Optic Perineuritis and its Association with Rheumatic Connective Tissue Disease

Objective Analyze the etiology and clinical characteristics of optic perineuritis (OPN) in a Chinese patient population Methods Neuro-ophthalmological examination and a series of blood samples were used in this retrospective observational cohort study to compare characteristics of OPN with idiopathic demyelination optic neuritis (IDON). Results 44 OPN cases (74 eyes) and 61 IDON cases (78 eyes) were analyzed. The causes of OPN with CTD were Graves’ disease, Immunoglobulin G4-related disease (IgG-4 RD), granulomatosis with polyangiitis (GAP), systemic lupus erythematosus (SLE), Sarcoidosis, Rheumatoid, scleroderma, Behcet's disease, and gout. Overall, 33 cases showed orbit fat inltration. Specically, 9 cases with IgG-4 RD showed trigeminal nerve branch involvement, 12 cases with Graves’ showed extraocular muscle belly enlargement, and 4 cases with GAP showed pterygopalatine fossa pseudotumor through orbital magnetic resonance imaging (MRI). Compared to IDON patients, OPN patients were older (p=0.004) and more likely bilateral involvement 26 (78.79%) patients had bilateral involvement in OPN group versus 17 (27.87%) in the IDON group (p<0.001). Visual acuity scores was better in OPN patients compared to those with IDON, 0.55±0.91versus 1.19±1.24 (p<0.001). 8 (13.11%) IDON patients also had multiple sclerosis (MS) and 7(11.48%) patients had neuromyelitis which was signicantly more than the 0 patients in OPN group (p=0.04). Conclusions OPN had distinct etiologies and clinical characteristics from IDON and is more often associated with rheumatic CTD. Using OPN characteristics to diagnose CTD should prove useful for clinicians when presented with patients that have multiorgan dysfunction that include ophthalmologic ndings. in its thickening, perineural be a characteristic imaging nding of OPN (26). The most prominent feature of thyroid-associated ophthalmopathy is the thickening and protruding of extraocular muscles (27). The trigeminal nerve branches were not involved in the OPN of the GPA patients in this study and the extraocular muscles were not thickened. We were unable to nd any prior reports of trigeminal nerve branching and extraocular muscle involvement in patients with GPA, Graves’, and sarcoidosis.


Introduction
Optic perineuritis (OPN) is a rare form of orbital in ammatory disease targeting the optic nerve sheath (1). OPN usually presents with minor visual impairment, optic disc edema, and visual eld abnormalities that include arcuate defects and peripheral island defects (2). OPN mimics optic neuritis but is distinguished by the classical optic nerve sheath (ONS) enhancement observed on MRI (3). OPN has long been considered an idiopathic in ammatory disease. However, recent reports suggest it may be related to other in ammatory and infectious diseases (4), yet most studies are case reports and lack a detailed analysis of OPN pathogenesis and clinical features.
OPN is a special optic neuropathy that has a distinct etiology from neuromyelitis optica spectrum disorders (NMOSDs) or multiple sclerosis (MS)-related optic neuritis (ON). Prior studies often found OPN associated with rheumatic connective tissue diseases (CTDs) (5), yet its pathogenic mechanisms are still unclear.
OPN differs from idiopathic demyelination optic neuritis (IDON) which is caused by demyelinating of the optic nerve due to in ammation(6). Optic nerve sheath biopsy from a prior study showed, thickening of the perioptic meninges and the pia mater due to brosis and in ammatory in ltration, without vasculitis or granulomas, yet mechanisms of how this in ammation developed and invaded the nerve sheath remain unknown (1).
In this study of 44 Chinese patients with OPN, we examine the most common etiologies and using patient imaging data, try to elucidate mechanisms underlying OPN related to connective tissue diseases.
Materials And Methods 1. Patients 44 patients with OPN were recruited from the ophthalmology department of Beijing Friendship Hospital (BFH) at Capital Medical University, in Beijing, China. Patient recruitment took place from September 2015 to November 2018, and patients meeting the inclusion criteria were offered participation in the study, which included consultation and follow-up outpatient visits. Inclusion criteria were contrast enhancement surrounding the intra-orbital optic nerve and at least one of the following clinical symptoms: 1) reduction of visual acuity, 2) impairment of visual eld, or 3) eye pain (1,2). Patient follow-up varied, lasting from 6-36 months. Exclusion: MRI contrast enhancement or T2 lesions of the intra-orbital optic nerve.

Neuro-ophthalmological Examination
Ophthalmic examinations included slit lamp examination, pupillary reaction testing, noncontact intraocular pressure examination, and fundus examination by senior neuro-ophthalmologists. Visual acuity was examined using the standard table of vision logarithms at a distance ve meters. Those unable to read any letters at one meter were further examined using nger counts, hand movements, or light perception. Visual eld testing was performed using a Humphrey eld Analyzer (30 − 2 SITA, Humphrey 750i, Zeiss, Germany). Optical coherence tomography (OCT) examinations were performed using enhanced depth imaging (EDI) and OCT (Spectralis; Heidelberg Engineering, Heidelberg, Germany).
Orbital MRI was performed in all patients and evaluated using MRI-3.0T (TW1WSPEED HDXT, GE, USA). Scanning sequence and parameters included coronal T1-weighted Fast spin-echo (TR = 660 ms; TE = 11.1 ms, matrix size = 256 × 256 mm, FOV = 18 × 18 cm, slice thickness = 3.0 mm) and Gd-DTPA 0.1 mmol/kg was used as contrast agent for enhanced MRI when combined with a fat suppression scan technique. We took care to not mistake normal dural enhancement due to the rich vascular supply of the region by looking for the "tram-track sign". Two senior radiologists reviewed the MRI images as necessary.
Serum was drawn at the Examination Center for Biomedical Research of BFH. Blood samples were collected as part of routine treatment for this study.

Statistical Analysis
Cohort differences in age and visual acuity were analyzed using the Mann-Whitney test, Pearson χ2 tests, or Fisher's exact test were used to control for gender, clinical symptoms, prognosis, and bilateral involvement. All statistical analyses were performed using Statistical Package for the Social Sciences software V. 19.0 (IBM Corporation). Statistical signi cance was de ned as p < 0.05.

Ethics Approval And Consent To Participate
This study was approved by the BFH Ethics Committee and was conducted following the latest iteration of the Declaration of Helsinki (version:2019-P2-201-01). Participants were given written informed consent (version V1.1/2019-09-16) before inclusion in the study.

Demographics and clinical characteristics
44 patients (23 males and 21 females) had unilateral or bilateral OPN which included a total of 74 eyes. Age at OPN diagnosis ranged from 26 to 64 years (mean±SD: 52.64±17.42). A summary of the demographics of our population can be found in Table 1. Notable ophthalmologic ndings include 11 patients with ptosis, 9 patients with diplopia, and 10 patients with exophthalmos. Visual eld abnormalities included irregular defects 27 52.94% ,peripheral island defects 16 31.37% and diffuse visual eld defect 8 15.69% . The optic disc was swollen in 55 eyes and MRI showed enhancement of the optic nerve sheath in all cases ( Figure 1).

Differences between OPN and IDON
We compared OPN and IDON in Table 2. OPN was more often associated with CTD and infection, IDON was more likely to be associated with MS and NMO

OPN and rheumatic CTD
Graves' disease, IgG-4, and GPA were the major causes of OPN. Common clinical symptoms of OPN are ocular pain, decreased vision, and visual eld defects and orbital MRI with abnormal enhancement around the optic nerve sheath (Table 3). However, OPN characteristics of patients with these rheumatic CTDs were different Table 4 . The most prominent feature of thyroid-associated ophthalmopathy (Graves' disease) was the thickening and protruding of extraocular muscles ( Figure 3). Characteristic ophthalmologic ndings in OPN patients with IgG-4 involved ocular herniation with involvement of trigeminal nerve branches, resulting in nerve thickening ( Figure 4). In GPA patients, formation of an orbital in ammatory pseudotumor was found in the external space of the muscle cone, especially in the inner inferior quadrant ( Figure 5). Soft tissue in ammation in the orbit was found in OPNs associated with CTDs along with otherwise abnormal contrast enhancement on the attachment point of the extraocular muscle ( Figure 6). This suggests that in ammation of the soft tissue extending to optic nerve sheath may be part of the pathogenesis of OPN which could be due to increased vascular permeability, in ammatory cell leakage, and tissue edema.

Discussion
OPN is an uncommon orbit in ammatory disease (7)  This may be due to the differing OPN etiologies, as many of the patients in this small cohort had idiopathic OPN not associated with another speci c condition.
It has been previously established that OPN is an orbital in ammatory disease that is different from IDON(9). Our study illustrates some of the differences between OPN and IDON, which include clinical characteristics, imaging features, and prognosis. We found that OPN are more often with CTD and IDON are more often associated with idiopathic in ammation, such as MS and NMO. Orbital MRI showed low or equal signal on T1WI and slightly low signal on T2WI.
In OPN, contrast-enhanced scans showed that most of the optic nerve sheath presented a strip-like or nodular uniform enhancement with unclear boundaries.
Optic nerve and sheath enhancement were present in IDON. Soft tissue in ammation in the orbit has also been found in OPN, yet in ammation of the orbit is rare in IDON. Unlike OPN, optic nerve sheath enhancement in IDON is almost always accompanied by more prominent optic nerve parenchyma enhancement.
In GPA, formation of an orbital in ammatory pseudotumor was mainly concentrated in the external space of the muscle cone, especially in the inner inferior quadrant (25). OPN patients with IgG-4 often had ocular herniation involving the trigeminal nerve branches, which resulted in its thickening, suggesting perineural growth may be a characteristic imaging nding of OPN (26). The most prominent feature of thyroid-associated ophthalmopathy is the thickening and protruding of extraocular muscles (27). The trigeminal nerve branches were not involved in the OPN of the GPA patients in this study and the extraocular muscles were not thickened. We were unable to nd any prior reports of trigeminal nerve branching and extraocular muscle involvement in patients with GPA, Graves', and sarcoidosis.
CTDs are a group of diseases that affect bones, joints, and surrounding soft tissue, such as muscles, bursa, tendons, fascia, and nerves (28). Chronic in ammation, mediated by T and B lymphocytes, eosinophils, and macrophages, activates broblasts to induce collagen deposition, and ultimately leads to tissue proliferation and dural thickening (29). The optic nerve is a continuation of the central nervous system with a dura, arachnoid, and pia mater. Therefore, the optic nerve sheath is also susceptible rheumatic CTDs. Orbital MRI showed low or equal signal on T1WI and slightly low signal on T2WI. Contrastenhanced scanning showed that most of the optic nerve sheath had strip-like or nodular uniform enhancement with unclear boundaries. Most cases of soft tissue in ammation in the orbit have been found in OPN, differing it from the imaging ndings in IDON. We speculate that OPN may be caused by orbital soft tissue in ammation and that the damage of the optic nerve sheath could be from antigen/antibody-mediated destruction associated with rheumatic disease.
Anti-myelin oligodendrocyte glycoprotein (MOG) autoantibodies have been identi ed in both children and adults with demyelination and are strongly associated with bilateral or recurrent optic neuritis (30). However, anti-MOG antibodies have not been found in patients with OPN (31) and we did not detect these antibodies in our study.
Limitations of this study include its retrospective design and recruitment of patients form only one medical center. Only 44 cases were included in this study due to inability to follow-up with some patients who initially met the inclusion criteria. Multi-center, large sample, case-control prospective studies are needed to further understand OPN pathogenesis and its relationship with other diseases.

Conclusions
OPN is often associated with CTDs such as Graves' disease, GPA, and IgG-4 disease. MRI ndings of OPN patients included orbital fat in ammation, pachymeningitis, in ammation of optic sheath vessels, and edema of the optic nerve sheath which may provide insights into OPN pathogenesis. The possibility of OPN should be considered in the differential diagnosis of atypical optic neuritis to avoid misdiagnosis as IDON or other similar ophthalmologic pathologies discussed in this study.  All of blood samples were collected as part of routine treatment for this study.

Consent for publication
Not applicable.

Availability of data and material
The datasets during and/or analyzed during the current study available from the corresponding author on reasonable request.

Competing interests
The authors declare that there is no con ict of interest regarding the publication of this article. In the role of collection data.