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  • Updated 01.15.2024
  • Released 10.13.2021
  • Expires For CME 01.15.2027

IgG4-related disease: neurologic manifestations



IgG4-related disease is an insidiously progressive autoimmune systemic condition characterized by IgG4+ plasma cell proliferation and infiltration of the affected organs associated with storiform fibrosis. It can affect nearly all the organs and the CNS--particularly the meninges and the pituitary. The disease affects men more frequently than women, and the median age at disease onset is around 50 to 60 years old.

The main presentations of the disease rely on inflammatory pseudotumors or infiltrative lesions. The most commonly affected organs are the biliopancreatic area, the lymph nodes, and the salivary glands. CNS involvement during IgG4-RD relies on hypertrophic pachymeningitis (affecting the brain, the spine, or both) and hypophysitis. The prevalence of IgG4-HP and IgG4-H is unknown; large cohorts of IgG4-RD patients usually report a very low prevalence (about 1% to 5% of all cases), whereas small cohorts report a prevalence of near 35%. This discrepancy is primarily due to the difference in the diagnostic workup, which uses whole-body imaging to diagnose asymptomatic locations of the disease. Thus, many instances of CNS involvement of IgG4-RD remain poorly symptomatic. Despite its low prevalence, neurologists must be aware of this disease because instances of idiopathic pachymeningitis or hypophysitis have been found to correlate with IgG4-RD pathological findings retrospectively.

Many symptoms have been described for IgG4-HP and IgG4-H and are mostly related to the compression of adjacent structures or organ failure. A clinical examination of patients with suspected CNS IgG4-RD should focus on extraneurologic symptoms because a systemic form of the disease occurs in about 60% of patients (16; 13; 14; 15).

In 2019, the American College of Rheumatology and the European League Against Rheumatism provided a "3 steps" new diagnostic criteria for IgG4-RD (24). This study provides an accurate life characterization of the disease and allows diagnosing IgG4-RD without pathological analysis. However, it is essential to understand that CNS involvement during IgG4-RD can present as isolated organ disease, and in such cases, most of the established diagnostic criteria may not apply. Thus, pathological analysis remains essential.

Apart from pathological analysis, there is no reliable biomarker to assess IgG4-HP or IgG4-H diagnosis. Serum IgG4 concentration increases in about half of the patients with IgG4-HP and 75% of patients with IgG4-H, mainly when other organs are involved. Therefore, elevated serum concentration of IgG4 should encourage physicians to perform whole-body scans, looking for a location that could guide a non-neural biopsy but cannot be sufficient to allow the diagnosis alone.

Treatment of IgG4-RD is based on steroid therapy, usually begin between 0.6 to 1 mg/kg/d. Steroids are often tapered over a 3- to 6-month period. During specific CNS involvement, decompressive surgery is often needed, and intravenous pulse methylprednisolone can be performed.

Relapses often occur during CNS IgG4-RD, and long-term immunosuppressive treatment can be necessary for such patients. Many therapies are studied in IgG4-RD, but the B-cell-depletive treatment rituximab has shown remarkable efficacy in reducing relapse rate, steroid use, inflammatory mass volume, and blood IgG4 concentrations. However, for CNS IgG4-RD, only retrospective data are available to support rituximab efficacy.

Key points

Little is known about IgG4-HP and IgG4-H, and our knowledge comes from case series and literature reviews.

IgG4-HP and IgG4-H are unusual syndromes, but many instances of idiopathic pachymeningitis or hypophysitis have been found to be IgG4-RD retrospectively.

The pathological analysis is essential to the diagnosis.

Systemic disease occurs in more than 50% of patients.

Historical note and terminology

The IgG4-RD is a recognized pathology with the following historical timeline:

In 2001

First description of IgG4-RD (10).

In 2003

First description of extra-pancreatic location of IgG4-RD.

Since 2003

Nearly all anatomic sites were described in association with IgG4-RD.

In 2004

First description of IgG4-related hypophysitis (22).

In 2009

First description of IgG4-related hypertrophic pachymeningitis (06).

In 2011

First diagnostic criteria for IgG4-related hypophysitis.

In 2012

Two Japanese teams provide the first comprehensive diagnostic criteria for systemic IgG4-RD (21).

In 2012

Massachusetts General Hospital physicians developed the Responder Index as a revised tool to assess IgG4-RD activity and severity (04).

In 2015

Massachusetts General Hospital IgG4-RD team shows the importance of blood total plasmablast count to assess IgG4-RD activity (23).

In 2015

A multicentric American prospective trial showed the efficacy of B-cell depletion in IgG4-RD (05).

In 2019

The American College of Rheumatology and the European League Against Rheumatism provided new international diagnostic criteria for IgG4-RD (24).

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