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					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 DISEASE
 Associated  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.
Treatment
 acute  congestive ophthalmopathy,
 compressive optic neuropathy,
 motility disorders,
 eyelid abnormalities.
TREATMENT
Acute 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.

				
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