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IgG4-Related Sclerosing Disease Causing Spinal Cord Compression: The First Reported Case in Literature

IgG4-Related Sclerosing Disease Causing Spinal Cord Compression: The First Reported Case in... Hindawi Case Reports in Immunology Volume 2019, Article ID 3618510, 7 pages https://doi.org/10.1155/2019/3618510 Case Report IgG4-Related Sclerosing Disease Causing Spinal Cord Compression: The First Reported Case in Literature 1 1 2 Nooraldin Merza , Ahmed Taha , John Lung , 3 4 Anthony W. Benderman, and Stephen E. Wright Department of Internal Medicine, Texas Tech University Health Sciences Center, Amarillo, TX, USA School of Medicine, Texas Tech University Health Sciences Center, Amarillo, TX, USA Department of Pathology, Veterans Affairs Medical Center, Amarillo, TX, USA Department of Hematology and Oncology Medicine, Veterans Affairs Medical Center, Amarillo, TX, USA Correspondence should be addressed to Nooraldin Merza; nooraldin.merza@ttuhsc.edu Received 15 April 2019; Accepted 4 June 2019; Published 18 June 2019 Academic Editor: Christian Drouet Copyright © 2019 Nooraldin Merza et al. is Th is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Immunoglobulin G4-related disease (IgG4-RD) is known for forming soft tissue mass lesions that may have compressive effects. It is an extremely rare disease that most frequently affects the pancreas causing autoimmune pancreatitis. It can also affect the gallbladder, salivary glands, and lacrimal glands causing respective organ-specific complications. In our report, we describe an IgG4-RD case that aec ff ted the spinal cord. A 60-year-old female presented with cervical spinal cord compression caused by IgG4-RD leading to several neurological deficits. Pathological examination of the excisional biopsy of the mass revealed dense lymphoplasmacytic cells infiltration and stromal fibrosis with IgG4 and plasma cells. eTh patient showed a dramatic response to the administration of systemic steroids with almost resolution of her neurological symptoms. is Th case highlights the first case in literature for IgG4-RD of the extradural tissue causing spinal compression. Hereby, we also demonstrate the dramatic response of IgG4-RD to the administration of systemic steroids as the patient had no recurrence aeft r 5 years of close follow-up, the longest reported period of follow-up reported in the literature to date. 1. Background spinal extradural tissue. We also demonstrate the dramatic response of the disease to the administration of systemic IgG4-related disease (IgG4-RD) is an extremely rare con- steroids as the patient had no recurrence after 5 years of close dition that can affect the pancreas, liver, salivary glands, follow-up. kidneys, lungs, central nervous system (CNS), and the heart. It is diagnosed based on the clinical presentation, hematolog- 2. Case Presentation ical data, and histopathological criteria. Very limited data is available about the CNS involvement in IgG4-RD because it A 60-year-old Caucasian female with medical history of is an extremely entity of the disease. obstructive sleep apnea, seasonal allergies, and osteoarthritis The manifestations of IgG4-RD when it affects the CNS who presented with weakness and numbness in all four depends typically on the location of the sclerotic mass. IgG4- extremities for 4 weeks. Initially, she had bilateral burning RD have been previously described in the literature as it pain at thetipsofher nfi gers andtoesthat progressed affected the pituitary gland and manifested as hypophysitis later to pin-and-needle paresthesia. The paresthesia was [1], the meninges and manifested as intracranial hypertrophic associated with low grade fever, bowel and bladder incon- pachymeningitis [2–4], or the brain parenchyma and pre- tinence, and vague dull neck pain. Her home medications sented as an inflammatory pseudotumor [5]. We, hereby, are acetaminophen, methocarbamol, and vitamin D supple- present the first case in literature to describe IgG4-RD of the mentation and she is allergic to aspirin, calcium, cortisone 2 Case Reports in Immunology Figure 1: T1-weighted o Th racic spine Magnetic Resonance Imaging showing diffuse extradural mass effect and enhancement from the T1 level to the T5 level anteriorly and to the T7 level posteriorly; most prominent at the T4-T5 level where there is marked spinal canal stenosis and mass effect upon the spinal cord. meperidine, phenytoin, gabapentin, ibuprofen, naproxen, Flow cytometry showed no immunophenotypic evidence of penicillin, salicylate, and sulfa drugs. She denied alcohol, non-Hodgkin’s lymphoma. tobacco, and illicit drug use. A laminectomy of T2 through T6 with excisional biopsy She has a past surgical history of 2 caesarian sections, of the epidural mass was performed. The histological exam- hemorrhoidectomy 31 years ago, and splenectomy after a ination of the extradural mass chronic inflammatory infil- remote vehicle accident 35 years ago. 5 months prior to this tration composed of lymphocytes, plasma cells, histiocytes, presentation, she underwent decompressive laminectomy for neutrophils, eosinophils, mast cells (Figure 2(a)). It also a C1-C5 cervical mass originating from the dorsal part of showed dense collagen deposition and fibrous tissue for- the cervical epidural space. The pathology report from the mation with focal germinal center formation (Figure 2(b)). resected mass revealed an inflammatory mass with extensive The classic storiform b fi rosis pattern was identiefi d in the collagenized background and a polymorphous-appearing cell biopsy material, but no phlebitis obliterans was identiefi d. infiltrates with a mixture of small lymphoid cells, plasmacy- KAPPA-ISH and lambda-ISH stains showed poly-clonality toid cells, very occasional eosinophils, and neutrophils. with an equal mixture of kappa positive and lambda positive At admission, she was alert and oriented and maintaining plasma cells. AFB and PAS stains show no mycobacterial or normal vital signs. Physical examination revealed that her fungal organisms. Immunohistochemistry was performed to neck was supple without lymphadenopathy but was signifi- evaluate the nature of the plasma cells, and it revealed an cant for neck tenderness. CNS examination revealed intact IgG4+/IgG+ ratio of 47% which was diagnostic for IgG4-RD. cranial nerves, 3/5 power strength and 2+ reflexes in upper Serum immunoglobulins were then checked and showed a extremities bilaterally, 2/5 strength and 3+ reflexes in lower total IgG of 17.65 g/L and elevated IgG4 fragment (2.07 g/L). extremities bilaterally, intact sensation in all four extremities, and no saddle anesthesia. The rest of the physical examination 3. Treatment/Follow Up was unremarkable. CBC, serum electrolytes, and blood chemistry were unre- After the surgery, the patient was discharged to an acute reha- markable. Magnetic resonance imaging (MRI) of the thoracic bilitation facility and then home but she continued to have spine showed T2-diffuse enhancement of extradural soft tis- quadriparesis, bowel and bladder incontinence, and limited sue mass with marked spinal canal stenosis, most prominent ambulation due to motor weakness and poor sensation. It was at the level of T4-T5 (Figure 1). Whole body positron emission almost 6 weeks until the final pathology report was received tomography (PET) scan showed no evidence of malignancy that confirmed the diagnosis of IgG4-RD, after which she was with no abnormality demonstrated in the spleen, liver, started on weekly pulse doses of oral dexamethasone 40 mg pancreas, salivary or adrenal glands. There were prominent split into 4 doses. Due to her corticosteroid allergy, she was bilateral jugular nodes with a standard uptake value of 2.6 on pretreated with 50 mg diphenhydramine 30 minutes before the right and 2.3 on the left. Lumbar puncture was performed the administration of dexamethasone. and cerebrospinal u fl id (CSF) cytological analysis revealed A dramatic clinical improvement was achieved, particu- mature lymphocytes and monocytes with no malignant cells. larly in her quadriparesis, aer ft the administration of systemic Case Reports in Immunology 3 (a) (b) Figure 2: Hematoxylin and Eosin (H&E) section of the epidural mass (200x magnification power for (a) and 100x magnification power for (b)) showing (a) chronic inflammatory infiltrates, predominantly mononuclear infiltrate, lymphoid hyperplasia (black arrow) and plasma cells emulating the classic storiform fibrosis pattern; no phlebitis obliterans were identified. (b) Dense collagen deposition and dense fibrous tissue formation (blue arrow) with focal germinal center formation (green arrows). corticosteroids. She was able to walk with walker within 3- The immunological mechanism of IgG4-related scleros- 4 months, then independently in about a year. Her hand ing disease is not completely understood. The prevailing Fine motor skills have improved tremendously and she is theory is the one that involves molecular mimicry based currently able to perform knitting. Her bowel and bladder on an immune response to self-antigens that results in an dysfunction also recovered completely. Over the course of increased regulatory T-cell and type 2 T-helper (TH2) cell 5 years of close follow up, she was kept on dexamethasone response that results in persistent inflammation [8]. IgG4 40 mg weekly preceded with diphenhydramine and she did antibodies bind to the epithelial lining of various organs and not experience any disease relapse. Annual follow-up MRI react with autoantigens causing the chronic inflammatory images have shown no disease recurrence and IgG levels reaction required to develop IgG4-RD [6]. However, the role remained suppressed for 5 years after the initial diagnosis of IgG4 in the pathogenesis is unclear, though higher levels of and treatment, the longest follow-up period for IgG4-RD IgG4 clearly correlate with disease severity [9]. reported. Serum IgG4 levels in relation to her compliance to IgG4-RD has been reported to aec ff t the CNS in lit- Dexamethasone is outlined in Figure 3. erature. The most common CNS manifestation of IgG4- RD is hypertrophic pachymeningitis where it lead to dural hypertrophy (and thickening) which will eventually lead to 4. Discussion symptoms such as headaches, cranial nerve dysfunctions, IgG4-RD is a rare disease which was rs fi t recognized as sensory and/or motor symptoms depending to the location, one of the causes of autoimmune and sclerosing cholangitis either intracranially or spinally [3]. Meningeal involvement of [6]. Subsequently, extra-pancreatic organ involvement was IgG4-RD might be confused with many differential diagnoses reported, these include the liver (e.g., sclerosing cholangitis including; Idiopathic hypertrophic pachymeningitis, inflam- when involving intrahepatic ducts), salivary glands (e.g., matory myob fi roblastic tumor, lymphoma, granulomatosis IgG4-sialadenitis and its variants), kidneys (e.g., interstitial with polyangiitis, giant-cell arteritis, Langerhans-cell histio- nephritis), lungs, and rarely the CNS or cardiac tissue [1]. cytosis, and sarcoidosis [10]. 17 cases were reported in the literature where IgG4-RD The diagnosis is so challenging, and in most cases, it ends up reported as an idiopathic inflammatory disorder. IgG4-RD hypertrophic pachymeningitis (Table 1) was causing nerve can also affect several organ systems making the differential compression symptoms lasting for months [11–13]. Our case diagnosis list too lengthy. report is thefirst casein literaturewhere IgG4-RD caused an The diagnosis of IgG4-RD relies on clinical, hemato- extradural mass complicated by spinal cord compression. logic, and histopathologic criteria. These include patients’ Unlike other systemic inafl mmatory diseases such as presentation with characteristic diffuse or localized masses sarcoidosis or systemic scleroderma, the immunological in single or multiple organs, elevated serum IgG4 levels manifestations of IgG4-RD are reversible with corticos- >1.35 g/L, marked fibrosis with lymphocytic and plasmacytic teroids. Once the diagnosis has been made, the disease often infiltration with positive immunohistochemical staining for dramatically responds to systemic corticosteroids. Some IgG4 on histological examination. IgG4+/IgG ratio >40% patients may not meet the histopathological criteria for IgG sclerosing disease, yet still, show clinical improvement with and >50 IgG4+ plasma cells/high power field are also very suggestive for IgG4-RD on pathological examination [7]. glucocorticoids [14]. A dramatic clinical improvement was 4 Case Reports in Immunology Table 1 Presence of Clinical Case Patient Age Gender extra-spinal Treatment Outcome presentation disease Bilateral lower extremity weakness, Chan et al. 2009 37 Male Not reported Not reported Not reported numbness, unsteady gait × 2 weeks Improved exam to ‘near normal’ aer ft Progressive initial surgery; bilateral lower progression 2 extremity months post op Choi et al. 2010 46 Female Not reported Steroids weakness and required second numbness × 2 resection (subtotal) weeks with full recovery; no recurrence at 8 months Lindstrom et al. Cord compression, Steroids; Radiation “Doing well” at 15 55 Male Not reported 2010 C3-C7 mass Therapy month follow up Bilateral hand Lindstrom et al. 63 Male numbness, C2-C3 Not reported Not reported Lost to follow-up mass Gradually Improvement of progressive and Slight swelling in symptoms and Tajima et al. 2012 64 Male worsening Steroids both kidneys-renal MRI findings at 3 dysphagia for 1 weeks month Weakness of Wallace et al. 2013 32 Male dorsum of right Not reported Not reported Lost to follow-up foot Diplegia of lower Able to ambulate at extremities and Ezzeldin et al. 2014 55 Male Not reported Steroids discharge (timing T4/T5 sensory not specified) level for 2 weeks Sudden weakness of bilateral lower Unchanged aeft r 2 Kim et al. 2014 52 Female extremities for 2 None Steroids months days; paraplegia, urinary retention Neck pain for 15 days, bilateral lower extremity Resolution of numb- Patient declined Gu et al. 2016 43 Male Not reported symptoms at 6 ness/weakness, testing months post-op bowel/bladder dysfunction for 4 days Progressive Marginal bilateral lower improvement in Radotra et al. 2016 50 Male extremity Not reported Steroids strength 7 months weakness for 6 post-op months back and left lower extremity pain for 1 Pain free at 6 Radotra et al. 2016 19 Male year; subtle knee Not reported Steroids months; stable extensor weakness exam bilaterally Case Reports in Immunology 5 Table 1: Continued. Presence of Clinical Case Patient Age Gender extra-spinal Treatment Outcome presentation disease Worsening low Recurrence and back pain for 2.5 progressive paresis years; bilateral later improved Ferreira et al. 2016 57 Female None Steroids lower extremity after third numbness and resection and weakness long-term steroids Diffuse numbness Recovered defeca- and weakness for 6 tion/urination at Steroids, Lu et al. 2016 55 Male months; Not reported 20 days; ambulated cyclophosphamide constipation and independently at 5 dysuria for 7 days months Rapidly progressive severe Right lung back pain at T6 Near normal lower associated with Rumalla et al. 2017 50 Male level for 3 months; Steroids extremity strength adjacent vertebral acute onset 2 months post-op involvement paraplegia, T6 sensory level Worsening neck pain and bilateral Improving strength upper extremity Steroids, Williams et al. 2017 46 Female Not reported at 6 month post-op paresthesias and azathioprine visit weakness for 4 months Intermittent thoracic spine pain for 3 years, Walking progressive trunk independently with numbness and Bridges et al. 2017 68 Male None Steroids resolution of pain bilateral lower at 3 months extremity post-op numbness for 6 months, dysequilibrium Lower back pain, neurogenic claudication, right Asymptomatic at 1 Winkel et al. 2018 48 Female lower extremity None Steroids year follow-up radiculopathy, extradural mass L2-L3 level achieved in our patient, particularly in her quadriparesis, of corticosteroids in a pulsatile manner i.e. Dexamethasone after the administration of systemic corticosteroids. She was 40 mg/week in our patient has been shown similar outcomes, able to walk independently in just a few months. Her bowel but with more acceptable side-effect prolfi e [18]. Intermittent and bladder dysfunction also recovered completely, but they glucocorticoid administration at a high dose has a strong took little longer, i.e. 6-9 months. effect due to 100% saturation of cytosolic receptors; however, Currently, there is no consensus about the dose or dura- the eeff ct would last only for a short period because receptor tion of systemic corticosteroid therapy for IgG4-RD. Some occupation rapidly reverts to the original value unless a new physicians treat with systemic steroids temporarily for several dose is given [18]. months, while some patients in Japan get corticosteroids Therefore, a single high dose is unlikely to have sustained permanently [15]. We elected to keep our patient on life- effect. Overall, the effects of corticosteroid pulses appear to long steroids due to the severe symptoms at initial presen- include downregulation of activation of immune cells and tation, the significant disease morbidity, and the immediate proinflammatory cytokine production, leading to reduced elevation of IgG4 levels at the time that Dexamethasone was expression of adhesion molecules and reduced movement briefly held (Figure 3) [16, 17]. The life-long administration of neutrophils into sites of inflammation. These effects are 2/19 11/18 7/18 2/18 11/17 8/17 5/17 2/17 11/16 9/16 7/16 4/16 1/16 7/15 5/15 1/15 11/14 7/14 4/14 1/14 12/13 11/13 6 Case Reports in Immunology IgG4 level and Dexamethasone trend 45 2.5 1.5 0.5 0 0 TIME (MM/YY) Dexamethasone levels (mg/week) Serum IgG4 levels (g/L) Figure 3: Double y-axis chart showing the IgG4 trends (orange line) and the Dexamethasone compliance (blue line) over time. Please note the immediate rise in serum IgG4 levels following the fall in Dexamethasone dosage. qualitatively similar to those seen with anti-TNF-alpha ther- review of the literature,” Journal of Korean Neurosurgical Society, vol. 55, no. 5, pp. 300–302, 2014. apy [19]. Corticosteroids are currently recommended orally [4] Y. Sireesha,M.Uppin, S. Ganti etal.,“A series of biopsy- for IgG4-RD according to the international consensus guid- proven patients with immunoglobulin G4-related neurological ance [20]. Other routes of glucocorticoids administration, disease,” Annals of Indian Academy of Neurology,vol. 22,no.1, such as intrathecal and epidural routes of administration pp.73–78,2019. have risks of arachnoiditis, spinal cord injury, and spinal [5] B. Baptista, A. Casian, H. Gunawardena, D. D’Cruz, and C. infection [17]. More recently, experiments in mice indicate M. Rice, “Neurological manifestations of IgG4-related disease,” that glucocorticoids may have a similar role in B lymphocytes Current Treatment Options in Neurology,vol.19,no.4,p.14,2017. [16, 21–24]; nonetheless, physicians are currently challenged [6] J. H. Stone, Y. Zen, and V. Deshpande, “IgG4-Related disease,” with the choice of which glucocorticoids to use, what dose, e New England Journal of Medicine,vol. 366,no. 6,pp.539– and for how long to use them. 551, 2012. [7] S.O.Nambiar and T.I.Oliver, IgG Related Disease (IgG-RD), StatPearls Publishing, Treasure Island, FL, USA, 2018. 5. Conclusions [8] A. Tanaka, M. Moriyama, H. Nakashima et al., “2Th and regula- Though extremely rare, spinal cord compression could be the tory immune reactions contribute to IgG4 production and the initial presentation of IgG4-RD. The IgG4-RD disease process initiation of Mikulicz disease,” Arthritis & Rheumatology,vol. can be rapidly ameliorated with systemic corticosteroid use, 64, no. 1, pp. 254–263, 2012. [9] E. Della-Torre, M. Lanzillotta, and C. Doglioni, “Immunology even in the late stages of the disease. Early diagnosis of this of IgG4-related disease,” Clinical & Experimental Immunology, rare IgG4-RD disease entity, extradural spinal cord compres- vol. 181, no. 2, pp. 191–206, 2015. sion, and early treatment with systemic corticosteroids can [10] T. Kamisawa,Y. Zen,S. Pillai,and J. H.Stone, “IgG4-related decrease the disease mortality and morbidity and improve disease,” e Lancet,vol.385, no.9976,Article ID 1460, pp. patients’ quality of life [25]. 1460–1471, 2015. [11] K. J. Bridges, C. H. DeDeaux, and K. D. an Th , “IgG4-related Conflicts of Interest disease presenting as intradural extramedullary lesion: a case report and review of the literature,” British Journal of Neuro- The authors declare that they have no conflicts of interest. surgery,pp. 1–7, 2017. [12] S. H. Kim, Y. Kang, S. H. Oh, S. Paik, and J. S. Kim, “Paraplegia in a patient with IgG4-related sclerosing disease: A case report,” References Annals of Rehabilitation Medicine,vol.38,no. 6,pp.856–860, [1] M.Divatia,S.A.Kim, and J. Y. Ro, “IgG4-related sclerosing [13] M.Winkel,C. Lawton,O. Sanusi,C.Horbinski, N.Dahdaleh, disease, an emerging entity: A review of a multi-system disease,” and Z. Smith, “Neuro-surgical considerations for treating IgG4- Yonsei Medical Journal,vol.53,no. 1, pp.15–34,2012. related disease with rare spinal epidural compression,” Surgical [2] S.-K. Chan, W. Cheuk, K.-T. Chan, and J. K. C. Chan, “IgG4- Neurology International, vol.9,no. 1, p.209, 2018. related sclerosing pachymeningitis: a previously unrecognized [14] M. Ezzeldin, A. Shawagfeh, V. Schnadig, R. Smith, and X. form of central nervous system involvement in IgG4-related Fang, “Spinal cord compression associated with a systemic IgG4 sclerosing disease,” e American Journal of Surgical Pathology, disease (P3.025),” Neurology, vol. 82, 10 Supplement, 2014. vol.33,no. 8, pp.1249–1252, 2009. [15] A. Ghazale, S. T. Chari, L. Zhang et al., “Immunoglobulin G4- [3] S.Takeuchi,H.Osada,S.Seno,andH.Nawashiro,“IgG4-related associated cholangitis: clinical profile and response to therapy,” intracranial hypertrophic pachymeningitis: A case report and Gastroenterology,vol.134,no. 3,pp.706–715, 2008. Dexamethasone level (mg/week) Serum IgG4 level (g/L) Case Reports in Immunology 7 [16] M. A. Pufall, “Glucocorticoids and cancer,” Advances in Experi- mental Medicine and Biology, vol. 872, pp. 315–333, 2015. [17] D.A.Nelson and W.M.Landau, “Intraspinal steroids:History, efficacy, accidentality, and controversy with review of United States Food and Drug Administration reports,” Journal of Neurology, Neurosurgery & Psychiatry,vol.70, no. 4,pp. 433– 443, 2001. [18] B. P. Schimmer and K. L. Parker, “Adrenocorticotropic hor- mones; adrenocortical steroids and their synthetic analogs; inhibitors of the synthesis and actions of adrenocortical hor- mones,” in Goodman & Gilmans e Pharmacological Basis of erapeutics,L.L.Brunton, J. S. Lazo,and K.L.Parker,Eds., pp. 1587–1612, McGraw-Hill, New York, NY, USA, 11th edition, [19] M. D. Smith, M. J. Ahern, P. J. Roberts-o Th mson, and P. P. Youssef, “Similar effects of pulse corticosteroid and tumor necrosis factor alpha blockade in rheumatoid arthritis: com- ment on the article by Taylor et al,” Arthritis & Rheumatology, vol. 44,no. 1, pp.245-246, 2001. [20] A. Khosroshahi, Z. S. Wallace, J. L. Crowe et al., “International consensus guidance statement on the management and treat- ment of IgG4-related disease,” Arthritis & Rheumatology,vol. 67,no.7,pp.1688–1699, 2015. [21] C.Ploner, S.Schmidt,E.Presul et al.,“Glucocorticoid-induced apoptosis and glucocorticoid resistance in acute lymphoblastic leukemia,” e Journal of Steroid Biochemistry and Molecular Biology,vol.93,no.2-5, pp. 153–160, 2005. [22] A.L.Gruver-Yates,M. A.Quinn, and J. A.Cidlowski,“Analysis of glucocorticoid receptors and their apoptotic response to dexamethasone in male murine B cells during development,” Endocrinology,vol.155, no.2,pp.463–474, 2014. [23] G. I. Lambrou, S. Vlahopoulos, C. Papathanasiou et al., “Pred- nisolone exerts late mitogenic and biphasic effects on resistant acute lymphoblastic leukemia cells: Relation to early gene expression,” Leukemia Research, vol.33,no.12,pp. 1684–1695, [24] L.Bonapace, B.C.Bornhauser, M. Schmitzetal., “Induction of autophagy-dependent necroptosis is required for childhood acute lymphoblastic leukemia cells to overcome glucocorticoid resistance,” e Journal of Clinical Investigation, vol.120,no. 4, pp. 1310–1323, 2010. [25] M. Ezzeldin, A.Shawagfeh,V.Schnadig, R. G. Smith, and X. Fang, “Hypertrophic spinal pachymeningitis: Idiopathic vs. IgG4-related,” Journal of the Neurological Sciences,vol.347, no. 1-2, pp. 398–400, 2014. 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IgG4-Related Sclerosing Disease Causing Spinal Cord Compression: The First Reported Case in Literature

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Abstract

Hindawi Case Reports in Immunology Volume 2019, Article ID 3618510, 7 pages https://doi.org/10.1155/2019/3618510 Case Report IgG4-Related Sclerosing Disease Causing Spinal Cord Compression: The First Reported Case in Literature 1 1 2 Nooraldin Merza , Ahmed Taha , John Lung , 3 4 Anthony W. Benderman, and Stephen E. Wright Department of Internal Medicine, Texas Tech University Health Sciences Center, Amarillo, TX, USA School of Medicine, Texas Tech University Health Sciences Center, Amarillo, TX, USA Department of Pathology, Veterans Affairs Medical Center, Amarillo, TX, USA Department of Hematology and Oncology Medicine, Veterans Affairs Medical Center, Amarillo, TX, USA Correspondence should be addressed to Nooraldin Merza; nooraldin.merza@ttuhsc.edu Received 15 April 2019; Accepted 4 June 2019; Published 18 June 2019 Academic Editor: Christian Drouet Copyright © 2019 Nooraldin Merza et al. is Th is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Immunoglobulin G4-related disease (IgG4-RD) is known for forming soft tissue mass lesions that may have compressive effects. It is an extremely rare disease that most frequently affects the pancreas causing autoimmune pancreatitis. It can also affect the gallbladder, salivary glands, and lacrimal glands causing respective organ-specific complications. In our report, we describe an IgG4-RD case that aec ff ted the spinal cord. A 60-year-old female presented with cervical spinal cord compression caused by IgG4-RD leading to several neurological deficits. Pathological examination of the excisional biopsy of the mass revealed dense lymphoplasmacytic cells infiltration and stromal fibrosis with IgG4 and plasma cells. eTh patient showed a dramatic response to the administration of systemic steroids with almost resolution of her neurological symptoms. is Th case highlights the first case in literature for IgG4-RD of the extradural tissue causing spinal compression. Hereby, we also demonstrate the dramatic response of IgG4-RD to the administration of systemic steroids as the patient had no recurrence aeft r 5 years of close follow-up, the longest reported period of follow-up reported in the literature to date. 1. Background spinal extradural tissue. We also demonstrate the dramatic response of the disease to the administration of systemic IgG4-related disease (IgG4-RD) is an extremely rare con- steroids as the patient had no recurrence after 5 years of close dition that can affect the pancreas, liver, salivary glands, follow-up. kidneys, lungs, central nervous system (CNS), and the heart. It is diagnosed based on the clinical presentation, hematolog- 2. Case Presentation ical data, and histopathological criteria. Very limited data is available about the CNS involvement in IgG4-RD because it A 60-year-old Caucasian female with medical history of is an extremely entity of the disease. obstructive sleep apnea, seasonal allergies, and osteoarthritis The manifestations of IgG4-RD when it affects the CNS who presented with weakness and numbness in all four depends typically on the location of the sclerotic mass. IgG4- extremities for 4 weeks. Initially, she had bilateral burning RD have been previously described in the literature as it pain at thetipsofher nfi gers andtoesthat progressed affected the pituitary gland and manifested as hypophysitis later to pin-and-needle paresthesia. The paresthesia was [1], the meninges and manifested as intracranial hypertrophic associated with low grade fever, bowel and bladder incon- pachymeningitis [2–4], or the brain parenchyma and pre- tinence, and vague dull neck pain. Her home medications sented as an inflammatory pseudotumor [5]. We, hereby, are acetaminophen, methocarbamol, and vitamin D supple- present the first case in literature to describe IgG4-RD of the mentation and she is allergic to aspirin, calcium, cortisone 2 Case Reports in Immunology Figure 1: T1-weighted o Th racic spine Magnetic Resonance Imaging showing diffuse extradural mass effect and enhancement from the T1 level to the T5 level anteriorly and to the T7 level posteriorly; most prominent at the T4-T5 level where there is marked spinal canal stenosis and mass effect upon the spinal cord. meperidine, phenytoin, gabapentin, ibuprofen, naproxen, Flow cytometry showed no immunophenotypic evidence of penicillin, salicylate, and sulfa drugs. She denied alcohol, non-Hodgkin’s lymphoma. tobacco, and illicit drug use. A laminectomy of T2 through T6 with excisional biopsy She has a past surgical history of 2 caesarian sections, of the epidural mass was performed. The histological exam- hemorrhoidectomy 31 years ago, and splenectomy after a ination of the extradural mass chronic inflammatory infil- remote vehicle accident 35 years ago. 5 months prior to this tration composed of lymphocytes, plasma cells, histiocytes, presentation, she underwent decompressive laminectomy for neutrophils, eosinophils, mast cells (Figure 2(a)). It also a C1-C5 cervical mass originating from the dorsal part of showed dense collagen deposition and fibrous tissue for- the cervical epidural space. The pathology report from the mation with focal germinal center formation (Figure 2(b)). resected mass revealed an inflammatory mass with extensive The classic storiform b fi rosis pattern was identiefi d in the collagenized background and a polymorphous-appearing cell biopsy material, but no phlebitis obliterans was identiefi d. infiltrates with a mixture of small lymphoid cells, plasmacy- KAPPA-ISH and lambda-ISH stains showed poly-clonality toid cells, very occasional eosinophils, and neutrophils. with an equal mixture of kappa positive and lambda positive At admission, she was alert and oriented and maintaining plasma cells. AFB and PAS stains show no mycobacterial or normal vital signs. Physical examination revealed that her fungal organisms. Immunohistochemistry was performed to neck was supple without lymphadenopathy but was signifi- evaluate the nature of the plasma cells, and it revealed an cant for neck tenderness. CNS examination revealed intact IgG4+/IgG+ ratio of 47% which was diagnostic for IgG4-RD. cranial nerves, 3/5 power strength and 2+ reflexes in upper Serum immunoglobulins were then checked and showed a extremities bilaterally, 2/5 strength and 3+ reflexes in lower total IgG of 17.65 g/L and elevated IgG4 fragment (2.07 g/L). extremities bilaterally, intact sensation in all four extremities, and no saddle anesthesia. The rest of the physical examination 3. Treatment/Follow Up was unremarkable. CBC, serum electrolytes, and blood chemistry were unre- After the surgery, the patient was discharged to an acute reha- markable. Magnetic resonance imaging (MRI) of the thoracic bilitation facility and then home but she continued to have spine showed T2-diffuse enhancement of extradural soft tis- quadriparesis, bowel and bladder incontinence, and limited sue mass with marked spinal canal stenosis, most prominent ambulation due to motor weakness and poor sensation. It was at the level of T4-T5 (Figure 1). Whole body positron emission almost 6 weeks until the final pathology report was received tomography (PET) scan showed no evidence of malignancy that confirmed the diagnosis of IgG4-RD, after which she was with no abnormality demonstrated in the spleen, liver, started on weekly pulse doses of oral dexamethasone 40 mg pancreas, salivary or adrenal glands. There were prominent split into 4 doses. Due to her corticosteroid allergy, she was bilateral jugular nodes with a standard uptake value of 2.6 on pretreated with 50 mg diphenhydramine 30 minutes before the right and 2.3 on the left. Lumbar puncture was performed the administration of dexamethasone. and cerebrospinal u fl id (CSF) cytological analysis revealed A dramatic clinical improvement was achieved, particu- mature lymphocytes and monocytes with no malignant cells. larly in her quadriparesis, aer ft the administration of systemic Case Reports in Immunology 3 (a) (b) Figure 2: Hematoxylin and Eosin (H&E) section of the epidural mass (200x magnification power for (a) and 100x magnification power for (b)) showing (a) chronic inflammatory infiltrates, predominantly mononuclear infiltrate, lymphoid hyperplasia (black arrow) and plasma cells emulating the classic storiform fibrosis pattern; no phlebitis obliterans were identified. (b) Dense collagen deposition and dense fibrous tissue formation (blue arrow) with focal germinal center formation (green arrows). corticosteroids. She was able to walk with walker within 3- The immunological mechanism of IgG4-related scleros- 4 months, then independently in about a year. Her hand ing disease is not completely understood. The prevailing Fine motor skills have improved tremendously and she is theory is the one that involves molecular mimicry based currently able to perform knitting. Her bowel and bladder on an immune response to self-antigens that results in an dysfunction also recovered completely. Over the course of increased regulatory T-cell and type 2 T-helper (TH2) cell 5 years of close follow up, she was kept on dexamethasone response that results in persistent inflammation [8]. IgG4 40 mg weekly preceded with diphenhydramine and she did antibodies bind to the epithelial lining of various organs and not experience any disease relapse. Annual follow-up MRI react with autoantigens causing the chronic inflammatory images have shown no disease recurrence and IgG levels reaction required to develop IgG4-RD [6]. However, the role remained suppressed for 5 years after the initial diagnosis of IgG4 in the pathogenesis is unclear, though higher levels of and treatment, the longest follow-up period for IgG4-RD IgG4 clearly correlate with disease severity [9]. reported. Serum IgG4 levels in relation to her compliance to IgG4-RD has been reported to aec ff t the CNS in lit- Dexamethasone is outlined in Figure 3. erature. The most common CNS manifestation of IgG4- RD is hypertrophic pachymeningitis where it lead to dural hypertrophy (and thickening) which will eventually lead to 4. Discussion symptoms such as headaches, cranial nerve dysfunctions, IgG4-RD is a rare disease which was rs fi t recognized as sensory and/or motor symptoms depending to the location, one of the causes of autoimmune and sclerosing cholangitis either intracranially or spinally [3]. Meningeal involvement of [6]. Subsequently, extra-pancreatic organ involvement was IgG4-RD might be confused with many differential diagnoses reported, these include the liver (e.g., sclerosing cholangitis including; Idiopathic hypertrophic pachymeningitis, inflam- when involving intrahepatic ducts), salivary glands (e.g., matory myob fi roblastic tumor, lymphoma, granulomatosis IgG4-sialadenitis and its variants), kidneys (e.g., interstitial with polyangiitis, giant-cell arteritis, Langerhans-cell histio- nephritis), lungs, and rarely the CNS or cardiac tissue [1]. cytosis, and sarcoidosis [10]. 17 cases were reported in the literature where IgG4-RD The diagnosis is so challenging, and in most cases, it ends up reported as an idiopathic inflammatory disorder. IgG4-RD hypertrophic pachymeningitis (Table 1) was causing nerve can also affect several organ systems making the differential compression symptoms lasting for months [11–13]. Our case diagnosis list too lengthy. report is thefirst casein literaturewhere IgG4-RD caused an The diagnosis of IgG4-RD relies on clinical, hemato- extradural mass complicated by spinal cord compression. logic, and histopathologic criteria. These include patients’ Unlike other systemic inafl mmatory diseases such as presentation with characteristic diffuse or localized masses sarcoidosis or systemic scleroderma, the immunological in single or multiple organs, elevated serum IgG4 levels manifestations of IgG4-RD are reversible with corticos- >1.35 g/L, marked fibrosis with lymphocytic and plasmacytic teroids. Once the diagnosis has been made, the disease often infiltration with positive immunohistochemical staining for dramatically responds to systemic corticosteroids. Some IgG4 on histological examination. IgG4+/IgG ratio >40% patients may not meet the histopathological criteria for IgG sclerosing disease, yet still, show clinical improvement with and >50 IgG4+ plasma cells/high power field are also very suggestive for IgG4-RD on pathological examination [7]. glucocorticoids [14]. A dramatic clinical improvement was 4 Case Reports in Immunology Table 1 Presence of Clinical Case Patient Age Gender extra-spinal Treatment Outcome presentation disease Bilateral lower extremity weakness, Chan et al. 2009 37 Male Not reported Not reported Not reported numbness, unsteady gait × 2 weeks Improved exam to ‘near normal’ aer ft Progressive initial surgery; bilateral lower progression 2 extremity months post op Choi et al. 2010 46 Female Not reported Steroids weakness and required second numbness × 2 resection (subtotal) weeks with full recovery; no recurrence at 8 months Lindstrom et al. Cord compression, Steroids; Radiation “Doing well” at 15 55 Male Not reported 2010 C3-C7 mass Therapy month follow up Bilateral hand Lindstrom et al. 63 Male numbness, C2-C3 Not reported Not reported Lost to follow-up mass Gradually Improvement of progressive and Slight swelling in symptoms and Tajima et al. 2012 64 Male worsening Steroids both kidneys-renal MRI findings at 3 dysphagia for 1 weeks month Weakness of Wallace et al. 2013 32 Male dorsum of right Not reported Not reported Lost to follow-up foot Diplegia of lower Able to ambulate at extremities and Ezzeldin et al. 2014 55 Male Not reported Steroids discharge (timing T4/T5 sensory not specified) level for 2 weeks Sudden weakness of bilateral lower Unchanged aeft r 2 Kim et al. 2014 52 Female extremities for 2 None Steroids months days; paraplegia, urinary retention Neck pain for 15 days, bilateral lower extremity Resolution of numb- Patient declined Gu et al. 2016 43 Male Not reported symptoms at 6 ness/weakness, testing months post-op bowel/bladder dysfunction for 4 days Progressive Marginal bilateral lower improvement in Radotra et al. 2016 50 Male extremity Not reported Steroids strength 7 months weakness for 6 post-op months back and left lower extremity pain for 1 Pain free at 6 Radotra et al. 2016 19 Male year; subtle knee Not reported Steroids months; stable extensor weakness exam bilaterally Case Reports in Immunology 5 Table 1: Continued. Presence of Clinical Case Patient Age Gender extra-spinal Treatment Outcome presentation disease Worsening low Recurrence and back pain for 2.5 progressive paresis years; bilateral later improved Ferreira et al. 2016 57 Female None Steroids lower extremity after third numbness and resection and weakness long-term steroids Diffuse numbness Recovered defeca- and weakness for 6 tion/urination at Steroids, Lu et al. 2016 55 Male months; Not reported 20 days; ambulated cyclophosphamide constipation and independently at 5 dysuria for 7 days months Rapidly progressive severe Right lung back pain at T6 Near normal lower associated with Rumalla et al. 2017 50 Male level for 3 months; Steroids extremity strength adjacent vertebral acute onset 2 months post-op involvement paraplegia, T6 sensory level Worsening neck pain and bilateral Improving strength upper extremity Steroids, Williams et al. 2017 46 Female Not reported at 6 month post-op paresthesias and azathioprine visit weakness for 4 months Intermittent thoracic spine pain for 3 years, Walking progressive trunk independently with numbness and Bridges et al. 2017 68 Male None Steroids resolution of pain bilateral lower at 3 months extremity post-op numbness for 6 months, dysequilibrium Lower back pain, neurogenic claudication, right Asymptomatic at 1 Winkel et al. 2018 48 Female lower extremity None Steroids year follow-up radiculopathy, extradural mass L2-L3 level achieved in our patient, particularly in her quadriparesis, of corticosteroids in a pulsatile manner i.e. Dexamethasone after the administration of systemic corticosteroids. She was 40 mg/week in our patient has been shown similar outcomes, able to walk independently in just a few months. Her bowel but with more acceptable side-effect prolfi e [18]. Intermittent and bladder dysfunction also recovered completely, but they glucocorticoid administration at a high dose has a strong took little longer, i.e. 6-9 months. effect due to 100% saturation of cytosolic receptors; however, Currently, there is no consensus about the dose or dura- the eeff ct would last only for a short period because receptor tion of systemic corticosteroid therapy for IgG4-RD. Some occupation rapidly reverts to the original value unless a new physicians treat with systemic steroids temporarily for several dose is given [18]. months, while some patients in Japan get corticosteroids Therefore, a single high dose is unlikely to have sustained permanently [15]. We elected to keep our patient on life- effect. Overall, the effects of corticosteroid pulses appear to long steroids due to the severe symptoms at initial presen- include downregulation of activation of immune cells and tation, the significant disease morbidity, and the immediate proinflammatory cytokine production, leading to reduced elevation of IgG4 levels at the time that Dexamethasone was expression of adhesion molecules and reduced movement briefly held (Figure 3) [16, 17]. The life-long administration of neutrophils into sites of inflammation. These effects are 2/19 11/18 7/18 2/18 11/17 8/17 5/17 2/17 11/16 9/16 7/16 4/16 1/16 7/15 5/15 1/15 11/14 7/14 4/14 1/14 12/13 11/13 6 Case Reports in Immunology IgG4 level and Dexamethasone trend 45 2.5 1.5 0.5 0 0 TIME (MM/YY) Dexamethasone levels (mg/week) Serum IgG4 levels (g/L) Figure 3: Double y-axis chart showing the IgG4 trends (orange line) and the Dexamethasone compliance (blue line) over time. Please note the immediate rise in serum IgG4 levels following the fall in Dexamethasone dosage. qualitatively similar to those seen with anti-TNF-alpha ther- review of the literature,” Journal of Korean Neurosurgical Society, vol. 55, no. 5, pp. 300–302, 2014. apy [19]. Corticosteroids are currently recommended orally [4] Y. Sireesha,M.Uppin, S. Ganti etal.,“A series of biopsy- for IgG4-RD according to the international consensus guid- proven patients with immunoglobulin G4-related neurological ance [20]. Other routes of glucocorticoids administration, disease,” Annals of Indian Academy of Neurology,vol. 22,no.1, such as intrathecal and epidural routes of administration pp.73–78,2019. have risks of arachnoiditis, spinal cord injury, and spinal [5] B. Baptista, A. Casian, H. Gunawardena, D. D’Cruz, and C. infection [17]. More recently, experiments in mice indicate M. 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