Original Investigation Involvement of Multiple Trigeminal Nerve Branches in IgG4-Related Orbital Disease Sahar M Elkhamary, M.D.*†, Antonio Augusto V Cruz, M.D.‡, Maria C Zotin, M.D.§, Murilo Cintra, M.D.§, Patricia Akaishi, M.D.‡, Alicia Galindo-Ferreiro, M.D.‖, Hind M Alkatan, M.D.¶, and Fernando Chahud, M.D.# *Radiology Department, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia; †Diagnostic Radiology Department, Mansoura Faculty of Medicine, Mansoura, Egypt; ‡Ophthalmology Department, School of Medicine of Ribeirão-Preto, University of São Paulo, São Paulo, Brazil; §Radiology Department, School of Medicine of RibeirãoPreto, University of São Paulo, São Paulo, Brazil; ‖Department of Ophthalmology, Complejo Asistencial Palencia, Palencia, Spain; ¶Ophthalmology Department, Pathology Department, College of Medicine, King Saud University, Saudi Arabia; and #Pathology Department, School of Medicine of Ribeirão-Preto, University of São Paulo, São Paulo, Brazil Purpose: To describe the occurrence of multiple trigeminal nerves (TGNs) enlargement in patients with orbital IgG4related disease Methods: Retrospective review of MRI findings and medical records of patients (10 orbits) with orbital IgG4-related disease and enlargement of more than TGN Orbital biopsies were performed in all cases revealing the typical lymphoplasmacytic infiltrate with significant plasma cell positivity for IgG4 (IgG4+/IgG ratio ≥ 40%) Three experienced neuroradiologists reviewed the MRI sequences using a digital imaging viewer system (Horos, https://horosproject.org/) Results: Bilateral involvement of at least TGNs divisions was detected in all patients Enlargement of both V1 and V2 nerves was diagnosed in patients, and in cases, all TGN divisions were involved V2 nerves were the most affected In this division, all 12 infraorbital nerves were enlarged, followed by lesser palatines (10/83.3%), superior alveolar (10/83.3%), and zygomatic (6/50%) V1 and V3 nerves were less affected albeit (75%) frontal branches (V1), and 50% of the inferior alveolar (V3) nerves were also enlarged Conclusions: Widespread involvement of the TGN is an important feature of IgG4-related disease (Ophthalmic Plast Reconstr Surg 2021;37:176–178) E nlargement of multiple branches of the trigeminal nerves (TGNs) is usually a sign of perineural spread of head and neck malignancies.1 In 2011, Katsura et al.2 reported a single patient with isolated enlargement of V2 and V3 branches who was diagnosed as having IgG4-related inflammatory pseudotumor of the TGN Following this early report, Immunoglobulin G4-related disease (IgG4-RD) has been strongly associated with enlargement of the infraorbital nerve (ION).3–17 The authors describe here a group of patients with IgG4-RD in whom several branches of the TGN were enlarged Accepted for publication May 5, 2020 The authors have no financial or conflicts of interest to disclose Address correspondence and reprint requests to Antonio Augusto V Cruz, M.D., Department of Ophthalmology, School of Medicine of Ribeirão Preto, Hospital das Clínicas-Campus, Av Bandeirantes 900, 14049-900 Ribeirão Preto, Brazil E-mail: aavecruz.fmrp@gmail.com DOI: 10.1097/IOP.0000000000001733 176 METHODS This is a retrospective noncomparative analysis of the medical records of patients who presented for assessment of orbital lesions and MRI evidence of trigeminal perineural disease The study was approved by the institutional review board of the hospital and adhered to the tenets of the Declaration of Helsinki Only patients with a biopsy-proven diagnosis of the orbital lesions and MRI imaging of both orbits and head were included Diagnoses were based on the histopathologic characteristics of the tissue samples and on the results of immunohistochemical staining for IgG, IgG4, CD20, CD3, CD68, S100, and CD1A Imaging Technique Patients underwent imaging either with a Philips Achieva 3T machine (Philips Healthcare, Best, the Netherlands) with a 16- or 32-channel Philips head array coil, or with a 3-T scanner (Magnetom Allegra; Siemens, Erlangen, Germany) with a dedicated 32-channel head coil The imaging protocol included T1- and T2weighted sequences on the sagittal, axial, and coronal planes of 3-mmthick sections and no interslice gap Postcontrast T1-weighted fatsuppressed images (Magnevist; Schering, Berlin, Germany; repetition time/echo time = 400–575/13–15 milliseconds) were also obtained for all patients Additional acquisition included high-resolution 3-dimensional constructive interference in steady-state sequences (constructive interference in steady state sequence, repetition time 10.76 milliseconds, echo time 5.38 milliseconds, 70° flip angle, 200 × 200 mm field of view, 512 × 512 mm matrix, and 64 slices The radiologic studies of the patients were reviewed by experienced neuroradiologists masked to patient history, symptoms, and histopathologic data, using a digital imaging and communications in Medicine viewer system (Horos, https://horosproject.org/) and Enterprise Imaging Agfa Health Care (Mortsel, Belgium) The diagnosis of trigeminal perineural disease was based on the classic findings of nerve enlargement or enhancement; obliteration of the fat planes around the nerves and their foramina; and enlargement and/or erosion of foramina, canals, and fissures.18 Perineural disease was characterized according to which right- or left-sided branch of V1, V2, and/or V3 was affected Pertinent intracranial and extracranial structures (cavernous sinus, Meckel’s cave, superior orbital fissure, pterygopalatine fossa, foramen rotundum, foramen ovale, and pterygoid canals) and cisternal segment of TGN were also carefully assessed RESULTS Patients’ demographic data, diagnosis, laterality, type of orbital involvement, and clinical findings are summarized in Table 1 No patient had any complaints associated with trigeminal dysfunction such as Ophthalmic Plast Reconstr Surg, Vol 37, No 2, 2021 Copyright © 2021 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc Unauthorized reproduction of this article is prohibited Ophthalmic Plast Reconstr Surg, Vol 37, No 2, 2021 Trigeminal Nerve Enlargement TABLE 1. Diagnoses, orbital involvement, and clinical findings Clinical findings Sex Age (years) F 37 Bilateral F M M F M 69 60 66 52 72 Bilateral Bilateral Bilateral Right Right Case Orbital involvement Laterality Proptosis Eye motility limitation Chemosis Y Y N N Y Y Y Y N Y N N N N N N N Y N Y N N Y N Y Y N Y N N Lacrimal gland, extraocular muscles, apex Lacrimal gland, apex Lacrimal gland Intraconal mass Lacrimal gland EOM, intraconal mass Conjunctival Optic hyperemia neuropathy EOM, extraocular muscles; F, female; M, male TABLE 2. Trigeminal branches enlarged in IgG4-RD V1 Orbital Patient involvement Total Bilateral Bilateral Bilateral Right Right Bilateral FR V2 NC LC IO ZYG V3 GP LP SA AT DT IA BC R L R L R L R L R L R L R L R L R L R L R L R L + + + + + − + + + + − −− − − − − − − − − + − − − − + − + − − − + − + − − + + + + + + + + + + + + + − − + + − + − + + − − + + − − + + + + + − − + + + − + + + + + + + − + + + + + − + + + + + − + − − − + − − − − − + − − − − − + + − − − − − + − − − − + + + − − − + + + − − − + + − − − − + + − 12 10 10 AT, anterior temporal; BC, buccal; DT, deep temporal; Fr, frontal; GP, greater palatine; IA, inferior alveolar; IO, infraorbital; L, left; LC, lacrimal; LP, lesser palatine; N, nasociliary; R, right; SA, superior alveolar; Zyg, zygomatic Multiple trigeminal nerves involvement in IgG4-RD Coronal (A) and axial slices (B) T1-weighted MRI with fat suppression and contrast enhancement of patient no Nerves (A) 1, frontal; 2, lacrimal; 3, zygomatic; 4, infraorbital; 5, inferior alveolar; and 6, posterior superior alveolar hypo- or hyperesthesia Orbital biopsies in all cases revealed the typical lymphoplasmacytic infiltrate with significant plasma cell positivity for IgG4 (IgG4+/IgG ratio ≥ 40%) Table 2 shows the distribution of different nerve enlargement TGN involvement was not restricted to a single TGN division in any patient Although V2 was the most affected in all groups, at least nerve of V1 or V3 was bilaterally enlarged in all patients, including those with unilateral orbital disease Figure shows an illustrative patient (case number 5) with massive ION enlargement and bilateral involvement of V1 and V3 branches DISCUSSION Although it is known that TGN enlargement in IgG4-RD is not restricted to V2, the literature on this topic is limited and mainly centered on the ION In 2011, articles from Japan associated © 2020 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc 177 Copyright © 2021 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc Unauthorized reproduction of this article is prohibited Ophthalmic Plast Reconstr Surg, Vol 37, No 2, 2021 S M Elkhamary et al ION enlargement with IgG4-RD Watanabe et al.13 were the first to show that ION enlargement was frequently observed in patients with autoimmune pancreatitis, and Katsura et al.2 reported a patient with a mass containing abundant IgG4 + plasma cells involving the ION, pterygopalatine fossa, and Meckel cave The ipsilateral foramen ovale was expanded without signs of bone destruction.2 One year later, Inoue et al.5 described lesions involving the ION and supraorbital nerves in patients with IgG4-RD Following these early reports, several articles have stressed the association between IgG4-related orbital disease and ION enlargement.6,11,14–17 The authors believe that the emphasis on ION enlargement may simply be related to the proximity of this branch to the orbital contents The nerve is easily assessed in both CT and MRI coronal and axial slices, and it is a natural part of the orbital imaging search pattern, while involvement of other TGN branches is visualized only if a thorough TGN examination is undertaken.18 In the authors’ patients, not only were other V2 branches affected, but also 75% of the supraorbital nerves were also involved If the entire course of the TGN is carefully studied, V1 and/or V3 branches may be found to be abnormally enlarged The authors are not in a position to estimate the rate of the involvement of several trigeminal branches in IgG4-RD because only few patients with this disease have a comprehensive MRI study of the whole TGN Although the term “perineural spread” has been used to describe IgG4-RD enlargement of the TGN,19 it is questionable whether this terminology is appropriate to describe these changes Perineural spread means that specific cells, usually malignant, have left the site of the primary lesion and are travelling along a nerve Perineural spread is thus a form of a metastatic disease where the tumor can disseminate along the endoneurium or perineurium to distant areas of the body.20 The pattern of distribution of TGN enlargement associated with IgG4-RD does not support this concept All patients with unilateral orbital infiltration showed at least branch enlarged on the side contralateral to the affected orbit The authors’ case series supports that TGN enlargement associated with IgG4-RD is a component of the systemic disease that affects simultaneously the orbit and the TGN and not a disease that is spreading in a primarily contiguous fashion through the TGN REFERENCES Badger D, Aygun N Imaging of perineural spread in head and neck cancer Radiol Clin North Am 2017;55:139–149 Katsura M, Morita A, Horiuchi H, et al IgG4-related inflammatory pseudotumor of the trigeminal nerve: another component of IgG4-related sclerosing disease? 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Imaging the trigeminal nerve Eur J Radiol 2010;74:323–340 19 Wu PC, Tien PT, Li YH, et al IgG4- related cerebral pseudotumor with perineural spreading along branches of the trigeminal nerves causing... N Imaging of perineural spread in head and neck cancer Radiol Clin North Am 2017;55:139–149 Katsura M, Morita A, Horiuchi H, et al IgG4- related inflammatory pseudotumor of the trigeminal nerve: