Jacqueline Carrasco

BASICS

DESCRIPTION

Thyroid eye disease (also referred to as Graves’ ophthalmopathy, thyroid-related or associated orbitopathy or ophthalmopathy; TED) is an autoimmune process affecting extraocular muscles and orbital fat and connective tissues, resulting in a spectrum of findings including upper and lower lid retraction, proptosis (exophthalmos), restrictive strabismus, and, in the worst cases, optic neuropathy.

EPIDEMIOLOGY

Incidence

• Age-adjusted incidence of ophthalmopathy is 16/100,000 population per year for women and 2.9/100,000 population per year for men.

• Majority (up to 70%) of Graves’ disease patients demonstrate extraocular muscle (EOM) enlargement on imaging although only ∼50% show clinical signs and only 20–30% are clinically relevant manifestations (symptomatic).

• 3–5% of cases are severe/sight threatening

• Bilateral in 85–95%

• Bimodal age distribution

– 5th and 7th decades of life

• More severe in men and older patients

RISK FACTORS

• Smoking

• Female gender

• Uncontrolled thyroid status (hyper- or hypothyroidism)

• Radioiodine therapy

Genetics

No known genetic predisposition identified at this time

GENERAL PREVENTION

• Smoking cessation is the most important modifiable risk factor.

• Smoking cessation or avoidance has been shown to reduce

– Risk of developing TED

– Severity of disease

– Rate of recurrence of Graves’ disease

– Better response to immunosuppressive therapy

• 15% of patients treated with radioactive iodine showed progression of ophthalmopathy. This is reduced to 5% with concomitant oral prednisone treatment.

PATHOPHYSIOLOGY

Enlargement of EOMs and orbital fat leads to proptosis, lid retraction, corneal exposure, diplopia, and optic nerve compression at the orbital apex.

ETIOLOGY

An autoimmune disorder with stimulating autoantibodies binding to thyrotropin receptors in the orbit

COMMONLY ASSOCIATED CONDITIONS

• Hyperthyroidism

– May occur concurrently, following diagnosis, or preceding diagnosis

– TED is the most common extrathyroid sign of hyperthyroidism.

• Hypothyroidism

• Euthyroid state

• Myasthenia gravis

DIAGNOSIS

• Ophthalmic features in thyroid eye disease include various degrees of:

– Lid retraction (scleral show)

– Lid lag (lids do not move down with downgaze)

– Lagophthalmos (incomplete lid closure)

– Corneal exposure

– Superior limbal keratitis (SLK)

– Lid edema¹

– Redness of eyelids^∗

– Conjunctival injection/redness^∗

– Chemosis^∗

– Inflammation of caruncle and/or plica^∗

– Exophthalmos

– Restrictive strabismus

– Compressive optic neuropathy

• Systemic findings depend on thyroid state.

HISTORY

• Inquire about

– Acuity of onset

– Periorbital ache^∗

– Pain with eye movement^∗

– Diplopia (primary gaze or extreme side gaze only?)

– Tearing, irritation, and foreign body sensation

– Change in vision

PHYSICAL EXAM

• Visual acuity

• Pupillary reaction (check for rAPD)

• Color plates

• Ocular motility (restriction of movement)

• Ocular alignment (measurable tropia)

• Presence of external signs (see Diagnosis)

• Hertel exophthalmometry (measures proptosis)

• Anterior segment exam, with careful attention to corneal surface and presence of SLK

• Funduscopy

– Examine for evidence of optic nerve swelling or pallor

– Presence of macular abnormalities (unrelated to TED but possibly contributing to visual loss, if present)

DIAGNOSTIC TESTS & INTERPRETATION

Lab

• TSH, T3, and Free T4

• Thyroid stimulating immunoglobulin (absence does not rule out disease. Positive test helps confirm diagnosis in mild disease; may be followed in treatment of Graves’ disease)

Imaging

• CT of orbits (axial and coronal projections)

• Other conditions are ruled out (see Differential Diagnosis)

• EOM enlargement is assessed (inferior and medial recti are most commonly involved)

• Orbital apex is assessed for evidence of optic nerve compression.

• Radiologic proptosis can be measured and correlated with clinical findings.

• Quiescent disease often shows fatty infiltration of EOMs (EOMs appear tubular in cross section).

Diagnostic Procedures/Other

• Visual field testing (may have various defects in cases of optic neuropathy)

• Single binocular Visual Field Test

• Hess screen (measures strabismus)

• External photography

• Color plate deficiencies (decreased color perception may be an indicator of optic neuropathy)

Pathological Findings

• Extraocular muscles are separated by granular material consisting of collagen fibrils and glycosaminoglycans.

• Focal and diffuse mononuclear cell infiltrates within EOMs and orbital fat in active disease.

• Fibrotic changes in inactive disease

DIFFERENTIAL DIAGNOSIS

• Idiopathic orbital inflammation

• Orbital tumor

• Orbital vascular malformation (e.g., varix, lymphocele)

• Carotid–cavernous fistula

• Metastatic disease

Note: many of the above conditions are typically unilateral in presentation.

TREATMENT

ADDITIONAL TREATMENT

General Measures

• Treatment is determined by level of activity [Clinical Activity Score (CAS) is a validated tool] and severity of the disease.

• Presence of inflammatory signs and/or worsening of signs and symptoms suggests active disease (CAS >3).

• Severity is graded mild, moderate-to-severe, and sight-threatening (optic neuropathy or corneal ulceration/breakdown).

• May be observed if mild or asymptomatic, otherwise treated based on severity

• Lubrication with artificial tears for symptoms of corneal exposure (e.g., dry, gritty, foreign body sensation, tearing)

• Prisms for mild degrees of diplopia

– Fresnel prisms—applied to back of spectacle lenses (con: decrease visual acuity, may cause glare)

– Prisms may be also be ground into glasses (con: expensive, increase weight of lens)

• Moderately Severe Disease

– If active: immunosuppression with pulse i.v. or p.o. steroids (Level Ib evidence for IV pulse)

– ∼1 mg/kg per day starting dose for oral prednisone

– Large cumulative doses (8–15 g) of i.v. methylprednisolone have led to death due to acute liver failure. (Level III) Total dose <4.25 g appears safe. Fewer side effects than p.o. steroids.

– Orbital radiation (typical dose: 20 Gy) may also be used

– Conflicting evidence regarding overall efficacy. Shown to be effective in improving motility and decreasing diplopia (Level Ib)

– Also used to shorten overall course of disease and allow reconstructive surgery to be performed

• Sight-Threatening Disease

– If due to corneal breakdown, it is imperative to restore adequate coverage of cornea with aggressive lubrication, tarsorrhaphy, etc.

– If due to optic neuropathy

High-dose i.v. pulse steroids (Level III) followed by orbital decompression

Urgent decompression if unable to tolerate steroids or no response to i.v. steroids

• Once disease is stable, may proceed with reconstructive surgery

SURGERY/OTHER PROCEDURES

A stepwise approach: Orbital Decompression → Strabismus surgery → Eyelid surgery

• Orbital surgery may alter strabismus measurements; strabismus surgery may, in turn, affect eyelid position

• Not all patients will need all 3 types of surgery

• Some patients may skip one of the steps (e.g., a patient with severe proptosis and lid retraction)

• Orbital decompression

– The orbit is a bony compartment with fixed volume (∼35 cc)

– Enlargement of EOMs may push the eye forward (proptosis), compress the optic nerve (optic neuropathy), and/or cause eyelid retraction.

– Decompression surgery involves removing parts of bony orbital walls in order to allow the enlarged EOMs and orbital fat to prolapse into the surrounding sinuses (floor and medial wall decompression, most commonly performed) or fossae (temporal fossa with lateral wall decompression, anterior cranial fossa with roof decompression—rarely done, neurosurgical involvement mandatory)

– Orbital fat may also be debulked at the same time

• Strabismus surgery

– Goal is to realign the eyes in primary (straight ahead) and reading gaze

– Diplopia in peripheral gazes may persist

– Adjustable suture technique is used to verify alignment once patient is awake

– May affect eyelid position [e.g., recession (weakening) of inferior rectus may worsen lower lid retraction]

• Eyelid surgery

– Goal is to restore eyelid closure, coverage during blink, and reduce symptoms of exposure

– Secondary goal is to improve cosmesis, restoring a more normal appearance (remove “thyroid stare”)

– Upper eyelids

– Transcutaneous or transconjunctival approaches may be utilized

– Upper eyelid retractors (Muller’s muscle and/or levator palpebrae) are cut (recessed)

– Lower eyelids

Lower lid retractors are recessed

Spacer graft (AlloDerm, buccal mucosa, banked sclera, etc.) may be used in severe cases to elevate lower lid position.

ONGOING CARE

FOLLOW-UP RECOMMENDATIONS

• Primary care provider and/or endocrinologist manage systemic thyroid disease

• Ophthalmologist with subspecialty involvement of an oculoplastic surgeon manages eye complications and surgery

• Others may include radiation oncologist, ENT, neuro-ophthalmology, and rarely neurosurgery

Patient Monitoring

Frequency depends on activity and severity of disease, ranging from once every 3–4 weeks to yearly if mild or stable.

PATIENT EDUCATION

• Patients are informed about the state of their disease (activity and severity) and advised as to the recommended treatment and prognosis.

• Smoking cessation is discussed and encouraged if applicable.

PROGNOSIS

• Most cases are mild and require supportive care and monitoring only.

• Smoking cessation is important in control of progression/severity of disease.

COMPLICATIONS

• Visual loss

• Persistent diplopia

• Disfigurement

ADDITIONAL READING

• Bahn RS. Graves’ ophthalmopathy. N Engl J Med 2010;362(8):726–738.

• Bartalena L, Baldeschi L, Dickinson A, et al. European Consensus Statement of the European Group on Graves’ Orbitopathy (EUGOGO) on Management of GO. Eur J Endocrinol 2008;158:273–285.

• Bradley EA, Gower EW, Bradley DJ, et al. Orbital radiation for Graves’ ophthalmopathy: A report by the American Academy of Ophthalmology. Ophthalmology 2008;115:398–409.

• Stiebel-Kalish H, Robenshtok E, Hasanreisoglu M, et al. Treatment modalities for Graves’ ophthalmopathy: Systematic review and metaanalysis. J Clin Endocrinol Metab 2009;94:2708–2716.

• Wiersinga WM, Bartalena L. Epidemiology and prevention of Graves’ ophthalmopathy. Thyroid 2002;12:855–860.

• Wiersinga WM. Management of Graves’ ophthalmopathy. Nat Clin Pract Endocrinol Metab 2007;3:396–404.

CODES

ICD9

• 242.00 Toxic diffuse goiter without mention of thyrotoxic crisis or storm

• 374.41 Lid retraction or lag

• 376.30 Exophthalmos, unspecified

CLINICAL PEARLS

• May occur in hyper-, hypo-, and euthyroid states

• Lid retraction is the most common sign.

• Number one cause of both unilateral and bilateral proptosis in adults

• Corneal exposure, optic neuropathy, and side effects of treatment (e.g., steroid-induced cataracts) can lead to visual loss.

^∗ Items marked with ^∗ comprise the Clinical Activity Score. 1 point is assigned to each. CAS>3 indicates active disease

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