Radiological Determinants of Complicated Immunoglobulin G4–Related Ophthalmic Disease: A Territory-Wide Cohort Study : The Asia-Pacific Journal of Ophthalmology

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Radiological Determinants of Complicated Immunoglobulin G4–Related Ophthalmic Disease: A Territory-Wide Cohort Study

Lai, Kenneth K.H. MBChB*; Chu, Winnie C.W. FRCR; Li, Emmy Y.M. FRCS (Ed), FCOphthHK; Chan, Regine Y.C. FCOphthHK§; Wei, Yingying PhD; Jia, Ruofan MPhil; Cheng, Andy C.O. FRCOphth, FRCSEd; Chan, Karen K.W. MRCSEd(Ophth)§; Chin, Joyce K.Y. FCOphthHK, FHKAM§; Kwok, Jeremy S.W. FCOphthHK, FHKAM#,**; Io, Ida Y.F. FCOphthHK††; Yip, Nelson K.F. FCOphthHK, FHKAM‡‡; Li, Kenneth K.W. FRCOphth(UK)‡‡; Chan, Wai Ho FCOphthHK§§; Lam, Nai Man FCOphthHK, FHKAM; Yip, Wilson W.K. FCOphthHK§; Young, Alvin L. MMedSc(Hons), FRCOphth§; Chan, Edwin FCOphthHK*; Ko, Callie K.L. FCOphthHK*; Ko, Simon T.C. FCOphthHK*; Yuen, Hunter K.L. FRCSEd, FCOphthHK‡,∥∥; Tham, Clement C.Y. FCOphthHK, FHKAM∥∥; Pang, Chi Pui DPhil∥∥; Chong, Kelvin K.L. FCOphthHK, FHKAM§,∥∥

Author Information
Asia-Pacific Journal of Ophthalmology: September/October 2022 - Volume 11 - Issue 5 - p 417-424
doi: 10.1097/APO.0000000000000552
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Abstract

Immunoglobulin G4–related disease (IgG4-RD) is an immune-mediated fibroinflammatory disease characterized by tumefactive lesion with prominent IgG4+ plasma cells infiltrating1 into multiple organs.2 Distinct patterns of affected organs in IgG4-RD patients were recently reported to have differential epidemiological features and prognostic outcomes.3–5 For example, East Asian race, female sex, and atopic background were more common among those with head and neck phenotype.3,4

IgG4-related ophthalmic disease (IgG4-ROD) causes infiltration, enlargement, fibrosis, and dysfunction of the lacrimal glands, extraocular muscles (EOMs), periorbital and optic nerves, as well as eyelid, orbital, and palpebral soft tissues.6 The lacrimal gland was commonly involved in Japanese patients with IgG4-ROD.7 EOMs were involved in 89% of patients in a Caucasian study.8 Infraorbital nerve enlargement (IONE) was specific to IgG4-ROD9 and reactive lymphoid hyperplasia.10

IgG4-RD poses clinical challenges due to its heterogeneous manifestations, as it can affect nearly any anatomic site.2 Delay in diagnosis may result in irreversible organ failure. We previously reported that 5% of IgG4-ROD patients suffered from IgG-related optic neuropathy (IgG4-RON), for which both clinical and radiological features of upper cranial nerve involvement were risk factors.11 IgG4-ROD has reported a strong association with orbital lymphoma.12,13 However, clinical implications of radiological features in IgG4-ROD remain unclear. In this study, we examine the frequencies and locations of lesions radiologically and investigate their associations with IgG4-RON and IgG4-related ocular adnexal lymphoma (IgG4-ROL).

METHODS

We conducted a retrospective study of all consecutive cases of biopsy-proven IgG4-ROD from 2005 to 2019. All patients were managed by all 7 Hospital Authority clusters, which cover the territory-wide, publicly funded ophthalmology service in Hong Kong, and the Hong Kong Sanatorium & Hospital.11 This study followed the Declaration of Helsinki and ethics approval was obtained from the institutional review board of each participating hospital.

Orbital adnexal specimens including the lacrimal glands (n=108), discrete masses (n=30), infiltrated fat (n=10), conjunctiva (n=2), and EOMs (n=3) were obtained by open surgical biopsies. Diagnosis of IgG4-ROD required histological evidence of lymphoplasmacytic infiltrates of >50 IgG4+ cells per high power field (×400) and IgG4+/IgG+ ratio of >40% of the specimen.14,15

Orbital images including computed tomography (CT) and magnetic resonance imaging (MRI) were reviewed independently by 2 ophthalmologists masked to clinical outcomes. Both reviewers were unaware of the measurements made by the other observer and had no access to the clinical data at the time of measurements. Radiological findings were further confirmed by a neuroradiologist with over 30 years of experience. The lacrimal gland was enlarged if the coronal length and width were >24.4 and 5.2 mm, or axial length and width were >18.3 and 6.4 mm, which is >95% of the normal population.16 Asymmetric lacrimal gland enlargement was defined by the difference in axial length of at least 5 mm.17 Thickness of an EOM was measured as the dimension perpendicular to the long axis on the coronal image and compared with the optic nerve sheath diameter (ONSD).18 EOM was enlarged if thicker than the ONSD on coronal images. Infraorbital and frontal nerves were enlarged if the nerve diameter was larger than that of the ONSD on coronal images.

Radiological risk factors were compared using the Fisher exact test. The mean difference of age between the 2 variables was compared using an unpaired t test. Multivariate logistic regression was also used to evaluate the associations of the radiological risk factors with IgG4-RON and IgG4-ROL. P value <0.05 was taken as significant. All statistical analyses were performed using the SPSS statistical software package (Window, version 24.0; IBM Corp., Armonk, NY).

RESULTS

A total of 122 Chinese patients with IgG4-ROD were identified. The average (SD) age of disease onset was 57±15 years (range, 15–88 years); 66/122 (54%) were males and 56/122 (46%) were females. The average follow-up was 73±48 months (range, 24–260 months). The most common ocular presentation was gradual onset (between 3 and 6 months) upper eyelid swelling in 82/122 (67%) patients, 60% being bilateral, followed by palpable mass (23/122, 19%), prominent eye (17/122, 14%), and blurred vision (4/122, 3%). Prebiopsy orbital images were obtained by CT in 105/122 (86%) of patients and by MRI in 40/122 (33%) of patients.

Radiological Features

Among the 115 patients with prebiopsy orbital images, 103/115 (90%) of patients had lacrimal gland enlargement. Among them, 66/103 (64%) showed lacrimal gland enlargement extending into the extraconal retrobulbar space, 50/103 (41%) had isolated lacrimal gland enlargement, and 12/115 (10%) had normal lacrimal gland radiologically (24 eyes) (Fig. 1). Twenty-six of 115 (23%) of patients had discrete orbital mass radiologically involving the extraconal (10 patients), intraconal (10 patients), and both extraconal and intraconal (6 patients) spaces (Fig. 2). IONE was observed in 31/115 (27%) patients, and frontal nerve enlargement in 17/115 (15%). Paranasal sinus inflammatory changes were observed in 57/115 (50%) of patients, 49 being bilateral. One patient had a lacrimal sac lesion presenting as dacryocystitis. The radiological features were summarized in Table 1.

F1
FIGURE 1:
A, Axial computed tomography orbit showing bilateral enlarged lacrimal glands. B, Axial computed tomography orbit showing unilateral enlarged left lacrimal gland.
F2
FIGURE 2:
A, Axial T1-weighted image magnetic resonance imaging orbit showing left intraconal mass. B, Coronal computed tomography orbit showing left infiltrative mass involving both intraconal and extraconal space.
TABLE 1 - Frequency and Locations of Lesions in IgG4-ROD Radiologically
Patients (N=115) Eyes (N=230) Bilateral [n (%)]
LGE 103 194 91 (88)
EOME 41 61 20 (49)
 LR 30 45 15 (50)
 IR 28 36 8 (29)
 MR 18 25 7 (39)
 SR 12 18 6 (50)
IR+LR 11 13 2 (18)
IR+MR 7 8 1 (14)
IR+SR 5 5 0
3 EOME or more 13 13 0
ION 31 41 10 (32)
FN 17 26 9 (53)
Discrete orbital mass 26 33 7 (27)
 EC 10 11 1 (11)
 IC 10 11 1 (11)
 EC and IC 6 11 5 (55)
Paranasal sinus inflammatory change 57 NA 49
EC indicates extraconal; EOME, extraocular muscle enlargement; FN, frontal nerve; IC, intraconal; IgG4-ROD, immunoglobulin G4–related ophthalmic disease; ION, infraorbital nerve; IR, inferior rectus; LGE, lacrimal gland enlargement; LR, lateral rectus; MR, medial rectus; NA, not applicable; SR, superior rectus.

At least 1 EOM enlargement was found in 41/115 (37%) patients. Among them, lateral rectus was the most frequently involved EOM in 30/41 (73%) patients. We identified 3 patterns of EOM enlargement: (1) 2 adjacent EOMs involving the inferior rectus in 23/41 (56%) patients, (2) at least 3 EOMs in 13/41 (32%) patients, and (3) single EOM in 5/41 (12%) patients. Among the 41 patients, 61 eyes with enlarged EOM. Among them, 54/61 (88%) had fusiform enlargement, 7/61 (12%) had nodular enlargement, and 33/61 (54%) showed tendon-sparing, fusiform EOM enlargement (Fig. 3).

F3
FIGURE 3:
A, Coronal T1-weighted image magnetic resonance imaging orbit showing bilateral enlarged inferior and lateral recti. B, Coronal computed tomography orbit showing right enlarged inferior, medial and lateral recti, and infraorbital nerve.

Presenting Radiological Features With IgG4-RON and IgG4-ROL

Six of the 115 (5.3%) patients suffered from IgG4-RON including 4 compressive and 2 infiltrative optic neuropathies as distinguished by radiological features (Fig. 4). Four (67%) IgG4-RON patients had intraconal lesions versus 12/109 (11%) of non–IgG4-RON patients (P<0.05) (Table 2). Likewise, nerve enlargement was significantly associated with IgG4-RON: infraorbital (5/6, 83% vs 25/109, 23%, P<0.005) and frontal (3/6, 50% vs 14/109, 13%, P<0.05), respectively. Despite the marginal associations identified by univariate analysis, no significant association with IgG4-RON was identified when all of the radiological features were added to the multivariate logistic regression model (Table 3).

F4
FIGURE 4:
A, Coronal computed tomography orbit of a patient with right compressive immunoglobulin G4–related optic neuropathy with intraconal mass compressing on the optic nerve (blue arrow). B, Axial T1-weighted image magnetic resonance imaging orbit of a patient with right infiltrative immunoglobulin G4–related optic neuropathy with infiltrative lesions along the optic nerve (blue arrow).
TABLE 2 - Radiological Features of IgG4-ROL and IgG4-RON
The Rest of the Cohort IgG4-RON P *
IgG4-RON
 No. patients 109 6 NA
 LGE 97 6 >0.05
 EOME 37 4 0.103
 Intraconal mass 12 4 <0.05
 IONE 26 5 <0.005
 FNE 14 3 <0.05
IgG4-ROL
 No. patients 106 9 NA
 LGE 94 9 0.594
 ALGE 14 7 <0.05
 EOME 37 4 0.719
 Discrete orbital mass 22 4 0.115
 IONE 31 0 0.1103
 FNE 17 0 0.352
Bold values indicate significant result.
*Use of Fisher exact test.
ALGE indicates asymmetric lacrimal gland enlargement; EOME, extraocular muscle enlargement; FNE, frontal nerve enlargement; IgG4-ROL, immunoglobulin G4–related ocular adnexal lymphoma; IgG4-RON, immunoglobulin G4–related optic neuropathy; IONE, infraorbital nerve enlargement; LGE, lacrimal gland enlargement; NA, not applicable.

TABLE 3 - Multivariate Analysis of the Associations With IgG4-ROL and IgG4-RON Radiologically
Variables Regression Coefficients SE P
IgG4-ROL
 Intercept −29.97363 6976.8180 0.9966
 LGE 19.7945 6976.8170 0.9977
 ALGE 3.7482 1.1715 0.0014*
 EOME −0.6322 1.1829 0.5931
 Discrete orbital mass 3.2828 1.3774 0.0172*
 IONE −20.3647 3806.3718 0.9957
 FNE −17.8206 4705.4764 0.9970
 Age 0.0897 0.0484 0.0637
 Sex 1.0275 1.1578 0.3749
IgG4-RON
 Intercept −19.05 2318 0.993
 LGE 14.33 2318 0.995
 ALGE 1.935 1.3 0.137
 EOME 0.8862 1.193 0.458
 Discrete orbital mass 1.278 1.389 0.358
 IONE 2.347 1.543 0.128
 FNE −0.0542 1.171 0.993
 Age −0.0062 0.0328 0.85
 Sex −0.9522 1.26 0.45
ALGE indicates asymmetric lacrimal gland enlargement; EOME, extraocular muscle enlargement; FNE, frontal nerve enlargement; IgG4-ROL, immunoglobulin G4–related ocular adnexal lymphoma; IgG4-RON, immunoglobulin G4–related optic neuropathy; IONE, infraorbital nerve enlargement; LGE, lacrimal gland enlargement; SE, standard errors.

IgG4-ROL was diagnosed in 9/115 (8%) of patients at the time of or after the IgG4-ROD diagnosis (Table 2). Six patients had extranodal marginal zone B-cell lymphoma mucosa-associated lymphoid tissue type, among which 3 affected the lacrimal glands, 2 the eyelids, and 1 the orbital soft tissue. Two patients had follicular lymphoma that affected the lacrimal glands and 1 patient had orbital diffuse large B-cell lymphoma. Seven of 9 (78%) of these IgG4-ROL patients had asymmetric lacrimal gland enlargement versus 14/106 (13%) of non–IgG4-ROL patients (P<0.05). Multivariate logistic regression analysis showed that both asymmetric lacrimal gland enlargement (P<0.05) and discrete orbital mass (P<0.05) were significantly related to IgG4-ROL (Table 3).

DISCUSSION

In this cohort of 122 patients, 115 patients with orbital images were reviewed. We found a significant association of IgG4-RON with both intraconal mass and trigeminal nerve enlargement radiologically. IgG4-ROL was significantly associated with asymmetric enlargement of the lacrimal gland and discrete orbital mass.

The lacrimal gland was the most frequently involved in 90% of our patients, similar to the Japanese,7,19 Korean,20 and American21 studies. 44% of our patients presented with isolated lacrimal gland enlargement, which was comparable to 48% in the Japanese cohort reported by Sogabe et al.7 In contrast, EOM was reported as the most common site of involvement in 1 European cohort.22 Forty-one of 115 (36%) of our patients had enlarged EOM, and only 9/41 (22%) of them suffered from diplopia, similar to previous reports.7,23,24 IONE was associated with IgG4-ROD9 and reactive lymphoid hyperplasia,10 and it was found in 27% of our patients. A review on the notable studies showing radiological features of IgG4-ROD was summarized in Table 4.

TABLE 4 - Literature Review on the Radiological Features of IgG4-ROD
References N Most Frequent Involved Site EOME Most Frequent Involved EOM IONE FNE Mass Bilateral CT MRI T1WI (Signal) MRI T2WI (Signal)
This cohort 115 LG (90%) 36% LR 27% 15% 23% (38% IC, 38% EC) (24% IC and EC) 80% Well-defined border, early homogenous enhancement with contrast Precontract: Hypointense: 50% Isointense:50% Hypointense: 80% Isointense: 20%
Ohshima et al25 16 NA NA NA 41% NA NA NA NA NA NA
Toyoda et al19 15 (IgG4-H&N disease) LG (53%) NA NA 27% 7% 33% (EC) 53% Well-defined borders NA Hypointense
Song et al20 18 LG (89%) NA NA 6% 6% 11% medial cantus lesion, 11% EC 67% Bilateral LG E Well homogenous attenuation, homogenous enhancement with contrast Well-defined margin Isointense Well-defined margin Hypointense
Ginat et al21 9 LG (56%) 56% NA 22% 11% 22% lacrimal sac 56% NA Intermediate Hypointense, heterogeneously hypointense and isointense
Sogabe et al7 65 LG (88%) 24.6% IR 32% 17% 12% unknown origin, 5% surrounding the ON 93% Bilateral LG E NA LG: hypointense Orbital mass: Isointense LG: Hypointense Orbital fat: Hyperintense on fat saturated T2WI Orbital mass: Isointense
Hardy et al10 7 NA NA NA 100% NA NA NA NA NA NA
Tiegs-Heiden et al8 27 EOM (89%) 89% LR 30% NA NA 88% Bilateral EOME NA NA NA
Soussan et al9 15 NA NA NA 52% NA NA NA NA NA Isointense
Li et al26 26 NA NA NA NA NA NA 81% NA NA NA
Yuan et al27 42 NA 60% NA NA NA NA 50% vs. 19% Unilateral in OAL Well-defined NA NA
Elkhamary et al28 6 Trigeminal nerve branches (100%) 16% NA 100% 9 of 12 eyes 17% IC 67% NA NA NA
Klingenstein et al22 13 EOM (77%) 77% LR 23% 19% NA 85% NA NA NA
CT indicates computed tomography; EC, extraconal; EOM, extraocular muscle; EOME, extraocular muscle enlargement; FNE, frontal nerve enlargement; IC, intraconal; IgG4-H&N disease, immunoglobulin G4–related head and neck disease; IgG4-ROD, immunoglobulin G4–related ophthalmic disease; IONE, infraorbital nerve enlargement; IR, inferior rectus; LG, lacrimal gland; LR, lateral rectus; MRI, magnetic resonance imaging; NA, not applicable; OAL, ocular adnexal lymphoma; ON, optic nerve; T1WI, T1-weighted image with contrast; T2WI, T2-weighted image.

EOM enlargement is found in multiple conditions such as IgG4-ROD, idiopathic orbital inflammatory disease, thyroid eye disease (TED), and orbital metastasis.29 Both IgG4-ROD and TED can have bilateral and multiple EOM enlargement radiologically.30,31 Komatsu et al32 reported that up to 27% of autoimmune pancreatitis patients were associated with hypothyroidism, indicative of thyroid involvement in IgG4-RD. Tooley et al33 suggested that the key features to distinguish IgG4-ROD from TED were disproportionately large lateral rectus muscle and the enlarged infraorbital nerves. In our cohort, the lateral rectus was also the most frequently involved EOM. Up to 27% and 15% of patients had infraorbital and frontal nerve enlargement, respectively. Both studies by Tiegs-Heiden et al8 and Klingenstein et al22 showed that the lateral rectus was the most frequently involved EOM; meanwhile, Sogabe et al7 described the inferior rectus as the most frequently involved EOM. TED typically involves the medial and inferior rectus, and the lateral rectus is rarely involved when multiple muscles are involved.30 Radiological features of TED in comparison to our IgG4-ROD cohort are summarized in Table 5. IgG4-ROD should be included for differential diagnosis in patients with isolated lacrimal gland and/or lateral rectus enlargement radiologically.29

TABLE 5 - Radiological Features of IgG4-ROD and TED
Our IgG4-ROD Series TED34–36
Most frequent involved ocular adnexa LG (90%) EOM
Bilateral/symmetric disease 80% 70%
EOME patterns 36% with EOME  Enlargement of 2 EOM involving the IR  Diffuse enlargement of at least 3 EOMs  Single EOME Recti muscle involvement (IR>MR>SR)
Most frequent EOME LR (73%) IR (up to 66%)
Tendon involvement 46% tendon sparing Limits to the nontendonous portion of EOM
ION/FNE 39%/16% Absence
Orbital mass 17% Absence
EOM indicates extraocular muscle; EOME, extraocular muscle enlargement; FNE, frontal nerve enlargement; IgG4-ROD, immunoglobulin G4–related ophthalmic disease; ION, infraorbital nerve; IR, inferior rectus; LG, lacrimal gland; LR, lateral rectus; MR, medial rectus; SR, superior rectus; TED, thyroid eye disease.

IONE has been reported as pathognomonic of IgG4-ROD.9 It had been previously found in both reactive lymphoid hyperplasia and IgG4-ROD.10 Both reports were on Caucasian patients. Recently, infraorbital nerve and/or frontal nerve enlargement were also found in Chinese lymphoma patients.37 Optic nerve sheath inflammation, compression by enlarged EOM, pseudotumor mass, hypertrophic cranial pachymeningitis, and hypophysis involving optic chiasma were reported as MRI features for IgG4-RON.26 We observed up to 27% of patients with enlarged infraorbital nerve. All 6 of our IgG4-RON patients had at least 1 branch of the trigeminal nerve enlargement. We recently recommended long-term ophthalmology follow-up in IgG4-ROD patients with radiological evidence of upper cranial nerve enlargement and intraconal lesions.11 We also advised patients on self-monitoring of drop in vision, ptosis, double-vision, and change in periocular sensation between follow-ups.11

IgG4-ROL was first reported in IgG4-ROD in Chinese patients by Cheuk et al.12 IgG4-ROD appeared to have a stronger association with orbital lymphoma when compared with other organ-specific involvement of IgG4-RD.2,12,13 Both IgG4-ROD and IgG4-ROL affect the lacrimal glands. Klingenstein et al22 reported that there is no radiological difference between these 2 conditions, and it is impossible to differentiate the 2 entities clinically. Yuan et al38 reported that orbital lymphoma was more commonly unilateral and showed molding features radiologically when compared with IgG4-ROD. Yoo et al39 reported that T2 isointensity on MRI and hyperattenuation on precontrast CT images were observed in some IgG4–mucosa-associated lymphoid tissue lymphoma cases. They suggested that IgG4-ROD patients who are refractory to glucocorticoid treatment should be aware of the potential development of lymphoma. Kubota et al40 reported that 9 of their 10 IgG4-ROL patients were presented unilaterally which was comparable to our cohort.

Diffusion-weighted imaging has been increasingly used in distinguishing the nature of orbital mass such as benign orbital lymphoproliferative disorder and orbital lymphoma.27 Lymphoma is typically hypercellular with cells of enlarged nuclei, which reduce the space for water proton diffusion in both intracellular and extracellular spaces, resulting in a decrease in the apparent diffusion coefficient value.41 Comparing to structural MRI, intravoxel incoherent motion MRI had been reported to yield a higher sensitivity in differentiating IgG4-ROD from other types of orbital inflammation.42 Since it is impossible to differentiate IgG4-ROL from IgG4-ROD clinically, the use of diffusion and perfusion MRI is warranted in future studies.

There are several limitations in the present study. First, this was a retrospective multicenter study with inherent differences in the documentation and detailed treatment regimens. Second, this is a study on Chinese patients only. Third, a few patients without prebiopsy images were excluded. Fourth, scanning protocol differed slightly among CT or MRI machines used in collaborating centeres.

CONCLUSIONS

In this territory-wide, IgG4-ROD cohort, the majority of patients had bilateral enlarged lacrimal glands, and the lateral rectus was the most frequently involved EOM as reported before. For the first time, intraconal lesion, infraorbital and frontal nerve enlargements were found to be associated with the development of IgG4-RON, while asymmetric lacrimal gland and discrete orbital mass were associated with IgG4-ROL.

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Keywords:

immunoglobulin G4–related disease; immunoglobulin G4–related ocular adnexal lymphoma; immunoglobulin G4–related ophthalmic disease; immunoglobulin G4–related optic neuropathy; infraorbital nerve enlargement

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