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Orbital Inflammation in Pregnant Women
Accepted Manuscript Orbital Inflammation in Pregnant Women Frederick A. Jakobiec, Zeba A. Syed, Anna M. Stagner, Gerald J. Harris, Jack Rootman, Michael K. Yoon, Ilse Mombaerts PII:
S0002-9394(16)30133-7
DOI:
10.1016/j.ajo.2016.03.029
Reference:
AJOPHT 9683
To appear in:
American Journal of Ophthalmology
Received Date: 4 February 2016 Revised Date:
18 March 2016
Accepted Date: 23 March 2016
Please cite this article as: Jakobiec FA, Syed ZA, Stagner AM, Harris GJ, Rootman J, Yoon MK, Mombaerts I, Orbital Inflammation in Pregnant Women, American Journal of Ophthalmology (2016), doi: 10.1016/j.ajo.2016.03.029. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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ABSTRACT Objective: To analyze overlaps between pregnancy and orbital inflammation (OI). Design: Retrospective observational case series.
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Methods: Eight new cases from 1997-2015 and two previously published cases were identified for inclusion in this investigation to provide the fullest clinical picture. Medical records, imaging studies and the results of biopsies were reviewed.
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Results: Three categories of association were discovered: 1) OI arising for the first time during pregnancy (5 cases); 2) OI arising within 3 months of delivery (2 cases); and 3) previously diagnosed OI reactivated or exacerbated by pregnancy (3 cases). One patient had a pre-existent systemic autoimmune disease and another’s was later diagnosed. One patient had attacks during sequential pregnancies. Findings included eyelid swelling and erythema, conjunctival chemosis, pain on eye movement, minimal diplopia, the usual absence of proptosis and general preservation of visual acuity. Imaging studies disclosed extraocular muscle swelling (8 cases), most frequently of a single lateral rectus muscle. There were two cases of dacryoadenitis; one of these and an additional case displayed inflammation of the retrobulbar fat. Corticosteroids effected resolution of most symptoms. Singleton-births were normal with the exceptions of an intrauterine fetal demise due to acrania and a molar pregnancy.
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Conclusion: OI usually affects a single rectus muscle (typically the lateral) and less often the lacrimal gland and is mild when it arises during or after pregnancy. Independent systemic autoimmune disease is an uncommon feature. Corticosteroids were efficacious except in one case with severe orbital scarring. No definitive causal relationships between pregnancy and OI could be established or based on the clinical data.
ACCEPTED MANUSCRIPT 1 Orbital Inflammation in Pregnant Women Frederick A. Jakobiec1,2 Zeba A. Syed,1 Anna M. Stagner,1,2 Gerald J. Harris,3 Jack Rootman,4 Michael K. Yoon,1 Ilse Mombaerts5
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1. Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA 2. David G. Cogan Laboratory of Ophthalmic Pathology, Massachusetts Eye and Ear Infirmary, Boston, MA, USA 3. Department of Ophthalmology, Medical College of Wisconsin, Milwaukee, WI, USA 4. Department of Ophthalmology & Visual Sciences, University of British Columbia, Vancouver, BC, Canada 5. Department of Ophthalmology, University Hospitals Leuven, Leuven, Belgium
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Key Words: idiopathic orbital inflammation, orbital pseudotumor, non-specific orbital inflammation, pregnancy, orbital myositis, idiopathic dacryoadenitis, fetal microchimerism, ocular autoimmune disease Short title: Orbital inflammation in pregnancy
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Corresponding author: Frederick A. Jakobiec, M.D., D.Sc. Massachusetts Eye and Ear Infirmary 243 Charles Street – Suite 328 Boston, MA 02114 E-mail: [email protected]
ACCEPTED MANUSCRIPT 2 INTRODUCTION
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Idiopathic, non-infectious orbital inflammations are by definition localized disorders.1,2 A significant number of orbital inflammations, however, may be associated with some underlying systemic condition or remote organ dysfunction. Examples of this phenomenon are granulomatosis with polyangiitis (previously known as Wegener granulomatosis),3 polyarteritis nodosa,4-6 multifocal fibrosclerosis (now sometimes categorized as IgG4-related disease),7,8 systemic lupus erythematosus,9-17 celiac disease,18,19 regional enteritis (Crohn disease)20-24 and ulcerative colitis.25,26 Despite its obvious frequency and accompanying pancorporeal metabolic, hormonal and immunologic perturbations, pregnancy is not known to most ophthalmologists as being linked to episodes of orbital inflammation. We summarize the findings in eight new cases of this phenomenon and compare them with two others27,28 that have been previously published.
ACCEPTED MANUSCRIPT 3 MATERIALS AND METHODS
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This retrospective, observational study was conducted in compliance with the rules of the Institutional Review Board at Massachusetts Eye and Ear. The office clinical records and eye pathology files were reviewed for cases of pregnant women diagnosed with orbital pseudotumor, idiopathic orbital inflammation, orbital inflammation and nonspecific orbital inflammation at four tertiary care centers. Inquiries were also made of a group of eight experienced orbital surgeons and no additional cases were identified. A total of eight cases were assembled from the period 1997-2015 from the practices of the co-authors of this paper. The new cases were included in this series if the attacks occurred either during pregnancy or within 3 months of delivery. The medical records were summarized (Table) and clinical photographs and imaging studies (CT and MRI scans, ultrasonograms) were reviewed. Four cases (Table, Cases 5, 7, 8, 9) are included that were part of a report of 16 cases of orbital myositis in which the patients were mentioned in passing as having been pregnant, but no information about the pregnancies or the ocular examinations were provided.29 The records and microscopic slides of the patients were retrieved and re-evaluated for the purposes of the current study. In the Table are additionally listed the data extracted from two detailed earlier reports27,28 in the literature (Cases 3 and 6). Microscopic sections of three biopsies were available for re-evaluation. A fourth biopsied case did not have microscopic slides or a pathology report available for review except for a notation in the medical chart regarding the salient findings. No change was made in the original diagnoses among the reviewed cases. One biopsy was submitted for immunohistochemical analysis of the subtypes of the infiltrating lymphoid cells.
ACCEPTED MANUSCRIPT 4 RESULTS
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In the overall series (Table), 3 categories emerged: 1) initial development of orbital inflammation usually during the third trimester of pregnancy (5 cases); 2) orbital inflammation initially appearing after pregnancy from 5 days to 3 months (2 cases); and 3) orbital inflammation already established before pregnancy but reactivated or exacerbated during or within 3 months after pregnancy (3 cases). The 10 patients ranged in age from 24 to 40 years (mean of 29.5 and median of 28 years). Graves orbitopathy was ruled out by appropriate serologic testing and orbital cellulitis by radiologic demonstration of clear sinuses. Only one patient (#5, Table) had two separate attacks of OI during sequential pregnancies. Typical complaints that developed acutely or subacutely (usually over several days) were eyelid erythema and fullness (with an accentuated lateral swelling and an S-shaped eyelid if the lacrimal gland was affected), conjunctival injection with exaggeration over the tendinous insertion of the involved muscle, pain with eye movement, diplopia in extremes of gaze and low grade or no proptosis (only two patients had 6 and 7 mm of proptosis) (Figure 1, bottom left and bottom right and Figure 2, top left and top right). Case 10 with 7 mm of proptosis had several recurrences leading to profound visual loss. Three patients had bilateral disease-- one with dacryoadenitis (Case 1) and the other two with myositis (Cases 5 and 9). One patient (Case 4, Figure 1, bottom left) had an already diagnosed systemic autoimmune disease before the orbital episode while another while another later developed one (ankylosing spondylitis, Case 7) that emerged after subsidence of the OI. Four of the five patients presenting with orbital inflammation during pregnancy had mild disease (mild spontaneous orbital pain / gaze-evoked orbital pain / minor eyelid swelling / proptosis <2 mm / limited eye movement only in extreme fields of gaze); one initially had moderately severe disease (moderately severe spontaneous orbital pain / moderate eyelid swelling / proptosis <3 mm / moderately limited eye movement) which progressed after delivery (Case 5). The 2 patients developing orbital inflammation after pregnancy also had myositis. Severe disease (severe orbital pain / severe soft tissue swelling / severe restriction of eye movement / proptosis >3 mm / optic neuropathy) characterized the group of 3 patients who already had OI before their pregnancy, which aggravated or reactivated the disease. A disastrous outcome was seen in only one patient in this group (Case 10, Figure 2, top left) who had involvement of the orbital fat at the orbital apex and became steroid-dependent, requiring radiotherapy and surgical debulking that did not avert loss of light perception. The lateral rectus was the most commonly involved single muscle followed far behind by the medial rectus. The orbital fat was found by imaging studies to be significantly infiltrated (Figure 1, bottom right and Figure 2, top right) in the 2 cases with significant proptosis (Cases 4 and 10). Myositis and dacryoadenitis cases did not display this finding. Therapy for mild disease was successful with short term courses of systemic corticosteroids or non-steroidal anti-inflammatory drugs. Triamcinolone 40 mg was directly injected into an inflammatory mass (Case 4) with some beneficial effects. For more severe disease longer courses and re-introduction of steroids were required, and occasionally low dose radiotherapy (15-20 Gy) was employed. Surgical debulking was performed in the most severe case (Case 10). Biopsies were obtained in only 4 cases (not deemed necessary in instances of
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distinctive myositis). Three biopsies were available for review and revealed differences depending on the sites and stages of the biopsies. In Case 1 with bilateral lacrimal gland swellings, only the more prominent left gland was biopsied and disclosed a light periductular and interacinar lymphocytic infiltrate that also focally formed small aggregates at the peripheries of the lobules. Interstitial fibrosis was minimal and concentrated in the vicinity of the ductules (Figure 2, middle left). There was disappearance of the zymogen-bearing acinar cells with survival of scattered ductules in zones where fibrosis radiated out towards the acini. Fibroadipose tissue adjacent to the gland displayed a more pronounced perivascular lymphocytic infiltrate that extended from the fibrous septa into the fat lobules between the individual adipocytes (Figure 2, middle right). In a certain sense the process resembled a periglandular (periadventital) inflammation which made the lacrimal glands themselves appear more enlarged on CT scanning than they actually were. Small lymphocytic collections were located at the peripheries of the lobules (Figure 2, bottom left) and periductally. Immunohistochemical studies demonstrated in the focal lymphoid aggregates and diffusely a mild excess of CD3+ T lymphocytes (Figure 2, bottom right, top panel) over CD20+ B lymphocytes (Figure 2, bottom right, bottom panel) with interspersed CD68+ histiocytes (Figure 3, top left). These findings are consistent with the normal polytypic immunoarchitecture of the gland and characteristic of its non-neoplastic, standing inter-acinar lymphocytic population. In early biopsies of other patients with inflamed orbital fat, the lymphoid infiltrate was unaccompanied by fibrosis (Figure 3, top right). Late biopsies of recurrences displayed the greatest degree of fibrosclerosis (Figure 3, bottom left and bottom right). Neither vasculitis nor IgG4-positive plasma cells were found.
ACCEPTED MANUSCRIPT 6 DISCUSSION
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Idiopathic orbital inflammation (IOI), also called nonspecific orbital inflammation or orbital inflammatory syndrome, has emerged as a term superseding pseudotumor for a nonorganismal, presumably autoimmune, or at least immune-mediated disease.1,2,30 It has generally been believed that this condition is strictly localized to the orbit without any systemic ramifications or implications, but with more intensive systemic investigations, conditions such thrombotic thrombocytopenic purpura have been found. Pathologically the condition is represented by a lymphocytic infiltrate of variable densities combined with fibrosclerosis (sometimes displaying a storiform or perivascular onion-skinning configuration). Noninfectious inflammations of the orbit that are allied to a systemic disease or a distant organ dysfunction should not be termed “idiopathic” but rather “inflammation associated with” (as in our patient #4 in the Table who had thrombotic thrombocytopenic purpura) or “inflammation involved with.” The latter term is preferred when the orbital tissue manifests a specific diagnostic histopathologic finding. These specific features are exemplified by granulomatous vasculitis in granulomatosis with polyangiitis (Wegener),3 polymorphonuclear and eosinophilic leukocyte infiltrates in vascular walls in polyarteritis nodosa with focal necrosis4-6 or lymphocytic vasculitis in lupus erythematosus.9,12-15 Idiopathic orbital inflammation has a cryptogenic cause which could be a non-replicative organismal molecular fragment, or some alteration of immune tolerance to foreign tissue or self-antigens. The conjunction of orbital inflammation with pregnancy has received scant attention.27,28 Pregnancy is sometimes a provocateur of nonorbital myositis and furthermore capable of worsening an already diagnosed systemic nonorbital myositis, especially dermatomyositis/polymyositis.31-33 Systemic lupus erythematosus is also stereotypically exacerbated by pregnancy34 and can rarely be associated with protean orbital inflammatory complications (myositis,11,16 panniculitis,12 enophthalmos, 13 proptosis,17 trochleitis,10 complete orbital infarction and melt9). In contrast, rheumatoid arthritis may undergo temporary improvement during pregnancy but become active again post-partum due to a return to a different immunopathologic status. Orbital inflammation, particularly monomyositis, can likewise be triggered during pregnancy or also appear postpartum for the first time.28 Recurrences of non-orbital systemic myositis are not necessarily seen with serial pregnancies.35 One of our patients had an episode of OI during separate pregnancies. Another lesson derived from our series is that onset of pregnancy-associated orbital inflammation does not require a pre-existent systemic autoimmune disease, but one may exist (Table, Case 4). The first five patients listed in the Table who were recognized as developing orbital inflammation during their pregnancies share several similarities. Their average age was 32.4 years; the oldest patient was 40 years. One patient had a history of a systemic autoimmune disease and none had clinical or laboratory evidence of prior Graves disease/orbitopathy. Clinical signs of inflammation were usually subtle and consisted of faint erythema and an S-shaped fullness of the upper eyelid (when there was lacrimal gland inflammation) or injection over the tendinous insertion of the involved rectus muscle without diffuse chemosis or proptosis. Among the three patients with myositis, all three had pain on eye movement and two exhibited diplopia only in extremes of gaze. Six mm of proptosis was noted in only one patient in this group who
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had radiologic evidence of involvement of the orbital fat. The orbital disease characteristically appeared sometime in the third trimester and failed to cause visual decline – probably the result of swelling of only either a single rectus muscle (typically the lateral rectus), the lateral orbital fat, or the lacrimal glands, all of which are at some remove from the optic nerve. The combination of inflammation of the medial rectus and superior rectus/levator muscles seen in idiopathic orbital inflammation was not present among our myositis cases with pregnancy. In Case 2 the disease was mild enough to not warrant prescription therapy and resolved with minimal doses of acetaminophen. After the end of their pregnancies, none of the patients had a recurrence. Of the two patients in the category of post-partum development of orbital inflammation (either at 6 days or 3 months), one had mild disease while the other had severe disease; both had lateral rectus muscle involvement. Corticosteroids were highly beneficial in resolving the symptoms, except for residual, mild limited adduction in Case 7. The last category consisted of 3 patients with an already established diagnosis of nonspecific orbital inflammation that was reactivated or exacerbated during or after pregnancy. These patients had the most severe myositic, orbital fat or lacrimal gland disease; one developed no light perception despite the performance of a debulking surgery. Multiple recurrences characterized this subgroup. Radiotherapy was attempted in two patients, successfully alleviating symptoms in one. New onset Graves ophthalmopathy must be considered in an orbital myositis associated with pregnancy, but according to the literature, this development is rare and as in orbital Graves disease spares the fat.36,37,38 It was ruled out in our cases by appropriate serologic testing (at a minimum, thyroid stimulating hormone, T3 and free T4 levels). The orbital disease in pregnancy is typically mild but can be severe and vision-threatening depending on the degree of muscle swelling impinging on the optic nerve at the orbital apex. Graves ophthalmopathy virtually never affects only the lateral rectus muscle (alleged in an unconvincing paper39,40), which was the most common single muscle involved with pregnancy. The feature of tendon involvement, present in 3 of 7 myositic patients, supports the diagnosis of non-Graves-related inflammation (but this appearance can be seen in other circumstances). Although usually a local process, dacryoadenitis (but more often myositis) has also been associated with Crohn disease23 and additionally systemic inflammatory conditions such as infectious mononucleosis41 and systemic IgG-4 related processes.42 Pregnancy-associated dacryoadenitis, however, has not been previously reported. The lacrimal gland in animals undergoes several metabolic changes during normal pregnancy. There are changes in Na(+)/K(+)-ATPase subunit expression43 as well as epithelial sodium channels, aquaporin 4 and aquaporin 5.44,45 More relevant than metabolic alterations are immunologic shifts in the lacrimal gland as part of maternal reinforced immunity for self-defense.46 Lymphocytes disperse from periductal foci to the interacinar compartment, possibly as part of a heightened state of immune readiness that develops during pregnancy.47 Pregnancy produces an increased release of growth factors and prolactin into the lacrimal fluid and lacrimal gland interstitium.48,49 Elevated prolactin may induce lacrimal epithelial cells to express a mixed exocrine/endocrine phenotype. This contributes to pregnancy-associated changes in the normal lacrimal gland immunoarchitecture50 and immune responsiveness for self-defense that can go
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awry.46,51 Within the lacrimal gland, prolactin plays a role in mediating the expression of several chemokines and cytokines, thereby potentiating severe chronic inflammation in rabbit models.48,49,51-53 Another important consideration is that of fetal microchimerism.54 Beginning early in pregnancy, fetal cells enter the maternal circulation and lodge in various anatomic sites where they can survive for up to several decades.55 Pregnancy loss, preeclampsia and cesarean section versus vaginal delivery all increase this trafficking of fetal cells. Abortion appears not to play a facilitating role with respect to microchemeric dispersion of fetal cells. The development of an auto-immune disease, possibly due to a later loss of immunologic tolerance promoted by microchimerism, reaches its peak during the first year post-partum then rapidly subsides.54 With respect to the foregoing, it should be recalled that one of our patients with orbital inflammation and pregnancy had experienced an intrauterine death (the fetus had acrania) and subsequent cesarean delivery of the fetus (Case 1); another had the onset of inflammation 3 months after a molar pregnancy (Case 7). The 4 biopsies obtained from cases in this series provided only a narrow window into the pathogenesis of pregnancy and orbital inflammation. Examples of the orbital myositis were considered radiographically sufficiently distinctive that a biopsy was not required for either diagnosis or management. The lacrimal gland biopsy in Case 1 displayed preservation of its normal immunoarchitecture50 with a minimal increase in the density of periductular and outer lobular lymphocytes. Instead it exhibited a multifocal, non-confluent lymphocytic infiltrate of the same immunophenotypic composition paralleling that of the normal lacrimal gland (T cells predominating over B cells), again concentrated in the periductular and interacinar regions, periphery of the lobules and the periglandular fat lobules and septa. In Case 4 that was biopsied early a moderate lymphoid infiltrate (polytypic T>B cells) of the adipose tissue without fibrosis was seen. This indicates that the process was non-clonal. Vasculitis and IgG4 positive plasma cells (evaluated in only Case 1) were not discovered, but the latter can be present in an orbital inflammatory infiltrate without necessarily denoting the existence of systemic IgG4 related disease (multifocal fibrosing disease of retroperitoneum, pancreas, orbit, etc.).42 Fibrosis was prominent in the biopsy of the orbital fat in in Case 10, thereby accounting for various serious muscular and visual dysfunctions. The fibrosis radiates out from the perivascular region in a storiform pattern to obliterate pre-existent orbital architecture. The most that can be concluded at the present is that orbital inflammation seen in pregnancy has an autoimmune basis, due either to an auto-aggressive T helper/suppressor cell intolerance, sensitization to an unknown autoantigen or fetal antigen that leads to a poorly modulated or misdirected B–lymphocytic response. The therapy for orbital inflammation associated with pregnancy is fundamentally not different from that for isolated idiopathic attacks. Radiotherapy must be employed carefully in pregnant women. Oral administration of corticosteroids for 1-2 weeks as required is the mainstay of treatment with slow tapering over months. Direct injection of 20-40 mg of triamcinolone into the inflamed orbital tissues has is advocates56-58 and can be highly efficacious with notably few local complications in cases of dacryoadenitis. It avoids systemic side effects but has not been carefully evaluated for myositis alone. No deleterious impact on the fetus was discovered with this regimen. It has been
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established that corticosteroids have a very low teratogenic potential.59 Fetal injury is actually closely related to the severity of any associated systemic disease rather than to steroid administration, as exampled by systemic lupus erythematous34 and dermatomyositis.60 For very mild orbital disease (erythema with either a palpable lacrimal gland or a monodirectional diplopia), either conservative watchful waiting for spontaneous resolution or the introduction of over-the-counter nonsteroidal anti-inflammatory agents can be resorted to (although these agents should not be used in the third trimester of pregnancy). Low dose radiotherapy (15-20 Gy) can be employed for refractory or steroid-dependent disease. The degree of response with this modality will depend on the relative amounts of lymphocytes and collagen in the lesion – the former predominates in early lesions and yields a favorable response, while the latter limits response to therapy. For orbital inflammatory attacks developing postpartum such considerations are not relevant if the patient is not breastfeeding. Finally, surgical debulking can be performed to relieve high grades of proptosis especially for lesions centered in the lacrimal gland region and temporal orbital fat.56 Care must be exercised to prevent damage to the lateral rectus muscle and superior rectus/levator complex. Damage to the latter can result in severe ptosis. Our study has significant limitations including its retrospective observational design, the extreme rarity of the conjunction of orbital inflammation and pregnancy, and the nature of our clinical data. Because of this, we cannot conclude that pregnancy is in any way causative or alternatively protective of orbital inflammation. Their conjunction may be merely coincidental or random, especially in view of the ubiquity of pregnancy and the rare overlap with orbital inflammation. One intriguing finding was the onset in patient 5 of an attack during two separate pregnancies. On the other hand, the cases we have discovered suggest that the orbital disease is no more, and maybe less severe, than that occurring outside of pregnancy because of the overall minimal to modest single extraocular muscle swelling noted in our patients. The frequent, isolated involvement of the lateral rectus muscle is totally atypical for Graves disease and relatively frequent in isolated idiopathic orbital inflammation. In cases of pregnancy and orbital inflammation, no deleterious impact on the fetus was found. A review of the literature points to a plausible hypothesis that an episodic selective loss of an aspect of tolerance to self-antigens, or else fetal microchimerism may be at fault in provoking the myositis. These possibilities could be elucidated by future biologically oriented investigations that concentrate on basic science mechanisms rather than clinical parameters.
ACCEPTED MANUSCRIPT 10 ACKNOWLEDGEMENTS a. Funding/Support (including none): None. b. Financial Disclosures (including none): None.
Design and conduct of the study: (FAJ)
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c. Contributions to Authors in each of these areas:
Collection, management, analysis, and interpretation of the data: (All authors) Preparation of manuscript: (FAJ, AMS, ZAS, IM)
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d. Other Acknowledgments: None
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Review and approval of the manuscript: (All authors)
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ACCEPTED MANUSCRIPT 14 2012;16(2):216-217; author reply 217. Aburn NS, Sullivan TJ. Infectious mononucleosis presenting with dacryoadenitis. Ophthalmology. 1996;103(5):776-778.
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Origuchi T, Yano H, Nakamura H, Hirano A, Kawakami A. Three cases of IgG4related orbital inflammation presented as unilateral pseudotumor and review of the literature. Rheumatol Int. 2013;33(11):2931-2936.
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Huang J, Lu M, Ding C. Na(+)/K(+)-ATPase expression changes in the rabbit lacrimal glands during pregnancy. Curr Eye Res. 2013;38(1):18-26.
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Ding C, Lu M, Huang J. Changes of the ocular surface and aquaporins in the lacrimal glands of rabbits during pregnancy. Mol Vis. 2011;17:2847-2855.
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Wang M, Huang J, Lu M, Zhang S, Ding C. ENaC in the rabbit lacrimal gland and its changes during Sjogren syndrome and pregnancy. Eye Contact Lens. 2015;41(5):297-303.
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Mor G, Cardenas I, Abrahams V, Guller S. Inflammation and pregnancy: the role of the immune system at the implantation site. Ann N Y Acad Sci. 2011;1221:8087.
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Ding C, Chang N, Fong YC, et al. Interacting influences of pregnancy and corneal injury on rabbit lacrimal gland immunoarchitecture and function. Invest Ophthalmol Vis Sci. 2006;47(4):1368-1375.
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Schechter J, Carey J, Wallace M, Wood R. Distribution of growth factors and immune cells are altered in the lacrimal gland during pregnancy and lactation. Exp Eye Res. 2000;71(2):129-142.
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Sullivan DA. Tearful relationships? Sex, hormones, the lacrimal gland, and aqueous-deficient dry eye. Ocul Surf. 2004;2(2):92-123.
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Wieczorek R, Jakobiec FA, Sacks EH, Knowles DM. The immunoarchitecture of the normal human lacrimal gland. Relevancy for understanding pathologic conditions. Ophthalmology. 1988;95(1):100-109.
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Mombaerts I. The many facets of dacryoadenitis. Curr Opin Ophthalmol. 2015;26(5):399-407.
Mircheff AK, Wang Y, Ding C, Warren DW, Schechter JE. Potentially pathogenic immune cells and networks in apparently healthy lacrimal glands. Ocul Surf. 2015;13(1):47-81.
ACCEPTED MANUSCRIPT 15 Wang Y, Chiu CT, Nakamura T, et al. Elevated prolactin redirects secretory vesicle traffic in rabbit lacrimal acinar cells. Am J Physiol Endocrinol Metab. 2007;292(4):E1122-1134.
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O'Donoghue K. Pregnancy and the risk of autoimmune disease: An exploration. Chimerism. 2011;2(3):84-85.
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O'Donoghue K, Chan J, de la Fuente J, et al. Microchimerism in female bone marrow and bone decades after fetal mesenchymal stem-cell trafficking in pregnancy. Lancet. 2004;364(9429):179-182.
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Mombaerts I, Cameron JD, Chanlalit W, Garrity JA. Surgical debulking for idiopathic dacryoadenitis: a diagnosis and a cure. Ophthalmology. 2014;121(2):603-609.
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El Nasser AMA. Local steroid injection for management of different types of acute idiopathic orbital inflammation: an 8-year study. Ophthal Plast Reconstr Surg. 2013;29(4):286-289.
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Leibovitch I, Prabhakaran VC, Davis G, Selva D. Intraorbital injection of triamcinolone acetonide in patients with idiopathic orbital inflammation. Arch Ophthalmol. 2007;125(12):1647-1651.
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Fraser FC, Sajoo A. Teratogenic potential of corticosteroids in humans. Teratology. 1995;51(1):45-46.
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Silva CA, Sultan SM, Isenberg DA. Pregnancy outcome in adult-onset idiopathic inflammatory myopathy. Rheumatology (Oxford). 2003;42(10):1168-1172.
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ACCEPTED MANUSCRIPT 16 FIGURE LEGENDS Figure 1. Orbital inflammation associated with pregnancy.
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Top left. Case 1. A 40-year-old pregnant woman developed a painful S-shaped upper eyelid with mild erythema due to inflammation of the lacrimal gland. Top right. Case 1. Top panel. An axial projection highlights the disproportionate glandular enlargements (arrows). Bottom panel. A coronal section discloses bilateral enlargement of the lacrimal glands (arrows), more obvious on the left side.
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Middle left. Case 2. A 29-year-old pregnant woman had painful eye movements with segmental conjunctival chemosis and injection where the medial rectus muscle inserted onto the globe
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Middle right. Case 4. Top and bottom panels. There is minimal thickening of the medial rectus muscle indicated by arrows in the axial (top) and coronal (bottom) projections. Bottom left. Case 4. Acute onset of erythema and edema of the right eyelids in a 36year-old pregnant woman. She experienced painful eye movements and upper eyelid ptosis. There were 6 mm of right relative proptosis and 20/20 vision bilaterally.
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Bottom right. Case 4. Top panel. Non-contrast T1 weighted axial image shows that the retro-orbital fat is involved with a mass (M). A small amount of orbital fat is spared (arrow). Bottom panel. T2 weighted image displays a slightly heterogenous retrobulbar mass (M). The arrow again shows residual uninvolved fat.
ACCEPTED MANUSCRIPT 17 Figure 2. Clinical and histopathologic features of pregnancy associated orbital inflammation.
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Top left. Case 10. A 25-year-old pregnant woman experienced the acute onset of orbital pain, mild eyelid swelling and 20/20 vision bilaterally. There was moderate limitation of extraocular movements and 7 mm of relative right proptosis. Top right. Case 10. Top panel. Axial CT projection demonstrates massive thickening of the lateral rectus muscle (arrow) extending to the orbital apex. Bottom panel. CT scan appearance in coronal projection of lateral rectus swelling (arrow) and surrounding inflammation of the superolateral orbital fat creating a mass (M). There is thickening of the contiguous bone (crossed arrow).
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Middle left. Case 1. Biopsy of the left lacrimal gland shortly after onset of the inflammatory episode shows tracts of collagen toward the bottom of the image with survival of dilated ductules.
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Middle right. Case 1. There is chronic inflammation of the orbital fat and fibrous septa located immediately adjacent to the lacrimal gland. Bottom left. Case 1. At the periphery of many lobules next to the bordering adventitial tissue (A) is an atypical concentration of lymphocytes (arrow).
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Bottom right. Case 1.Top panel. Immunoperoxidase stating reveals T cells (Tc) in the periphery of the lobules (arrows) as well as scattered throughout the parenchyma, the latter a normal finding. Bottom panel. B lymphocytes (Bc, arrows) are less conspicuous in the lacrimal parenchyma.
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(Middle left, middle right and bottom left, hematoxylin and eosin, x100, x100, x200; bottom right, immunoperoxidase reaction, diaminobenzine chromogen, hematoxylin counterstain, top and bottom panels, x100)
ACCEPTED MANUSCRIPT 18 Figure 3. Further immunopathologic studies of biopsies of orbital inflammation in pregnant women. Top left. Case 1. CD68 positive histiocytes are dispersed among the lymphocytes causing the dacryoadenitis.
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Top right. Case 4. An early biopsy of orbital retrobulbar fat reveals infiltration of lymphocytes within the lobules in the absence of reactive fibrosis.
Bottom left. Case 10. Top panel. Relatively early-stage lacrimal gland biopsy with a prominent lymphoplasmacytic infiltrate and obliteration of many acini with remaining ductules. Bottom panel. Beginning fibrosis with remaining lacrimal ductules.
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Bottom right. Case 10. Destructive, progressive fibrosis of the orbital fat with distinctive lamellated collagen deposition, sometimes producing onion skinning around vascular channels.
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(Top left, immunoperoxidase reaction, diaminobenzine chromogen, hematoxylin counterstain, x200; Top right, bottom left and bottom right, hematoxylin and eosin, x40, x200 (top and bottom panels), x100)
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Table: Summary of Eight New Cases and Two Reported Cases of Orbital Inflammation Associated with Pregnancy Orbital inflammation initially during pregnancy
Orbital inflammation initially after pregnancy
Orbital inflammatory recurrences during or after subsequent pregnancies
Left superolateral upper eyelid pain and swelling increasing over 3 weeks; normal vision, pupils and motility; no proptosis
Bilateral dacryoadenitis (CT)
Not applicable
Not applicable
24 hours of right eye redness; pain worse with horizontal eye movement; VA 20/30; motility full; pain with adduction; no proptosis; mild upper eyelid edema; mild segmental conjunctival chemosis medially Painful diplopia for 3 days; VA 20/20; 30 prism diopters of left esodeviation; abduction deficit; normal pupils; otherwise unremarkable examination
Right medial rectus myositis without tendon involvement (CT)
28 weeks gestation; intrauterine fetal demise due to acraina, anencephaly and a complex heart malformation 28 weeks pregnant
Not applicable
Left lateral rectus myositis without tendon involvement (MRI)
38 weeks pregnant
Not applicable
16 weeks pregnant
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Case 325
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Case 4
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Acute erythema and edema of eyelids progressing over 3 weeks; painful horizontal diplopia; limitation of elevation and abduction; 3 mm ptosis; conjunctival injection and chemosis; 6 mm proptosis; VA 20/20 OU, normal pupils; intraocular pressure mildly elevated
Right retrobulbar tissues (ultrasound, MRI)
Case 5
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Subacute onset of orbital pain; eyelid swelling; diplopia; moderately limited adduction OD; normal vision; progression after pregnancy
Left lateral, medial, superior, inferior rectus; right medial rectus myositis without tendon involvement (CT)
New onset after pregnancy
Systemic disease
Biopsy and results
Followup (years)
Treatment and outcome
Not applicable
Diabetes Mellitus Type 2
Light lymphoplasmacytic infiltrate and early fibrosis of lacrimal gland
9 months
Complete resolution of pain and swelling with oral corticosteroids (60 mg/day with 6 week taper)
Not applicable
Not applicable
None
Not done
16 years
Complete resolution without treatment in 1 week (occasional acetaminophen)
Not applicable
Not applicable
None
Not done
6 months
Not applicable
Not applicable
Thrombotic thrombocytopenic purpura; lichen sclerosis
Moderate non-fibrotic lymphocytic infiltrate of fat
4 months
Bilateral worsening immediately after first delivery; severe pain and motility restriction OU; mild right orbital recurrence during second pregnancy
4 recurrences (OD>OS)
None
Not done
5 years
Complete resolution of pain and abduction deficit with oral corticosteroids (1.0 mg/kg/day with taper over 6 weeks) Improvement in symptoms with 30 mg prednisone + 2 month taper and injection of 40 mg prednisone into inferolateral fat pad; residual ptosis with reduced proptosis Treated with NSAIDs, corticosteroids (6080mg/day) and radiation therapy (2000 rad); residual mild limitation of elevation OD and elevation/ adduction OS
Not applicable
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Orbital inflammatory recurrences not associated with pregnancy
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Orbital site initially involved (confirmed by imaging)
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New onset during pregnancy Case 1 40
Presenting complaint/ severity
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Unknown gestational date
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Table: Summary of Eight New Cases and Two Reported Cases of Orbital Inflammation Associated with Pregnancy
26
Acute upper eyelid edema and painful diplopia of 5 days duration; moderate adduction/abduction deficits; normal pupils
Right lateral rectus myositis without tendon involvement (MRI)
Not applicable
Symptoms began 8 days after normal delivery
Not applicable
Case 7
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Acute onset of right orbital pain with eyelid swelling with diplopia; severe limitation in adduction OD and normal vision
Right lateral rectus myositis including tendon (CT)
Not applicable
Symptoms began 3 months after molar pregnancy
Not applicable (
Acute onset of orbital pain and eyelid swelling; painful and limited adduction OS; normal vision; milder symptoms during pregnancy attack
Left medial rectus myositis including tendon (CT)
Not applicable
Not applicable
Not applicable
None
Not done
Not available
Developed ankylosing spondylitis 3 years after pregnancy
Not done
18 years
Left medial rectus myositis (2 episodes total prior to pregnancy)
None
Pathology report and slides unavailable for review
3 years
3 recurrences (right medial rectus; left lateral rectus x2; 4 episodes prior to pregnancy)
None
Not done
12 years
3 more recurrences after pregnancy
None
Progressive fibrosis with diminishing lymphocytic infiltrate
15 years
Not applicable
Complete resolution after 3 days of corticosteroid treatment (dose not specified) Improvement with corticosteroids (6080mg/day); remaining mildly limited adduction OD
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Acute onset of orbital pain and eyelid swelling; painful adduction and severely limited abduction OD; normal vision
Right lateral rectus myositis including tendon (CT)
Not applicable
Case 10
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Acute onset of orbital pain and eyelid swelling; VA 20/20 OU; moderately limited abduction, elevation and depression ; 7 mm proptosis OD
Lateral orbital mass including right lateral rectus myositis; dacryoadenitis; superior orbital fissure involvement (CT)
Not applicable
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Case 9
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Recurrence of existing orbital disease during or after pregnancy Case 8 24
Not applicable
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(within 3 months) Case 626
Not applicable
Mild recurrence during pregnancy; orbital pain and pain with eye movement; normal motility and no treatment Recurrence at 3 months gestation; left myositis with limited abduction; left orbital recurrence at end of pregnancy; right orbital recurrence 4 months postpartum Steroid-dependent orbital disease; recurrence of existing disease at 3 months gestation; 20/32 vision; optic neuropathy
Complete resolution with NSAID therapy (ibuprofen 12002400 mg/day for 2 weeks with 6 week taper) Complete resolution with corticosteroids (multiple courses, 60-80mg/day); also received radiation therapy (2000 rad)
Steroiddependent for many years (2030mg/day) with courses of 6080mg/day; underwent radiation and surgical debulking; no light perception; limited abduction/ elevation/ depression
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S0002-9394(16)30133-7
DOI:
10.1016/j.ajo.2016.03.029
Reference:
AJOPHT 9683
To appear in:
American Journal of Ophthalmology
Received Date: 4 February 2016 Revised Date:
18 March 2016
Accepted Date: 23 March 2016
Please cite this article as: Jakobiec FA, Syed ZA, Stagner AM, Harris GJ, Rootman J, Yoon MK, Mombaerts I, Orbital Inflammation in Pregnant Women, American Journal of Ophthalmology (2016), doi: 10.1016/j.ajo.2016.03.029. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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ABSTRACT Objective: To analyze overlaps between pregnancy and orbital inflammation (OI). Design: Retrospective observational case series.
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Methods: Eight new cases from 1997-2015 and two previously published cases were identified for inclusion in this investigation to provide the fullest clinical picture. Medical records, imaging studies and the results of biopsies were reviewed.
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Results: Three categories of association were discovered: 1) OI arising for the first time during pregnancy (5 cases); 2) OI arising within 3 months of delivery (2 cases); and 3) previously diagnosed OI reactivated or exacerbated by pregnancy (3 cases). One patient had a pre-existent systemic autoimmune disease and another’s was later diagnosed. One patient had attacks during sequential pregnancies. Findings included eyelid swelling and erythema, conjunctival chemosis, pain on eye movement, minimal diplopia, the usual absence of proptosis and general preservation of visual acuity. Imaging studies disclosed extraocular muscle swelling (8 cases), most frequently of a single lateral rectus muscle. There were two cases of dacryoadenitis; one of these and an additional case displayed inflammation of the retrobulbar fat. Corticosteroids effected resolution of most symptoms. Singleton-births were normal with the exceptions of an intrauterine fetal demise due to acrania and a molar pregnancy.
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Conclusion: OI usually affects a single rectus muscle (typically the lateral) and less often the lacrimal gland and is mild when it arises during or after pregnancy. Independent systemic autoimmune disease is an uncommon feature. Corticosteroids were efficacious except in one case with severe orbital scarring. No definitive causal relationships between pregnancy and OI could be established or based on the clinical data.
ACCEPTED MANUSCRIPT 1 Orbital Inflammation in Pregnant Women Frederick A. Jakobiec1,2 Zeba A. Syed,1 Anna M. Stagner,1,2 Gerald J. Harris,3 Jack Rootman,4 Michael K. Yoon,1 Ilse Mombaerts5
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1. Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA 2. David G. Cogan Laboratory of Ophthalmic Pathology, Massachusetts Eye and Ear Infirmary, Boston, MA, USA 3. Department of Ophthalmology, Medical College of Wisconsin, Milwaukee, WI, USA 4. Department of Ophthalmology & Visual Sciences, University of British Columbia, Vancouver, BC, Canada 5. Department of Ophthalmology, University Hospitals Leuven, Leuven, Belgium
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Key Words: idiopathic orbital inflammation, orbital pseudotumor, non-specific orbital inflammation, pregnancy, orbital myositis, idiopathic dacryoadenitis, fetal microchimerism, ocular autoimmune disease Short title: Orbital inflammation in pregnancy
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Corresponding author: Frederick A. Jakobiec, M.D., D.Sc. Massachusetts Eye and Ear Infirmary 243 Charles Street – Suite 328 Boston, MA 02114 E-mail: [email protected]
ACCEPTED MANUSCRIPT 2 INTRODUCTION
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Idiopathic, non-infectious orbital inflammations are by definition localized disorders.1,2 A significant number of orbital inflammations, however, may be associated with some underlying systemic condition or remote organ dysfunction. Examples of this phenomenon are granulomatosis with polyangiitis (previously known as Wegener granulomatosis),3 polyarteritis nodosa,4-6 multifocal fibrosclerosis (now sometimes categorized as IgG4-related disease),7,8 systemic lupus erythematosus,9-17 celiac disease,18,19 regional enteritis (Crohn disease)20-24 and ulcerative colitis.25,26 Despite its obvious frequency and accompanying pancorporeal metabolic, hormonal and immunologic perturbations, pregnancy is not known to most ophthalmologists as being linked to episodes of orbital inflammation. We summarize the findings in eight new cases of this phenomenon and compare them with two others27,28 that have been previously published.
ACCEPTED MANUSCRIPT 3 MATERIALS AND METHODS
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This retrospective, observational study was conducted in compliance with the rules of the Institutional Review Board at Massachusetts Eye and Ear. The office clinical records and eye pathology files were reviewed for cases of pregnant women diagnosed with orbital pseudotumor, idiopathic orbital inflammation, orbital inflammation and nonspecific orbital inflammation at four tertiary care centers. Inquiries were also made of a group of eight experienced orbital surgeons and no additional cases were identified. A total of eight cases were assembled from the period 1997-2015 from the practices of the co-authors of this paper. The new cases were included in this series if the attacks occurred either during pregnancy or within 3 months of delivery. The medical records were summarized (Table) and clinical photographs and imaging studies (CT and MRI scans, ultrasonograms) were reviewed. Four cases (Table, Cases 5, 7, 8, 9) are included that were part of a report of 16 cases of orbital myositis in which the patients were mentioned in passing as having been pregnant, but no information about the pregnancies or the ocular examinations were provided.29 The records and microscopic slides of the patients were retrieved and re-evaluated for the purposes of the current study. In the Table are additionally listed the data extracted from two detailed earlier reports27,28 in the literature (Cases 3 and 6). Microscopic sections of three biopsies were available for re-evaluation. A fourth biopsied case did not have microscopic slides or a pathology report available for review except for a notation in the medical chart regarding the salient findings. No change was made in the original diagnoses among the reviewed cases. One biopsy was submitted for immunohistochemical analysis of the subtypes of the infiltrating lymphoid cells.
ACCEPTED MANUSCRIPT 4 RESULTS
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In the overall series (Table), 3 categories emerged: 1) initial development of orbital inflammation usually during the third trimester of pregnancy (5 cases); 2) orbital inflammation initially appearing after pregnancy from 5 days to 3 months (2 cases); and 3) orbital inflammation already established before pregnancy but reactivated or exacerbated during or within 3 months after pregnancy (3 cases). The 10 patients ranged in age from 24 to 40 years (mean of 29.5 and median of 28 years). Graves orbitopathy was ruled out by appropriate serologic testing and orbital cellulitis by radiologic demonstration of clear sinuses. Only one patient (#5, Table) had two separate attacks of OI during sequential pregnancies. Typical complaints that developed acutely or subacutely (usually over several days) were eyelid erythema and fullness (with an accentuated lateral swelling and an S-shaped eyelid if the lacrimal gland was affected), conjunctival injection with exaggeration over the tendinous insertion of the involved muscle, pain with eye movement, diplopia in extremes of gaze and low grade or no proptosis (only two patients had 6 and 7 mm of proptosis) (Figure 1, bottom left and bottom right and Figure 2, top left and top right). Case 10 with 7 mm of proptosis had several recurrences leading to profound visual loss. Three patients had bilateral disease-- one with dacryoadenitis (Case 1) and the other two with myositis (Cases 5 and 9). One patient (Case 4, Figure 1, bottom left) had an already diagnosed systemic autoimmune disease before the orbital episode while another while another later developed one (ankylosing spondylitis, Case 7) that emerged after subsidence of the OI. Four of the five patients presenting with orbital inflammation during pregnancy had mild disease (mild spontaneous orbital pain / gaze-evoked orbital pain / minor eyelid swelling / proptosis <2 mm / limited eye movement only in extreme fields of gaze); one initially had moderately severe disease (moderately severe spontaneous orbital pain / moderate eyelid swelling / proptosis <3 mm / moderately limited eye movement) which progressed after delivery (Case 5). The 2 patients developing orbital inflammation after pregnancy also had myositis. Severe disease (severe orbital pain / severe soft tissue swelling / severe restriction of eye movement / proptosis >3 mm / optic neuropathy) characterized the group of 3 patients who already had OI before their pregnancy, which aggravated or reactivated the disease. A disastrous outcome was seen in only one patient in this group (Case 10, Figure 2, top left) who had involvement of the orbital fat at the orbital apex and became steroid-dependent, requiring radiotherapy and surgical debulking that did not avert loss of light perception. The lateral rectus was the most commonly involved single muscle followed far behind by the medial rectus. The orbital fat was found by imaging studies to be significantly infiltrated (Figure 1, bottom right and Figure 2, top right) in the 2 cases with significant proptosis (Cases 4 and 10). Myositis and dacryoadenitis cases did not display this finding. Therapy for mild disease was successful with short term courses of systemic corticosteroids or non-steroidal anti-inflammatory drugs. Triamcinolone 40 mg was directly injected into an inflammatory mass (Case 4) with some beneficial effects. For more severe disease longer courses and re-introduction of steroids were required, and occasionally low dose radiotherapy (15-20 Gy) was employed. Surgical debulking was performed in the most severe case (Case 10). Biopsies were obtained in only 4 cases (not deemed necessary in instances of
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distinctive myositis). Three biopsies were available for review and revealed differences depending on the sites and stages of the biopsies. In Case 1 with bilateral lacrimal gland swellings, only the more prominent left gland was biopsied and disclosed a light periductular and interacinar lymphocytic infiltrate that also focally formed small aggregates at the peripheries of the lobules. Interstitial fibrosis was minimal and concentrated in the vicinity of the ductules (Figure 2, middle left). There was disappearance of the zymogen-bearing acinar cells with survival of scattered ductules in zones where fibrosis radiated out towards the acini. Fibroadipose tissue adjacent to the gland displayed a more pronounced perivascular lymphocytic infiltrate that extended from the fibrous septa into the fat lobules between the individual adipocytes (Figure 2, middle right). In a certain sense the process resembled a periglandular (periadventital) inflammation which made the lacrimal glands themselves appear more enlarged on CT scanning than they actually were. Small lymphocytic collections were located at the peripheries of the lobules (Figure 2, bottom left) and periductally. Immunohistochemical studies demonstrated in the focal lymphoid aggregates and diffusely a mild excess of CD3+ T lymphocytes (Figure 2, bottom right, top panel) over CD20+ B lymphocytes (Figure 2, bottom right, bottom panel) with interspersed CD68+ histiocytes (Figure 3, top left). These findings are consistent with the normal polytypic immunoarchitecture of the gland and characteristic of its non-neoplastic, standing inter-acinar lymphocytic population. In early biopsies of other patients with inflamed orbital fat, the lymphoid infiltrate was unaccompanied by fibrosis (Figure 3, top right). Late biopsies of recurrences displayed the greatest degree of fibrosclerosis (Figure 3, bottom left and bottom right). Neither vasculitis nor IgG4-positive plasma cells were found.
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Idiopathic orbital inflammation (IOI), also called nonspecific orbital inflammation or orbital inflammatory syndrome, has emerged as a term superseding pseudotumor for a nonorganismal, presumably autoimmune, or at least immune-mediated disease.1,2,30 It has generally been believed that this condition is strictly localized to the orbit without any systemic ramifications or implications, but with more intensive systemic investigations, conditions such thrombotic thrombocytopenic purpura have been found. Pathologically the condition is represented by a lymphocytic infiltrate of variable densities combined with fibrosclerosis (sometimes displaying a storiform or perivascular onion-skinning configuration). Noninfectious inflammations of the orbit that are allied to a systemic disease or a distant organ dysfunction should not be termed “idiopathic” but rather “inflammation associated with” (as in our patient #4 in the Table who had thrombotic thrombocytopenic purpura) or “inflammation involved with.” The latter term is preferred when the orbital tissue manifests a specific diagnostic histopathologic finding. These specific features are exemplified by granulomatous vasculitis in granulomatosis with polyangiitis (Wegener),3 polymorphonuclear and eosinophilic leukocyte infiltrates in vascular walls in polyarteritis nodosa with focal necrosis4-6 or lymphocytic vasculitis in lupus erythematosus.9,12-15 Idiopathic orbital inflammation has a cryptogenic cause which could be a non-replicative organismal molecular fragment, or some alteration of immune tolerance to foreign tissue or self-antigens. The conjunction of orbital inflammation with pregnancy has received scant attention.27,28 Pregnancy is sometimes a provocateur of nonorbital myositis and furthermore capable of worsening an already diagnosed systemic nonorbital myositis, especially dermatomyositis/polymyositis.31-33 Systemic lupus erythematosus is also stereotypically exacerbated by pregnancy34 and can rarely be associated with protean orbital inflammatory complications (myositis,11,16 panniculitis,12 enophthalmos, 13 proptosis,17 trochleitis,10 complete orbital infarction and melt9). In contrast, rheumatoid arthritis may undergo temporary improvement during pregnancy but become active again post-partum due to a return to a different immunopathologic status. Orbital inflammation, particularly monomyositis, can likewise be triggered during pregnancy or also appear postpartum for the first time.28 Recurrences of non-orbital systemic myositis are not necessarily seen with serial pregnancies.35 One of our patients had an episode of OI during separate pregnancies. Another lesson derived from our series is that onset of pregnancy-associated orbital inflammation does not require a pre-existent systemic autoimmune disease, but one may exist (Table, Case 4). The first five patients listed in the Table who were recognized as developing orbital inflammation during their pregnancies share several similarities. Their average age was 32.4 years; the oldest patient was 40 years. One patient had a history of a systemic autoimmune disease and none had clinical or laboratory evidence of prior Graves disease/orbitopathy. Clinical signs of inflammation were usually subtle and consisted of faint erythema and an S-shaped fullness of the upper eyelid (when there was lacrimal gland inflammation) or injection over the tendinous insertion of the involved rectus muscle without diffuse chemosis or proptosis. Among the three patients with myositis, all three had pain on eye movement and two exhibited diplopia only in extremes of gaze. Six mm of proptosis was noted in only one patient in this group who
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had radiologic evidence of involvement of the orbital fat. The orbital disease characteristically appeared sometime in the third trimester and failed to cause visual decline – probably the result of swelling of only either a single rectus muscle (typically the lateral rectus), the lateral orbital fat, or the lacrimal glands, all of which are at some remove from the optic nerve. The combination of inflammation of the medial rectus and superior rectus/levator muscles seen in idiopathic orbital inflammation was not present among our myositis cases with pregnancy. In Case 2 the disease was mild enough to not warrant prescription therapy and resolved with minimal doses of acetaminophen. After the end of their pregnancies, none of the patients had a recurrence. Of the two patients in the category of post-partum development of orbital inflammation (either at 6 days or 3 months), one had mild disease while the other had severe disease; both had lateral rectus muscle involvement. Corticosteroids were highly beneficial in resolving the symptoms, except for residual, mild limited adduction in Case 7. The last category consisted of 3 patients with an already established diagnosis of nonspecific orbital inflammation that was reactivated or exacerbated during or after pregnancy. These patients had the most severe myositic, orbital fat or lacrimal gland disease; one developed no light perception despite the performance of a debulking surgery. Multiple recurrences characterized this subgroup. Radiotherapy was attempted in two patients, successfully alleviating symptoms in one. New onset Graves ophthalmopathy must be considered in an orbital myositis associated with pregnancy, but according to the literature, this development is rare and as in orbital Graves disease spares the fat.36,37,38 It was ruled out in our cases by appropriate serologic testing (at a minimum, thyroid stimulating hormone, T3 and free T4 levels). The orbital disease in pregnancy is typically mild but can be severe and vision-threatening depending on the degree of muscle swelling impinging on the optic nerve at the orbital apex. Graves ophthalmopathy virtually never affects only the lateral rectus muscle (alleged in an unconvincing paper39,40), which was the most common single muscle involved with pregnancy. The feature of tendon involvement, present in 3 of 7 myositic patients, supports the diagnosis of non-Graves-related inflammation (but this appearance can be seen in other circumstances). Although usually a local process, dacryoadenitis (but more often myositis) has also been associated with Crohn disease23 and additionally systemic inflammatory conditions such as infectious mononucleosis41 and systemic IgG-4 related processes.42 Pregnancy-associated dacryoadenitis, however, has not been previously reported. The lacrimal gland in animals undergoes several metabolic changes during normal pregnancy. There are changes in Na(+)/K(+)-ATPase subunit expression43 as well as epithelial sodium channels, aquaporin 4 and aquaporin 5.44,45 More relevant than metabolic alterations are immunologic shifts in the lacrimal gland as part of maternal reinforced immunity for self-defense.46 Lymphocytes disperse from periductal foci to the interacinar compartment, possibly as part of a heightened state of immune readiness that develops during pregnancy.47 Pregnancy produces an increased release of growth factors and prolactin into the lacrimal fluid and lacrimal gland interstitium.48,49 Elevated prolactin may induce lacrimal epithelial cells to express a mixed exocrine/endocrine phenotype. This contributes to pregnancy-associated changes in the normal lacrimal gland immunoarchitecture50 and immune responsiveness for self-defense that can go
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awry.46,51 Within the lacrimal gland, prolactin plays a role in mediating the expression of several chemokines and cytokines, thereby potentiating severe chronic inflammation in rabbit models.48,49,51-53 Another important consideration is that of fetal microchimerism.54 Beginning early in pregnancy, fetal cells enter the maternal circulation and lodge in various anatomic sites where they can survive for up to several decades.55 Pregnancy loss, preeclampsia and cesarean section versus vaginal delivery all increase this trafficking of fetal cells. Abortion appears not to play a facilitating role with respect to microchemeric dispersion of fetal cells. The development of an auto-immune disease, possibly due to a later loss of immunologic tolerance promoted by microchimerism, reaches its peak during the first year post-partum then rapidly subsides.54 With respect to the foregoing, it should be recalled that one of our patients with orbital inflammation and pregnancy had experienced an intrauterine death (the fetus had acrania) and subsequent cesarean delivery of the fetus (Case 1); another had the onset of inflammation 3 months after a molar pregnancy (Case 7). The 4 biopsies obtained from cases in this series provided only a narrow window into the pathogenesis of pregnancy and orbital inflammation. Examples of the orbital myositis were considered radiographically sufficiently distinctive that a biopsy was not required for either diagnosis or management. The lacrimal gland biopsy in Case 1 displayed preservation of its normal immunoarchitecture50 with a minimal increase in the density of periductular and outer lobular lymphocytes. Instead it exhibited a multifocal, non-confluent lymphocytic infiltrate of the same immunophenotypic composition paralleling that of the normal lacrimal gland (T cells predominating over B cells), again concentrated in the periductular and interacinar regions, periphery of the lobules and the periglandular fat lobules and septa. In Case 4 that was biopsied early a moderate lymphoid infiltrate (polytypic T>B cells) of the adipose tissue without fibrosis was seen. This indicates that the process was non-clonal. Vasculitis and IgG4 positive plasma cells (evaluated in only Case 1) were not discovered, but the latter can be present in an orbital inflammatory infiltrate without necessarily denoting the existence of systemic IgG4 related disease (multifocal fibrosing disease of retroperitoneum, pancreas, orbit, etc.).42 Fibrosis was prominent in the biopsy of the orbital fat in in Case 10, thereby accounting for various serious muscular and visual dysfunctions. The fibrosis radiates out from the perivascular region in a storiform pattern to obliterate pre-existent orbital architecture. The most that can be concluded at the present is that orbital inflammation seen in pregnancy has an autoimmune basis, due either to an auto-aggressive T helper/suppressor cell intolerance, sensitization to an unknown autoantigen or fetal antigen that leads to a poorly modulated or misdirected B–lymphocytic response. The therapy for orbital inflammation associated with pregnancy is fundamentally not different from that for isolated idiopathic attacks. Radiotherapy must be employed carefully in pregnant women. Oral administration of corticosteroids for 1-2 weeks as required is the mainstay of treatment with slow tapering over months. Direct injection of 20-40 mg of triamcinolone into the inflamed orbital tissues has is advocates56-58 and can be highly efficacious with notably few local complications in cases of dacryoadenitis. It avoids systemic side effects but has not been carefully evaluated for myositis alone. No deleterious impact on the fetus was discovered with this regimen. It has been
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established that corticosteroids have a very low teratogenic potential.59 Fetal injury is actually closely related to the severity of any associated systemic disease rather than to steroid administration, as exampled by systemic lupus erythematous34 and dermatomyositis.60 For very mild orbital disease (erythema with either a palpable lacrimal gland or a monodirectional diplopia), either conservative watchful waiting for spontaneous resolution or the introduction of over-the-counter nonsteroidal anti-inflammatory agents can be resorted to (although these agents should not be used in the third trimester of pregnancy). Low dose radiotherapy (15-20 Gy) can be employed for refractory or steroid-dependent disease. The degree of response with this modality will depend on the relative amounts of lymphocytes and collagen in the lesion – the former predominates in early lesions and yields a favorable response, while the latter limits response to therapy. For orbital inflammatory attacks developing postpartum such considerations are not relevant if the patient is not breastfeeding. Finally, surgical debulking can be performed to relieve high grades of proptosis especially for lesions centered in the lacrimal gland region and temporal orbital fat.56 Care must be exercised to prevent damage to the lateral rectus muscle and superior rectus/levator complex. Damage to the latter can result in severe ptosis. Our study has significant limitations including its retrospective observational design, the extreme rarity of the conjunction of orbital inflammation and pregnancy, and the nature of our clinical data. Because of this, we cannot conclude that pregnancy is in any way causative or alternatively protective of orbital inflammation. Their conjunction may be merely coincidental or random, especially in view of the ubiquity of pregnancy and the rare overlap with orbital inflammation. One intriguing finding was the onset in patient 5 of an attack during two separate pregnancies. On the other hand, the cases we have discovered suggest that the orbital disease is no more, and maybe less severe, than that occurring outside of pregnancy because of the overall minimal to modest single extraocular muscle swelling noted in our patients. The frequent, isolated involvement of the lateral rectus muscle is totally atypical for Graves disease and relatively frequent in isolated idiopathic orbital inflammation. In cases of pregnancy and orbital inflammation, no deleterious impact on the fetus was found. A review of the literature points to a plausible hypothesis that an episodic selective loss of an aspect of tolerance to self-antigens, or else fetal microchimerism may be at fault in provoking the myositis. These possibilities could be elucidated by future biologically oriented investigations that concentrate on basic science mechanisms rather than clinical parameters.
ACCEPTED MANUSCRIPT 10 ACKNOWLEDGEMENTS a. Funding/Support (including none): None. b. Financial Disclosures (including none): None.
Design and conduct of the study: (FAJ)
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c. Contributions to Authors in each of these areas:
Collection, management, analysis, and interpretation of the data: (All authors) Preparation of manuscript: (FAJ, AMS, ZAS, IM)
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d. Other Acknowledgments: None
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Review and approval of the manuscript: (All authors)
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ACCEPTED MANUSCRIPT 13 Haslinda AR, Shatriah I, Azhany Y, Nik-Ahmad-Zuky NL, Yunus R. Lateral rectus myositis mimicking an abducens nerve palsy in a pregnant woman. Ophthal Plast Reconstr Surg. 2014;30(1):e13-15.
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ACCEPTED MANUSCRIPT 15 Wang Y, Chiu CT, Nakamura T, et al. Elevated prolactin redirects secretory vesicle traffic in rabbit lacrimal acinar cells. Am J Physiol Endocrinol Metab. 2007;292(4):E1122-1134.
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ACCEPTED MANUSCRIPT 16 FIGURE LEGENDS Figure 1. Orbital inflammation associated with pregnancy.
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Top left. Case 1. A 40-year-old pregnant woman developed a painful S-shaped upper eyelid with mild erythema due to inflammation of the lacrimal gland. Top right. Case 1. Top panel. An axial projection highlights the disproportionate glandular enlargements (arrows). Bottom panel. A coronal section discloses bilateral enlargement of the lacrimal glands (arrows), more obvious on the left side.
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Middle left. Case 2. A 29-year-old pregnant woman had painful eye movements with segmental conjunctival chemosis and injection where the medial rectus muscle inserted onto the globe
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Middle right. Case 4. Top and bottom panels. There is minimal thickening of the medial rectus muscle indicated by arrows in the axial (top) and coronal (bottom) projections. Bottom left. Case 4. Acute onset of erythema and edema of the right eyelids in a 36year-old pregnant woman. She experienced painful eye movements and upper eyelid ptosis. There were 6 mm of right relative proptosis and 20/20 vision bilaterally.
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Bottom right. Case 4. Top panel. Non-contrast T1 weighted axial image shows that the retro-orbital fat is involved with a mass (M). A small amount of orbital fat is spared (arrow). Bottom panel. T2 weighted image displays a slightly heterogenous retrobulbar mass (M). The arrow again shows residual uninvolved fat.
ACCEPTED MANUSCRIPT 17 Figure 2. Clinical and histopathologic features of pregnancy associated orbital inflammation.
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Top left. Case 10. A 25-year-old pregnant woman experienced the acute onset of orbital pain, mild eyelid swelling and 20/20 vision bilaterally. There was moderate limitation of extraocular movements and 7 mm of relative right proptosis. Top right. Case 10. Top panel. Axial CT projection demonstrates massive thickening of the lateral rectus muscle (arrow) extending to the orbital apex. Bottom panel. CT scan appearance in coronal projection of lateral rectus swelling (arrow) and surrounding inflammation of the superolateral orbital fat creating a mass (M). There is thickening of the contiguous bone (crossed arrow).
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Middle left. Case 1. Biopsy of the left lacrimal gland shortly after onset of the inflammatory episode shows tracts of collagen toward the bottom of the image with survival of dilated ductules.
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Middle right. Case 1. There is chronic inflammation of the orbital fat and fibrous septa located immediately adjacent to the lacrimal gland. Bottom left. Case 1. At the periphery of many lobules next to the bordering adventitial tissue (A) is an atypical concentration of lymphocytes (arrow).
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Bottom right. Case 1.Top panel. Immunoperoxidase stating reveals T cells (Tc) in the periphery of the lobules (arrows) as well as scattered throughout the parenchyma, the latter a normal finding. Bottom panel. B lymphocytes (Bc, arrows) are less conspicuous in the lacrimal parenchyma.
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(Middle left, middle right and bottom left, hematoxylin and eosin, x100, x100, x200; bottom right, immunoperoxidase reaction, diaminobenzine chromogen, hematoxylin counterstain, top and bottom panels, x100)
ACCEPTED MANUSCRIPT 18 Figure 3. Further immunopathologic studies of biopsies of orbital inflammation in pregnant women. Top left. Case 1. CD68 positive histiocytes are dispersed among the lymphocytes causing the dacryoadenitis.
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Top right. Case 4. An early biopsy of orbital retrobulbar fat reveals infiltration of lymphocytes within the lobules in the absence of reactive fibrosis.
Bottom left. Case 10. Top panel. Relatively early-stage lacrimal gland biopsy with a prominent lymphoplasmacytic infiltrate and obliteration of many acini with remaining ductules. Bottom panel. Beginning fibrosis with remaining lacrimal ductules.
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Bottom right. Case 10. Destructive, progressive fibrosis of the orbital fat with distinctive lamellated collagen deposition, sometimes producing onion skinning around vascular channels.
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(Top left, immunoperoxidase reaction, diaminobenzine chromogen, hematoxylin counterstain, x200; Top right, bottom left and bottom right, hematoxylin and eosin, x40, x200 (top and bottom panels), x100)
ACCEPTED MANUSCRIPT
Table: Summary of Eight New Cases and Two Reported Cases of Orbital Inflammation Associated with Pregnancy Orbital inflammation initially during pregnancy
Orbital inflammation initially after pregnancy
Orbital inflammatory recurrences during or after subsequent pregnancies
Left superolateral upper eyelid pain and swelling increasing over 3 weeks; normal vision, pupils and motility; no proptosis
Bilateral dacryoadenitis (CT)
Not applicable
Not applicable
24 hours of right eye redness; pain worse with horizontal eye movement; VA 20/30; motility full; pain with adduction; no proptosis; mild upper eyelid edema; mild segmental conjunctival chemosis medially Painful diplopia for 3 days; VA 20/20; 30 prism diopters of left esodeviation; abduction deficit; normal pupils; otherwise unremarkable examination
Right medial rectus myositis without tendon involvement (CT)
28 weeks gestation; intrauterine fetal demise due to acraina, anencephaly and a complex heart malformation 28 weeks pregnant
Not applicable
Left lateral rectus myositis without tendon involvement (MRI)
38 weeks pregnant
Not applicable
16 weeks pregnant
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Case 325
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Case 4
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Acute erythema and edema of eyelids progressing over 3 weeks; painful horizontal diplopia; limitation of elevation and abduction; 3 mm ptosis; conjunctival injection and chemosis; 6 mm proptosis; VA 20/20 OU, normal pupils; intraocular pressure mildly elevated
Right retrobulbar tissues (ultrasound, MRI)
Case 5
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Subacute onset of orbital pain; eyelid swelling; diplopia; moderately limited adduction OD; normal vision; progression after pregnancy
Left lateral, medial, superior, inferior rectus; right medial rectus myositis without tendon involvement (CT)
New onset after pregnancy
Systemic disease
Biopsy and results
Followup (years)
Treatment and outcome
Not applicable
Diabetes Mellitus Type 2
Light lymphoplasmacytic infiltrate and early fibrosis of lacrimal gland
9 months
Complete resolution of pain and swelling with oral corticosteroids (60 mg/day with 6 week taper)
Not applicable
Not applicable
None
Not done
16 years
Complete resolution without treatment in 1 week (occasional acetaminophen)
Not applicable
Not applicable
None
Not done
6 months
Not applicable
Not applicable
Thrombotic thrombocytopenic purpura; lichen sclerosis
Moderate non-fibrotic lymphocytic infiltrate of fat
4 months
Bilateral worsening immediately after first delivery; severe pain and motility restriction OU; mild right orbital recurrence during second pregnancy
4 recurrences (OD>OS)
None
Not done
5 years
Complete resolution of pain and abduction deficit with oral corticosteroids (1.0 mg/kg/day with taper over 6 weeks) Improvement in symptoms with 30 mg prednisone + 2 month taper and injection of 40 mg prednisone into inferolateral fat pad; residual ptosis with reduced proptosis Treated with NSAIDs, corticosteroids (6080mg/day) and radiation therapy (2000 rad); residual mild limitation of elevation OD and elevation/ adduction OS
Not applicable
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Orbital inflammatory recurrences not associated with pregnancy
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Orbital site initially involved (confirmed by imaging)
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New onset during pregnancy Case 1 40
Presenting complaint/ severity
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Case number
Unknown gestational date
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Table: Summary of Eight New Cases and Two Reported Cases of Orbital Inflammation Associated with Pregnancy
26
Acute upper eyelid edema and painful diplopia of 5 days duration; moderate adduction/abduction deficits; normal pupils
Right lateral rectus myositis without tendon involvement (MRI)
Not applicable
Symptoms began 8 days after normal delivery
Not applicable
Case 7
33
Acute onset of right orbital pain with eyelid swelling with diplopia; severe limitation in adduction OD and normal vision
Right lateral rectus myositis including tendon (CT)
Not applicable
Symptoms began 3 months after molar pregnancy
Not applicable (
Acute onset of orbital pain and eyelid swelling; painful and limited adduction OS; normal vision; milder symptoms during pregnancy attack
Left medial rectus myositis including tendon (CT)
Not applicable
Not applicable
Not applicable
None
Not done
Not available
Developed ankylosing spondylitis 3 years after pregnancy
Not done
18 years
Left medial rectus myositis (2 episodes total prior to pregnancy)
None
Pathology report and slides unavailable for review
3 years
3 recurrences (right medial rectus; left lateral rectus x2; 4 episodes prior to pregnancy)
None
Not done
12 years
3 more recurrences after pregnancy
None
Progressive fibrosis with diminishing lymphocytic infiltrate
15 years
Not applicable
Complete resolution after 3 days of corticosteroid treatment (dose not specified) Improvement with corticosteroids (6080mg/day); remaining mildly limited adduction OD
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Acute onset of orbital pain and eyelid swelling; painful adduction and severely limited abduction OD; normal vision
Right lateral rectus myositis including tendon (CT)
Not applicable
Case 10
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Acute onset of orbital pain and eyelid swelling; VA 20/20 OU; moderately limited abduction, elevation and depression ; 7 mm proptosis OD
Lateral orbital mass including right lateral rectus myositis; dacryoadenitis; superior orbital fissure involvement (CT)
Not applicable
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Case 9
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Recurrence of existing orbital disease during or after pregnancy Case 8 24
Not applicable
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(within 3 months) Case 626
Not applicable
Mild recurrence during pregnancy; orbital pain and pain with eye movement; normal motility and no treatment Recurrence at 3 months gestation; left myositis with limited abduction; left orbital recurrence at end of pregnancy; right orbital recurrence 4 months postpartum Steroid-dependent orbital disease; recurrence of existing disease at 3 months gestation; 20/32 vision; optic neuropathy
Complete resolution with NSAID therapy (ibuprofen 12002400 mg/day for 2 weeks with 6 week taper) Complete resolution with corticosteroids (multiple courses, 60-80mg/day); also received radiation therapy (2000 rad)
Steroiddependent for many years (2030mg/day) with courses of 6080mg/day; underwent radiation and surgical debulking; no light perception; limited abduction/ elevation/ depression
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