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No Specs Thyroid Eye Disease

The Relationship Between Sex And Symmetry In Thyroid Eye Disease

NEET PG-Thyroid Eye Disease-Ophthalmology

Accepted for publication 27 March 2014

10 July 2014Volume 2014:8 Pages 12951300


Thyroid eye disease is an autoimmune inflammatory disorder involving the orbital tissues. It is the most common extrathyroidal manifestation of Graves disease but may also be associated with Hashimotos thyroiditis.13 Although its pathogenesis is not completely understood, autoimmune activation of pre-adipocytic orbital fibroblasts by circulating thyroid-stimulating hormone receptor-directed antibodies and infiltration of inflammatory cells are thought to play a central role.4 The increase in the intraorbital tissue volume results in proptosis, as well as the many clinical symptoms and signs of TED. Proptosis is a key parameter in the assessment of disease severity and activity.

Although TED is more frequent in women, the female-to-male ratio is reversed at 1:4 in severe disease.58 Unilateral or asymmetric presentation is also less common than bilateral, sometimes requiring additional work-up to rule out other pathological processes.9 The aim of this study was to investigate the relationships between sex, symmetry, and thyroid status with respect to disease activity and severity.


Table 1 Asymmetry of symptoms, external findings, anterior segment abnormalities, and optic nerve compressionAbbreviations: N/A, not available OCT, optical coherence tomography.


Figure 1 Overall asymmetry .

Figure 2 Percentage of patients with asymmetry of extraocular findings by sex.

Table 2 Clinical Activity Score

Retrobulbar pain 0-2: inactive TAO3-7: active TAO

The VISA classificationVision, Inflammation, Strabismus and Appearancewas developed to permit grading of both clinical severity and activity based on both subjective and objective inputs .20 This system helps direct appropriate management in a logical sequence by targeting the most relevant aspect of the disease affecting the patient. For example, vision dysfunction from the optic nerve is the first priority. VISA is also beneficial in assessing TAO and grading changes and can act as a guide for therapy.20 The International Thyroid Disease Society has adopted it, and it is used in recent clinical trials.

Another popular method grades TAO from mild to severe.21 The European Group on Graves Orbitopathy defines mild disease as minimal eyelid swelling, lid retraction or proptosis with little or no extraocular muscle dysfunction. Moderate to severe TAO consists of some form of active disease with or without ocular motility dysfunction with diplopia and inflammatory features interfering with the ability to function. It may also include significant proptosis. Serious disease refers to sight-threatening conditions such as dysthyroid optic neuropathy and corneal ulceration.9

Fig. 5. The VISA classification form allows clinicians to monitor the severity and the activity of TAO.

Potential Adverse Effects And Contraindications

Cataract, radiation retinopathy, and radiation optic neuropathy are possible risks of orbital irradiation. These effects are not common if treatment is appropriately fractionated and the eyes are shielded. Marquez et al found that 12% of their study patients developed cataracts after irradiation .

Wakelkamp et al also believed that orbital irradiation for thyroid-associated orbitopathy is a safe treatment modality, except possibly for patients with diabetes mellitus. Radiation may be a relative contraindication for patients with diabetes mellitus because of the risk of worsening retinopathy.

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Signs And Symptoms Of Graves’ Eye Disease

In Graves eye disease the tissue around the eye is attacked, and the result is inflammation and swelling, causing:

  • Redness and pain
  • Dry eye and irritation, occurring when the eyelids cannot close completely over bulging eyes

Progressive swelling may cause:

  • Increased pressure inside the eye socket
  • Pressure-pain or deep headache, which worsens with eye movements

The muscles around the eye are particularly susceptible to the attack of lymphocytes. As they tighten and lose their ability to stretch, these symptoms can occur:

  • The eye is pushed forward in its socket causing a staring appearance
  • Restriction of the eyes normal movements, resulting in double vision

As symptoms build, many patients fear they will lose their vision. Fortunately, patients almost never go blind from Graves eye disease.

Systemic And Locally Injected Glucocorticoids

Recurrent proptosis and thyroid eye disease

High-dose systemic glucocorticoids have potent anti-inflammatory and immunosuppressive effects that have been applied successfully for the management of moderate-to-severe and active GO. Intravenous glucocorticoids have been indicated as the first-line treatment in moderate-to-severe and active GO . A proof-of-concept RCT showed a significant improvement of GO outcome in patients treated with i.v. methylprednisolone compared to placebo . Although oral glucocorticoids are effective, glucocorticoids are preferentially administered i.v. as the i.v. route has been shown in RCTs to be more effective and better tolerated . The most common protocol employs a cumulative dose of 4.5 g methylprednisolone, given in 12 weekly infusions . This 4.5 g regimen is very well tolerated and significantly improves QoL . While this regimen is appropriate for most patients, a higher cumulative dose of 7.5 g is reserved for more severe cases within the spectrum of moderate-to-severe and active GO, as the higher dose bears a higher risk of drug-induced adverse events . Safety data suggest that, with the exception of sight-threatening GO, single i.v. doses should not exceed 0.75 g, cumulative doses should be less than 8.0 g per cycle, and consecutive-day therapy should be avoided, because these schedules are associated with a significantly higher rate and clinically relevant glucocorticoid-induced AEs, including liver toxicity and serious cardiovascular AEs .

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Thyroid Glands Relation To The Eye

Although Graves’ disease and Graves’ eye disease both stem from the immune systems attack on healthy tissue, one disease does not directly cause the other. Thats why treatment of the thyroid gland, while important, does not improve the eye disease. The two diseases run their separate courses and do not necessarily occur at the same time.

Overview Of Surgical Intervention

Approximately 5% of patients with thyroid-associated orbitopathy may require surgical intervention. Alert the patient to the possibility that multiple-staged procedures may be required. In elective cases, listen carefully to what the patient desires the patient’s expectations may not be realistic and these should be addressed before proceding with any surgeries.

The timing of surgery is important. Unless compressive optic neuropathy or severe corneal exposure is present, surgery is generally delayed during the active inflammatory phase of thyroid-associated orbitopathy. Rather, surgery is usually performed during the quiescent cicatricial phase of the disease.

Taking preoperative photographs is advised. With strabismus surgery, document prism measurements or fields of single binocular vision. Recording baseline-automated perimetry is also useful. In patients with thyroid-associated orbitopathy who have proptosis and inferior scleral show, simple horizontal tightening of the lower lid will result in increased globe exposure.

The sequence of surgery is also important, because the outcome of each procedure may determine the necessary goals of the next. If the patient has marked proptosis, strabismus, and lid deformity, perform surgery in the following order :

  • Orbital decompression

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    Management Protocols Of Graves’ Ophthalmopathy

    Treatment plan should be individually designed for each patient. An appropriate approach should be performed by a multidisciplinary team of ophthalmologists, endocrinologists, radiologists, and orbital surgeons . It is vital to identify those patients who are likely to progress to serious complications such as restrictive strabismus or dysthyroid optic neuropathy before they develop.

    Any patient with symptoms or signs of orbitopathy in the high-risk group , positive family history of orbitopathy, a recent history of progression, or any moderate inflammatory changes should be referred to the ophthalmologist within a few weeks. Cases with reported color or central visual loss, progressive diplopia, rapid deterioration in symptoms, or significant inflammatory scores should be urgently evaluated within a few days. Any patient who is undergoing radioiodine therapy for hyperthyroidism suspected of having active disease should be previously referred for an ocular examination to decide on the opportunity of prophylactic corticosteroid therapy .

    Lymphocytic Infiltration Fibroblast Reaction And Increased Orbital Volume

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    Lymphocytic infiltration of the orbital tissue causes a release of cytokines from CD4+ T cells stimulating the orbital fibroblasts to produce mucopolysaccharides, which, by hyperosmotic shift, cause tissue edema in the extraocular muscles.

    Fibroblasts are believed to be the target and effector cells in thyroid-associated orbitopathy. Fibroblasts are extremely sensitive to stimulation by cytokines and other soluble proteins and immunoglobulins that are released in the course of an immune reaction. The cytokines activate previously quiescent fibroblasts to secrete hyaluronic acid, a glycosaminoglycan. Doubling the hyaluronic acid content in the orbital tissue causes a 5-fold increase in the tissue osmotic load. In addition, preadipocyte fibroblasts are influenced to transform into adipocytes, especially in young patients.

    The orbit can be described as a pear-shaped box with an anterior opening the stalk of the pear represents the optic nerve. In thyroid-associated orbitopathy, the increase in orbital volume from the extraocular muscles and fat causes forward protrusion and, occasionally, optic nerve compression at the narrow posterior apex of the orbit. The edema results in tissue damage and fibrosis, with restriction in extraocular motility and lagophthalmos.

    Usually within 1-2 years of the onset of orbital involvement, the inflammation settles to a more quiescent, fibrotic phase predominated by scarring of the orbital tissues.

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    Table 1 Tao Evaluation

    • Intraocular pressure
    • Adnexal examination
    • Orbital ultrasound to assess extraocular muscle size
    • Orbital CT without contrast or MRI to assess extraocular muscle size, orbital fat and proptosis

    You can make the diagnosis of TAO based on presenting ocular signs and symptoms. Changes in appearance and exposure symptoms are the most common early findings in TAO.9 Other symptoms are vague and often attributed to normal aging, especially in middle-aged women with eyelid swelling that is worse in the morning.12

    The most common sign in TAO is lid retraction, which occurs in 82% of patients.13 This may be due to increased sympathetic tone, overaction of the levator and superior rectus muscles to compensate for inferior rectus restriction, or inflammation and scarring of the levator complex .

    The second most common sign is proptosis , which is caused by expansion of the orbital fat, muscles or both . Proptosis can be measured with an exophthalmometer. Values greater than 18mm to 20mm for Caucasians, 16mm to 18mm for Asians and 20mm to 22mm for African-Americans suggest proptosis. Asymmetry of 2mm or greater also suggests proptosis.14,15 If a clinician does not have an exophthalmometer, orbital CT scans can evaluate the amount of proptosis as well.

    Fig. 3. Upper eyelid retraction and proptosis in a patient with orbital congestion in the active phase.

    Clinical Presentation Of Ted

    About 90% of patients with TED also have some thyroid dysfunction – usually the thyroid is overactive , but occasionally the thyroid is underactive . Most times, the diagnosis of TED and diagnosis of a thyroid dysfunction occur within the same year. Patients who are diagnosed with TED but have no known thyroid dysfunction should see their primary care physician for an evaluation of their thyroid function.

    The disease course for TED involves 2 phases – active and stable. In the active phase there is active swelling and inflammation. This presents as redness in and around the eye, eye pain with or without eye movement, as well as swelling around the eyes and eyelids. The active phase of TED involves a waxing/waning period of these symptoms, and can last months to years. On average, the active phase of TED lasts about 1 year for non-smokers, and 2-3 years for smokers . The active phase of TED spontaneously transitions to the stable phase, but can recur. Active TED has a recurrence rate of about 5-10%, but is less likely to recur after 18 months in the stable phase.

    Figure 3. Active vs. Stable TED. Active TED is characterized by signs of inflammation . TED activity waxes and wanes, and usually transitions to stable TED within 1-3 years.

    Figure 4. Rundle’s curve. As seen in the representation of TED activity over time in Rundle’s curve, initiating therapy early is crucial to diminish the overall severity of the chronic disease.

  • In severe cases, damage to the cornea can result
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    Pearls And Other Issues

    Important to note is that the clinical signs of lid lag and lid retraction are not specifically due to Graves orbitopathy. These signs can present in any thyrotoxic state due to sympathetic hyperactivity. The mechanism is related to excess catecholamines acting on the smooth muscle portion of the levator palpebrae superioris muscle called Muller’s muscle, resulting in lid retraction and then subsequently lid lag.

    Another important association is that of Graves orbitopathy and ocular myasthenia gravis. Not only is myasthenia gravis a differential for Graves orbitopathy, but the two diseases may also occur concurrently. Studies have shown that 0.2% of patients with thyroid disease develop myasthenia gravis, and conversely, in those with established myasthenia gravis, 5 to 7.5% of patients have or develop autoimmune thyroid disease. Therefore it is vital to be vigilant when examining the eye, paying particular attention towards the end of the examination to see if any fatiguability is present that will manifest as ptosis. Ptosis is not a clinical feature of Graves eye disease, and so when noticed, it should prompt further investigation for ruling out myasthenia gravis.

    Whether Managing Associated Side Effects Or Referring And Comanaging You Are Integral To These Patients Care Teams

    Read what this Eye Doctor Observed in His T4

    Thyroid-associated ophthalmopathy , also known as thyroid eye disease or Graves ophthalmopathy, is the most common autoimmune inflammatory disorder of the orbit and periorbital tissue, with approximately three million Americans affected.1,2 This prevalence is similar to that of glaucoma in the United States. Historically, TAO was limited to patients with Graves disease and the clinical triad of orbital signs, hyperthyroidism and pretibial myxedema.3 Now, research shows only 80% of patients with TAO have Graves the other 20% consists of patients who are hypothyroid and euthyroid .4 Because TAO can precede, coincide with or succeed the diagnosis of thyroid dysfunction, optometrists need to be capable of making an early diagnosis, as TAO can be vision-threatening, impact a patients appearance and result in loss of quality of life.5,6

    Fig. 1. Hypotropia of the right eye in a patient with TAO.

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    Eye Symptoms And Treatment

    Thyroid eye disease can affect many different parts of the eye and surrounding tissues. Inflamed lacrimal glands may cause wet eyes or dry eyes, and these can both happen in the same patient at different times. Lubrication with eyedrops or ointment can help to soothe this irritation. The abnormal immune reaction causes swelling in the tissues of the eyelids and orbit which can make the eyelids look puffy or as if the person has “baggy” eyelids. This can also create a sensation of pressure around the eyes. The swelling can be surgically altered to bring the lids back to a more normal shape.

    The muscles in the eyelids tighten and pull the upper lid up and the lower lid down. This creates a startled look with too much of the whites of the eyes showing. This also can be surgically improved. The muscles which control movement of the eyes may be increased in size by the swelling. This can create problems with double vision and focusing. Prism glasses may be helpful, and this can also be improved by surgically moving the eye muscles.

    The treatment options for vision-threatening problems in thyroid eye disease include corticosteroids or other anti-inflammatory medications, radiation and surgery. A combination of these may be necessary to protect vision. Most people with thyroid eye disease do not get corneal ulcers or optic neuropathy, but it is important to understand the symptoms so you know when to seek help.

    Thyroid Eye Disease No More No Specs


    Thyroid eye disease is an autoimmune condition affecting the ocular tissues. It occurs in up to 25% of patients with Graves disease. It is most common in patients who have hyperthyroidism , however, it can also occur under eurthyroid or autoimmune mediated hypothyroid conditions. Thyroid eye disease is more common in women, typically around 30 years old, but with another peak near 60 years of age. Men, older individuals, and smokers tend to develop more severe disease.

    The most common course is triggered by the immune system recognizing the thyroid stimulating hormone receptor as an antigen. This triggers an inflammatory cascade mediated by T-cells and B-cells that results in fibroblast and adipocyte proliferation through activation of TSHR and connected insulin like growth factor receptors. These receptors may also be upregulated in retro-orbital tissues of patients with thyroid eye disease. Hydrophilic glycosaminoglycans such as hyaluronic acid are produced and lead to swelling of soft tissues.

    • Image 1: Lid retraction and mild edema of upper eyelids, mild injection of conjunctiva
    • Image 2: Mild edema and erythema of upper eyelids

    Table 1: Clinical Activity Score

    Table 2: Severity Chart for Graves Orbitopathy

    Norm is < /= 2mm between eyes < 3mm from norm
    None Compression


    Ross, D.S. Graves hyperthyroidism in nonpregnant adults: Overview of treatment. In J.E. Mulder . UpToDate. Retrieved on 07/20/2021 from

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    Measures For Patients With Mild Ophthalmopathy

    Local measures are the mainstay therapy for patients with mild ophthalmopathy that generally have a self-limiting process. In the majority of studies which have investigated the natural history of GO in untreated patients, the orbitopathy improved in about a half of the patients, remained stable in about 35%, and worsened in approximately 15% . Since up to 15% of the patients with mild disease may experience progression, a safe and well-tolerated preventive protocol as an alternative to the wait and see strategy seems to be justified. A recent study showed that a 6-month course with oral selenium significantly improved quality of life, reduced ocular involvement, and slowed progression of the disease in patients with mild GO . The use of oral corticosteroids is usually not recommended in patients with mild GO. Botulinum toxin injection may be considered to reduce upper lid retraction and is a valuable therapeutic option in active disease where definitive surgery remains contraindicated. Rehabilitative surgery should be considered providing that the GO remains stable and inactive .

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