http://informahealthcare.com/mor ISSN 1439-7595 (print), 1439-7609 (online) Mod Rheumatol, 2014; 24(5): 798–801 © 2014 Japan College of Rheumatology DOI: 10.3109/14397595.2013.865884
ORIGINAL ARTICLE
A study of infraorbital nerve swelling associated with immunoglobulin G4 Mikulicz’s disease Kenichi Takano1, Ryoto Yajima1, Nobuhiko Seki1, Ayumi Abe1, Motohisa Yamamoto2, Hiroki Takahashi2, and Tetsuo Himi1 1Department of Otolaryngology, Sapporo Medical University School of Medicine, Sapporo, Japan and 2Department of the Gastroenterology,
Rheumatology and Clinical Immunology, Sapporo Medical University School of Medicine, Sapporo, Japan Abstract Objectives. Recent studies revealed that Mikulicz’s disease (MD) should be considered as an immunoglobulin (Ig) G4-related disease with aspects of systemic disorders involving the orbit. This study aimed to analyze the relationship between Immunoglobulin G4 (IgG4)-related MD and infraorbital nerve thickness. Methods. We measured infraorbital nerve thickness in 68 patients diagnosed as IgG4-related MD at our hospital and performed computed tomography scans of the head and neck region before treatment and compared these scans with those of the control group. Results. The mean infraorbital nerve diameter (⫾ standard deviation) was 3.2 ⫾ 1.2 mm in patients with IgG4-related MD, and 2.6 ⫾ 0.3 mm in the control group. Infraorbital nerves were significantly thicker in patients with IgG4-related MD. Nerve swelling was found in 20 of 68 patients (29.4%) with a cutoff value of 3.3 mm because this value was obtained from diameter of nerves in the control group ⫹ 2 standard deviation mm. No patients in the control group showed nerve swelling. In addition, we found significant correlations between infraorbital nerve swelling and serum IgG4 levels as well as the existence of multiple organ lesions. Conclusions. We found that significant infraorbital nerve swelling occurred in patients with IgG4related MD and was thought to be a part of IgG4-related disease.
Keywords
IgG4, Infraorbital nerve, Mikulicz’s disease History Received 19 July 2013 Accepted 11 November 2013 Published online 23 December 2013
Introduction Immunoglobulin G4-related disease (IgG4-RD) is a newly categorized disease that has received much attention in the last decade [1–4]. The hallmarks of IgG4-RD are lymphoplasmacytic tissue infiltration with a dominance of IgG4-positive plasmacytes accompanied by fibrosis, obliterative phlebitis, dacryoadenitis, and elevated IgG4 levels [2,3]. Most often, the diagnosis is made in patients with Mikulicz’s disease (MD) and type 1 autoimmune pancreatitis (AIP) [3,4]. The main relevance of immunohistochemical detection of increased IgG4 levels in involved tissues is that IgG4 is a surrogate marker, enabling exclusion of its neoplastic mimics. IgG4-related MD, which was once thought to be a subset of Sjögren’s syndrome, presents as idiopathic, bilateral, painless, and symmetrical swelling of the lacrimal, parotid, and submandibular glands [1,2]. It is well known that IgG4-related MD has been associated with various extrasalivary complications such as tubulointerstitial nephritis, pulmonary involvement, prostatitis, and retroperitoneal fibrosis and can also be involved in other complications. In addition, extrasalivary lesions have been reported as IgG4-RD [5], and IgG4-RD shows a wide variety of orbital manifestations such as lacrimal gland enlargement, lacrimal sac involvement, extraoccular muscle thickening, preseptal involvement, and orbital fat involvement [6,7]. However, a detailed analysis of the clinicopathological correlation between Correspondence to: Kenichi Takano, Department of Otolaryngology, Sapporo Medical University School of Medicine, S1 W16, Chuo-ku, Sapporo 060-8543, Japan. Tel. ⫹ 81-11-611-2111. Fax: ⫹ 81-11-6155405. E-mail: [email protected]
cranial nerve involvement and IgG4-related MD has not yet been reported. Here, we examined the frequency of infraotbital nerve swelling (ION) swelling in patients with IgG4-related MD and present new information on ION swelling associated with IgG4-related MD.
Methods Patients The subjects of this study were 68 patients (31 men and 37 women; mean age 58.8 ⫾ 12.4 years) with IgG4-related MD treated at Sapporo Medical University between 1997 and 2012. MD was diagnosed according to the diagnostic criteria for IgG4-related MD proposed by the Japanese Society for Sjögren’s syndrome in 2008 [8], which was as follows: (1) persistent (⬎ 3 months) symmetrical swelling of more than two lacrimal and major salivary glands, (2) elevated serum IgG4 levels (1.35 g/L), and (3) abundant infiltration of IgG4-positive plasmacytes and fibrosis. Other diseases that presented with glandular swelling, such as sarcoidosis and lymphoproliferative disease, were excluded. All patients with IgG4-related MD underwent computed tomography (CT) examinations of the head and neck regions. For the control group, 20 patients (11 men and 9 women; mean age 59.5 ⫾ 8.2 years old) who underwent a CT scan during 2012, 10 for chronic sinusitis, and 10 for head and neck cancer, were selected by random sampling. Written consent to use the information from these cases was obtained from the patients in accordance with the Declaration of
Infraorbital nerve swelling 799
DOI 10.3109/14397595.2013.865884
Helsinki. This study proceeded under the approval of our institutional IRB (SMU 22-57). Image analysis The thickness of the right and left infraorbital nerves was measured on a coronal section CT in the IgG4-related MD (68 patients, 136 nerves) and control (20 patients, 40 nerves) groups. The inferior orbital wall is considered to be nearly vertical to the coronal plane, but the ION running along the wall is not always vertical to the coronal plane. Hence, we classified nerve thickness as the vertical thickness of the inferior orbital wall to avoid overestimation. Two radiologists independently measured the thickness at the maximum point on coronal images and decided on the appropriate cutoff value for nerve swelling. The mean thickness of the nerve measured by these radiologists was used as the measured value. We calculated the mean value of the thicker side in the left and right. We compared the means of the measured values between the IgG4-related MD before therapy and control groups. Because approximately 95% of the values lie with two standard deviations (SD) in statistics, the cutoff value for ION swelling was defined as the mean value for ION ⫹ 2 SD. Statistical analysis Student’s t-test and chi-square test were used to determine differences in the measured ION diameters in the IgG4-related MD and control groups and the relevance of ION swelling with or without extrasalivary complications or olfactory dysfunction (OD). Data was expressed as means ⫾ standard deviation. P-values ⬍ 0.05 were considered to be statistically significant.
Infraorbital nerve swelling ION thickness in the IgG4-related MD and control groups was measured (Figure 1). In the IgG4-related MD group, the mean thickness was 3.2 ⫾ 1.2 mm (range, 2.0–7.9 mm). In the control group, the mean thickness was 2.6 ⫾ 0.3 mm (range 2.1–3.1 mm). ION swelling was observed in 20 of 68 patients with IgG4-related MD (29.4%) with a cutoff value of 3.3 mm, for which selected images are shown in Figure 2. This cutoff value was calculated as the mean ION diameter of the control group ⫾ 2SD. Asymmetrical ION swelling (Figure 2) was observed in 7 of 20 patients with ION swelling. In contrast, asymmetrical ION thickness as well as symmetrical thickness was not observed in the control group. Correlation between ION swelling and clinical features Serological analysis revealed that the mean IgG4 level was 1344.3 ⫾ 790.4 mg/dL (32.2% ⫾ 10.2%) in the ION swelling group and 656.3 ⫾ 656.9 mg/dL (21.8% ⫾ 8.3%) in the non-ION swelling group (Figure 3). Significant serological differences were observed between the two groups (P ⬍ 0.01). The correlation between serum IgG4 levels and ION diameter is shown in Figure 4. There was a positive relationship between serum IgG4 levels and ION diameter. The complications of patients with IgG4-related MD included AIP, interstitial tubular nephritis, sclerosing cholangitis, retroperitoneal fibrosis, autoimmune hypophysitis, and interstitial pneumonia, which were collectively regarded as extrasalivary gland lesions. Multiple organ lesions were observed in 49 of 68 patients
Results Clinical feature of patients Background characteristics of patients with IgG4-related MD are shown in Table 1. The mean age of the patients with IgG4related MD was 58.8 ⫾ 12.4 years (range, 25–81 years), and that of the control group was 59.5 ⫾ 8.4 years (range, 44–71 years). Serological analysis of patients with IgG4-related MD revealed that the mean total IgG level was 2503.3 ⫾ 1491.9 mg/dL and the mean IgG4 level was 858.6 ⫾ 761.3 mg/dL. Histological examination also revealed that IgG4-positive plasmacytes were abundant in the salivary glands of patients with IgG4-related MD. Extra salivary and lacrimal gland lesions included retroperitoneal fibrosis, kidney, pancreas, prostate, lung, pituitary, thyroid, and mammary gland. Neurological symptoms involving the ION, such as pain or sensory disturbance, were not observed in any patients with IgG4-related MD. Table 1. Clinical features of 68 patients with IgG4-related MD who participated in this study. Mean age Sex ratio (M:F) Mean serum IgG (mg ⫾ SD) Mean serum IgG4 (mg ⫾ SD) Mean serum IgG4 (% ⫾ SD) Extra salivary and lacrimal gland lesions (%) Retroperitoneal fibrosis Tubulointerstitial nephritis Autoimmune pancreatitis Prostatitis Interstitial pneumonitis Hypophysitis Thyroiditis Mastitis
58.8 ⫾ 12.4 31: 37 2503.3 ⫾ 1491.9 858.6 ⫾ 761.3 24.8 ⫾ 10.0 23.5 22.1 20.1 8.8 8.8 2.9 1.5 1.5
Figure 1. Infraorbital nerve (ION) thickness in the control and IgG4related Mikulicz’s disease (MD) groups. The ION thickness values of each individual in thicker side were plotted. IONs were significantly thicker in the MD group than those in the control group; *P ⬍ 0.05.
800
K. Takano et al.
Figure 2. Coronal CT of a patient with IgG4-related MD. Symmetrical (a) and asymmetrical (b) ION swellings (shaded triangles). Swelling of the frontal nerve (arrow), lacrimal glands (asterisks), and inferior rectus muscle (shaded circle) was also observed. We measured the ION thickness at the maximum point on coronal images (two-way arrow).
with IgG4-related MD (72.1%), and the number of patients with these multiple organ lesions detected in the ION swelling and nonION swelling groups was 18 and 31, respectively (Table 2). The complications rates were significantly higher in the ION swelling group (P ⬍ 0.05). OD is known to occur in patients with IgG4-related MD [9–11]. We had previously reported that among patients with IgG4-related MD showing an elevated serum IgG4 level, 45.5% had OD, and IgG4-positive plasmacytes were found in the nasal mucosa specimens of patients with IgG4-related MD who complained of OD [10,11]. By measuring ION swelling in patients who underwent CT examination, OD was detected in the ION swelling and nonION swelling groups for four and nine patients, respectively. No significant differences were observed between the two groups (Person’s correlation coefficient ⫽ 0.88).
Mod Rheumatol, 2014; 24(5): 798–801
Figure 3. Serum IgG4 levels in the ION swelling group and non-ION swelling group. Serum IgG4 levels were significantly higher in the ION swelling group; *P ⬍ 0.01.
Nerve swelling in the head and neck region is observed in various diseases such as schwannoma [12], malignant lymphoma [13], nasopharyngeal carcinoma [14], neurofibromatosis [15], and inflammatory pseudotumor [16]. Our patients with IgG4-related MD having ION swelling had no neurological symptoms in the trigeminal nerve regions. This finding suggests that nerve swelling associated with IgG4-related MD is a unique condition in comparison with other neuropathies. Bilateral nerve swelling is unusual in neoplastic tumors of the nerve, such as perineural invasion of carcinoma or schwannoma; therefore, these diseases may be excluded when nerve swelling is unilateral. In contrast, it is important to distinguish unilateral nerve swelling associated with IgG4-related MD from other diseases including neoplastic lesions.
Other orbital lesions associated with IgG4-related MD In this study, we observed orbital lesions other than lacrimal gland swelling and ION swelling (Figure 4). Frontal nerve swelling and thickening of the inferior rectus muscles (Figure 2) were observed in seven patients (10.3%) and two patients (2.9%), respectively. These lesions were not observed in the control patients.
Discussion In this study, we examined the relationship between IgG4-related MD and ION swelling and showed that ION swelling was observed in 20 of 68 patients with IgG4-related MD. In addition, nerve swelling was significantly correlated with serum IgG4 levels and the existence of multiple organ lesions. Little is known about nerve abnormalities associated with IgG4-related MD. This report is the first clinical study of ION abnormalities associated with IgG4related MD.
Figure 4. The correlation between serum IgG4 levels and ION diameter. The ION thickness values in thicker side and serum IgG4 levels in each IgG4-related MD patients were plotted (n ⫽ 68). There was a positive relationship (Person’s correlation coefficient ⫽ 0.35).
Infraorbital nerve swelling 801
DOI 10.3109/14397595.2013.865884
Table 2. A comparison of ION diameter in ION swelling and non-ION swelling groups with the occurrence of extrasalivary gland lesions. Diameter of ION Multiple organ lesions involved Only salivary and lacrimal gland lesion involved
ⱖ 3.3 mm 18 2
⬍ 3.3 mm 31 17
49 19
20
48
68
In the control group, none of the patients showed nerve swelling. Because of difficulties in nerve biopsy, we could not evaluate IgG4-positive plasmacyte infiltration into the nerve tissue by histological analysis. However, we had experienced a case of remarkable ION swelling (over 10 mm), and performed an ION biopsy via the maxillary sinus. The specimen from the patient, very interestingly, exhibited abundant infiltration of IgG4-positive plasmacytes, and this specimen was perineural connective tissue. The patient showed no swelling of the lacrimal and salivary glands, making the relationship between nerve swelling and IgG4-related MD uncertain. However, this pathological finding suggests that ION swelling may be caused by IgG4-positive plasmacyte infiltration into perineural tissue rather than nerve tissue. The reason that no patients with ION swelling had any neurological symptoms is because nerve swelling associated IgG4 MD was possibly perineuritis. In our study, some patients showed unilateral nerve swelling. Typical IgG4-related MD is characterized by symmetrical lacrimal and salivary gland swelling [1–3]. Although it is unclear why the lateral distribution of nerve swelling associated with IgG4-related MD differed from that of the glandular lesions, this is similar to IgG4-related Küttner tumors that show unilateral hard swelling of only the submandibular glands [9]. IgG4-related MD presents a wide variety of extrasalivary and lacrimal gland lesions including AIP [17], hypophysitis [18], Riedel thyroiditis [19], interstitial pneumonitis [20], interstitial nephritis, prostatitis [21], lymphadenopathy [22], retroperitoneal fibrosis [23], inflammatory aortic aneurysm [24], and inflammatory pseudotumor [25]. In this study, 49 of 68 patients with IgG4related MD (72.1%) had multiple organ lesions as shown in Table 1, and ION swelling was observed in 18 of 49 patients with MD having multiple organ diseases. The frequency of ION swelling was significantly higher in these patients. Multiple organ disease may be present at the time of diagnosis but can also evolve over months and years. Therefore, detecting ION swelling will possibly be helpful in the clinical diagnosis of multiple organ lesions.
Conclusions Patients with IgG4-related MD showed significant ION swelling, and the swelling correlated with multiple extrasalivary gland lesions and increased serum IgG4 levels. ION swelling associated with IgG4-related MD causes unobtrusive lesions, as observed in this study. In patients with IgG4-related MD, it is necessary to pay careful attention to nerve swelling as well as lacrimal and salivary gland lesions. Accurate pathogenesis of ION swelling associated with IgG4-related MD still remains unclear. Therefore, we will attempt to accumulate data on patients with IgG4-related MD who have nerve swelling to further study pathogenesis in such patients at the cellular and molecular levels.
Conflict of interest None.
References 1. Yamamoto M, Takahashi H, Ohara M, Suzuki C, Naishiro Y, Yamamoto H, et al. A new conceptualization for Mikulicz’s disease as an IgG4-related plasmacytic disease. Mod Rheumatol. 2006;16(6):335–40.
2. Himi T, Takano K, Yamamoto M, Naishiro Y, Takahashi H. A novel concept of Mikulicz’s disease as IgG4-related disease. Auris Nasus Larynx. 2012;39(1):9–17. 3. Stone JS, Yoh Z, Vikram D. IgG4-related disease. N Engl J Med 2012;366(6):539–51. 4. Umehara H, Okazaki K, Masaki Y, Kawano M, Yamamoto M, Saeki T, et al. A novel clinical entity, IgG4-related disease (IgG4RD): general concept and details. Mod Rheumatol. 2012;22(1):1–14. 5. Yamamoto M, Takahashi H, Shinomura Y. Mikulicz’s disease and its extraglandular lesions. Current Immunology Reviews 2011;7(2): 162–71. 6. Ginat DT, Freitag SK, Kieff D, Grove A, Fay A, Cunnane M, Moonis G. Radiographic patterns of orbital involvement in IgG4-related disease. Ophthal Plast Reconstr Surg. 2013;29(4):261–6. 7. Andrew N, Kearney D, Selva D. IgG4-related orbital disease: a meta-analysis and review. Acta Ophthalmol. 2012;91(8):694–700. doi:10.1111/j.1755-3768.2012.02526.x. 8. Masaki Y, Sugai S, Umehara H. IgG4-related diseases including Mikulicz’s disease and sclerosing pancreatitis: diagnostic insights. J Rheum. 2010;37(7):1380–5. 9. Takano K, Yamamoto M, Takahashi H, Shinomura Y, Imai K, Himi T. Clinicopathologic similarities between Mikulicz disease and Küttner tumor. Am J Otolaryngol. 2010;31(6):429–34. 10. Takano K, Yamamoto M, Takahashi H, Shinomura Y, Imai K, Himi T. A clinical study of olfactory dysfunction in patients with Mikulicz’s disease. Auris Nasus Larynx. 2011;38(3):347–51. 11. Takano K, Yamamoto M, Kondo A, Himi T. A case of reversible hyposmia associated with Mikulicz’s disease. Otolaryngol Head Neck Surg. 2009;141(3):430–1. 12. Karkas AA, Schmerber SA, Bettega GV, Reyt EP, Righini CA. Osteoplastic maxillotomy approach for infraorbital nerve schwannoma, a case report. Head Neck. 2008;30(3):401–4. 13. Kinoshita M, Izumoto S, Oshino S, Nonaka M, Moriuchi S, Maruno M, Yoshimine T. Primary malignant lymphoma of the trigeminal region treated with rapid infusion of high-dose MTX and radiation: case report and review of the literature. Surg Neurol. 2003;60(4):343–8. 14. Chong VF, Fan YF. Pterygopalatine fossa and maxillary nerve infiltration in nasopharyngeal carcinoma. Head Neck. 1997;19(2): 121–5. 15. Nager GT. Neurinomas of the trigeminal nerve. Am J Otolaryngol. 1984;5(5):301–33. 16. McKinney AM, Short J, Lucato L, SantaCruz K, McKinney Z, Kim Y. Inflammatory myofibroblastic tumor of the orbit with associated enhancement of the meninges and multiple cranial nerves. Am J Neuroradiol. 2006;27(10):2217–20. 17. Hamano H, Kawa S, Horiuchi A, Unno H, Furuya N, Akamatsu T, et al. High serum IgG4 concentrations in patients with sclerosing pancreatitis. N Engl J Med. 2001;344(10):732–8. 18. Yamamoto M, Takahashi H, Ohara M, Suzuki C, Naishiro Y, Yamamoto H, et al. A case of Mikulicz’s disease (IgG4-related plasmacytic disease) complicated by autoimmune hypophysitis. Scand J Rheumatol. 2006;35(5):410–1. 19. Dahlgren M, Khosroshahi A, Nielsen GP, Deshpande V, Stone JH. Riedel’s thyroiditis and multifocal fibrosclerosis are part of the IgG4related systemic disease spectrum. Arthritis Care Res. 2010;62(9): 1312–8. 20. Zen Y, Inoue D, Kitao A, Onodera M, Abo H, Miyayama S, et al. IgG4-related lung and pleural disease: a clinicopathologic study of 21 cases. Am J Surg Pathol. 2009;33(12):1886–93. 21. Saeki T, Saito A, Yamazaki H, Emura I, Imai N, Ueno M, et al. Tubulointerstitial nephritis associated with IgG4-related systemic disease. Clin Exp Nephrol. 2007;11(2):168–73. 22. Cheuk W, Yuen HK, Chu SY, Chiu EK, Lam LK, Chan JK. Lymphadenopathy of IgG4-related sclerosing disease. Am J Surg Pathol. 2008;32(5):671–81. 23. Hamano H, Kawa S, Ochi Y, Unno H, Shiba N, Wajiki M, et al. Hydronephrosis associated with retroperitoneal fibrosis and sclerosing pancreatitis. Lancet. 2002;359(9315):1403–4. 24. Kasashima S, Zen Y, Kawashima A, Konishi K, Sasaki H, Endo M, et al. Inflammatory abdominal aortic aneurysm: close rela- tionship to IgG4-related periaortitis. Am J Surg Pathol 2008;32(2):197–204. 25. Tsuboi H, Inokuma S, Setoguchi K, Shuji S, Hagino N, Tanaka Y, et al. Inflammatory pseudotumors in multiple organs associated with elevated serum IgG4 level: recovery by only a small replacement dose of steroid. Intern Med. 2008;47(12):1139–42.
Copyright of Modern Rheumatology (Informa Healthcare) is the property of Informa Healthcare and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
ORIGINAL ARTICLE
A study of infraorbital nerve swelling associated with immunoglobulin G4 Mikulicz’s disease Kenichi Takano1, Ryoto Yajima1, Nobuhiko Seki1, Ayumi Abe1, Motohisa Yamamoto2, Hiroki Takahashi2, and Tetsuo Himi1 1Department of Otolaryngology, Sapporo Medical University School of Medicine, Sapporo, Japan and 2Department of the Gastroenterology,
Rheumatology and Clinical Immunology, Sapporo Medical University School of Medicine, Sapporo, Japan Abstract Objectives. Recent studies revealed that Mikulicz’s disease (MD) should be considered as an immunoglobulin (Ig) G4-related disease with aspects of systemic disorders involving the orbit. This study aimed to analyze the relationship between Immunoglobulin G4 (IgG4)-related MD and infraorbital nerve thickness. Methods. We measured infraorbital nerve thickness in 68 patients diagnosed as IgG4-related MD at our hospital and performed computed tomography scans of the head and neck region before treatment and compared these scans with those of the control group. Results. The mean infraorbital nerve diameter (⫾ standard deviation) was 3.2 ⫾ 1.2 mm in patients with IgG4-related MD, and 2.6 ⫾ 0.3 mm in the control group. Infraorbital nerves were significantly thicker in patients with IgG4-related MD. Nerve swelling was found in 20 of 68 patients (29.4%) with a cutoff value of 3.3 mm because this value was obtained from diameter of nerves in the control group ⫹ 2 standard deviation mm. No patients in the control group showed nerve swelling. In addition, we found significant correlations between infraorbital nerve swelling and serum IgG4 levels as well as the existence of multiple organ lesions. Conclusions. We found that significant infraorbital nerve swelling occurred in patients with IgG4related MD and was thought to be a part of IgG4-related disease.
Keywords
IgG4, Infraorbital nerve, Mikulicz’s disease History Received 19 July 2013 Accepted 11 November 2013 Published online 23 December 2013
Introduction Immunoglobulin G4-related disease (IgG4-RD) is a newly categorized disease that has received much attention in the last decade [1–4]. The hallmarks of IgG4-RD are lymphoplasmacytic tissue infiltration with a dominance of IgG4-positive plasmacytes accompanied by fibrosis, obliterative phlebitis, dacryoadenitis, and elevated IgG4 levels [2,3]. Most often, the diagnosis is made in patients with Mikulicz’s disease (MD) and type 1 autoimmune pancreatitis (AIP) [3,4]. The main relevance of immunohistochemical detection of increased IgG4 levels in involved tissues is that IgG4 is a surrogate marker, enabling exclusion of its neoplastic mimics. IgG4-related MD, which was once thought to be a subset of Sjögren’s syndrome, presents as idiopathic, bilateral, painless, and symmetrical swelling of the lacrimal, parotid, and submandibular glands [1,2]. It is well known that IgG4-related MD has been associated with various extrasalivary complications such as tubulointerstitial nephritis, pulmonary involvement, prostatitis, and retroperitoneal fibrosis and can also be involved in other complications. In addition, extrasalivary lesions have been reported as IgG4-RD [5], and IgG4-RD shows a wide variety of orbital manifestations such as lacrimal gland enlargement, lacrimal sac involvement, extraoccular muscle thickening, preseptal involvement, and orbital fat involvement [6,7]. However, a detailed analysis of the clinicopathological correlation between Correspondence to: Kenichi Takano, Department of Otolaryngology, Sapporo Medical University School of Medicine, S1 W16, Chuo-ku, Sapporo 060-8543, Japan. Tel. ⫹ 81-11-611-2111. Fax: ⫹ 81-11-6155405. E-mail: [email protected]
cranial nerve involvement and IgG4-related MD has not yet been reported. Here, we examined the frequency of infraotbital nerve swelling (ION) swelling in patients with IgG4-related MD and present new information on ION swelling associated with IgG4-related MD.
Methods Patients The subjects of this study were 68 patients (31 men and 37 women; mean age 58.8 ⫾ 12.4 years) with IgG4-related MD treated at Sapporo Medical University between 1997 and 2012. MD was diagnosed according to the diagnostic criteria for IgG4-related MD proposed by the Japanese Society for Sjögren’s syndrome in 2008 [8], which was as follows: (1) persistent (⬎ 3 months) symmetrical swelling of more than two lacrimal and major salivary glands, (2) elevated serum IgG4 levels (1.35 g/L), and (3) abundant infiltration of IgG4-positive plasmacytes and fibrosis. Other diseases that presented with glandular swelling, such as sarcoidosis and lymphoproliferative disease, were excluded. All patients with IgG4-related MD underwent computed tomography (CT) examinations of the head and neck regions. For the control group, 20 patients (11 men and 9 women; mean age 59.5 ⫾ 8.2 years old) who underwent a CT scan during 2012, 10 for chronic sinusitis, and 10 for head and neck cancer, were selected by random sampling. Written consent to use the information from these cases was obtained from the patients in accordance with the Declaration of
Infraorbital nerve swelling 799
DOI 10.3109/14397595.2013.865884
Helsinki. This study proceeded under the approval of our institutional IRB (SMU 22-57). Image analysis The thickness of the right and left infraorbital nerves was measured on a coronal section CT in the IgG4-related MD (68 patients, 136 nerves) and control (20 patients, 40 nerves) groups. The inferior orbital wall is considered to be nearly vertical to the coronal plane, but the ION running along the wall is not always vertical to the coronal plane. Hence, we classified nerve thickness as the vertical thickness of the inferior orbital wall to avoid overestimation. Two radiologists independently measured the thickness at the maximum point on coronal images and decided on the appropriate cutoff value for nerve swelling. The mean thickness of the nerve measured by these radiologists was used as the measured value. We calculated the mean value of the thicker side in the left and right. We compared the means of the measured values between the IgG4-related MD before therapy and control groups. Because approximately 95% of the values lie with two standard deviations (SD) in statistics, the cutoff value for ION swelling was defined as the mean value for ION ⫹ 2 SD. Statistical analysis Student’s t-test and chi-square test were used to determine differences in the measured ION diameters in the IgG4-related MD and control groups and the relevance of ION swelling with or without extrasalivary complications or olfactory dysfunction (OD). Data was expressed as means ⫾ standard deviation. P-values ⬍ 0.05 were considered to be statistically significant.
Infraorbital nerve swelling ION thickness in the IgG4-related MD and control groups was measured (Figure 1). In the IgG4-related MD group, the mean thickness was 3.2 ⫾ 1.2 mm (range, 2.0–7.9 mm). In the control group, the mean thickness was 2.6 ⫾ 0.3 mm (range 2.1–3.1 mm). ION swelling was observed in 20 of 68 patients with IgG4-related MD (29.4%) with a cutoff value of 3.3 mm, for which selected images are shown in Figure 2. This cutoff value was calculated as the mean ION diameter of the control group ⫾ 2SD. Asymmetrical ION swelling (Figure 2) was observed in 7 of 20 patients with ION swelling. In contrast, asymmetrical ION thickness as well as symmetrical thickness was not observed in the control group. Correlation between ION swelling and clinical features Serological analysis revealed that the mean IgG4 level was 1344.3 ⫾ 790.4 mg/dL (32.2% ⫾ 10.2%) in the ION swelling group and 656.3 ⫾ 656.9 mg/dL (21.8% ⫾ 8.3%) in the non-ION swelling group (Figure 3). Significant serological differences were observed between the two groups (P ⬍ 0.01). The correlation between serum IgG4 levels and ION diameter is shown in Figure 4. There was a positive relationship between serum IgG4 levels and ION diameter. The complications of patients with IgG4-related MD included AIP, interstitial tubular nephritis, sclerosing cholangitis, retroperitoneal fibrosis, autoimmune hypophysitis, and interstitial pneumonia, which were collectively regarded as extrasalivary gland lesions. Multiple organ lesions were observed in 49 of 68 patients
Results Clinical feature of patients Background characteristics of patients with IgG4-related MD are shown in Table 1. The mean age of the patients with IgG4related MD was 58.8 ⫾ 12.4 years (range, 25–81 years), and that of the control group was 59.5 ⫾ 8.4 years (range, 44–71 years). Serological analysis of patients with IgG4-related MD revealed that the mean total IgG level was 2503.3 ⫾ 1491.9 mg/dL and the mean IgG4 level was 858.6 ⫾ 761.3 mg/dL. Histological examination also revealed that IgG4-positive plasmacytes were abundant in the salivary glands of patients with IgG4-related MD. Extra salivary and lacrimal gland lesions included retroperitoneal fibrosis, kidney, pancreas, prostate, lung, pituitary, thyroid, and mammary gland. Neurological symptoms involving the ION, such as pain or sensory disturbance, were not observed in any patients with IgG4-related MD. Table 1. Clinical features of 68 patients with IgG4-related MD who participated in this study. Mean age Sex ratio (M:F) Mean serum IgG (mg ⫾ SD) Mean serum IgG4 (mg ⫾ SD) Mean serum IgG4 (% ⫾ SD) Extra salivary and lacrimal gland lesions (%) Retroperitoneal fibrosis Tubulointerstitial nephritis Autoimmune pancreatitis Prostatitis Interstitial pneumonitis Hypophysitis Thyroiditis Mastitis
58.8 ⫾ 12.4 31: 37 2503.3 ⫾ 1491.9 858.6 ⫾ 761.3 24.8 ⫾ 10.0 23.5 22.1 20.1 8.8 8.8 2.9 1.5 1.5
Figure 1. Infraorbital nerve (ION) thickness in the control and IgG4related Mikulicz’s disease (MD) groups. The ION thickness values of each individual in thicker side were plotted. IONs were significantly thicker in the MD group than those in the control group; *P ⬍ 0.05.
800
K. Takano et al.
Figure 2. Coronal CT of a patient with IgG4-related MD. Symmetrical (a) and asymmetrical (b) ION swellings (shaded triangles). Swelling of the frontal nerve (arrow), lacrimal glands (asterisks), and inferior rectus muscle (shaded circle) was also observed. We measured the ION thickness at the maximum point on coronal images (two-way arrow).
with IgG4-related MD (72.1%), and the number of patients with these multiple organ lesions detected in the ION swelling and nonION swelling groups was 18 and 31, respectively (Table 2). The complications rates were significantly higher in the ION swelling group (P ⬍ 0.05). OD is known to occur in patients with IgG4-related MD [9–11]. We had previously reported that among patients with IgG4-related MD showing an elevated serum IgG4 level, 45.5% had OD, and IgG4-positive plasmacytes were found in the nasal mucosa specimens of patients with IgG4-related MD who complained of OD [10,11]. By measuring ION swelling in patients who underwent CT examination, OD was detected in the ION swelling and nonION swelling groups for four and nine patients, respectively. No significant differences were observed between the two groups (Person’s correlation coefficient ⫽ 0.88).
Mod Rheumatol, 2014; 24(5): 798–801
Figure 3. Serum IgG4 levels in the ION swelling group and non-ION swelling group. Serum IgG4 levels were significantly higher in the ION swelling group; *P ⬍ 0.01.
Nerve swelling in the head and neck region is observed in various diseases such as schwannoma [12], malignant lymphoma [13], nasopharyngeal carcinoma [14], neurofibromatosis [15], and inflammatory pseudotumor [16]. Our patients with IgG4-related MD having ION swelling had no neurological symptoms in the trigeminal nerve regions. This finding suggests that nerve swelling associated with IgG4-related MD is a unique condition in comparison with other neuropathies. Bilateral nerve swelling is unusual in neoplastic tumors of the nerve, such as perineural invasion of carcinoma or schwannoma; therefore, these diseases may be excluded when nerve swelling is unilateral. In contrast, it is important to distinguish unilateral nerve swelling associated with IgG4-related MD from other diseases including neoplastic lesions.
Other orbital lesions associated with IgG4-related MD In this study, we observed orbital lesions other than lacrimal gland swelling and ION swelling (Figure 4). Frontal nerve swelling and thickening of the inferior rectus muscles (Figure 2) were observed in seven patients (10.3%) and two patients (2.9%), respectively. These lesions were not observed in the control patients.
Discussion In this study, we examined the relationship between IgG4-related MD and ION swelling and showed that ION swelling was observed in 20 of 68 patients with IgG4-related MD. In addition, nerve swelling was significantly correlated with serum IgG4 levels and the existence of multiple organ lesions. Little is known about nerve abnormalities associated with IgG4-related MD. This report is the first clinical study of ION abnormalities associated with IgG4related MD.
Figure 4. The correlation between serum IgG4 levels and ION diameter. The ION thickness values in thicker side and serum IgG4 levels in each IgG4-related MD patients were plotted (n ⫽ 68). There was a positive relationship (Person’s correlation coefficient ⫽ 0.35).
Infraorbital nerve swelling 801
DOI 10.3109/14397595.2013.865884
Table 2. A comparison of ION diameter in ION swelling and non-ION swelling groups with the occurrence of extrasalivary gland lesions. Diameter of ION Multiple organ lesions involved Only salivary and lacrimal gland lesion involved
ⱖ 3.3 mm 18 2
⬍ 3.3 mm 31 17
49 19
20
48
68
In the control group, none of the patients showed nerve swelling. Because of difficulties in nerve biopsy, we could not evaluate IgG4-positive plasmacyte infiltration into the nerve tissue by histological analysis. However, we had experienced a case of remarkable ION swelling (over 10 mm), and performed an ION biopsy via the maxillary sinus. The specimen from the patient, very interestingly, exhibited abundant infiltration of IgG4-positive plasmacytes, and this specimen was perineural connective tissue. The patient showed no swelling of the lacrimal and salivary glands, making the relationship between nerve swelling and IgG4-related MD uncertain. However, this pathological finding suggests that ION swelling may be caused by IgG4-positive plasmacyte infiltration into perineural tissue rather than nerve tissue. The reason that no patients with ION swelling had any neurological symptoms is because nerve swelling associated IgG4 MD was possibly perineuritis. In our study, some patients showed unilateral nerve swelling. Typical IgG4-related MD is characterized by symmetrical lacrimal and salivary gland swelling [1–3]. Although it is unclear why the lateral distribution of nerve swelling associated with IgG4-related MD differed from that of the glandular lesions, this is similar to IgG4-related Küttner tumors that show unilateral hard swelling of only the submandibular glands [9]. IgG4-related MD presents a wide variety of extrasalivary and lacrimal gland lesions including AIP [17], hypophysitis [18], Riedel thyroiditis [19], interstitial pneumonitis [20], interstitial nephritis, prostatitis [21], lymphadenopathy [22], retroperitoneal fibrosis [23], inflammatory aortic aneurysm [24], and inflammatory pseudotumor [25]. In this study, 49 of 68 patients with IgG4related MD (72.1%) had multiple organ lesions as shown in Table 1, and ION swelling was observed in 18 of 49 patients with MD having multiple organ diseases. The frequency of ION swelling was significantly higher in these patients. Multiple organ disease may be present at the time of diagnosis but can also evolve over months and years. Therefore, detecting ION swelling will possibly be helpful in the clinical diagnosis of multiple organ lesions.
Conclusions Patients with IgG4-related MD showed significant ION swelling, and the swelling correlated with multiple extrasalivary gland lesions and increased serum IgG4 levels. ION swelling associated with IgG4-related MD causes unobtrusive lesions, as observed in this study. In patients with IgG4-related MD, it is necessary to pay careful attention to nerve swelling as well as lacrimal and salivary gland lesions. Accurate pathogenesis of ION swelling associated with IgG4-related MD still remains unclear. Therefore, we will attempt to accumulate data on patients with IgG4-related MD who have nerve swelling to further study pathogenesis in such patients at the cellular and molecular levels.
Conflict of interest None.
References 1. Yamamoto M, Takahashi H, Ohara M, Suzuki C, Naishiro Y, Yamamoto H, et al. A new conceptualization for Mikulicz’s disease as an IgG4-related plasmacytic disease. Mod Rheumatol. 2006;16(6):335–40.
2. Himi T, Takano K, Yamamoto M, Naishiro Y, Takahashi H. A novel concept of Mikulicz’s disease as IgG4-related disease. Auris Nasus Larynx. 2012;39(1):9–17. 3. Stone JS, Yoh Z, Vikram D. IgG4-related disease. N Engl J Med 2012;366(6):539–51. 4. Umehara H, Okazaki K, Masaki Y, Kawano M, Yamamoto M, Saeki T, et al. A novel clinical entity, IgG4-related disease (IgG4RD): general concept and details. Mod Rheumatol. 2012;22(1):1–14. 5. Yamamoto M, Takahashi H, Shinomura Y. Mikulicz’s disease and its extraglandular lesions. Current Immunology Reviews 2011;7(2): 162–71. 6. Ginat DT, Freitag SK, Kieff D, Grove A, Fay A, Cunnane M, Moonis G. Radiographic patterns of orbital involvement in IgG4-related disease. Ophthal Plast Reconstr Surg. 2013;29(4):261–6. 7. Andrew N, Kearney D, Selva D. IgG4-related orbital disease: a meta-analysis and review. Acta Ophthalmol. 2012;91(8):694–700. doi:10.1111/j.1755-3768.2012.02526.x. 8. Masaki Y, Sugai S, Umehara H. IgG4-related diseases including Mikulicz’s disease and sclerosing pancreatitis: diagnostic insights. J Rheum. 2010;37(7):1380–5. 9. Takano K, Yamamoto M, Takahashi H, Shinomura Y, Imai K, Himi T. Clinicopathologic similarities between Mikulicz disease and Küttner tumor. Am J Otolaryngol. 2010;31(6):429–34. 10. Takano K, Yamamoto M, Takahashi H, Shinomura Y, Imai K, Himi T. A clinical study of olfactory dysfunction in patients with Mikulicz’s disease. Auris Nasus Larynx. 2011;38(3):347–51. 11. Takano K, Yamamoto M, Kondo A, Himi T. A case of reversible hyposmia associated with Mikulicz’s disease. Otolaryngol Head Neck Surg. 2009;141(3):430–1. 12. Karkas AA, Schmerber SA, Bettega GV, Reyt EP, Righini CA. Osteoplastic maxillotomy approach for infraorbital nerve schwannoma, a case report. Head Neck. 2008;30(3):401–4. 13. Kinoshita M, Izumoto S, Oshino S, Nonaka M, Moriuchi S, Maruno M, Yoshimine T. Primary malignant lymphoma of the trigeminal region treated with rapid infusion of high-dose MTX and radiation: case report and review of the literature. Surg Neurol. 2003;60(4):343–8. 14. Chong VF, Fan YF. Pterygopalatine fossa and maxillary nerve infiltration in nasopharyngeal carcinoma. Head Neck. 1997;19(2): 121–5. 15. Nager GT. Neurinomas of the trigeminal nerve. Am J Otolaryngol. 1984;5(5):301–33. 16. McKinney AM, Short J, Lucato L, SantaCruz K, McKinney Z, Kim Y. Inflammatory myofibroblastic tumor of the orbit with associated enhancement of the meninges and multiple cranial nerves. Am J Neuroradiol. 2006;27(10):2217–20. 17. Hamano H, Kawa S, Horiuchi A, Unno H, Furuya N, Akamatsu T, et al. High serum IgG4 concentrations in patients with sclerosing pancreatitis. N Engl J Med. 2001;344(10):732–8. 18. Yamamoto M, Takahashi H, Ohara M, Suzuki C, Naishiro Y, Yamamoto H, et al. A case of Mikulicz’s disease (IgG4-related plasmacytic disease) complicated by autoimmune hypophysitis. Scand J Rheumatol. 2006;35(5):410–1. 19. Dahlgren M, Khosroshahi A, Nielsen GP, Deshpande V, Stone JH. Riedel’s thyroiditis and multifocal fibrosclerosis are part of the IgG4related systemic disease spectrum. Arthritis Care Res. 2010;62(9): 1312–8. 20. Zen Y, Inoue D, Kitao A, Onodera M, Abo H, Miyayama S, et al. IgG4-related lung and pleural disease: a clinicopathologic study of 21 cases. Am J Surg Pathol. 2009;33(12):1886–93. 21. Saeki T, Saito A, Yamazaki H, Emura I, Imai N, Ueno M, et al. Tubulointerstitial nephritis associated with IgG4-related systemic disease. Clin Exp Nephrol. 2007;11(2):168–73. 22. Cheuk W, Yuen HK, Chu SY, Chiu EK, Lam LK, Chan JK. Lymphadenopathy of IgG4-related sclerosing disease. Am J Surg Pathol. 2008;32(5):671–81. 23. Hamano H, Kawa S, Ochi Y, Unno H, Shiba N, Wajiki M, et al. Hydronephrosis associated with retroperitoneal fibrosis and sclerosing pancreatitis. Lancet. 2002;359(9315):1403–4. 24. Kasashima S, Zen Y, Kawashima A, Konishi K, Sasaki H, Endo M, et al. Inflammatory abdominal aortic aneurysm: close rela- tionship to IgG4-related periaortitis. Am J Surg Pathol 2008;32(2):197–204. 25. Tsuboi H, Inokuma S, Setoguchi K, Shuji S, Hagino N, Tanaka Y, et al. Inflammatory pseudotumors in multiple organs associated with elevated serum IgG4 level: recovery by only a small replacement dose of steroid. Intern Med. 2008;47(12):1139–42.
Copyright of Modern Rheumatology (Informa Healthcare) is the property of Informa Healthcare and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
