Adenocarcinoma metastasis causing discrete extraocular muscle enlargement

Optometry (2009) 80, 367-374

Adenocarcinoma metastasis causing discrete extraocular muscle enlargement William Scott Slagle, O.D.,a,b Daniel R. Eckermann, O.D.,a,b Angela N. Musick, O.D.,a,b and Amber M. Slagle, O.D. a

Salem Veterans Affairs Medical Center, Salem, Virginia; and bEdward Via Virginia College of Osteopathic Medicine, Blacksburg, Virginia.

KEYWORDS Metastasis; Adenocarcinoma; Myositis; Extraocular muscle; Diplopia; Proptosis; Orbital pain

Abstract BACKGROUND: Discrete extraocular muscle (EOM) metastasis is rarely reported. Clinical signs and symptoms of EOM metastasis can often be indistinguishable from primary idiopathic orbital myositis, posing a significant clinical challenge. CASE REPORT: A case of a 61-year-old man with acute-onset unilateral periorbital pain and diplopia is presented. Magnetic resonance imaging showed an isolated edematous superior rectus/levator muscle complex with an isointense T2-weighted signal, supporting a diagnosis of orbital myositis. He was started on corticosteroids, with resolution of pain and improved motilities. Subsequently, his condition worsened. Repeat imaging results suggested the possibility of neoplastic infiltration of the muscle because of the newly demonstrated hyperintensity of the T2-weighted signal and perineural extension along the trigeminal nerve. Fine-needle aspiration biopsy showed adenocarcinoma cytology in the muscle. CONCLUSIONS: This case illustrates discrete adenocarcinoma metastasis of an EOM, initially displaying characteristics predominantly consistent with orbital myositis. There is a paucity of epidemiologic data on EOM cancer, and clinical characteristics are derived only from a selection of case reports in the literature. Thus, the predominant features of global orbital metastatic cancer versus primary inflammation are highlighted in this presentation. This case shows that the variable characteristics of each process prohibit identification of any clinical feature that would prove pathognomonic for either disorder. The varied practice philosophies and standard of care regarding the proper time to biopsy are reviewed. This case shows the importance of early referral for orbital biopsy, even in the presentation of isolated, discretely edematous, and painful EOM enlargement. Optometry 2009;80:367-374

Metastatic cancer may distribute to the orbit via hematogenous dissemination. Isolated metastasis to an extraocular muscle (EOM) is considered relatively rare with limited availability of epidemiologic data. Therefore, we can only examine global ophthalmic cancer data in reference to EOM cancer. In general, overall estimates of ocular Corresponding author: W. Scott Slagle, O.D., Salem Veterans Affairs Medical Center, 1970 Roanoke Blvd. (112E1), Salem, Virginia 24153. E-mail: [email protected]

and orbital metastasis range from 0.7% to 12% in patients with known metastatic cancer with a ratio of intraocular to orbital metastases ranging from 1.4:1 to 8:1.1 It is also prudent to consider the prevalence of metastatic disease among all patients presenting with any type of orbital neoplasm. It is estimated that approximately 8% to 12% of these orbital neoplasms are metastatic.1-3 To our knowledge, discrete metastasis to EOMs without concomitant soft tissue involvement has only been

1529-1839/09/$ -see front matter Ó 2009 American Optometric Association. All rights reserved. doi:10.1016/j.optm.2008.12.010

368 presented by a selection of case reports within the literature. Friedman et al.4 presented a case of isolated thyroid carcinoma metastasis to the medial rectus in 1990 and identified 7 prior reports. That same year, Capone and Slamovits5 presented 5 cases of isolated EOM metastasis and conducted a comprehensive review of the literature to identify 9 reports of discrete EOM metastasis in addition to those identified by Friedman et al. They also reviewed 10 case reports that appear to represent exclusive EOM metastasis, although they were not specifically reported as such. We have been able to identify 22 other case presentations since that time. Identified etiologies of the discrete EOM metastases include breast carcinoma, thyroid follicular carcinoma, prostate carcinoma, renal cell carcinoma, lymphoma, carcinoma from the lung, melanoma and neuroendocrine carcinoma of the skin, carcinoid metastases, liposarcoma, and gastric carcinomas.4-23 A comprehensive report of EOM enlargement associated with metastatic cancer is, however, more profound because metastasis may cause muscle enlargement either by direct infiltration, local invasion, or orbital apical compression with secondary vascular congestion of the muscle. Clinical ophthalmic signs and symptoms of carcinomatous metastases to an EOM present variably, but can include gaze restriction and diplopia, enophthalmos or proptosis, ptosis, hyperemia at muscle insertion, pupillary defects, visual loss and color perception defects from optic nerve compression, chemosis, eyelid and periorbital swelling, ocular irritation, and pain.4-23 In comparison, the clinical presentation of EOM metastases may parallel the signs and symptoms of generalized orbital neoplasia. Goldberg et al.2 delineated the prevalence of the most consistent symptoms presented by patients with any orbital neoplasia, which are diplopia (38%), proptosis (35%), pain (23%), decreased vision (20%), and ptosis (16%). Of the clinical signs observed by the examiner, proptosis was the most prevalent, noted to be present in 64% of patients with orbital neoplasm. Although proptosis was seen most often, enophthalmos was noted in 10% of cases.2 The reason that either proptosis or enophthalmos may be seen depends on the biological activity of the tumor. Although mass effect causes proptosis, the most common mechanism of enophthalmos is contraction of fibroblasts contained within certain tumors (especially metastatic breast cancer) with consequent posterior retraction of the globe.1 Bony destruction of the orbital walls with resultant decompression may also cause enophthalmos.

Case report A 61-year-old white man was referred by his primary care physician for evaluation of an abrupt onset of constant binocular diplopia and periorbital facial pain on the right side. His pain intensity was 10 on a 10-point scale, and his exact comment was ‘‘fix me or shoot me,’’ because of the pain. He reported that 3 weeks before the sudden onset of

Optometry, Vol 80, No 7, July 2009 pain and diplopia, he believed that he had conjunctivitis in the right eye (O.D.) because of ocular tearing and burning, with mattering of the lids. He reported the absence of photophobia and mucus discharge during the day. Just before these symptoms presented, the patient had seen a dentist who had surgically treated an abscessed tooth on the right side, and he reported numbness along the nose and upper lip since his dental surgery. At that time, he was taking 2 different antibiotics for postsurgical infection, which was presumed to cause the maxillary nerve anesthesia. Otherwise, his medical history only included hypertension, for which he was taking hydrochlorothiazide and atenolol. He had no previously diagnosed ocular disease or conditions. His visual acuities on presentation were 20/20 bilaterally without correction. His pupillary testing and visual fields by confrontation were normal. Cover test results showed an esophoria in primary gaze, which became an esotropia in right gaze. He also was noted to have a right hyperdeviation, which increased in right gaze. Significant abduction and supraduction deficits of the right eye were noted on pursuits. Exophthalmometer measurements were 21 O.D. and 20 in the left eye (O.S.). Slit lamp examination was ageappropriately normal except for a mild ptosis of the right eyelid. Goldmann tonometry measurements were 16 mmHg O.D. and 14 mmHg O.S. in primary gaze. Measurement in upgaze increased to 20 mmHg in the right eye, and the left remained stable. On dilated fundus examination, cup-todisc ratios were 0.6 round O.D. and 0.5 round O.S., and neuroretinal rims were normal bilaterally. Funduscopic examination was age-appropriately normal except for an isolated operculated retinal hole in the temporal periphery of the right eye. Serology tests returned normal results for C-reactive protein, Westergren erythrocyte sedimentation rate, thyroxine, thyroid-stimulating hormone, thyroid antibodies, and complete blood count with differentials. Because results of a head computed tomography (CT) evaluation ordered by his primary care physician were reported to be normal, head and orbit magnetic resonance imaging (MRI) studies were ordered to better visualize the orbital apex and evaluate for soft tissue lesions. MRI showed an isolated, fusiform-shaped enlargement of the superior rectus and levator palpebrae muscles O.D (see Figure 1). The T1-weighted images showed that the abnormal muscles were isodense to the unaffected muscles. The T2 signal showed tissue that was isodense to brain parenchyma. Although the T2 signal intensity was slightly higher than orbital fat, it was not considered to be hyperdense to the central nervous system. The muscle borders were well defined, and there was significant contrast enhancement with gadolinium. The enhancement was homogenous within the superior rectus and levator palpebrae muscles and demonstrated no dissemination into the orbit. Because the muscle displayed a fusiform enlargement with a T2-weighted signal that was not hyperdense to the central nervous system, the differentials were deemed to be

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Figure 1

Initial MRI study shows characteristics of inflammation. Yellow arrow identifies fusiform-shaped enlargement of the superior rectus muscle. Blue arrow shows the T2-isodense signal of the superior rectus/levator complex relative to brain parenchyma.

idiopathic myositis versus lymphoma. His acute onset of symptoms and severity of pain along with the significant contrast enhancement led us to initially consider a diagnosis of orbital myositis. We then started him on 80 mg prednisone and 20 mg of omeprazole daily. The following is a synopsis of the clinical course referenced to the day of prednisone initiation: Day 1: The patient reported complete resolution of pain, but the diplopia persisted. Day 3: The patient reported improvement in eye movement and mobility of the upper eyelid. Day 12: The patient was seen in the clinic. He had selfadjusted his prednisone to 40 mg a day on day 5; despite this adjustment, he had some visible improvement in levator palpebrae function. Significant abduction and supraduction deficit returned to pretreatment status; prednisone was increased to 80 mg a day. Day 20: The patient continued taking prednisone with questionable compliance, after which the eyelid and EOM deficits became worse than their pretreatment state. New features included pupillary involvement on the right side with a fixed, mid-dilated pupil and complete paresthesia along the distribution of the maxillary branch of cranial nerve five (CNV) on the right side. A repeat MRI

showed some heterogeneity with regions of EOM enlargement displaying T2 signal hyperdensity relative to the central nervous system (see Figure 2). There was also mild erosion of the skull base without changes in globe position and significant perineural neoplastic spread along the trigeminal nerve. Contrast enhancement was noted through the inferior orbital fissure, along the Gasserian ganglion, through the foramen rotundum, and into the pterygopalatine fossa. The patient was referred to a neuro-ophthalmologist for orbital biopsy, which was performed on day 25. Fine needle aspiration biopsy (FNAB) indicated undifferentiated adenocarcinoma. He was subsequently referred to a medical oncologist who ordered neck, thorax, and pelvic CTs, along with a full-body positron emission tomography (PET) scan, from which no abnormalities were found. He was then referred to radiation oncology where he was treated with 5 days of 6 Gy (gray) daily fractions of radiation via cyberknife. Extraocular movements and motility of the eyelid increased dramatically after radiation, such that he no longer experienced diplopia in most gazes, though there was still restriction in up-gaze. Four months after cyberknife radiation, the patient experienced increased pain and diplopia. MRI findings confirmed

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Figure 2

Follow-up T1-weighted, T2-weighted, and contrast-enhanced MRI images. Blue arrows indicate edematous superior rectus/levator complex. Yellow arrow identifies contrast enhancement into the cavernous sinus. White arrow identifies contrast enhancement into the pterygopalatine fossa.

recurrence of his adenocarcinoma and showed an additional dural-based metastasis on the anterior medial aspect of the contralateral temporal lobe. Because the cancer was more expansive, direct radiation was recommended. Two months after radiation treatment, the patient reported subsequent photophobia but no visual field loss and no reduction in acuity. His pain had completely been relieved. He had mild improvement in elevation of his right eyelid, but noticed constant diplopia. After multiple repeat

CTs and 2 full-body PET scans, a primary malignancy had not been found.

Discussion There are many differentials that a clinician must consider when presented with EOM edema (see Table 1). The most common cause is thyroid-related orbitopathy, which can typically

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Extraocular muscle edema differentials1,5,6,11,13,17,25

Thyroid-related orbitopathy Idiopathic myositis/orbital pseudotumor Manifestation from systemic inflammatory diseases such as: Wegener’s granuloma, myositis with Chrohn’s colitis, myositis with systemic lupus erythematosus, myositis with dermatomyositis, eosinophilic granuloma of soft tissue, and sarcoidosis Toxic orbital myositis Primary or locally invasive tumors Lymphoma and lymphoid tumors, rhabdomyosarcoma, meningioma, granular cell tumor, alveolar soft part sarcoma, liposarcoma, maxillary sinus tumor, nasopharyngeal carcinoma Leukemic infiltration Metastatic carcinomas: Breast carcinoma, lung carcinoma, metastatic carcinoid, pancreatic carcinoma, gastric adenocarcinoma, prostate carcinoma, thyroid carcinoma Other metastatic cancers Melanoma, metastatic seminoma, fibrosarcoma, plasmacytoma, neuroblastoma, Erdheim-Chester disease, malignant nonchromaffin paraganglioma Mesodermal dysplasia Arteriovenous malformation Carotid cavernous fistula Venous varix Angioma Acromegaly Facial hemangiomatosis Dural-venous shunt Amyloidosis Orbital infections from Trichinosis, cysticerosis, orbital cellulitis, mucormycosis, tuberculosis, syphilis, and echinococcal cyst Traumatic muscle hematoma

be differentiated by its associated painless EOM restriction, proptosis, and lid retraction. Anti-thyroid antibodies are usually detectable on serology, and radiographic studies show EOM edema with spared tendons. The presented case shows the relatively rare presentation of an isolated metastatic adenocarcinoma to an EOM, which initially showed clinical signs and symptoms most consistent with orbital myositis. Differentiating these conditions is difficult when metastatic cancer discretely invades a single muscle because these conditions share a similar profile of common clinical signs and symptoms, although their predominance may be different. The most common presenting symptoms of orbital metastasis are diplopia and proptosis, with pain only being associated in approximately 23% of neoplastic cases.2 Restriction of EOM motility that exceeds the amplitude that would be expected from the observed proptosis is considered characteristic of orbital metastasis.2 Orbital myositis is a primary, idiopathic, inflammatory manifestation in a single muscle or multiple EOMs. It most frequently occurs within the first 3 decades of life. It is characterized by acute, painful, proptosis and radiographic evidence of EOM swelling, along with associated diplopia and focal conjunctival injection over the involved muscle insertion. The most common muscles to encounter this primary inflammation are the superior and medial rectus muscles.24

Radiologic differentiation can be challenging and sometimes impossible because of the variable radiographic characteristics of different neoplastic processes as well as variability with idiopathic orbital inflammation. For example, muscle swelling involving the tendons has historically been considered a characteristic seen in myositis, whereas sparing of muscle tendon swelling has generally been attributed to thyroid-related eye disease or neoplastic extraocular muscle infiltration. However, multiple presentations in the literature have later shown tendon-sparing in a significant number of myositic cases.25-27 Many of the clinical and radiographic characteristics of EOM metastasis and myositis were highlighted in a retrospective review of cases pertaining to nonthyroid-related extraocular muscle enlargement. In this evaluation, Patrinely et al.25 analyzed the CT features of 60 patients with nonthyroid EOM enlargement. Twenty-five percent were caused by idiopathic inflammation, 20% resulted from metastatic disease, and 25% were classified as primary or local invasion of neoplasm. Adenocarcinoma was a prevalent cause of metastatic disease, mostly from breast cancer. Of the patients with metastatic carcinoma, the most typical CT finding was a unilateral presentation of isolated rectus involvement. Nodular enlargement of the muscle was the most common appearance of swelling (50%), with fusiform and cylindrical enlargement also observed in metastatic disease. The tendons were typically uninvolved, and muscle borders were sharp in 92% of cases.

372 In comparison to metastatic cases, idiopathic orbital inflammation as in myositis involved multiple muscles in 53% of cases. Muscle borders were sharply delineated in 66% of the cases, and orbital fat and surrounding structures were involved in 26%. The most prevalent form of muscle enlargement was fusiform followed by cylindrical. Interestingly, the Patrinely et al.25 series showed EOM enlargement with tendon-sparing in 47% of the inflammatory cases and 92% of metastatic tumor cases. The typical CT presentation of orbital inflammation is of a homogenous, illdefined signal hyperintensity, sometimes with a molding pattern, and usually mild to moderate iodized contrast enhancement is noted.28 Although some CT imaging characteristics predominate within one differential versus another, the variable presentation of each process prohibits identification of any imaging feature that would prove pathognomonic for any disorder. An MRI may sometimes offer differentiation between orbital myositis and neoplastic infiltration of an EOM. Orbital inflammation typically presents as isodense to muscle on T1-weighted imaging and isodense or minimally hyperdense to fat on T2-weighted imaging.29,30 Typically, an additional characteristic of inflammation is that it will present slightly darker or unchanged on T2-weighted images relative to their appearance on T1-weighted images.28 Alternatively, most metastases show a signal strength that is isodense to muscle on T1-weighted imaging, and they characteristically present a signal intensity that is hyperdense to the central nervous system on T2-weighted imaging.29 In our case, the initial T2 signal on MRI of the involved muscle was isodense to the central nervous system, and thus we did not consider the possibility of metastatic cancer at that time, except for lymphoma. Lymphoma was considered because it can show quite variable presentations on MRI and may present as either hyper- or hypodense on T2-weighted images. Our decision to initially diagnose myositis was substantiated by considering the results of a review by Yan et al.28 that focused on differentiating lymphoid processes from primary orbital inflammation. They presented a retrospective review of the radiographic and clinical characteristics relative to these 2 conditions.28 The most predominant differentiating symptom was pain associated with the inflammatory process and its absence with lymphoid tumors (P,0.0001). Other significant symptoms that they presented to be associated with idiopathic orbital inflammation were the presence of eyelid or conjunctival congestion (P50.001) and retinal folds and hemorrhage (P50.004). Differentiating MRI characteristics were: (1) greater contrast enhancement in idiopathic inflammation versus lymphoid infiltration, and (2) the T2-weighted image became slightly darker or unchanged relative to the T1-weighted image for primary orbital inflammatory process versus the T2-weighted signal being slightly brighter than T1 for lymphomatous infiltrates. The case we present above is atypical and supports the value of early biopsy in such presentations. Although most

Optometry, Vol 80, No 7, July 2009 orbital metastases are adenocarcinomatous in nature, the typical MRI presentation is of hyperintense T2 signal, which was initially not observed in this case. The initial thought was that the differentials included myositis versus lymphoma. Lymphoma was considered because of the patient’s age, but he had no prior history of cancer. A diagnosis of myositis was substantiated by the patient’s report of excruciating pain along with the abrupt onset of symptoms. He was treated with prednisone where the patient experienced an initial dramatic improvement in pain and moderate improvement in function. The patient’s noncompliance with the treatment protocol also contributed to some delay in diagnosing adenocarcinomatous infiltration of the EOM because his return of motility restriction to pretreatment state was initially attributed to an inflammatory rebound. On repeat MRI, erosion of the skull base was noted along with T2 signal hyperintensity of the superior rectus/ levator palpebrae muscle complex. In addition, perineural spread of the tumor to the maxillary branch of the trigeminal nerve was demonstrated by the strong contrast enhancement along the course of the nerve into the cavernous sinus, through the foramen rotundum, and into the pterygopalatine fossa. This aggressive perineural spread is confirmatory for cancer. A diagnostic indication of neoplastic activity in the pterygopalatine fossa can also be confirmed by the obliteration of the normal, high T1 signal intensity of fat in this region.31 As shown in the case presented above, a diagnostic challenge presents when a metastasis enlarges an extraocular muscle without other orbital affects. Clinical and radiographic characteristics of orbital myositis and neoplastic infiltration of an EOM are often similar (see Table 2), leading to the importance of tissue biopsy. There are varied practice philosophies regarding the proper time to biopsy cases presenting with clinical characteristics most consistent with idiopathic inflammation. It is generally accepted that idiopathic orbital inflammation is a diagnosis of exclusion and that a meticulous history and thorough physical examination are of utmost importance. The clinician must consider previous episodes, antecedent trauma or history of infection, acute versus chronic symptom presentation, associated constitutional symptoms, systemic disorders (especially cancer), and risk factors for potential immunologic compromise. Emphasis should be placed on the identification and evaluation for symptoms and signs of cancer. Currently, it is considered within the standard of care that cases consistent with orbital inflammation can be treated with steroids, even without histopathologic confirmation. An immediate, dramatic response of improvement in pain and function is viewed as pathognomic for idiopathic orbital inflammation.32 This philosophy has been substantiated by Ahn Yuen and Rubin26 who present a treatment algorithm that indicates biopsy should be performed in the event that such cases result in persistent or recurrent clinical courses that are refractory to systemic steroid

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Diagnostic comparison of myositis versus metastasis Myositis

Metastasis

 Painful ocular motility  Diplopia

 Diplopia  Proptosis

 Proptosis  EOM restriction  Focal conjunctival injection over the involved muscle

 Proptosis  Extraocular muscle motility restriction that is greater than expected by the amount of proptosis  Restricted motility in the direction of the involved muscle

 Muscle borders are usually sharply delineated  Most prevalent muscle shape is fusiform followed by cylindrical  Most have tendon swelling, but a significant number have tendon sparing

 Nodular enlargement of the muscle is predominant (50%) with fusiform and cylindrical enlargement also observed  Muscles have sharp borders  Edema typically spares the tendons

 Isodense to muscle on T1-weighted imaging  Isodense to fat on T2-weighted imaging

 Isodense to muscle on T1-weighted imaging  Most metastases are T2-hyperdense to CNS  Lymphomas may present as either hypodense or hyperdense on T2

Predominant symptoms

Predominant signs

Typical CT characteristics

Typical MRI characteristics

treatment. Such a protocol has been disputed. A therapeutic challenge with corticosteroids before histopathologic confirmation is shown to have a sensitivity of only 78% and a false-positive rate of 11%.33,34 Because a false-positive result may be encountered with neoplastic infiltration of an EOM, especially with lymphoma, this therapeutic challenge test could delay a cancer diagnosis in a significant number of patients. For this reason, Char29 recommends biopsy on all cases presenting as orbital inflammation, except: (1) in a young patient with painful ophthalmoplegia, ptosis, and mild proptosis along with an orbital CT pattern showing only myositis and (2) patients with orbital apex syndrome (Tolosa-Hunt syndrome). Fine-needle aspiration biopsy (FNAB) is considered an effective diagnostic tool to differentiate inflammatory and neoplastic lesions of the orbit35 and entails the use of a 22-gauge or smaller needle. It is considered safe, with only a few nonophthalmic cases that have documented either local or distant tumor dissemination.29 Kennerdell et al.36 report that FNAB along with clinical findings allowed correct cytologic identification in 80% of 156 ophthalmic cases, such that this technique provided sufficient information in 80% of biopsied patients to treat the pathology without further tissue analysis. In their evaluation of the 156 patients in whom FNAB was performed, 18% of the biopsies manifested insufficient specimens for interpretation, and 2% yielded false results. Their study only encountered 2 false-positives and 1 false-negative, in which a malignancy was identified as nonspecific inflammation. Zeppa et al.37 also evaluated the reliability of FNAB in 1997. In their study of 51 orbital masses, they found that FNAB achieved a 91% sensitivity rate without any false-

positives. They did, however, find 2 false-negatives. Although FNAB in our presented case identified adenocarcinoma, the primary tumor had not been determined, as is the case for approximately 11% of orbital metastatic cancers.2 Our patient had undergone extensive radiologic testing, and though we recommended that he undergo a colonoscopy and upper gastrointestinal endoscopy, the patient refused these tests. It is possible that these tests could have revealed the primary tumor for this biopsy-proven adenocarcinoma. Even though many sources of metastatic cancer pose a grave prognosis, correct identification of a neoplasm via biopsy can guide diagnostic testing for identification of its primary source, and, in many cases, treatment can be initiated for extended quantity and improved quality of life.

Conclusions EOM enlargement can be caused by multiple etiologies. This case shows a rare presentation of discrete EOM metastasis from adenocarcinoma. It is additionally distinctive because it displays a typical constellation of clinical signs and symptoms, initially most consistent with orbital myositis. A primary, idiopathic inflammatory etiology was considered initially because of the acute presentation of restricted motility along with an abrupt onset of intense pain. The practicing optometrist is obligated to correctly identify pathology causing these symptoms and to understand the clinical and radiologic characteristics that discriminate etiologies of discrete EOM swelling. This report highlights the imaging and clinical characteristics of

374 metastatic disease and orbital inflammation to enhance the optometrist’s acumen in distinguishing these pathologies. Although many clinicians incorporate a practice philosophy of using steroids to treat cases consistent with orbital inflammation without obtaining initial histopathologic confirmation, this case underscores the value of referral for early orbital biopsy, even in the presentation of isolated, discretely edematous, and painful EOM enlargement.

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