We report the case of a 58-year-old male presenting with an impairment of the left-sided visual acuity caused by compressiveoptic neuropathy, and marked bilateral proptosis. Blood test showed markedly elevated IgG4 (1830 mg/dl) and positiveTSH receptor-stimulating antibodies (200%), but the thyroid function test were normal. Orbital MRI revealed abnormal soft tissueproliferation around the optic nerve and fusiform enlargement of the extraocular muscles. Systemic CT analysis detectedmultiple lymph node swelling, pseudotumor in the lung, retroperitoneal fibrosis, and kidney lesions. We considered that the eyemanifestation was most likely caused by IgG4-related idiopathic orbital inflammation. Systemic administration of a moderatedose of prednisolone dramatically improved the compression of the optic nerve, as shown by the improvement of the visualacuity and the MRI findings. The clinical course made thyroid-associated ophthalmopathy unlikely. In conclusion, an overallconsideration of the clinical picture and extensive work-up of any possible differential diagnosis including measurement of theserum levels of IgG4 was highly useful in making the diagnosis of the patient

Ando Takao

Haraguchi Ai

Horie Ichiro

Imaizumi Misa

Kawakami Atsushi

Origuchi Tomoki

Ueki Ikuko

Usa Toshiro

Yamasaki Satoshi

Nagasaki University's Academic Output SITE: NAOSITE

IntroductionIdiopathic orbital inflammation is an idiopathic benigninflammatory space-occupying lesion (1). Presenting symp-toms include proptosis, oculomotor deficits, pain, lid swel-ling or mass, ptosis, and chemosis. The disease progressionof idiopathic orbital inflammation can be acute to subacuteor occasionally chronic and idiopathic orbital inflammationis usually unilateral but may occasionally be bilateral. Asmall subset of patients may have decreased visual acuitybecause of optic nerve compression (2). It has recently beensuggested that idiopathic orbital inflammation is one of thecomponents of IgG4-related disease (3-6). IgG4-related dis-ease is characterized by dense infiltration of IgG4-positiveplasma cells into multiple organs or tissues in associationwith increased serum levels of IgG4 (>135 mg/dl). Thisdisorder is frequently seen in older males, often older maleswith allergic disorders, and the most common organs in-volved are the salivary glands and pancreas. Among the en-docrine organs, the pituitary gland (7, 8) and the thyroid (9)have been shown to be affected.Here we present a patent with marked proptosis andcompressive optic neuropathy putatively caused by IgG4-related idiopathic orbital inflammation with positive TSHreceptor-stimulating antibodies.Acta Med. Nagasaki 57: 29－32Address correspondence: Takao Ando, M.D., Ph.D.Unit of Translational Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Nagasaki, Japan, 852-8501Voice: 81-95-819-7268; Fax: 81-95-849-7270; Email: takaoando@gmail.comReceived September 6, 2011; Accepted February 2, 2012MS#AMN 07093Case ReportA case of compressive optic neuropathy putatively caused by IgG4-relatedidiopathic orbital inflammation.Ai HARAGUCHI, Takao ANDO, Ikuko UEKI, Ichiro HORIE, Misa IMAIZUMI, Toshiro USA, Satoshi YAMASAKI,Tomoki ORIGUCHI, and Atsushi KAWAKAMIUnit of Translational Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Nagasaki, Japan.We report the case of a 58-year-old male presenting with an impairment of the left-sided visual acuity caused by compres-sive optic neuropathy, and marked bilateral proptosis. Blood test showed markedly elevated IgG4 (1830 mg/dl) and positiveTSH receptor-stimulating antibodies (200%), but the thyroid function test were normal. Orbital MRI revealed abnormal soft tis-sue proliferation around the optic nerve and fusiform enlargement of the extraocular muscles. Systemic CT analysis detectedmultiple lymph node swelling, pseudotumor in the lung, retroperitoneal fibrosis, and kidney lesions. We considered that the eyemanifestation was most likely caused by IgG4-related idiopathic orbital inflammation. Systemic administration of a moderatedose of prednisolone dramatically improved the compression of the optic nerve, as shown by the improvement of the visualacuity and the MRI findings. The clinical course made thyroid-associated ophthalmopathy unlikely. In conclusion, an overallconsideration of the clinical picture and extensive work-up of any possible differential diagnosis including measurement of theserum levels of IgG4 was highly useful in making the diagnosis of the patient.ACTA MEDICA NAGASAKIENSIA 57: 29－32, 2012Keywords: compressive optic neuropathy, proptosis, IgG4Ai Haraguchi et al.: optic neuropathy and IgG4 elevation.PatientA 58-year-old male smoker was referred to our hospitaldue to reduced visual acuity and bilateral proptosis. He hadno allergic diathesis and no family history of thyroid disor-ders. He had had proptosis of the left eye for three yearsand had had glucocorticoids treatment with prednisolonestarting from 30 mg per day for compressive optic neuropathytwo years before the referral. There had been clinical im-provement of proptosis and the visual acuity, but the patientterminated prednisolone by himself and then noticed grad-ual aggravation of proptosis and impairment of the visualacuity.On physical examination, there was marked proptosis(35 mm, bilaterally, determined by an exophthalmometer)with intact eyeball movement. His visual acuity was 20/30after correction and hand motion at 30 cm in the right andleft eye, respectively. There were no enlarged thyroid orpalpable superficial lymph nodes and no skin lesions iden-tified. Ophthalmologic investigation did not reveal any signssuggestive of uveitis. Blood test revealed mild eosinophilia(10% of 8500 white blood cells /uL) and a marked increaseof total protein (10.5 g/dl). Serum levels of IgG and IgEwere increased to 4940 mg/dl (reference range 879-1700mg/dl) and 1765.6 mg/dl (reference range <269 mg/dl),respectively. There was no monoclonal immunoglobulin.Subclass analysis of serum IgG disclosed a marked in-creased in IgG4 to 1830 mg/dl (>135 mg/dl being consid-ered abnormally high (10, 11)). The serum level of solubleIL-2 receptor was increased (1463 U/ml; reference range124-466 U/ml). Proteinase 3- and myeloperoxidase-anti-neutrophil cytoplasmic antibodies were negative. Thyroidfunction was normal: free T3 3.15 pg/ml (2.37-3.91 pg/ml),free T4 1.28 ng/dl (0.95-1.57 ng/dl), and TSH 4.044uIU/mL (0.48-5.08 uIU/mL); however, TSH receptor-stimulating antibodies were 200% (<180%) and positive.The orbital MRI (Figure 1A and B) showed proliferation ofaberrant soft tissue in both sides of the orbit and mild en-largement of the extraocular muscles.The marked elevation of serum IgG4 suggested IgG4-related idiopathic orbital inflammation. Since IgG4-relateddisease is known to show systemic involvement, we inves-tigated putative lesions caused by IgG4-related disease bywhole body CT. We were able to identify a lung pseudotumor,retroperitoneal fibrosis, and multiple less enhanced areas inthe bilateral kidneys as well as swollen LNs from the neck tothe mediastinum (not shown). Positron emission tomography-CT also documented fluorodeoxyglucose accumulation inthe bilateral orbits, nasal sinus, mediastinal and hilar lymphnodes and lung pseudotumor. Since the patient refused atissue biopsy or surgical decompression of the left opticnerve, we were not able to make a definitive diagnosis.Considering the organs affected and the high levels of serumIgG4 and soluble IL-2 receptor, Wegener's granulomatosisand malignant lymphoma were the most important differen-tial diagnoses. Wegener's granulomatosis was unlikely be-cause of the negative anti-neutrophil cytoplasmic antibod-ies. His previous medical history of improvement of thevisual acuity and proptosis by a moderate dose of prednisolonemade malignant lymphoma unlikely. Based on the typicalclinical findings, we considered that a diagnosis of IgG4-related disease including idiopathic orbital inflammation wasmost likely.It was apparent that IgG4-related idiopathic orbital in-flammation was the major element causing the proptosisand compressive optic neuropathy (Figure 1A and B), andthus the patient was treated with 20 mg of prednisolone.There was gradual improvement of the visual acuity (20/30after correction and 20/1000 in the right and left eye, re-spectively) and dramatic amelioration of proptosis (17 mm,bilaterally), and there was also a decrease in the serum lev-els of IgG4 (468 mg/dl) and soluble IL-2 receptor (~500U/ml). The aberrant orbital soft tissue dramatically declinedand the extraocular muscles became slightly reduced in size(Figure 1C and D), and similar improvements in the lungand kidney were also noted in the follow-up CT (notshown). Therefore, the dose of prednisolone was taperedgradually down to 10 mg per day. However, there wassymptomatic aggravation of the visual acuity shortly afterthe reduction of prednisolone. Therefore, a final mainte-nance dose of 13 mg was used, and resulted in no apparentrelapse of the clinical symptoms.DiscussionIgG4-related disease is an emerging disease concept inwhich the affected organs or tissues may become tumorousas a result of a chronic inflammatory process, includingIgG4-positive cell infiltration associated with fibrosis (10,11). IgG4-related idiopathic orbital inflammation can occuralone or in association with other organ manifestation. Theprecise mechanism(s) by which IgG4-related disease devel-ops have not been elucidated. It has been reported thatIgG4 concentrations are closely associated with disease ac-tivity in IgG4-related disease (12). However, it is notknown whether IgG4 has any pathogenic roles in IgG4-related disease. It has been shown that allergic rhinitis and30Ai Haraguchi et al.: optic neuropathy and IgG4 elevation.bronchial asthma are frequently associated with IgG4-relateddisease (10). The allergic aspect of IgG4-related diseasemay be further supported by the fact that a moderate doseof glucocorticoids has a favorable therapeutic response.Thyroid-associated ophthalmopathy (TAO) is the majorcause of proptosis seen in individuals suffering from Gravesdisease. TAO can develop in euthyroid patients without con-current or previous history of Graves disease, but thyrotropinreceptor autoantibodies are generally present in the sera ofmost such patients. In addition, increased volume of the or-bital adipose tissue and/or extraocular muscles as retro-ocular alterations on CT and MRI are also always seen inpatients with TAO (13). Several potential mechanisms havebeen put forward to explain the pathogenesis of TAO, in-cluding thyrotropin receptor autoantibodies and anti-insulinlike growth factor-1 receptor autoantibodies interactingwith its cognate receptor expressing in the orbital fibroblast(13). These findings support the idea of an autoimmunepathogenesis of TAO. Treatment of severe TAO consists ofa high dose of glucocorticoids including steroid pulsetherapy with or without external beam radiation to theretro-orbital space, occasionally followed by surgery (14).Our patient reported herein showed the favorable clinicalresponse to the moderate dose of prednisolone and, there-fore, it was highly unlikely that TAO was the major com-ponent in making the extraocular muscle enlarged. This no-tion was also supported by the fact that TSH receptor-stimulating antibodies seen in our patient was onlymarginally positive and, therefore, too low to develop TAOsince the levels of TSH receptor antibodies have beenshown a tendency to correlate with the severity of TAO(15). Thus, positive TSH receptor-stimulating antibodiesseen in our patient were, most likely, not more than coinci-dental. Although a clinical association between TAO andIgG4-related idiopathic orbital inflammation has not beenreported so far, it is intriguing to consider that IgG4-relatedidiopathic orbital inflammation can expand and involve theorbital tissues, releasing the TSH receptor autoantigen lo-cally which in turn generates the autoantibodies to the TSHreceptor.31Figure 1. Ocular MRI before and after prednisolone treatment.Panels (A) and (B) show massive proliferation of soft tissue around the optic nerve adjoining theextraocular muscles. The extraocular muscles show fusiform enlargement relatively sparing the ten-dons in the left eye. The soft tissue proliferation and extraocular muscle enlargement in the righteye are less prominent. There is also the marked mucosal thickening in the nasal sinus as well asthe soft tissue swelling around the infraorbital nerves. Panels (C) and (D) show orbital MRI imagesobtained one month after prednisolone treatment. The dramatic reduction of the proliferating softtissue in both the eyes and nasal mucosa was noteworthy, as well as the slight improvement of theextraocular muscle enlargement. T1-weighted images of the axial section are shown in panels (A)and (C) and T2-weighted images of the coronal section are shown in (B) and (D).Ai Haraguchi et al.: optic neuropathy and IgG4 elevation.Here we reported a patient with compressive opticneuropathy and marked proptosis caused by IgG4-relatedidiopathic orbital inflammation with positive TSH receptor-stimulating antibodies. This case suggests an importance ofoverall consideration of the clinical picture and extensivework-up of any possible differential diagnosis.AcknowledgementsThis work was supported in part by Health and LaborScience Grants for Research on Measures for IntractableDiseases from the Ministry of Health, Labor and Welfare ofJapan.References1. Shields JA, Shields CL, Scartozzi R. Survey of 1264 patients with or-bital tumors and simulating lesions: The 2002 Montgomery Lecture,part 1. Ophthalmology 111:997-1008, 2004.2. Mendenhall WM, Lessner AM. Orbital pseudotumor. Am J Clin Oncol33:304-306, 2010.3. Sato Y, Ohshima K, Ichimura K, Sato M, Yamadori I, Tanaka T,Takata K, Morito T, Kondo E, Yoshino T. Ocular adnexal IgG4-relateddisease has uniform clinicopathology. Pathol Int 58:465-470, 2008.4. Kishi K, Fujii T, Kohno T, Yoshimura K. Inflammatory pseudotumouraffecting the lung and orbit. Respirology 14:449-451, 2009.5. Mehta M, Jakobiec F, Fay A. Idiopathic fibroinflammatory disease ofthe face, eyelids, and periorbital membrane with immunoglobulin G4-positive plasma cells. Arch Pathol Lab Med 133:1251-1255, 2009.6. Takuma K, Kamisawa T, Tabata T, Inaba Y, Egawa N, Ozaki N,Horiguchi S, Takuma S. Visual field deficit: a rare initial symptom ofautoimmune pancreatitis. Intern Med 50:887-891, 2010.7. Shimatsu A, Oki Y, Fujisawa I, Sano T. Pituitary and stalk lesions(Infundibulo-hypophysitis) associated with immunoglobulin G4-relatedsystemic disease: an emerging clinical entity. Endocr J 56:1033-1041,2009.8. Haraguchi A, Era A, Yasui J, Ando T, Ueki I, Horie I, Imaizumi M,Usa T, Abe K, Origuchi T, Eguchi K. Putative IgG4-related pituitarydisease with hypopituitarism and/or diabetes insipidus accompaniedwith elevated serum levels of IgG4. Endocr J 57:719-725, 2010.9. 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A case of compressive optic neuropathy putatively caused by IgG4-related idiopathic orbital inflammation.

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A case of compressive optic neuropathy putatively caused by IgG4-related idiopathic orbital inflammation.

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