Abstract
IgG4-related disease has evolved from originally being recognized as a form of pancreatitis to encompass diseases of numerous organs including the hypophysis and one reported case of dural involvement. A search of the University of Virginia, Division of Neuropathology files for 10 years identified ten cases of unexplained lymphoplasmacytic meningeal inflammation that we then evaluated using immunohistochemical stains for IgG4 and IgG. Ten control cases including sarcoidosis (4), tuberculosis (1), bacterial abscess (2), Langerhans cell histiocytosis (2), and foreign body reaction (1) were also examined. The number of IgG4-positive plasma cells was counted in five high power fields (HPFs) and an average per HPF was calculated. Cases that contained greater than ten IgG4-positive cells/HPF were considered to be IgG4-related. Five of the study cases met these criteria, including one case of leptomeningeal inflammation. All cases exhibited the typical histological features of IgG4-related disease including lymphoplasmacytic inflammation, fibrosis, and phlebitis. The dural-based lesions appear to represent a subset of the cases historically diagnosed as idiopathic hypertrophic pachymeningitis. While the leptomeningeal process most closely resembles non-vasculitic autoimmune inflammatory meningoencephalitis. Given these findings, IgG4-related meningitis should be considered in the differential diagnosis of meningeal inflammatory lesions after stringent clinical and histologic criteria are used to rule out other possible diagnoses.
Similar content being viewed by others
References
Aalberse RC, Stapel SO, Schuurman J, Rispens T (2009) Immunoglobulin G4: an odd antibody. Clin Exp Allergy 39:469–477. doi:10.1111/j.1365-2222.2009.03207.x
Adler JR, Sheridan W, Kosek J, Linder S (1991) Pachymeningitis associated with a pulmonary nodule. Neurosurgery 29:283–287
Alexander GE, Provost TT, Stevens MB, Alexander EL (1981) Sjogren syndrome: central nervous system manifestations. Neurology 31:1391–1396
Aoki S, Nakazawa T, Ohara H, Sano H, Nakao H, Joh T et al (2005) Immunohistochemical study of autoimmune pancreatitis using anti-IgG4 antibody and patients’ sera. Histopathology 47:147–158. doi:10.1111/j.1365-2559.2005.02204.x
Ashkenazi E, Constantini S, Pappo O, Gomori M, Averbuch-Heller L, Umansky F (1991) Hypertrophic spinal pachymeningitis: report of two cases and review of the literature. Neurosurgery 28:730–732
Bateman AC, Deheragoda MG (2009) IgG4-related systemic sclerosing disease—an emerging and under-diagnosed condition. Histopathology 55:373–383. doi:10.1111/j.1365-2559.2008.03217.x
Berger JR, Snodgrass S, Glaser J, Post MJ, Norenberg M, Benedetto P (1989) Multifocal fibrosclerosis with hypertrophic intracranial pachymeningitis. Neurology 39:1345–1349
Caselli RJ, Boeve BF, Scheithauer BW, O’Duffy JD, Hunder GG (1999) Nonvasculitic autoimmune inflammatory meningoencephalitis (NAIM): a reversible form of encephalopathy. Neurology 53:1579–1581
Castillo P, Woodruff B, Caselli R, Vernino S, Lucchinetti C, Swanson J et al (2006) Steroid-responsive encephalopathy associated with autoimmune thyroiditis. Arch Neurol 63:197–202. doi:10.1001/archneur.63.2.197
Chan SK, Cheuk W, Chan KT, Chan JK (2009) IgG4-related sclerosing pachymeningitis: a previously unrecognized form of central nervous system involvement in IgG4-related sclerosing disease. Am J Surg Pathol 33:1249–1252. doi:10.1097/PAS.0b013e3181abdfc2
Charcot JM, Joffroy A (1869) Deux cas d’atrophie musculaire progressive avec lesions de las substance grise et des faisceaux anterolateraux de la moelle epiniere. Arch Physiol Norm Pathol 2:354–367; 629–649, 744–769
Chari ST, Smyrk TC, Levy MJ, Topazian MD, Takahashi N, Zhang L et al (2006) Diagnosis of autoimmune pancreatitis: the Mayo Clinic experience. Clin Gastroenterol Hepatol 4:1010–1016. doi:10.1016/j.cgh.2006.05.017; quiz 934
Cheuk W, Yuen HK, Chan JK (2007) Chronic sclerosing dacryoadenitis: part of the spectrum of IgG4-related Sclerosing disease? Am J Surg Pathol 31:643–645. doi:10.1097/01.pas.0000213445.08902.11
Cheuk W, Yuen HK, Chu SY, Chiu EK, Lam LK, Chan JK (2008) Lymphadenopathy of IgG4-related sclerosing disease. Am J Surg Pathol 32:671–681. doi:10.1097/PAS.0b013e318157c068
Church NI, Pereira SP, Deheragoda MG, Sandanayake N, Amin Z, Lees WR et al (2007) Autoimmune pancreatitis: clinical and radiological features and objective response to steroid therapy in a UK series. Am J Gastroenterol 102:2417–2425. doi:10.1111/j.1572-0241.2007.01531.x
Clark A, Zeman RK, Choyke PL, White EM, Burrell MI, Grant EG et al (1988) Pancreatic pseudotumors associated with multifocal idiopathic fibrosclerosis. Gastrointest Radiol 13:30–32. doi:10.1007/BF01889019
D’Andrea G, Trillo G, Celli P, Roperto R, Crispo F, Ferrante L (2004) Idiopathic intracranial hypertrophic pachymeningitis: two case reports and review of the literature. Neurosurg Rev 27:199–204. doi:10.1007/s10143-004-0321-1
Deheragoda MG, Church NI, Rodriguez-Justo M, Munson P, Sandanayake N, Seward EW et al (2007) The use of immunoglobulin g4 immunostaining in diagnosing pancreatic and extrapancreatic involvement in autoimmune pancreatitis. Clin Gastroenterol Hepatol 5:1229–1234. doi:10.1016/j.cgh.2007.04.023
Deshpande V, Chicano S, Finkelberg D, Selig MK, Mino-Kenudson M, Brugge WR et al (2006) Autoimmune pancreatitis: a systemic immune complex mediated disease. Am J Surg Pathol 30:1537–1545. doi:10.1097/01.pas.0000213331.09864.2c
Dumont AS, Clark AW, Sevick RJ, Myles ST (2000) Idiopathic hypertrophic pachymeningitis: a report of two patients and review of the literature. Can J Neurol Sci 27:333–340
Epstein O, Chapman RW, Lake-Bakaar G, Foo AY, Rosalki SB, Sherlock S (1982) The pancreas in primary biliary cirrhosis and primary sclerosing cholangitis. Gastroenterology 83:1177–1182
Guidetti B, La Torre E (1967) Hypertrophic spinal pachymeningitis. J Neurosurg 26:496–503. doi:10.3171/jns.1967.26.5.0496
Hamano H, Kawa S, Horiuchi A, Unno H, Furuya N, Akamatsu T et al (2001) High serum IgG4 concentrations in patients with sclerosing pancreatitis. N Engl J Med 344:732–738
Hamano H, Kawa S, Ochi Y, Unno H, Shiba N, Wajiki M et al (2002) Hydronephrosis associated with retroperitoneal fibrosis and sclerosing pancreatitis. Lancet 359:1403–1404
Hori M, Makita N, Andoh T, Takiyama H, Yajima Y, Sakatani T et al (2010) Long-term clinical course of IgG4-related systemic disease accompanied by hypophysitis. Endocr J 57(6):485–492
Kamisawa T, Egawa N, Nakajima H (2003) Autoimmune pancreatitis is a systemic autoimmune disease. Am J Gastroenterol 98:2811–2812. doi:10.1111/j.1572-0241.2003.08758.x
Kamisawa T, Funata N, Hayashi Y, Eishi Y, Koike M, Tsuruta K et al (2003) A new clinicopathological entity of IgG4-related autoimmune disease. J Gastroenterol 38:982–984. doi:10.1007/s00535-003-1175-y
Kamisawa T, Funata N, Hayashi Y, Tsuruta K, Okamoto A, Amemiya K et al (2003) Close relationship between autoimmune pancreatitis and multifocal fibrosclerosis. Gut 52:683–687
Kamisawa T, Chen PY, Tu Y, Nakajima H, Egawa N, Tsuruta K et al (2006) Pancreatic cancer with a high serum IgG4 concentration. World J Gastroenterol 12:6225–6228
Kamisawa T, Okamoto A (2006) Autoimmune pancreatitis: proposal of IgG4-related sclerosing disease. J Gastroenterol 41:613–625. doi:10.1007/s00535-006-1862-6
Kamisawa T, Okamoto A (2008) IgG4-related sclerosing disease. World J Gastroenterol 14:3948–3955
Kanno A, Satoh K, Kimura K, Masamune A, Asakura T, Unno M et al (2005) Autoimmune pancreatitis with hepatic inflammatory pseudotumor. Pancreas 31:420–423
Kasashima S, Zen Y, Kawashima A, Endo M, Matsumoto Y, Kasashima F (2009) A new clinicopathological entity of IgG4-related inflammatory abdominal aortic aneurysm. J Vasc Surg 49:1264–1271. doi:10.1016/j.jvs.2008.11.072 (discussion 1271)
Kawa S, Hamano H (2003) Autoimmune pancreatitis and bile duct lesions. J Gastroenterol 38:1201–1203. doi:10.1007/s00535-003-1213-9
Kawaguchi K, Koike M, Tsuruta K, Okamoto A, Tabata I, Fujita N (1991) Lymphoplasmacytic sclerosing pancreatitis with cholangitis: a variant of primary sclerosing cholangitis extensively involving pancreas. Hum Pathol 22:387–395
Kim KP, Kim MH, Song MH, Lee SS, Seo DW, Lee SK (2004) Autoimmune chronic pancreatitis. Am J Gastroenterol 99:1605–1616. doi:10.1111/j.1572-0241.2004.30336.x
Kitagawa S, Zen Y, Harada K, Sasaki M, Sato Y, Minato H et al (2005) Abundant IgG4-positive plasma cell infiltration characterizes chronic sclerosing sialadenitis (Kuttner’s tumor). Am J Surg Pathol 29:783–791
Kloppel G, Luttges J, Lohr M, Zamboni G, Longnecker D (2003) Autoimmune pancreatitis: pathological, clinical, and immunological features. Pancreas 27:14–19
Kojima M, Sipos B, Klapper W, Frahm O, Knuth HC, Yanagisawa A et al (2007) Autoimmune pancreatitis: frequency, IgG4 expression, and clonality of T and B cells. Am J Surg Pathol 31:521–528. doi:10.1097/01.pas.0000213390.55536.47
Komatsu K, Hamano H, Ochi Y, Takayama M, Muraki T, Yoshizawa K et al (2005) High prevalence of hypothyroidism in patients with autoimmune pancreatitis. Dig Dis Sci 50:1052–1057
Kupersmith MJ, Martin V, Heller G, Shah A, Mitnick HJ (2004) Idiopathic hypertrophic pachymeningitis. Neurology 62:686–694
Li Y, Bai Y, Liu Z, Ozaki T, Taniguchi E, Mori I et al (2009) Immunohistochemistry of IgG4 can help subclassify Hashimoto’s autoimmune thyroiditis. Pathol Int 59:636–641. doi:10.1111/j.1440-1827.2009.02419.x
Lyons MK, Caselli RJ, Parisi JE (2008) Nonvasculitic autoimmune inflammatory meningoencephalitis as a cause of potentially reversible dementia: report of 4 cases. J Neurosurg 108:1024–1027. doi:10.3171/JNS/2008/108/5/1024
Mamelak AN, Kelly WM, Davis RL, Rosenblum ML (1993) Idiopathic hypertrophic cranial pachymeningitis report of three cases. J Neurosurg 79:270–276. doi:10.3171/jns.1993.79.2.0270
Masaki Y, Dong L, Kurose N, Kitagawa K, Morikawa Y, Yamamoto M et al (2009) Proposal for a new clinical entity, IgG4-positive multiorgan lymphoproliferative syndrome: analysis of 64 cases of IgG4-related disorders. Ann Rheum Dis 68:1310–1315. doi:10.1136/ard.2008.089169
Miyoshi H, Uchida K, Taniguchi T, Yazumi S, Matsushita M, Takaoka M et al (2008) Circulating naive and CD4 + CD25 high regulatory T cells in patients with autoimmune pancreatitis. Pancreas 36:133–140. doi:10.1097/MPA.0b013e3181577553
Montefusco PP, Geiss AC, Bronzo RL, Randall S, Kahn E, McKinley MJ (1984) Sclerosing cholangitis, chronic pancreatitis, and Sjogren’s syndrome: a syndrome complex. Am J Surg 147:822–826
Naffzinger HC, Stern WE (1949) Chronic pachymeningitis; report of a case and review of the literature. Arch Neurol Psychiatry 62:383–411
Neild GH, Rodriguez-Justo M, Wall C, Connolly JO (2006) Hyper-IgG4 disease: report and characterisation of a new disease. BMC Med 4:23. doi:10.1186/1741-7015-4-23
Okazaki K, Uchida K, Ohana M, Nakase H, Uose S, Inai M et al (2000) Autoimmune-related pancreatitis is associated with autoantibodies and a Th1/Th2-type cellular immune response. Gastroenterology 118:573–581
Otsuki M, Chung JB, Okazaki K, Kim MH, Kamisawa T, Kawa S et al (2008) Asian diagnostic criteria for autoimmune pancreatitis: consensus of the Japan-Korea symposium on autoimmune pancreatitis. J Gastroenterol 43:403–408. doi:10.1007/s00535-008-2205-6
Riku S, Kato S (2003) Idiopathic hypertrophic pachymeningitis. Neuropathology 23:335–344
Shimatsu A, Oki Y, Fujisawa I, Sano T (2009) Pituitary and stalk lesions (infundibulo-hypophysitis) associated with immunoglobulin G4-related systemic disease: an emerging clinical entity. Endocr J 56:1033–1041
Shrestha B, Sekiguchi H, Colby TV, Graziano P, Aubry MC, Smyrk TC et al (2009) Distinctive pulmonary histopathology with increased IgG4-positive plasma cells in patients with autoimmune pancreatitis: report of 6 and 12 cases with similar histopathology. Am J Surg Pathol 33:1450–1462. doi:10.1097/PAS.0b013e3181ac43b6
Taniguchi T, Ko M, Seko S, Nishida O, Inoue F, Kobayashi H et al (2004) Interstitial pneumonia associated with autoimmune pancreatitis. Gut 53:770 (author reply 770–771)
Uchida K, Okazaki K, Asada M, Yazumi S, Ohana M, Chiba T et al (2003) Case of chronic pancreatitis involving an autoimmune mechanism that extended to retroperitoneal fibrosis. Pancreas 26:92–94
Uchiyama-Tanaka Y, Mori Y, Kimura T, Sonomura K, Umemura S, Kishimoto N et al (2004) Acute tubulointerstitial nephritis associated with autoimmune-related pancreatitis. Am J Kidney Dis 43:e18–e25
van Dongen JJ, Langerak AW, Bruggemann M, Evans PA, Hummel M, Lavender FL et al (2003) Design and standardization of PCR primers and protocols for detection of clonal immunoglobulin and T-cell receptor gene recombinations in suspect lymphoproliferations: report of the BIOMED-2 Concerted Action BMH4-CT98–3936. Leukemia 17:2257–2317. doi:10.1038/sj.leu.2403202
Wong S, Lam WY, Wong WK, Lee KC (2007) Hypophysitis presented as inflammatory pseudotumor in immunoglobulin G4-related systemic disease. Hum Pathol 38:1720–1723. doi:10.1016/j.humpath.2007.06.011
Yamamoto H, Yamaguchi H, Aishima S, Oda Y, Kohashi K, Oshiro Y et al (2009) Inflammatory myofibroblastic tumor versus IgG4-related sclerosing disease and inflammatory pseudotumor: a comparative clinicopathologic study. Am J Surg Pathol 33:1330–1340
Yamamoto M, Takahashi H, Sugai S, Imai K (2005) Clinical and pathological characteristics of Mikulicz’s disease (IgG4-related plasmacytic exocrinopathy). Autoimmun Rev 4:195–200. doi:10.1016/j.autrev.2004.10.005
Yamamoto M, Takahashi H, Ohara M, Suzuki C, Naishiro Y, Yamamoto H et al (2006) A case of Mikulicz’s disease (IgG4-related plasmacytic disease) complicated by autoimmune hypophysitis. Scand J Rheumatol 35:410–411. doi:10.1080/03009740600758110
Yamashita K, Haga H, Mikami Y, Kanematsu A, Nakashima Y, Kotani H et al (2008) Degree of IgG4+ plasma cell infiltration in retroperitoneal fibrosis with or without multifocal fibrosclerosis. Histopathology 52:404–409. doi:10.1111/j.1365-2559.2007.02959.x
Yoneda K, Murata K, Katayama K, Ishikawa E, Fuke H, Yamamoto N et al (2007) Tubulointerstitial nephritis associated with IgG4-related autoimmune disease. Am J Kidney Dis 50:455–462. doi:10.1053/j.ajkd.2007.05.018
Yoshimura Y, Takeda S, Ieki Y, Takazakura E, Koizumi H, Takagawa K (2006) IgG4-associated prostatitis complicating autoimmune pancreatitis. Intern Med 45:897–901
Zamboni G, Luttges J, Capelli P, Frulloni L, Cavallini G, Pederzoli P et al (2004) Histopathological features of diagnostic and clinical relevance in autoimmune pancreatitis: a study on 53 resection specimens and 9 biopsy specimens. Virchows Arch 445:552–563. doi:10.1007/s00428-004-1140-z
Zen Y, Harada K, Sasaki M, Sato Y, Tsuneyama K, Haratake J et al (2004) IgG4-related sclerosing cholangitis with and without hepatic inflammatory pseudotumor, and sclerosing pancreatitis-associated sclerosing cholangitis: do they belong to a spectrum of sclerosing pancreatitis? Am J Surg Pathol 28:1193–1203
Zen Y, Kasahara Y, Horita K, Miyayama S, Miura S, Kitagawa S et al (2005) Inflammatory pseudotumor of the breast in a patient with a high serum IgG4 level: histologic similarity to sclerosing pancreatitis. Am J Surg Pathol 29:275–278
Zen Y, Kitagawa S, Minato H, Kurumaya H, Katayanagi K, Masuda S et al (2005) IgG4-positive plasma cells in inflammatory pseudotumor (plasma cell granuloma) of the lung. Hum Pathol 36:710–717. doi:10.1016/j.humpath.2005.05.011
Zen Y, Sawazaki A, Miyayama S, Notsumata K, Tanaka N, Nakanuma Y (2006) A case of retroperitoneal and mediastinal fibrosis exhibiting elevated levels of IgG4 in the absence of sclerosing pancreatitis (autoimmune pancreatitis). Hum Pathol 37:239–243. doi:10.1016/j.humpath.2005.11.001
Zen Y, Fujii T, Harada K, Kawano M, Yamada K, Takahira M et al (2007) Th2 and regulatory immune reactions are increased in immunoglobin G4-related sclerosing pancreatitis and cholangitis. Hepatology 45:1538–1546. doi:10.1002/hep.21697
Zen Y, Fujii T, Sato Y, Masuda S, Nakanuma Y (2007) Pathological classification of hepatic inflammatory pseudotumor with respect to IgG4-related disease. Mod Pathol 20:884–894. doi:10.1038/modpathol.3800836
Zen Y, Inoue D, Kitao A, Onodera M, Abo H, Miyayama S et al (2009) IgG4-related lung and pleural disease: a clinicopathologic study of 21 cases. Am J Surg Pathol 33:1886–1893. doi:10.1097/PAS.0b013e3181bd535b
Zen Y, Onodera M, Inoue D, Kitao A, Matsui O, Nohara T et al (2009) Retroperitoneal fibrosis: a clinicopathologic study with respect to immunoglobulin G4. Am J Surg Pathol 33:1833–1839
Zhang L, Notohara K, Levy MJ, Chari ST, Smyrk TC (2007) IgG4-positive plasma cell infiltration in the diagnosis of autoimmune pancreatitis. Mod Pathol 20:23–28. doi:10.1038/modpathol.3800689
Acknowledgments
We would like to thank Michael W. Cruise, M.D., Ph.D. for working up the IgG4 antibody in our laboratory.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Lindstrom, K.M., Cousar, J.B. & Lopes, M.B.S. IgG4-related meningeal disease: clinico-pathological features and proposal for diagnostic criteria. Acta Neuropathol 120, 765–776 (2010). https://doi.org/10.1007/s00401-010-0746-2
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00401-010-0746-2