Background
Exophthalmos is defined in Dorland's Medical Dictionary as an "abnormal protrusion of the eyeball; also labeled as proptosis." Proptosis in the same reference is defined as exophthalmos. Another resource suggests that the terms exophthalmos and proptosis can be used to describe eyes appearing to bulge out of the face due to an increase in the volume of the tissue behind the eyes. Proptosis can describe any organ that is displaced forward, while exophthalmos refers to only the eyes.[1] Proptosis can include any directional forward displacement.
Henderson reserves the use of the word exophthalmos for those cases of proptosis secondary to endocrinological dysfunction.[2] Therefore, this dictum will be followed, and non–endocrine-mediated globe protrusion will be referred to as proptosis and exophthalmos will be reserved for protrusion secondary to endocrinopathies. See the image below.
View Image | Bilateral exophthalmos and upper lid retraction secondary to Graves disease. |
View Image | Exophthalmos due to thyroid dysfunction. The patient has significant forward protrusion of the eyes with bilateral upper- and lower-lid retraction. Im.... |
View Image | Exophthalmos due to thyroid dysfunction. The patient has significant forward protrusion of the eyes and bilateral upper- and lower-lid retraction. Als.... |
Pathophysiology
The etiological basis of proptosis can include inflammatory, vascular, infectious, cystic, neoplastic (both benign and malignant, metastatic disease), and traumatic factors. Some representative examples (not a complete list of proptosis from different causes) include infectious causations such as orbital cellulitis and subperiosteal abscesses. Traumatic causations could be orbital emphysema, retro-orbital hemorrhage, and carotid-cavernous fistula. Vascular causations not traumatically related would be orbital arteriovenous malformation (AVM) varices and aneurysms. Neoplastic causations include adenocarcinoma of the lacrimal gland, pleomorphic adenoma of the lacrimal gland, meningioma, lymphoma, and metastatic disease.
For instance, lymphangiomas, by their histologic nature, can increase in size during viral illnesses and result in an increase in orbital volume. A ruptured lymphangioma can enlarge after its rupture and sequestering of heme, which pathologically is described as a chocolate cyst. Orbital varices can result in proptosis with increased venous pressure in the orbit, as seen with a Valsalva maneuver or change in postural position.
Unusual cases are also encountered, such as bilateral proptosis due to orbital hemorrhage caused by factor IX deficiency (hemophilia B).[3]
In children, unilateral proptosis is often due to an orbital cellulitis–type picture, and, in bilateral cases, neuroblastoma and leukemia are more likely. Other causes in children include rhabdomyosarcoma, retinoblastoma, capillary hemangioma, dermoid cyst, glioma of the optic nerve, and metastatic disease.
Thyroid orbitopathy, also referred to as thyroid ophthalmopathy, is categorized as an inflammatory process that is autoimmune-mediated.[4, 5, 6] As it affects the orbit, the author prefers to use thyroid orbitopathy and, more particularly, thyroid-associated orbitopathy, commonly referred to as Graves disease. In adults, it is the most common cause of unilateral and bilateral exophthalmos. Noninflammatory thyroid orbitopathy has also been reported.[7]
The etiology of the thyroid-related orbitopathy is an autoimmune-mediated inflammatory process of the orbital tissues, predominantly affecting the fat and the extraocular muscles. Lymphocytes, plasma, and mast cells are the cellular constituents in this process. The deposition of glycosaminoglycans and the influx of water increase the orbital contents. Over time, fibrosis can occur.[8, 9] Genetic factors have been associated with Graves disease.[10] Obstruction of the superior ophthalmic vein with resultant diminished venous outflow also contributes to the orbital engorgement.
Nunery has segregated patients with thyroid-related orbitopathy into type I and type II.[11] Those with type I do not have restrictive myopathy, whereas those with type II do. Type I was believed to be caused by a profundity of hyaluronic acid manufactured by the orbital fibroblasts, stimulating lipoid hyperplasia and edema. Patients with type II experience restrictive myopathy and have diplopia within 20° of fixation.
Orbital emphysema can be a significant cause of proptosis and requires emergency treatment.
No matter what the etiology may be, globular protrusion is secondary to the increase in volume within the fixed bony orbital confines. Since the orbit is widest toward its anterior aspect, the orbital contents are displaced anteriorly, resulting in proptosis and exophthalmos.
Epidemiology
Frequency
Five percent of the general population is affected by thyroid autoimmunity problems.[5]
United States
Bartley et al had reported a frequency of 2.9 cases per 100,000 population per year in men and 16 cases per 100,000 population per year in women. They also observed a bimodal distribution in both sexes, with women showing one peak at age 40-44 years and the other peak at age 60-64 years. In men, the bimodal occurrence was at age 45-49 years and age 65-69 years. Both peaks incidences in men were 5 years later than in women.[12]
International
Tellez et al, in another small study consisting of 155 patients who were newly diagnosed with Graves ophthalmopathy, 26% were male and 36% were female; however, the prevalence was higher in the Europeans, at a rate of 42% versus 7.7% in Asians. Analysis of the data indicated that Europeans were 6.4 times more likely to have Graves ophthalmopathy than Asians.[13] In northern India, the prevalence of Graves orbitopathy was reported as being similar to that in European patients but with less severity.[14]
Predictive
In a report from the European Group on Graves’ Orbitopathy (EUGOGO), 15% of patients who did not have orbitopathy at the time of diagnosis of Graves hyperthyroidism went on to develop orbitopathy.[15]
Mortality/Morbidity
Proptosis due to any cause can compromise visual function and the integrity of the eye.
A proptotic eye not adequately protected by the lids, as with lagophthalmos, can develop exposure punctuate keratopathy. Such disruption of the finely orchestrated homeostatic mechanism to protect the eye will result in corneal compromise, epithelial death, ulceration, and possible corneal perforation in severe cases. At a minimum, the disruption of the tear film layer and incomplete moisturizing of the eye will adversely affect vision and ocular comfort.
Proptosis secondary to a space-occupying process can result in a compressive optic neuropathy. Impeded optic nerve blood flow results in irreversible neuronal death and diminished optic nerve function. Such manifestations as depression of visual and color acuities, pupillary dysfunction, and constriction of visual field can occur.
Proptotic compressive effects are remedied initially by forward protrusion of the eye, thereby reducing the compressive effect within the orbit. However, the eye can extend only so far, and severe stretching can adversely affect the eye and compromise the optic nerve.
A difference of more than 2 mm between the 2 eyes of any given patient is considered abnormal.
Race
Epstein et al state that proptosis is a globe that protrudes 18 mm or less and exophthalmos is protrusion of greater than 18 mm. The upper limit of normal was 21 mm.[16]
In adult white males, the average distance of globe protrusion is 16.5 mm, with the upper limit of normal at 21.7 mm.[17]
In adult African American males, it averages 18.5 mm, with the upper limit of normal reported as 24.7 mm.[17] A separate study reported the average as 18.2 mm, with an upper normal limit of 24.14 mm in males and 22.74 mm in females.[18]
In Mexican adults, males averaged 15.18 mm and females averaged 14.83 mm.[19]
In Tehran, Iran, for the age group of 20-70 years, the average was 14.7 mm.[20]
In Taiwanese adults, comparing normal subjects to those with Graves disease, the normal group had an average reading of 13.91 mm versus 18.32 mm for the Graves disease group.[21]
Even within a group of people, there can be variability. Four ethnic groups in Southern Thailand had exophthalmometry measurement averages ranging from 15.4 mm to 16.6 mm.[22]
In 2477 Turkish patients, the median Hertel measurement was 13 mm, with an upper limit of 17 mm.[23]
In a Dutch study, the upper limit by Hertel measurement was 20 mm in males and 16 mm in females.[24]
Sex
Females also show racial variation. The average in white women was 15.4 mm and the average was 17.8 mm in African American women. The upper limits of normal in each group were 20.1 mm and 23 mm, respectively.
In general, adult females across all races have lower exophthalmometry readings than adult males.
Thyroid orbitopathy has a female preponderance, with a female-to-male ratio of 5:1. However, these differences diminish for the more serve cases of ophthalmopathy. The incidence of severe ophthalmopathy is 3-5%.[25] The female to male ratio in this subgroup is 1.4:1.[26, 8, 27]
Age
Proptosis occurs in both adults and children at any age. Thyroid orbitopathy and the resultant exophthalmos show a predilection for females aged 30-50 years.
Ahmadi et al showed that with increasing age occurs a "linear reduction in ocular protrusion." With advancing age, there was no asymmetries between the eyes noted.[28]
A US pediatric population showed exophthalmometry measurements that increased with increasing age, as one would expect. The results were stratified into age groups with the following corresponding averages:
Of the 673 subjects in this study, only 2 had a 2-mm difference between the eyes.[29]
In Tehran, Iran, for the age group 6-12 years, the average was 14.2 mm and for the age group 13-19 years, the average was 15.2 mm.[20]
In Chinese children and adolescents from Xiamen, in the age range from 5-17 years, the average exophthalmometry reading was 14.48 mm.[30]
Note that CT scanning and exophthalmometry yield measurements that are not identical, especially when proptosis is present.[31] In addition, parallax errors exist with most commonly used measuring devices.[32]
History
A meticulous history of the patient's ocular and systemic systems is key in establishing a diagnosis.
The ophthalmic history should address the duration and the rate of onset of the proptosis. The patient should be queried about pain, change in visual acuity or refraction, diplopia, and decreased fields of vision. Transient visual loss or blackout periods may signify optic nerve compromise and may call for rapid intervention.
Complaints of foreign body sensation or dry gritty eyes are symptoms that may indicate corneal decompensation.
In performing a thorough medical history and a review of systems, the ophthalmologist should consider orbital involvement secondary to systemic pathology.
Past trauma and family history also may aid in the diagnosis.
Physical
Evaluation of the patient with exophthalmos begins with a thorough ophthalmic and medical history. When concomitant sinus disease or an intranasal source is suspected, a speculum or endoscopic intranasal examination is warranted. Special emphasis on the duration and rate of progression of the patient's signs and symptoms is essential. Pain, diplopia, pulsation, change in effect or size with position or Valsalva maneuver, and disturbance of visual acuity are symptoms that should be explored. In general, a difference of more than 2 mm between a person's 2 eyes is abnormal.
A complete ophthalmic examination is paramount. Periorbital changes can be noted easily on gross examination in a well-illuminated examination room. Hypertelorism, exorbitism, eyeball protrusion (proptosis), eyelid lesions or edema, chemosis, and engorged conjunctival vessels are several periorbital signs. Blepharoptosis, lagophthalmos (incomplete lid closure), and interpalpebral fissure distance are additional signs to be considered during the examination.
Palpation of the anterior orbit can assess the level of tenderness, texture, and mobility of the mass. Tenderness may denote an inflammatory process or neural invasion by a neoplasm. Attention should be paid to regional lymph nodes. Tactile inspection of the globe may reveal pulsations secondary to arteriovenous communications or physiological intracranially pulsations transmitted through a bony defect of the orbit, such as an encephalocele.
Protrusion of the eye is an important clinical manifestation of orbital disease. In addition to proptosis, one should note the displacement of the eye in planes other than the anteroposterior dimension (eg, downward, lateral). Hertel exophthalmometry is a well-accepted tool to quantitate proptosis. The base is determined by the interlateral canthal space. The transection of the central cornea by the premarked millimeter ruler records the amount of anterior displacement of the globe. Its use requires intact lateral orbital rims. If the rim is not intact, a Luedde exophthalmometer. Relative protrusion can be observed by simply standing behind a seated patient and gazing downward toward the chin from the forehead to assess the displacement of one globe as compared to the contralateral side.
Auscultation of the orbit may detect a high flow state in the orbit or intracranially. The bell is useful for this examination. If a high-flow lesion is suspected (eg, carotid cavernous fistula), arteriography should be sought to further qualify these lesions. It is important to have the contralateral eye remain fixated on a target while auscultating the orbit.
Decreased visual acuity, change of refraction, and pupillary abnormalities should be noted.
Extraocular motility dysfunction and diplopia should be carefully assessed and documented.
Forced duction testing may qualify the dysfunction as restrictive or neurogenic in nature. Intraocular pressure may be elevated, and slit lamp examination can discern chemosis and engorged or sentinel vessels.
Dilated funduscopic examination may reveal optic disc edema or pallor, retinal detachment, choroidal folds, vascular engorgement or shunt vessels, or indentation of the posterior pole.
Laboratory Studies
Patients with thyroidopathy should undergo the appropriate thyroid function studies, even though some patients are euthyroid at the time of presentation with exophthalmos. Approximately 80% of those with Graves disease manifest orbital signs within 18 months, supporting the need for ophthalmic evaluation.
Any patient suspected of having a neoplasm as the cause of the proptosis should undergo imaging studies (see Imaging Studies). The imaging results should direct further laboratory studies. For example, in a patient with proptosis due to lymphoma, hematologic studies, further body imaging, and a bone marrow biopsy may be indicated.
In patients with proptosis due to orbital cellulitis, complete blood counts, blood and nasal cultures, and sinus imaging studies may be warranted.
Imaging Studies
CT scan, first used in the 1970s, is the product of tissue density calculations. X-rays with different vectors are emitted, penetrating through target tissues with resulting radioabsorbencies. These differences in radioabsorbencies are assigned value-specific gray shades to create the 2-dimensional image. CT scan can produce detailed axial and coronal views of soft tissue and bony structures. Image windows from 1.0-3.0 mm in thickness allow for detailed evaluation of orbital masses. Contrast-enhanced images may be obtained and can help in identifying inflammatory processes, vascular tumors, and engorged vessels. Calcified lesions are discernible without the addition of contrast.
Magnetic resonance imaging (MRI) excites protons by applying a radio frequency with a strong magnetic field. Hydrogen nuclei emit signal intensities that are assigned specific gray tones to create an anatomical reproduction. Three-dimensional views can be gained directly, in any anatomical plane, offering excellent spatial resolution of orbital masses and soft-tissue enhancement. MRI may provide excellent soft-tissue resolution, but CT scan is superior for gleaning details about orbital bony structures.
Ocular ultrasonography can be used to visualize anterior and middle orbital lesions. Sound waves of 5-15 MHz breech orbital tissues that reflect echogenic energy captured by an oscilloscope. A-scan ultrasonography allows for a 1-dimensional description of echoes, while B-scan ultrasonography provides a 2-dimensional image. C-scan ultrasonography affords coronal views, and D-scan ultrasonography creates 3-dimensional orbital views. With the advent of CT scan, C- and D-scan ultrasonography remains unpopular. Doppler ultrasonography may be used to evaluate orbital vasculature and blood flow.
Long-Term Monitoring
Patients should be monitored in intervals tailored to the degree of exophthalmos and complications arising from this ocular malady. Measurement of exophthalmos, visual and color acuities, pupillary function, extraocular motilities, and visual fields should be obtained. In addition, any corneal breakdown should be assessed and remedied.
Author
Michael Mercandetti, MD, MBA, FACS, Private Practice
Disclosure: Nothing to disclose.
Coauthor(s)
Adam J Cohen, MD, Physician/CEO, Eyelid and Facial Plastic Surgery and MediSpa
Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Triad Inc.<br/>Serve(d) as a speaker or a member of a speakers bureau for: Mimedx.
Specialty Editors
Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
J James Rowsey, MD, Former Director of Corneal Services, St Luke's Cataract and Laser Institute
Disclosure: Nothing to disclose.
Chief Editor
Hampton Roy, Sr, MD, Associate Clinical Professor, Department of Ophthalmology, University of Arkansas for Medical Sciences
Disclosure: Nothing to disclose.
Additional Contributors
Brian A Phillpotts, MD,
Disclosure: Nothing to disclose.
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