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Neurological and Orbital
Involvement of Systemic
IgG4-related Sclerosing Disease
Jad El Bulbul, MD; Abdulrahman Hashem, MD; Ari Goldberg, MD, PhD
Dept of Radiology, Loyola University Medical Center

Case Summary
A 70-year-old male presented to neurology with acomplaint of persistent tinnitus. Contrast-enhanced
magnetic resonance imaging (CEMRI) of the brain
revealed enhancing lesions within the pons, left middle cerebellar peduncle, right hypothalamus, andleft hippocampal regions. The diagnostic work-up
included an abdominal computed tomography (CT)study, which revealed significant retroperitoneal
stranding, for which the patient underwent CT-guided
biopsy. Histopathology demonstrated features suggestive of Immunoglobulin G4 (IgG4)-related retroperitoneal fibrosis. The patient began a 6-month taper oforal prednisone but eventually experienced abnormal
visual changes. A follow-up CEMRI of the brain andorbits revealed new left retrobulbar involvement. Subsequently, rituximab was added to his management
regimen and MRI was repeated at 6-month intervals.
Asymptomatic periods were punctuated by periodsof seizure activity and memory loss, and mycophenolate and dexamethasone were added to the patient’stherapy. Due to concerns of disease progression of
the ocular lesion, neurosurgical intervention was performed. Today, the patient remains clinically stablen©

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on dexamethasone and continues to follow-up withhematological and MRI surveillance.

Diagnosis
IgG4-related sclerosing disease of the central nervous systems (CNS) with orbital involvement.

Imaging Findings
Initial Dotarem ® (gadolinium-based contrast)
enhanced brain MRI (Figure 1) demonstrated evidenceof postcontrast, T1 hyper-enhancing signal abnormality
in the pontine tegmentum and tectum and extending
from the pons into the lower midbrain. The lesion wascentral and slightly lateralized to the right. No otherabnormal enhancement was observed.
A CEMRI scan of the brain (Figure 2) performed 3
years after the initial MRI, showed slight increase inenhancement of the pons, as well as medial temporal
lobe involvement. The scan also revealed a new left
ocular globe and optic nerve enhancement.

Discussion
Immunoglobulin G4- related disease (IgG4-RD) isa chronic, autoimmune, fibro-inflammatory disorderwww.appliedradiology.com

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FIGURE 1. (A) Initial axial pre-contrast T1 image and (B) axial post-contrast T1 image. Contrast enhanced image demonstrated extensive abnormal
signal in the midbrain.

AB

C

FIGURE 2. (A) Coronal T1 contrast-enhanced imaging showed progression of the disease into the temporal lobes (blue arrow) and (B) evolutionof the lesions in the mid-brain and pons. (C) Axial T1 contrast-enhanced sequence also demonstrates development of left orbital “pseudotumor”(white arrow).

first recognized as a unified entity early in the 20thcentury in Japan.1 Often misdiagnosed as malignancy
or infection, the disease can affect any organ system,
including the nervous system. While orbital diseaseremains a rare complication on the IgG4-RD spectrum, a Japanese study found that it comprises about
20 percent of all the infiltrative processes (malignancy

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or inflammation) that can affect the orbital tissue andstructures.2 Regardless of the organ system, the hallmark of IgG4-RD is a subacute tumor-like swelling of
the involved organ3. To date, the precise prevalenceof IgG4-RD disease remains undetermined, although
an outdated estimate in Japan reported a prevalenceof approximately 1.08 per 100,000 of population. 4©

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IgG4-RD demographics had a minor, albeit noteworthy,
predilection to elderly males in almost all categoriesof the disease except for head, neck, and neurological involvements, which were more common amongfemales5.
From a histopathological standpoint, IgG4-RD
lesions share a common triad of dense, IgG4-producing plasma cell infiltrates, obliterative
phlebitis, and ‘storiform’ fibrosis. 6 The exact pathogenesis of IgG4-RD remains under investigation but
likely reflects an antigen-driven inflammatory process.
Both B-cell (blasmablast) and T-cell (T-follicular helper
cells and CD4+ cytotoxic T-lymphocytes (CTL)) linage
are believed to play the main role in IgG4-RD pathogenesis 5. Though not confirmed, recent evidencepoints to the role of autoantigens such as annexin
A11, galectin 3, and laminin 111 in initiating theimmune cascade.7 The concentration of plasmablasts
in the serum of a patient with IgG4-RD appears to correlate well with disease activity 10. This suggests aninteraction of plasmablasts and plasma cells with theCTL and the T-helper lymphocytes, the latter of which
control IgG4 production and are abundant in IgG4-RD
involved tissue.10
The constellation of autoimmune manifestationsof IgG4-RD are often subacute, with tissue involvements often found incidentally on imaging or progressing over months or years before becoming
detectable. Most patients present to ambulatory settings with nonspecific complaints.11 Systemic disease
may present acutely with constitutional symptoms,
although fever is not typical.11 Neurological manifestations result either from direct tissue infiltration orfrom space-occupying lesion compression. The mostcommon IgG4-RD neurological involvements manifest in pachymeningitis and hypophysitis (pituitary
gland and stalk), along with brain parenchyma andperipheral nervous system involvement. Nearly 50%
of patients with IgG4-related neurological disease
present with orbital and perineural disease.11 Clinicalmanifestations of IgG4-related orbital disease dependn©

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on the location and the orbital structures involved,
with infra-orbital nerve involvement most suggestiveof IgG4- related disease.11
Multiple attempts to construct diagnostic criteria
for IgG4-RD have been published; however, several
challenges with the proposed criteria have been
identified in clinical practice.12 Nonetheless, conclusive diagnosis of IgG4-RD classically requires thecorrelation of clinical manifestations with MRI findings, serology, and tissue biopsy. 13 On neurologic
MRI, IgG4-related lesions demonstrate both patchy
and confluent postcontrast hyper-enhancement andappear hypointense on T2-weighted sequencing due
to fibrosis. In the orbit, a tumefactive appearance ofabnormal signal and enhancement is often seen as an“orbital pseudotumor.”14
Early diagnosis and intervention are key determinants of IgG4-RD prognosis. Initial therapy is aimed atinducing remission and is often indicated in the settingof debilitating active symptomatic disease or asymptomatic evidence of progressive disease. 15 Glucocorticoid monotherapy is the mainstay of therapy forsystemic disease, although patients with multi-organ,neurological, or orbital disease may benefit from theaddition of a biologic agent such as rituximab, which
derives its therapeutic function by depleting B cells.16
Owing to the conspicuity of the lesions, particularlyon post-contrast imaging, MRI is useful for monitoring
therapy response and disease progression.

Conclusion
We report a case of systemic sclerotic IgG4-RD,
with CNS and orbital involvement, in which CEMRI isintegral to diagnosis and to surveillance. Diagnosis of
IgG4-RD is multifactorial, but some imaging findings
have been well described and lend a degree of specificity. Inflammatory modulator therapy is most effective
during the proliferative and inflammatory stages of thedisease. Glucocorticoids are usually effective at inducing remission. Patients with evidence of recurrence or
failure of therapy, may benefit from a combination of

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glucocorticoids and rituximab. Given the limited pathogenic understanding of IgG4, further research into
IgG4-RD imaging and treatment is warranted and will
likely be of value.

References

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