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IgG4-Related Hypertrophic Pachymeningitis Clinical Features, Diagnostic Criteria, and Treatment

Lucy X. Lu, PhD1; Emanuel Della-Torre, MD2; John H. Stone, MD, MPH3; Stephen W. Clark, MD, PhD1,4
[+] Author Affiliations
1Vanderbilt University School of Medicine, Nashville, Tennessee
2Unit of Medicine and Clinical Immunology, Università Vita-Salute San Raffaele, San Raffaele Scientific Institute, Milan, Italy
3Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston
4Department of Neurology, Vanderbilt University School of Medicine, Nashville, Tennessee
JAMA Neurol. 2014;71(6):785-793. doi:10.1001/jamaneurol.2014.243.
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Importance  IgG4-related hypertrophic pachymeningitis (IgG4-RHP) is an increasingly recognized manifestation of IgG4-related disease, a fibroinflammatory condition that can affect virtually any organ. It is estimated that IgG4-RHP may account for a high proportion of cases of hypertrophic pachymeningitis once considered idiopathic.

Objective  To summarize the current knowledge on IgG4-RHP including its pathological, clinical, and radiological presentations. Particular emphasis is placed on diagnostic and therapeutic implications.

Evidence Review  This review is based on 21 reports published in the English medical literature since 2009. PubMed was searched with the following terms: IgG4, pachymeningitis, IgG4-related pachymeningitis, IgG4-related disease, IgG4-related, and IgG4 meningitis. Only cases with biopsy-proven IgG4-RHP were considered and included in this review.

Findings  Little is known with certainty regarding the pathogenesis of IgG4-RHP. The presence of oligoclonally restricted IgG4-positive plasma cells within inflammatory meningeal niches strongly suggests a specific response against a still unknown antigen. Clinical presentation of IgG4-RHP is not distinguishable from other forms of hypertrophic pachymeningitis and reflects mechanical compression of vascular or nerve structures, leading to functional deficits. Signs of systemic IgG4-related disease may concomitantly be present. Diagnostic process should rely primarily on magnetic resonance imaging, cerebrospinal fluid analysis, and meningeal biopsy. In particular, hallmark histopathological features of IgG4-RHP are a lymphoplasmacytic infiltration of IgG4-positive plasma cells, storiform fibrosis, and obliterative phlebitis. High-dose glucocorticoids are still the treatment of choice for IgG4-RHP because immunosuppressive agents have shown variable efficacy in reducing the meningeal hypertrophy. Rituximab is a promising therapeutic approach but experience with B-cell depletion strategies remains limited.

Conclusions and Relevance  IgG4-related disease accounts for an increasing proportion of cases of idiopathic hypertrophic pachymeningitis. Clinicians should become familiar with this alternative differential diagnosis because a prompt, specific therapeutic approach may avoid long-term neurological complications.

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Figure 1.
Pathogenic Model of IgG4-Related Hypertrophic Pachymeningitis

Activated T-helper and T-regulatory cells produce interleukins (ILs) that recruit eosinophils and macrophages and activate fibroblasts. Interleukin 4 and IL-10 drive class switching of autoreactive B cells to IgG4 and IgE and induce the differentiation and expansion of IgG4+ plasma cells. Heavy chains are inserted from different IgG4 molecules and separate and recombine randomly (Fab-arm exchange), thereby generating asymmetric bispecific antibodies. pMHC indicates peptide major histocompatibility complex; TGFβ, transforming growth factor β; Th2, type 2 helper T cell; and Treg, regulatory helper T cell.

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Figure 2.
Oligoclonal Bands in IgG4-Related Hypertrophic Pachymeningitis

Magnetic resonance imaging of a patient with IgG4-related hypertrophic pachymeningitis (arrowheads) (A) showing resolution of dural thickness after therapy (C). Concomitant cerebrospinal fluid (CSF) analysis findings demonstrate IgG and IgG4 oligoclonal bands (arrowheads) (B) that disappear after treatment (D).

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Figure 3.
Radiological Features of IgG4-Related Hypertrophic Pachymeningitis

T1-weighted magnetic resonance (MR) imaging, showing hyperintense linear dural thickening (arrowheads) overlying the supratentorial hemispheres (A and B) and the tentorium cerebelli (C) as well as nodular pachymeningeal enhancement along the clivus (D and E). Dural thickening appears hypointense on the T2-weighted MR image (F, asterisks). Pachymeningitis involving the cranial nerves’ canals (arrowheads) shown by gadolinium-enhanced T1-weighted MR imaging (G) and positron-emission tomography (H). Dural thickening is seen throughout the cervical spine with focal nodularity at the C2-3 and C6-7 levels (arrowheads) (I).

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Figure 4.
Anatomic Pathology of IgG4-Related Hypertrophic Pachymeningitis

A, The IgG4-related disease causes hypertrophic thickening of the dura mater (and likely leptomeninges) with mass effect on neighboring structures. Healthy dura mater consists of dense fibrous connective tissue with only scattered fibroblasts (hematoxylin-eosin, original magnification ×200). B, IgG4-related hypertrophic pachymeningitis disrupts this ordered structure and leads to a characteristic pattern of storiform fibrosis (hematoxylin-eosin, original magnification ×200).

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Figure 5.
Histopathology of IgG4-Related Hypertrophic Pachymeningitis

Dural perivascular lymphoplasmacytic infiltrate surrounded by stromal fibrosis (hematoxylin-eosin, original magnification ×200 [A] and ×400 [B]). C, T lymphocytes are interspersed throughout the tissue, but B cells tend to localize within lymphoid aggregates or germinal centers (hematoxylin-eosin, original magnification ×300). D, Stain shows obliterative phlebitis (hematoxylin-eosin, original magnification ×400). Immunohistochemistry staining reveals abundant IgG4+ plasma cells (hematoxylin-eosin, original magnification ×200 [E] and hematoxylin-eosin, original magnification ×400 [F]).

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