Final Diagnosis -- IgG4-related meningeal disease


IgG4-related meningeal disease, previously classified as idiopathic hypertrophic pachymeningitis (IHP).


Idiopathic hypertrophic pachymeningitis (IHP) was originally described by Charcot and Joffroy in 1869 with many subsequent reports. Patients typically present with headaches, along with ataxia and various cranial nerve palsies. On MRI examination, it is characterized by a marked thickening of the dura that enhances along the edges. The cervical spine and thoracic cord are more commonly involved, and intracranially, it's typically seen along the base of the brain. Microscopic examination of these sites revealed extensive fibrotic tissue with a chronic inflammatory infiltrate containing small lymphocytes, plasma cells and rare eosinophils. More recently, Chan et al (1) described a 37 year-old man with spinal cord compression at the thoracic level, an elongated dural mass on MRI and a biopsy showing a dense lymphoplasmacytic infiltrate with a significant subset of the plasma cells being immunoreactive for IgG4, and a high IgG4 to IgG ratio. Chan proposed that a subset of those cases previously described as IHP might represent part of the spectrum of IgG4-related disorders (1).

IgG4 was first recognized as being associated with sclerosing disorders in 2001, when Hamano et al reported that patients with autoimmune pancreatitis had elevated serum levels of IgG4 in comparison to patients with other causes of chronic pancreatitis (4). Since then a number of different disorders, predominantly idiopathic in nature, emerged as a spectrum of diseases linked to the IgG4 subclass (2, 5, 7).

Within the central nervous system, IgG4-related meningeal disease has been recently recognized as a distinct entity. Lindstrom et al (7) described 5 patients with intracranial disease, all of which exhibited the typical lymphoplasmacytic infiltrate and fibrosis of IgG4-related sclerosing diseases, along with increased number of IgG4+ plasma cells. The mean number of IgG4+ cells was 36.2/HPF and the percentage (IgG4/IgG ratio) was 42%. The plasma cells were characteristically polytypic by in-situ hybridization. In addition, there was no evidence of a clonal IGH gene rearrangement by PCR analysis. The authors recommended the use of 10 IgG4+ plasma cells/HPF, as a cutoff, for a diagnosis of IgG4-related meningeal disease. It is now recognized that IgG4 antibodies can be detected in patients with IgG4 pachymeningitis (3). MALT lymphomas can enter in the differential diagnosis, and a recent study by Venkataraman et al (8) has shown that an increased number of IgG4-plasma cells can be seen in intracranial MALTs. The treatment recommendations include high-dose corticosteroid therapy and decompressive surgery if emergently required. The response to steroids is variable (7).

In summary, this case represents one of a few cases of IgG4-related meningeal disease reported. Our patient presented with the typical clinical features of IHP, including visual and hearing loss with associated diffuse leptomeningeal thickening and enhancement. The typical histologic features of IgG4-related meningeal disease were also seen in our case (lymphoplasmacytic infiltrate with fibrosis). Molecular studies and in-situ hybridization confirmed the lack of a clonal population of B-cells or plasma cells. These features along with the high serum IgG4 levels and rich IgG4+ infiltrate were diagnostic of the disease.


  1. Chan SK, Cheuk W, Chan KT, Chan JK. IgG4-related sclerosing pachymeningitis: a previously unrecognized form of central nervous system involvement in IgG4-related sclerosing disease. Am J Surg Pathol. 2009 Aug;33(8):1249-52.
  2. 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
  3. Della Torre E, Bozzolo EP, Passerini G, Doglioni C, Sabbadini MG. IgG4-related pachymeningitis: evidence of intrathecal IgG4 on cerebrospinal fluid analysis. Ann Intern Med. 2012 Mar 6;156(5):401-3
  4. 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
  5. Kamisawa T, Okamoto A (2006) Autoimmune pancreatitis: proposal of IgG4-related sclerosing disease. J Gastroenterol 41:613-625.
  6. Kupersmith MJ, Martin V, Heller G, Shah A, Mitnick HJ (2004) Idiopathic hypertrophic pachymeningitis. Neurology 62:686-694
  7. Lindstrom KM, Cousar JB, Lopes MB. IgG4-related meningeal disease: clinico-pathological features and proposal for diagnostic criteria. Acta Neuropathol. 2010 Dec;120(6):765-76.
  8. Venkataraman G, Rizzo KA, Chavez JJ, Streubel B, Raffeld M, Jaffe ES, Pittaluga S. Marginal zone lymphomas involving meningeal dura: possible link to IgG4-related diseases. Mod Pathol. 2011 Mar;24(3):355-66

Contributed by Gru AA, Kolar G, Wagner-Johnston ND, Schmidt R , Yaseen NR

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