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      The protean manifestations of central nervous system IgG4-related hypertrophic pachymeningitis: a report of two cases

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          Abstract

          Background

          IgG4-related hypertrophic pachymeningitis is a relative newly recognized and rare manifestation of IgG4-related disease, an immune-mediated fibroinflammatory tumefactive disorder. Fewer than 80 patients have been reported in the literature, and it can mimic common neurosurgical conditions. We describe the clinical presentation of two patients that were initially considered to have a subdural collection, tuberculous meningitis, and a cervical spinal meningioma, but were eventually diagnosed with this disease.

          Case presentation

          Two ethnic Chinese men, 86 and 62 years old, experienced a 4-week history of headache. Both patients had a history of autoimmune disease, namely glomerulonephritis and Grave’s disease, respectively. Magnetic resonance brain imaging revealed diffuse dural thickening with the latter patient exhibiting homogeneous and intense gadolinium-contrast enhancement. Since the 86-year-old patient also had progressive bilateral visual loss, giant cell arteritis was suspected and a 2-week course of glucocorticoid therapy was prescribed, but his symptoms failed to improve. The 62-year-old patient also had accompanying low-grade fever and was treated empirically as having tuberculous meningitis although there were no confirmatory microbiological findings. This patient further developed right hemiparesis, and additional imaging revealed a C4/5 intradural-extramedullary contrast-enhancing lesion resembling a meningioma causing cord compression. Both patients underwent neurosurgical intervention with the former undergoing a dural biopsy and the latter having the cervical lesion resected. The final diagnosis was IgG4-related hypertrophic pachymeningitis with the hallmark histological features of lymphoplasmacytic infiltration of IgG4+ plasma cells, storiform fibrosis, and obliterative phlebitis. In addition, their serum IgG4 levels were elevated (i.e., > 135 mg/dL). Both patients received at least 6 months of glucocorticoid therapy while the latter also had azathioprine. Their symptoms improved significantly and recurrent lesions were not detected on follow-up imaging.

          Conclusions

          A high index of suspicion for this condition is suggested when a male patient with a history of autoimmune disease and compatible radiological findings, experiences subacute headache that is disproportionate to the degree of dural involvement. Neurosurgeons should consider early meningeal biopsy to establish a definitive histological diagnosis in order for early effective immunosuppressive treatment to be initiated and to avoid unnecessary morbidity.

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          Most cited references17

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          Consensus statement on the pathology of IgG4-related disease.

          IgG4-related disease is a newly recognized fibro-inflammatory condition characterized by several features: a tendency to form tumefactive lesions in multiple sites; a characteristic histopathological appearance; and-often but not always-elevated serum IgG4 concentrations. An international symposium on IgG4-related disease was held in Boston, MA, on 4-7 October 2011. The organizing committee comprising 35 IgG4-related disease experts from Japan, Korea, Hong Kong, the United Kingdom, Germany, Italy, Holland, Canada, and the United States, including the clinicians, pathologists, radiologists, and basic scientists. This group represents broad subspecialty expertise in pathology, rheumatology, gastroenterology, allergy, immunology, nephrology, pulmonary medicine, oncology, ophthalmology, and surgery. The histopathology of IgG4-related disease was a specific focus of the international symposium. The primary purpose of this statement is to provide practicing pathologists with a set of guidelines for the diagnosis of IgG4-related disease. The diagnosis of IgG4-related disease rests on the combined presence of the characteristic histopathological appearance and increased numbers of IgG4⁺ plasma cells. The critical histopathological features are a dense lymphoplasmacytic infiltrate, a storiform pattern of fibrosis, and obliterative phlebitis. We propose a terminology scheme for the diagnosis of IgG4-related disease that is based primarily on the morphological appearance on biopsy. Tissue IgG4 counts and IgG4:IgG ratios are secondary in importance. The guidelines proposed in this statement do not supplant careful clinicopathological correlation and sound clinical judgment. As the spectrum of this disease continues to expand, we advocate the use of strict criteria for accepting newly proposed entities or sites as components of the IgG4-related disease spectrum.
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            Rituximab therapy leads to rapid decline of serum IgG4 levels and prompt clinical improvement in IgG4-related systemic disease.

            Patients with IgG4-related systemic disease (IgG4-RSD) frequently show an incomplete response to treatment with glucocorticoids and traditional disease-modifying antirheumatic drugs (DMARDs). B lymphocyte depletion is a therapeutic strategy known to be effective for pemphigus vulgaris, an autoimmune condition mediated by IgG4 autoantibodies. This study was performed to assess the clinical and serologic responses to B lymphocyte depletion therapy with rituximab in patients with IgG4-RSD. Four patients with IgG4-RSD were treated with 2 intravenous doses (1 gram each) of rituximab. Clinical improvement was assessed by monitoring the tapering/discontinuation of prednisone and DMARDs, and by measuring the serum concentrations of B lymphocytes, immunoglobulins, and IgG subclasses before and after therapy. Clinical features of IgG4-RSD in these 4 patients included autoimmune pancreatitis, sclerosing cholangitis, lymphoplasmacytic aortitis, salivary gland involvement, orbital pseudotumor, and lacrimal gland enlargement. The 3 patients with elevated serum IgG and IgG4 levels at baseline had a mean IgG concentration of 2,003 mg/dl (normal range 600-1,500 mg/dl) and a mean IgG4 concentration of 2,160 mg/dl (normal range 8-140 mg/dl). Among these patients, the serum IgG4 concentrations declined by a mean of 65% within 2 months of rituximab administration. All 4 patients demonstrated striking clinical improvement within 1 month of the initiation of rituximab therapy, and tapering or discontinuation of their treatment with prednisone and DMARDs was achieved in all 4 patients. A decrease in IgG concentration was observed for the IgG4 subclass only. Treatment with rituximab led to prompt clinical and serologic improvement in these patients with refractory IgG4-RSD, and is a viable treatment option for this condition. The decline in serum IgG4 concentrations was substantially steeper than that of the autoantibody concentrations in immune-mediated conditions in which rituximab is effective, such as in rheumatoid arthritis. In addition, the reduction in IgG-subclass levels appeared to be specific for IgG4. The swift improvement of IgG4-RSD suggests that rituximab achieves its effects in IgG4-RSD by depleting the pool of B lymphocytes that replenish short-lived IgG4-secreting plasma cells.
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              Immunology of IgG4-related disease.

              Immunoglobulin G4-related disease (IgG4-RD) is a fibroinflammatory condition that derives its name from the characteristic finding of abundant IgG4(+) plasma cells in affected tissues, as well as the presence of elevated serum IgG4 concentrations in many patients. In contrast to fibrotic disorders, such as systemic sclerosis or idiopathic pulmonary fibrosis in which the tissues fibrosis has remained largely intractable to treatment, many IgG4-RD patients appear to have a condition in which the collagen deposition is reversible. The mechanisms underlying this peculiar feature remain unknown, but the remarkable efficacy of B cell depletion in these patients supports an important pathogenic role of B cell/T cell collaboration. In particular, aberrant T helper type 2 (Th2)/regulatory T cells sustained by putative autoreactive B cells have been proposed to drive collagen deposition through the production of profibrotic cytokines, but definitive demonstrations of this hypothesis are lacking. Indeed, a number of unsolved questions need to be addressed in order to fully understand the pathogenesis of IgG4-RD. These include the identification of an antigenic trigger(s), the implications (if any) of IgG4 antibodies for pathophysiology and the precise immunological mechanisms leading to fibrosis. Recent investigations have also raised the possibility that innate immunity might precede adaptive immunity, thus further complicating the pathological scenario. Here, we aim to review the most recent insights on the immunology of IgG4-RD, focusing on the relative contribution of innate and adaptive immune responses to the full pathological phenotype of this fibrotic condition. Clinical, histological and therapeutic features are also addressed.
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                Author and article information

                Contributors
                wym307@ha.org.hk
                Journal
                Chin Neurosurg J
                Chin Neurosurg J
                Chinese Neurosurgical Journal
                BioMed Central (London )
                2095-9370
                2057-4967
                4 February 2021
                4 February 2021
                2021
                : 7
                : 13
                Affiliations
                [1 ]GRID grid.415591.d, ISNI 0000 0004 1771 2899, Department of Neurosurgery, , Kwong Wah Hospital, ; Hong Kong, Hong Kong
                [2 ]Department of Internal Medicine, Caritas Medical Center, Hong Kong, Hong Kong
                [3 ]GRID grid.415591.d, ISNI 0000 0004 1771 2899, Department of Pathology, , Kwong Wah Hospital, ; 25 Waterloo Road, Yaumatei, Hong Kong, Hong Kong
                [4 ]GRID grid.415499.4, ISNI 0000 0004 1771 451X, Department of Neurosurgery, , Queen Elizabeth Hospital, ; Hong Kong, Hong Kong
                Author information
                http://orcid.org/0000-0002-7345-7904
                Article
                233
                10.1186/s41016-021-00233-5
                7860623
                33536053
                d63974b3-f252-41e1-aa10-a88e86a0100e
                © The Author(s) 2021

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                History
                : 1 March 2020
                : 7 January 2021
                Categories
                Case Report
                Custom metadata
                © The Author(s) 2021

                hypertrophic pachymeningitis,igg4-related disease,igg4-related sclerosing disease,central nervous system

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