of testing for such antibodies, instructions for result interpretation, and an agreed laboratory protocol (Appendix A) are reported for the communicative community of neurologists and clinical pathologists.
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http://dx.doi.org/10.1007/s10072-017-3032-4DOI Listing
October 2017

Diagnostics of paraneoplastic neurological syndromes.

Neurol Sci 2017 Oct;38(Suppl 2):237-242

Ospedale S. Antonio AULSS Euganea, Padua, Italy.

This document presents the guidelines for onconeural antibody testing that have been developed following a consensus process built on questionnaire-based surveys, internet contacts, and discussions at workshops of the sponsoring Italian Association of Neuroimmunology (AINI) congresses. Essential clinical information on paraneoplastic neurological syndromes, indications and limits of onconeural antibody testing, instructions for result interpretation, and an agreed laboratory protocol (Appendix) are reported for the communicative community of neurologists and clinical pathologists.
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http://dx.doi.org/10.1007/s10072-017-3031-5DOI Listing
October 2017

Voltage-Gated Potassium Channel Antibodies in Slow-Progression Motor Neuron Disease.

Neurodegener Dis 2017 7;17(1):59-62. Epub 2016 Oct 7.

Neurology Unit, Sant'Andrea Hospital, La Spezia, Italy.

Background: The spectrum of autoimmune neurological diseases associated with voltage-gated potassium channel (VGKC)-complex antibodies (Abs) ranges from peripheral nerve disorders to limbic encephalitis. Recently, low titers of VGKC-complex Abs have also been reported in neurodegenerative disorders, but their clinical relevance is unknown.

Objective: The aim of the study was to explore the prevalence of VGKC-complex Abs in slow-progression motor neuron disease (MND).

Methods: We compared 11 patients affected by slow-progression MND with 9 patients presenting typical progression illness. Sera were tested for VGKC-complex Abs by radioimmunoassay. The distribution of VGKC-complex Abs was analyzed with the Mann-Whitney U test.

Results: The statistical analysis showed a significant difference between the mean values in the study and control groups. A case with long-survival MND harboring VGKC-complex Abs and treated with intravenous immunoglobulins is described.

Conclusion: Although VGKC-complex Abs are not likely to be pathogenic, these results could reflect the coexistence of an immunological activation in patients with slow disease progression.
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http://dx.doi.org/10.1159/000447715DOI Listing
July 2017

Multicentre comparison of a diagnostic assay: aquaporin-4 antibodies in neuromyelitis optica.

J Neurol Neurosurg Psychiatry 2016 09 25;87(9):1005-15. Epub 2016 Apr 25.

Faculty of Medecine RTH Laennec, Lyon Neurosciences Research Centre, Neuro-inflammation and Neuro-oncology Team, Lyon, France.

Objective: Antibodies to cell surface central nervous system proteins help to diagnose conditions which often respond to immunotherapies. The assessment of antibody assays needs to reflect their clinical utility. We report the results of a multicentre study of aquaporin (AQP) 4 antibody (AQP4-Ab) assays in neuromyelitis optica spectrum disorders (NMOSD).

Methods: Coded samples from patients with neuromyelitis optica (NMO) or NMOSD (101) and controls (92) were tested at 15 European diagnostic centres using 21 assays including live (n=3) or fixed cell-based assays (n=10), flow cytometry (n=4), immunohistochemistry (n=3) and ELISA (n=1).

Results: Results of tests on 92 controls identified 12assays as highly specific (0-1 false-positive results). 32 samples from 50 (64%) NMO sera and 34 from 51 (67%) NMOSD sera were positive on at least two of the 12 highly specific assays, leaving 35 patients with seronegative NMO/spectrum disorder (SD). On the basis of a combination of clinical phenotype and the highly specific assays, 66 AQP4-Ab seropositive samples were used to establish the sensitivities (51.5-100%) of all 21 assays. The specificities (85.8-100%) were based on 92 control samples and 35 seronegative NMO/SD patient samples.

Conclusions: The cell-based assays were most sensitive and specific overall, but immunohistochemistry or flow cytometry could be equally accurate in specialist centres. Since patients with AQP4-Ab negative NMO/SD require different management, the use of both appropriate control samples and defined seronegative NMOSD samples is essential to evaluate these assays in a clinically meaningful way. The process described here can be applied to the evaluation of other antibody assays in the newly evolving field of autoimmune neurology.
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http://dx.doi.org/10.1136/jnnp-2015-312601DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5013123PMC
September 2016

Plasma exchange in pediatric anti-NMDAR encephalitis: A systematic review.

Brain Dev 2016 Aug 28;38(7):613-22. Epub 2016 Feb 28.

Pediatric Neurology Unit, Department of Woman's and Child's Health, University Hospital of Padua, Italy.

Objective: To clarify the most frequent modalities of use of plasma exchange (PE) in pediatric anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis and to establish the most effective association with other immunotherapies.

Methods: Systematic literature review on PE in pediatric anti-NMDAR encephalitis (2007-2015).

Results: Seventy-one articles were included (mostly retrospective), reporting a total of 242 subjects (73.2%, 93/127 females; median age at onset 12years, range 1-18). Median time to immunotherapy was 21days (range 0-190). In most cases, PE was given with steroids and IVIG (69.5%, 89/128), or steroids only (18%, 23/128); in a minority, it was associated with IVIG only (7%, 9/128), or was the only first-line treatment (5.5%, 7/128). In 54.5% (65/119), PE was the third treatment after steroids and IVIG, in 31.1% (37/119) the second after steroids or IVIG; only in 14.3% (17/119) was it the first treatment. Second-line immunotherapies were administered in 71.9% (100/139). Higher rates of full/substantial recovery at follow-up were observed with immunotherapy given ⩽30days from onset (69.4%, 25/36) compared to later (59.2%, 16/27), and when PE was associated with steroids (66.7%, 70/105) rather than not (46.7%, 7/15). Significant adverse reactions to PE were reported in 6 patients.

Conclusion: Our review disclosed a paucity of quality data on PE in pediatric anti-NMDAR encephalitis. PE use in this condition has been increasingly reported, most often with steroids and IVIG. Despite the limited number of patients, our data seem to confirm the trend towards a better outcome when PE was administered early, and when given with steroids.
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http://dx.doi.org/10.1016/j.braindev.2016.01.009DOI Listing
August 2016

Intravenous thrombolysis for acute stroke in a patient on treatment with rivaroxaban.

Neurol Sci 2015 Dec 26;36(12):2291-2. Epub 2015 Jul 26.

Clinica Neurologica II, Department of Neuroscience, University of Padova, via Facciolati 71, 35127, Padua, Italy.

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http://dx.doi.org/10.1007/s10072-015-2336-5DOI Listing
December 2015

Glycine receptor antibodies in 2 cases of new, adult-onset epilepsy.

Neurol Neuroimmunol Neuroinflamm 2014 Aug 3;1(2):e16. Epub 2014 Jul 3.

Department of Neurology (L.Z., M.Z., B.G.), Ospedale Ca'Foncello, Treviso, Italy; Magna Græcia University of Catanzaro and Regional Epilepsy Centre, Bianchi-Melacrino-Morelli Hospital (E.F., V.C., U.A.), Reggio Calabria, Italy; Ospedale di Arzignano ULSS5 (C.A., A.C., E.D.M., M.M.) Ovest Vicentino, Italy; and Nuffield Department of Clinical Neurosciences (M.I.L., P.W., M.W., A.V.), University of Oxford, UK.

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http://dx.doi.org/10.1212/NXI.0000000000000016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4202683PMC
August 2014

Longitudinal electroencephalographic (EEG) findings in pediatric anti-N-methyl-D-aspartate (anti-NMDA) receptor encephalitis: the Padua experience.

J Child Neurol 2015 Feb 5;30(2):238-45. Epub 2014 Jan 5.

Pediatric Neurology Unit, Department of Pediatrics, University of Padua, Italy

To contribute to characterize electroencephalographic (EEG) activity in pediatric anti-N-methyl-d-aspartate (anti-NMDA) receptor encephalitis, we reviewed electroclinical data of 5 children with anti-NMDA receptor encephalitis diagnosed in our department. We identified 4 longitudinal electroencephalographic phases: in the early phase, background activity was normal, with intermixed nonreactive slow waves; in the florid phase, background activity deteriorated with appearance of sequences of peculiar rhythmic theta and/or delta activity unrelated to clinical changes, unresponsive to stimuli and antiepileptic medications; in the recovery phase, these sequences decreased and reactive posterior rhythm re-emerged; electroencephalogram normalized 2 to 5 months after onset. In conclusion, in the presence of evocative clinical history, recognizing a characteristic longitudinal electroencephalographic activity could provide ancillary aspects addressing the diagnosis and the overall management of children with anti-N-methyl-d-aspartate receptor encephalitis; in particular, knowing that peculiar and recurrent paroxysmal nonepileptic rhythmic theta-delta patterns can occur in these patients could help distinguish paroxysmal epileptic and nonepileptic electroencephalographic activity.
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http://dx.doi.org/10.1177/0883073813515947DOI Listing
February 2015

Aquaporin-4 antibody neuromyelitis optica following anti-NMDA receptor encephalitis.

J Neurol 2013 Dec 20;260(12):3185-7. Epub 2013 Nov 20.

Department of Neurology, Ospedale Ca'Foncello, Azienda Unità Locale Socio-Sanitaria 9 Treviso, Piazza Ospedale 1, 31100, Treviso, Italy.

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http://dx.doi.org/10.1007/s00415-013-7182-xDOI Listing
December 2013

CACNA1H antibodies associated with headache with neurological deficits and cerebrospinal fluid lymphocytosis (HaNDL).

Cephalalgia 2013 Jan 30;33(2):123-9. Epub 2012 Oct 30.

Department of Neurology, Acibadem University School of Medicine, Turkey.

Background: Patients with the syndrome of headache with neurological deficits and lymphocytosis (HaNDL) typically present with recurrent and temporary attacks of neurological symptoms and cerebrospinal fluid lymphocytosis.

Aim And Methods: To identify potential HaNDL-associated antibodies directed against neuronal surface and/or synapse antigens, sera of four HaNDL patients and controls were screened with indirect immunohistochemistry, immunofluorescence, cell-based assay, radioimmunoassay, protein macroarray and enzyme-linked immunosorbent assay (ELISA).

Results: Although HaNDL sera did not yield antibodies to any of the well-characterized neuronal surface or synapse antigens, protein macroarray and ELISA studies showed high-titer antibodies to a subunit of the T-type voltage-gated calcium channel (VGCC), CACNA1H, in sera of two HaNDL patients.

Conclusion: Our results support the notion that ion channel autoimmunity might at least partially contribute to HaNDL pathogenesis and occurrence of neurological symptoms.
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http://dx.doi.org/10.1177/0333102412463494DOI Listing
January 2013

Morvan syndrome: clinical and serological observations in 29 cases.

Ann Neurol 2012 Aug 4;72(2):241-55. Epub 2012 Apr 4.

Neurosciences Group, Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, Oxford, United Kingdom.

Objective: A study was undertaken to describe the clinical spectrum, voltage-gated potassium channel (VGKC) complex antibody specificities, and central nervous system localization of antibody binding in 29 patients diagnosed with Morvan syndrome (MoS).

Methods: Clinical data were collected using questionnaires. Radioimmunoassay, cell-based assays, and mouse brain immunohistochemistry were used to characterize the serum antibodies.

Results: Neuromyotonia (100%), neuropsychiatric features (insomnia 89.7%, confusion 65.5%, amnesia 55.6%, hallucinations 51.9%), dysautonomia (hyperhidrosis 86.2%, cardiovascular 48.3%), and neuropathic pain (62.1%) were the most common manifestations. A total of 93.1% of MoS patients were male. VGKC-complex antibodies were present in 23 of 29 (79%) MoS patients at referral; 24 of 27 available sera had CASPR2, LGI1, or both CASPR2 and LGI1 antibodies (3 also with contactin-2 antibodies). CASPR2 antibodies were generally higher titer than LGI1 antibodies. Tumors (41.4%), mainly thymomas, were associated with CASPR2 antibodies and a poor prognosis, whereas LGI1 antibodies were associated with serum hyponatremia. In brain tissue regions including the hypothalamus, raphe, and locus coeruleus, commercial antibodies to LGI1 bound to neuronal cell bodies including the antidiuretic hormone-secreting and orexin-secreting hypothalamic neurons, whereas CASPR2 commercial antibodies bound more often to the neuropil. MoS antibodies bound similarly, but there was evidence of additional antibodies in some sera that were not adsorbed by LGI1- or CASPR2-expressing cells and bound to mouse Caspr2(-/-) tissue.

Interpretation: MoS is clinically distinct from other VGKC-complex antibody-associated conditions, and usually is associated with high-titer CASPR2 antibodies, often accompanied by lower-titer LGI1 antibodies. CASPR2 and LGI1 antibodies bind to multiple brain regions, which helps to explain the multifocal clinical features of this disease, but other antibodies are likely to play a role in some patients and need to be characterized in future studies.
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http://dx.doi.org/10.1002/ana.23577DOI Listing
August 2012

Central nervous system neuronal surface antibody associated syndromes: review and guidelines for recognition.

J Neurol Neurosurg Psychiatry 2012 Jun 24;83(6):638-45. Epub 2012 Mar 24.

Department of Neurology,Ospedale Ca'Foncello, Treviso,Italy.

The concept of antibody mediated CNS disorders is relatively recent. The classical CNS paraneoplastic neurological syndromes are thought to be T cell mediated, and the onconeural antibodies merely biomarkers for the presence of the tumour. Thus it was thought that antibodies rarely, if ever, cause CNS disease. Over the past 10 years, identification of autoimmune forms of encephalitis with antibodies against neuronal surface antigens, particularly the voltage gated potassium channel complex proteins or the glutamate N-methyl-D-aspartate receptor, have shown that CNS disorders, often without associated tumours, can be antibody mediated and benefit from immunomodulatory therapies. The clinical spectrum of these diseases is not yet fully explored, there may be others yet to be discovered and some types of more common disorders (eg, epilepsy or psychosis) may prove to have an autoimmune basis. Here, the known conditions associated with neuronal surface antibodies are briefly reviewed, some general aspects of these syndromes are considered and guidelines that could help in the recognition of further disorders are suggested.
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http://dx.doi.org/10.1136/jnnp-2011-301237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3348613PMC
June 2012

Contactin-associated protein-2 antibodies in non-paraneoplastic cerebellar ataxia.

J Neurol Neurosurg Psychiatry 2012 Apr 15;83(4):437-40. Epub 2012 Feb 15.

Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, Oxford University, Oxford, UK.

Background: Relatively few studies have searched for potentially pathogenic antibodies in non-paraneoplastic patients with cerebellar ataxia.

Methods And Results: We first screened sera from 52 idiopathic ataxia patients for binding of serum IgG antibodies to cerebellar neurons. One strong-binding serum was selected for immunoprecipitation and mass spectrometry, which resulted in the identification of contactin-associated protein 2 (CASPR2) as a major antigen. CASPR2 antibodies were then found by a cell-based assay in 9/88 (10%) ataxia patients, compared to 3/144 (2%) multiple sclerosis or dementia controls (p=0.011). CASPR2 is strongly expressed in the cerebellum, only partly in association with voltage-gated potassium channels.

Conclusions: Prospective studies are now needed to see whether identification of CASPR2 antibodies has relevance for the diagnosis and treatment of idiopathic cerebellar ataxia.
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http://dx.doi.org/10.1136/jnnp-2011-301506DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3297806PMC
April 2012

Anti-neuronal and stress-induced-phosphoprotein 1 antibodies in neuro-Behçet's disease.

J Neuroimmunol 2011 Oct 27;239(1-2):91-7. Epub 2011 Aug 27.

Department of Genetics, Institute for Experimental Medicine, Istanbul University, Istanbul, Turkey.

No disease-specific neuronal antibodies have so far been defined in neuro-Behçet's disease (NBD). Immunohistochemistry and immunocytochemistry studies showed antibodies to hippocampal and cerebellar molecular layers and the surface antigens of cultured hippocampal neurons in sera and/or cerebrospinal fluids (CSF) of 13 of 20 NBD and 6 of 20 BD patients but not in multiple sclerosis or headache controls. Screening with a protein macroarray led to identification of stress-induced-phosphoprotein-1 (STIP-1) as an antigenic target. High-titer STIP-1-antibodies were detected in 6 NBD patients' sera but not in controls. These results suggest that neuronal antibodies could be useful as diagnostic biomarkers in NBD.
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http://dx.doi.org/10.1016/j.jneuroim.2011.08.008DOI Listing
October 2011

Steroid-responsive recurrent limbic encephalitis associated with small cell lung cancer and neuropil antibodies.

Acta Neurol Belg 2011 Jun;111(2):139-42

Istanbul University, Istanbul Faculty of Medicine, Department of Neurology, Istanbul, Turkey.

Paraneoplastic limbic encephalitis (PLE) associated with small cell lung cancer (SCLC) often presents with antibodies to intracellular antigens and a poor outcome even after tumor resection and immunotherapy. We report a PLE patient presenting with generalized seizures, shortterm memory impairment and medial temporal lobe hyperintensity in MRI. Initial screening revealed significantly elevated thyroid antibody levels suggesting Hashimoto's encephalopathy. Following methylprednisolone treatment, her seizures ceased, MRI findings disappeared and memory impairment showed a partial resolution in 5 months. Two months later, she developed further generalized seizures. Chest X-ray showed a mass lesion, which was demonstrated by needle biopsy to be a small cell lung carcinoma (SCLC). The panel of onconeural antibodies including cell-membrane antigens was negative. However, the patient's serum and cerebrospinal fluid IgG, obtained during both exacerbations, immunolabeled cytoplasm and dendrites of Purkinje cells, cerebellar and hippocampal molecular layers, basal ganglia, thalamus, and the surface of cultured hippocampal neurons, in a manner distinct from previously identified neuropil antibodies associated with SCLC. These neuropil antibodies appear to be associated with a favorable response to treatment. Further studies are required for determination of the target antigen.
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June 2011

Antibodies to Kv1 potassium channel-complex proteins leucine-rich, glioma inactivated 1 protein and contactin-associated protein-2 in limbic encephalitis, Morvan's syndrome and acquired neuromyotonia.

Brain 2010 Sep 27;133(9):2734-48. Epub 2010 Jul 27.

Neurosciences Group, Department of Clinical Neurology, University of Oxford, John Radcliffe Hospital, Oxford, UK.

Antibodies that immunoprecipitate (125)I-alpha-dendrotoxin-labelled voltage-gated potassium channels extracted from mammalian brain tissue have been identified in patients with neuromyotonia, Morvan's syndrome, limbic encephalitis and a few cases of adult-onset epilepsy. These conditions often improve following immunomodulatory therapies. However, the proportions of the different syndromes, the numbers with associated tumours and the relationships with potassium channel subunit antibody specificities have been unclear. We documented the clinical phenotype and tumour associations in 96 potassium channel antibody positive patients (titres >400 pM). Five had thymomas and one had an endometrial adenocarcinoma. To define the antibody specificities, we looked for binding of serum antibodies and their effects on potassium channel currents using human embryonic kidney cells expressing the potassium channel subunits. Surprisingly, only three of the patients had antibodies directed against the potassium channel subunits. By contrast, we found antibodies to three proteins that are complexed with (125)I-alpha-dendrotoxin-labelled potassium channels in brain extracts: (i) contactin-associated protein-2 that is localized at the juxtaparanodes in myelinated axons; (ii) leucine-rich, glioma inactivated 1 protein that is most strongly expressed in the hippocampus; and (iii) Tag-1/contactin-2 that associates with contactin-associated protein-2. Antibodies to Kv1 subunits were found in three sera, to contactin-associated protein-2 in 19 sera, to leucine-rich, glioma inactivated 1 protein in 55 sera and to contactin-2 in five sera, four of which were also positive for the other antibodies. The remaining 18 sera were negative for potassium channel subunits and associated proteins by the methods employed. Of the 19 patients with contactin-associated protein-antibody-2, 10 had neuromyotonia or Morvan's syndrome, compared with only 3 of the 55 leucine-rich, glioma inactivated 1 protein-antibody positive patients (P < 0.0001), who predominantly had limbic encephalitis. The responses to immunomodulatory therapies, defined by changes in modified Rankin scores, were good except in the patients with tumours, who all had contactin-associated-2 protein antibodies. This study confirms that the majority of patients with high potassium channel antibodies have limbic encephalitis without tumours. The identification of leucine-rich, glioma inactivated 1 protein and contactin-associated protein-2 as the major targets of potassium channel antibodies, and their associations with different clinical features, begins to explain the diversity of these syndromes; furthermore, detection of contactin-associated protein-2 antibodies should help identify the risk of an underlying tumour and a poor prognosis in future patients.
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http://dx.doi.org/10.1093/brain/awq213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2929337PMC
September 2010

N-methyl-D-aspartate antibody encephalitis: temporal progression of clinical and paraclinical observations in a predominantly non-paraneoplastic disorder of both sexes.

Brain 2010 Jun;133(Pt 6):1655-67

Department of Clinical Neurology, L6 West Wing, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, UK.

Antibodies to the N-methyl-d-aspartate subtype of glutamate receptor have been associated with a newly-described encephalopathy that has been mainly identified in young females with ovarian tumours. However, the full clinical spectrum and treatment responses are not yet clear. We established a sensitive cell-based assay for detection of N-methyl-d-aspartate receptor antibodies in serum or cerebrospinal fluid, and a quantitative fluorescent immunoprecipitation assay for serial studies. Although there was marked intrathecal synthesis of N-methyl-d-aspartate receptor antibodies, the absolute levels of N-methyl-d-aspartate receptor antibodies were higher in serum than in cerebrospinal fluid. N-methyl-d-aspartate receptor antibodies were of the immunoglobulin G1 subclass and were able to activate complement on N-methyl d-aspartate receptor-expressing human embryonic kidney cells. From questionnaires returned on 44 N-methyl-d-aspartate receptor antibody-positive patients, we identified a high proportion without a detected tumour (35/44, 80%: follow-up 3.6-121 months, median 16 months). Among the latter were 15 adult females (43%), 10 adult males (29%) and 10 children (29%), with four in the first decade of life. Overall, there was a high proportion (29%) of non-Caucasians. Good clinical outcomes, as defined by reductions in modified Rankin scores, correlated with decreased N-methyl-d-aspartate receptor antibody levels and were associated with early (<40 days) administration of immunotherapies in non-paraneoplastic patients (P < 0.0001) and earlier tumour removal in paraneoplastic patients (P = 0.02). Ten patients (23%) who were first diagnosed during relapses had no evidence of tumours but had received minimal or no immunotherapy during earlier episodes. Temporal analysis of the onset of the neurological features suggested progression through two main stages. The time of onset of the early features, characterized by neuropsychiatric symptoms and seizures preceded by a median of 10-20 days, the onset of movement disorders, reduction in consciousness and dysautonomia. This temporal dichotomy was also seen in the timing of cerebrospinal fluid, electroencephalographic and in the rather infrequent cerebral imaging changes. Overall, our data support a model in which the early features are associated with cerebrospinal fluid lymphocytosis, and the later features with appearance of oligoclonal bands. The immunological events and neuronal mechanisms underlying these observations need to be explored further, but one possibility is that the early stage represents diffusion of serum antibodies into the cortical grey matter, whereas the later stage results from secondary expansion of the immunological repertoire within the intrathecal compartment acting on subcortical neurons. Four patients, who only had temporal lobe epilepsy without oligoclonal bands, may represent restriction to the first stage.
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http://dx.doi.org/10.1093/brain/awq113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2877907PMC
June 2010

Revised diagnostic criteria for neuromyelitis optica (NMO). Application in a series of suspected patients.

J Neurol 2007 Sep 2;254(9):1233-7. Epub 2007 Apr 2.

Service of Neurology, Hospital Clinic and Institut d'Investigació Biomèdica August Pi i Sunyer (IDIBAPS), University of Barcelona, Villarroel 170, Barcelona, 08036 Spain.

We analyzed neuromyelitis optica (NMO) IgG in the serum or CSF samples from 46 patients with suspected NMO (28) and limited forms of NMO (18). One hundred and fifteen samples from multiple sclerosis (MS) patients were included as controls. The final clinical diagnosis after follow-up was 16 NMO, 12 MS, 11 transverse myelitis (TM) and seven recurrent optic neuritis (RON). NMO-IgG was detected in 62.5% of NMO, 50% of the recurrent longitudinally extensive TM, 14.3% of the RON but in none of the MS patients. The authors then compared the newly revised diagnostic criteria for NMO with the criteria published in 1999, in the 28 patients with suspected NMO. The revised criteria had higher specificity, and positive and negative predictive value (83.3% vs. 25%; 87.5% vs. 62.5; 83.3% vs. 75%), but slightly lower sensitivity (87.5% vs. 93.7%). Our study confirms NMO-IgG as a highly specific marker of NMO, and the usefulness of the revised diagnostic criteria in predicting a diagnosis of NMO.
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http://dx.doi.org/10.1007/s00415-007-0509-8DOI Listing
September 2007