THYROID EYE DISEASE

Autoimmune disorder characterised by infiltrative orbitopathy

Graves' disease Graves' disease is the most common thyroid

abnormality associated with thyroid orbitopathy, but other disorders of the thyroid can have similar ocular manifestations. These include Hashimoto's thyroiditis, thyroid carcinoma, primary hyperthyroidism, and neck irradiation.

Approximately 40% of patients with Graves' disease have or will develop thyroid orbitopathy.

THYROID EYE DISEASEAssociated with normal to abnormal

thyroid function which may coexist, precede or follow the orbitopathy.

Related to but not the same as Graves Ophthalmopathy (GO) The natural history was described by Rundle and Wilson in 1945

Thyroid status- Of those patients with thyroid orbitopathy,

approximately 80% are clinically hyperthyroid and 20% are clinically euthyroid.4 Most patients with euthyroid Graves' orbitopathy, however, have some detectable laboratory evidence of subclinical hyperthyroidism.

Both hyperthyroid and euthyroid patients can develop clinical signs and symptoms of thyroid orbitopathy. In general, patients with euthyroid Graves' disease tend to have less severe orbitopathy

THYROID EYE DISEASE The goal is to identify and treat patients who are at

particular risk of sight threatening complications. The disease has a finite period of activity until it becomes burnt out.The yellow region shows the early phase where there is the best response to treatment.

Type 1 younger age group, whiter eyes with proptosis. Inflammation is mostly in orbital fat not muscles.

Type 11 older patient with red eyes, severe sight threatening disease, tobacco addiction is frequent.

General Considerations Severe exophthalmos and compressive optic

neuropathy are slightly more common in older men.

There appears to be an increased prevalence of thyroid disease in smokers, for whom the relative risk of developing Graves' orbitopathy is twice as high as it is for nonsmokers.

The reason for this difference is not known, but one possibility is that the decreased immunosuppression in smokers may allow greater expression of autoimmune processes.

PATHOGENESIS

Type II reaction:- autoimmune antibodies target somatic tissues such as extraocular muscles causing an antigen-antibody reaction. A large number of lymphokines are implicated in the inflammatory process.

Inflammation results in production of mucopolysaccharides by fibroblasts leading to swelling followed by collagen production resulting in restriction.

There is a high concentration of macrophages in the inferior rectus muscle as well as CD4+ memory T cells and CD8 T cells. This may account for the clinical observation of maximal disease activity in this muscle.

ETIOLOGY In 1956, Adams and Purves isolated a factor in the serum of

patients with Graves' hyperthyroidism that caused stimulation of the animal thyroid gland. This factor was very similar to TSH but had a longer half-life. It was therefore called long-acting thyroid stimulator (LATS).

In 1964, Kriss and colleagues showed that LATS had the structure of an IgG immunoglobulin and its action could be neutralized by thyroid tissue, indicating that it was an antibody.

Further experiments showed that the antibody was directed against the receptor for TSH on the follicular cell of the thyroid gland.

Thyrotropin receptor antibodies (TRAb).antibodies were originally classified into

those with stimulatory properties called thyroid-stimulating immunoglobulin or antibody (TSI, TSAb) and those with inhibitory properties called TSH-binding inhibiting immunoglobulin or antibody (TBII, TBIA). Both of these groups are now referred to as thyrotropin receptor antibodies (TRAb).

PHYSIOLOGY

Hypothalamus TRH pituitary TSH thyroid T3 and T4

85% of T4 converted to T3 in tissues.T3 has 5 times the activity of T4.

Pathology The predominant orbital pathology is

inflammation of the orbital soft tissues and extraocular muscles. This immune-mediated inflammation consists mostly of lymphocytes and plasma cells, with a scattering of mast cells. These inflammatory changes differ from the more exuberant lymphocytic infiltration of the orbital fat and muscles, including their tendinous insertions seen in orbital pseudotumor

Pathology The earliest change in extraocular muscles

appears to be inflammation of the endomysial connective tissues, which stimulates endomysial fibroblasts to produce first hyaluronic acid and then collagen. In the acute stage there is inflammation, edema, and deposition of glycosaminoglycans. Eventually there is tethering of orbital tissues due to fibroblast proliferation.

CLINICAL

(orbitopathy in general is worst in the older age groups.)   LID RETRACTION1. sympathetic overactivity2. infiltration of levator / SR complex3. hypotropia

(retraction disappears on downgaze) SIGNS:- Dalrymples (lid retraction), von Graefe (lid lag), Kocher´s (staring appearance)     INFILTRATION 1. soft tissue involvement :- chemosis, conjunctival injection over the recti insertions, puffy lids     Superior limbic keratoconjunctivitis (SLK) due to redundant conjunctiva     2. muscle involvement :- diplopia due to restriction. Order of involvement IR, MR, SR (LR) Braley´s sign = increased IOP on upgaze (>4mmHg)   3. proptosis :- TED is the commonest cause of unilateral or bilateral proptosis  

Sight Threatening Complications optic nerve compression :- <5% affected, due to

compression of orbital apex by enlarged EOM. Look for decreased VA, colour vision defects, arcuate or central scotomata, swollen optic disc. Confirmation by orbital CT.

Treatment by medical or surgical decompression.   corneal exposure:- potentially serious:- treat with

lubricants, lid taping, tarsorrhaphy, decompression  less common causes of visual loss:- glaucoma,

vascular compression

Corneal involvement Corneal involvement due to exposure keratitis

may result from proptosis, upper eyelid retraction, lower eyelid retraction, lagophthalmos, or a combination of these. A primary lacrimal gland dysfunction may also be present in Graves' orbitopathy. Although still speculative, there is some evidence of a change in the protein composition of tears in patients with thyroid orbitopathy. This change might be caused by an altered rate of tear production or by a general change in tear composition

CLINICAL ASSESSMENT MOURITS CLASSIFICATION Indicates position on Rundles curve (the

score reduces as inflammation decreases).Parameters of disease activity: Integrated severity score of Graves ophthalmopathy (GO).Oppressive feelingPain on deviation from primary positn, redness of lids (ie. recent inflammation), diffuse redness of conjunctiva, chemosis, swollen caruncle, oedema of eyelids, Proptosis (increase of 2mm or more)....

WERNER´S CLASSIFICATION Indicates the damage level (so the score may not reverse as activity diminishes).0 Nil (no symptoms or signs).1 Only signs of: a) stare b) lid lag,2. Soft tissue involvement: 0) absent a) minimal b) moderate c) marked.3 Proptosis of 3mm or more: 0) absent a) 3-4 mm b) 5-7 mm c) 8 or more mm.4 Diplopia: 0) absent a) limitation at extremes of gaze b) evident restriction of motion c) fixation of globe.5 Corneal involvement: 0) absent a) SPE b) corneal ulceration, c) necrosis or perforation.6 Sight loss (due to optic nerve): 0) absent a) 20/20-20/60

b)20/70-20/200 c)Worse than 20/200.

THYROID EYE DISEASE LID RETRACTION1.

sympathetic overactivity infiltration of levator / SR complex. hypotropia (retraction disappears on downgaze)

SIGNS:- Dalrymples (lid retraction), von Graefe (lid lag), Kocher´s (staring appearance)

THYROID EYE DISEASE INFILTRATION 1. soft tissue

involvement :- chemosis, conjunctival injection over the recti insertions, puffy lids

THYROID EYE DISEASE Superior limbic

keratoconjunctivitis (SLK)

Optic neuropathy with visual loss The prevalence of optic neuropathy with visual loss in

patients with thyroid orbitopathy is less than 5%. Optic neuropathy is, however, the most common

cause of blindness secondary to thyroid orbitopathy. Its onset is often insidious and may be masked by other symptoms. These patients are usually older (age 50 to 70) are more frequently male, have a later onset of thyroid disease, and more often have diabetes.

Optic neuropathy is usually bilateral, but up to one third of cases may be unilateral.

Optic neuropathy Although a history of decreased vision should be carefully

sought, it is important to realize that optic neuropathy can occur in a significant number (18%) of patients with visual acuities in the range of 20/20 to 20/25 (6/6 to 6/7.5).*An afferent pupillary defect is present in 35%. An abnormal disc (either swollen or pale) is seen in only 52%. Visual field defects are present in 66%.Other tests that can be useful include color vision testing and visual evoked potentials (VEPs). The Farnsworth-Munsell 100-hue test is a sensitive indicator of optic nerve dysfunction, but pseudoisochromatic screening procedures (e.g.,Ishihara plates) rarely identify an acquired color defect unless optic neuropathy is severe.The pattern reversal VEP is very sensitive at detecting early optic neuropathy and may be a useful means of following patients after treatment.

Intraocular pressure The increased intraocular pressure measured during

upgaze in patients with thyroid orbitopathy has been a controversial finding. When restriction of the inferior rectus muscle occurs, the intraocular pressure may increase by 6 mm Hg or more in upgaze as compared with primary gaze. The increased intraocular pressure in upgaze is a normal phenomenon exaggerated by thyroid orbitopathy

In patients with severe infiltrative disease there is an increased pressure on upgaze as compared with normal controls and patients with mild disease. It is often not an indicator of early disease because it occurs infrequently in patients with minimal eye findings

INVESTIGATION SEROLOGICALT3 (hyperthyroid)T4 TSH

(hypothyroid)TSI (thyroid stimulating immunoglobulin). RADIOLOGICAL TESTSOrbital CT (enlarged muscle

belly, tendon normal). Coca-Cola bottle sign = muscle swelling deforming ethmoidal bones.MRI T2 showing oedema of muscles; repeating the scan in different positions of gaze can create a pseudo-video of eye movements (for assessment of muscle restriction).

RADIOISOTOPE TESTS Octreoscan: quantitative uptake of radio-labelled octreotide (which is a somatostatin analogue).

VISUAL FIELD

A visual field should be performed in all patients suspected to have optic neuropathy and is useful when following patients after initiation of treatment. Characteristically, a central scotoma or an inferior altitudinal defect is seen in cases of compressive optic neuropathy. Other visual field defects include an enlarged blind spot, paracentral scotoma, nerve fiber bundle defect, or generalized constriction.

ULTRASONOGRAPHY

Ultrasonography can be useful to detect early thyroid disease in patients with equivocal laboratory tests. Most patients with Graves' disease, even those without overt eye findings, have ultrasonographic evidence of extraocular muscle involvement.46 Ultrasonography is believed by some to be more accurate than CT in detecting enlargement of the extraocular muscles. Also, visualization of the tendinous insertions onto the globe may be more accurately assessed using ultrasonography when differentiating enlarged extraocular muscles secondary to myositis from hyperthyroid orbitopathy. Ultrasonography is, however, less suited than CT to assessing muscle thickness at the orbital apex.

This test may also be helpful in distinguishing between active and inactive disease. Examination of the extraocular muscles shows that there is a lower internal reflectivity in active as compared with inactive disease.

CT findings in thyroid orbitopathy The most characteristic CT finding in thyroid orbitopathy is

enlargement of the extraocular muscles with normal tendinous insertions onto the globe. Other findings include proptosis and anterior prolapse of the orbital septum due to excessive orbital fat and muscle swelling (see Fig. 4).Patients at risk for developing optic neuropathy may also have severe apical crowding, a dilated superior ophthalmic vein, and anterior displacement of the lacrimal gland. Of these, apical crowding is the most sensitive indicator for the presence of optic neuropathy The CT scan should be done in the coronal plane to assess the enlargement of the extraocular muscles at the apex because axial sections can sometimes be misleading.

THYROID EYE DISEASE Orbital CT -

(enlarged muscle belly, tendon normal)

MAGNETIC RESONANCE IMAGING MRI using 1.5 tesla units and orbital surface coils

provides optimal spatial resolution of the orbit.34 MRI may also be useful in distinguishing between active and inactive disease. The changing intensities between T1- and T2-weighted images may differentiate the active edematous from the inactive fibrotic muscle changes.

Extraocular muscles that have acute inflammation have longer T2 times owing to the higher water content. Because acute inflammatory disease responds better to radiation therapy than chronic fibrosis, the information gained from MRI may theoretically be helpful in choosing patients for radiation therapy.

SYSTEMIC THYROID DISEASE

There are no good recent studies of the natural history of untreated hyperthyroidism, but based on older reports, Wilson56 determined that about one third of patients spontaneously improve, one third remain chronically hyperthyroid, and one third progress to thyroid storm and occasionally death. Because it is not possible to predict which patients will spontaneously improve, treatment of thyroid dysfunction is recommended.

Treatmentacute congestive ophthalmopathy, compressive optic neuropathy, motility disorders,eyelid abnormalities.

TREATMENTAcute Congestive Orbitopathy

1. SYMPTOMATIC:- elevate bedhead, lubricants, lid taping, diuretics

  2. SYSTEMIC:- a) Normalise thyroid function with or without thyroxine.

Patients rendered euthyroid do improve their GO score

Tallstedt trial N Eng J Med 1992

antithyroid drugs cause a 10% chance of new or worsening GO

but radio-iodine causes a 30% chance of new or worsening GO.

Corticosteroids have been used successfully in the treatment of acute congestive orbitopathy

Corticosteroids have been used successfully in the treatment of acute congestive orbitopathy. They are believed to work by altering cell-mediated immune response and diminishing the production of mucopolysaccharides by the orbital fibroblasts.Corticosteroids result in improvement of soft tissue involvement and compressive optic neuropathy (but do not have as much of an effect on diplopia Traditionally, a "short burst" of high-dose corticosteroids has been given, usually in the range of 60 to 120 mg/day of oral prednisone. Improvement in subjective symptoms such as pain and tearing usually occurs first, often as early as 24 to 48 hours, followed by improvement in soft tissue congestion and muscle function over a period of days to weeks.

Steroid Therapy Prednisone or prednisolone This is standard treatment but there are frequent side effects.

No response in 35% of patients and anyway the response is only partial. High dose steroids given early in the disease when muscle swelling occurs does not necessarily limit the long term course of the disease. If there is no response to high dose steroids in the first three weeks they should be rapidly reduced. Prednisolone + orbital radiotherapy has slightly more effect than either alone.Use high dose pulsed methylprednisolone if urgent optic nerve decompression is required, This is more effective than oral treatment but it is expensive and not justified in most cases of TED.

Radiation therapy During the past few years, radiation therapy has reemerged as

a useful form of treatment of severe orbitopathy. The rationale for the use of radiation therapy is reduction or elimination of the pathogenic orbital lymphocytes, which are markedly radiosensitive. It is also thought that the glycosaminoglycan production by fibroblasts is reduced, thereby reducing orbital edema, orbital tension, and conjunctival injection. Although congestive findings improve most consistently, significant improvement in proptosis and extraocular muscle function has been reported.Like corticosteroids, radiation therapy is most effective within the first year, when significant fibrotic changes have not yet occurred. Mourits and associates,135 however, suggest that periods of active orbital inflammation within the long natural history of thyroid orbitopathy would benefit from corticosteroids or radiation therapy.

Radiotherapy RETROBULBAR RADIOTHERAPY:- Trial of

prednisone versus radiotherapy showed no difference in clinical improvement (about 50%).The patients all tolerated retrobulbar radiotherapy better than steroids Consider if steroid maintenance > 25mg/ day. Best effect in acute disease.Do not irradiate patients with diabetes mellitus as they are more susceptible to radiation retinopathy.2000rads/ 10days, effect starts at 4 weeks, maximal 4 months.

Compressive Optic Neuropathy

Compressive optic neuropathy can cause permanent visual loss. The treatment possibilities include high doses of corticosteroids, irradiation, and orbital decompression. Some patients require only one of these modalities, while other patients need combined therapies.

Compressive Optic Neuropathy As in the treatment of acute congestive thyroid

orbitopathy, radiation therapy is becoming increasingly popular. A retrospective series of 84 patients with compressive optic neuropathy treated with either corticosteroids or radiation therapy supports mounting evidence that radiation therapy may be safer and more effective than corticosteroids.

Radiation therapy, however, must be administered in fractionated doses, which delays its beneficial effect. For this reason, if visual dysfunction progresses while the patient is on corticosteroids, surgical decompression is usually recommended if the patient is a surgical candidate.

Orbital decompression Orbital decompression is indicated for compressive

optic neuropathy when there has been failure of or contraindication for corticosteroids or radiation therapy or if corticosteroid dependence has developed with intolerable side effects. Other indications include excessive proptosis with exposure keratitis and corneal ulceration, pain relief, and cosmesis for disfiguring exophthalmos. Orbital decompression may also be indicated as a preliminary procedure to extraocular muscle surgery on a patient with sufficient proptosis to suggest that decompression might ultimately be required.

Orbital decompression A variety of approaches may be used, each with

its own advantages and associated complications.

The transorbital (via fornix or eyelid) approach to inferior and medial wall decompression is the most common approach used by ophthalmologists. The addition of a lateral wall advancement has the advantage of both further increasing the orbital volume and simultaneously improving upper eyelid retraction; this is the technique we prefer.

ORBITAL DECOMPRESSION Subciliary approach.Inferior & medial wall

(6mm proptosis).Remove bone to posterior wall maxillary sinus (5mm more posterior on medial wall), Avoid IO neurovascular bundle, and the anterior and posterior ethmoidal arteries.Incise periosteum in A-P direction posteriorly and circumferentially anteriorly.

Complications: visual loss, A pattern ET

Motility Disorders

A major source of morbidity in thyroid orbitopathy, and the most frequent problem associated with orbital decompression surgery, has been strabismus. In patients with relatively minimal degrees of ocular misalignment, diplopia can be avoided with a compensatory head posture, Fresnel plastic press-on prisms, or temporary occlusion. Unfortunately there is significant image degradation as larger prisms are used, limiting their efficacy. If there is marked asymmetry in ocular deviation in different fields of gaze, prisms are also less effective. In some cases during the inflammatory period, use of intramuscular botulinum toxin has shown some efficacy.

Extraocular muscle surgery should be postponed until the muscles are no longer inflamed and the deviation has remained stable for at least 6 months.

Surgery STRABISMUS SURGERY:-Aim for maximal area of fusion without

abnormal head posture.IR recession on adjustable +/- contra SR recession

iii) EYELID SURGERY:-  Upper Lid retraction - Muller´s tenotomy (<2mm), levator Z myotomy or

recession on hangback sutures, levator tenotomy +/- horns. Lower Lid retraction - Usually needs a spacer from donor sclera (lid

retraction X 2 = amount of sclera required)

iv) BLEPHAROPLASTY for excess skin and fat  Ideally treatment combines a multidisciplinary coherent approach such

as Combined radiotherapy and immunosuppression trial

Eyelid Abnormalities

As with other thyroid eye problems, eyelid retraction will often improve with time, and only an estimated 50% of patients with eyelid retraction have a significant eyelid abnormality 5 years later.

Eyelid retraction can result from excessive autonomic discharge, levator fibrosis, or contraction of the inferior rectus muscle.

Surgical correction of eyelid abnormalities should be performed only after orbital or extraocular muscle surgery because these operations may change eyelid position. For example, inferior rectus muscle restriction may cause upper eyelid retraction because of the superior rectus/levator palpebrae superioris overaction against the restriction. Specific techniques for repair of eyelid retraction are discussed in other chapters.