Thyroid-related eye disease

Introduction to thyroid associated ophthalmopathy Thyroid associated ophthalmopathy (TAO) is one of the most common diseases of the eyelids. In the past, there were many naming, such as thyroid eye disease, thyroid toxic eye disease, endocrine eye muscle disease, endocrine eyeball protrusion, ocular protrusion goiter, thyroid associated eyelid disease, malignant eye and infiltrative eye, etc., Graves described in 1835. The clinical manifestations of toxic goiter, so most scholars also call Graves disease. Basedow was discussed in detail in 1840, which is also known as Basedow disease. In order to distinguish between those with simple eye signs and those with hyperthyroidism, it is customary to have ocular symptoms with thyroid dysfunction as Graves' ophthalmopathy, and those without thyroid function and their history are called ocular Graves' disease. About 10% of patients have normal or mild thyroid function, which is ocular Graves disease. Weetman believes that it is best to call it thyroid-related eye disease to emphasize that the disease can be accompanied by different degrees of thyroid symptoms in addition to eye signs. This naming has gradually been accepted by scholars. basic knowledge The proportion of illness: 0.001% Susceptible people: no special people Mode of infection: non-infectious Complications: corneal disease, oppressive optic neuropathy

Causes of thyroid associated ophthalmopathy

Genetic factors (20%)

From the epidemiological point of view, thyroid-associated eye disease has a difference in susceptibility to population genes. In addition to the decrease in the proportion of males and females in elderly patients, the average female patient is 4-5 times that of male patients. HLA-DR histocompatibility loci (mainly related to T cell responses) are linked to thyroid associated ophthalmopathy.

Autoimmune response (20%)

Eyelid connective tissue, adipocytes, and possibly extraocular muscle cells are the target tissues of T lymphocytes, and thyrotropin receptor (TSHR) may act as a self-antigen in Graves' hyperthyroidism, thyroid-associated eye disease, and pre-tibial mucinous edema. Play a role. Another theory is that there is a primary autoantigen in the extraocular muscles, and activated lymphocytes (especially T cells) infiltrate into the orbital tissue, especially in the early stages of the disease, and cause corresponding eyelid lesions.

Environmental factors (15%)

Clinical investigations have found that the susceptibility and severity of disease may be related to environmental factors. Therefore, environmental factors are also the predisposing factors of the disease.

Pathogenesis

The exact pathogenesis is still unclear. For more than 200 years, many scholars have studied this disease, and accumulated a lot of information on the pathogenesis, especially in the past 10 years, along with immunohistochemistry, molecular biology and genetics. Rapid development, the updating of research methods and the adoption of some new technologies have given new insights into the disease. Currently, it is considered to be an ocular lesion associated with the hypothalamic-pituitary-thyroid axis. It is also an extremely complex autoimmune disease, that is, the imbalance of T lymphocyte subsets, resulting in increased B lymphocytes, elevated levels of immunoglobulins, increased lymphokines, activation of fibroblasts, excessive cellular extracellular material and Collagen fiber, Trokel believes that intraocular inflammation in patients with Graves may be an organ-specific autoimmune disorder of unknown cause, lymphocytes or immunoglobulins attacking autoantigens, ie certain antigens on the extraocular muscles, whether fibroblasts Or the surface membrane antigen of the striated muscle itself, or it may be that the antigen-antibody complex is deposited in the soft tissue of the sputum and causes Invasion of Ba cells, circulating T lymphocytes in patients with severe Graves disease, B lymphocyte proliferation is out of control, and the production of immunoglobulin can attack the extraocular muscles, but the nature of the autoantigen is unknown, and no sputum has been found in the patient's serum. Antigen, Sergott and Robert believe that ocular lesions in Graves' disease may be related to immune complexes. According to Konishi et al., thyroglobulin, anti-thyroglobulin immune complex, affinity for extraocular muscle musculature compared to skeletal muscle, myocardium The liver, kidney and spleen have strong affinity. Kohn found that some patients' immunoglobulin IgG has the effect of stimulating fibroblasts to form collagen fibers, and this effect is directly proportional to the degree of clinically observed eye disease. IgG is one of the causes of post-ball soft tissue hyperplasia and ocular protrusion. Some studies on the histopathology and IgA and IgE expression of Graves' ophthalmopathy have found that IgA and IgE play an important role in the autoimmune response of Graves' ophthalmopathy. Causes the accumulation of mucopolysaccharide between tissues and the destruction of extraocular muscles, and the clinical application of corticosteroids Good results can also explain the pathogenesis of ocular lesions in Graves' disease.

1. Common antigens Some researchers have proposed that the common antigen of the eye and the thyroid is the hypothesis that causes the root cause of the disease. However, it is still inconclusive as to what substance acts as the common antigen. The most suspicious and most studied is the thyroid stimulating hormone receptor ( TSHR), thyroglobulin (Tg), thyroid peroxidase (TPO).

(1) Thyroid Stimulating Hormone Receptor (TSHR): TSH is an antigenic extracellular protein produced by the anterior pituitary and binds to the thyroid stimulating hormone receptor (TSHR) on thyroid cells, causing adenylate. Activation of the cyclase and phosphatidylinositol pathways ultimately leads to the production of thyroid hormones in which the tyrosine residues of thyroglobulin (Tg) are iodinated and then coupled by the catalysis of thyroid peroxidase. Forms the precursor of thyroid hormone, tetraiodothyronine (T4), which de-iodines in the periphery to form triiodothyronine (T3), which binds to its receptor to form a complex. This complex can be combined with the gene's thyroid hormone response element. Interactions and their effects, the maintenance of normal thyroid function is achieved by the positive feedback effect of thyroid stimulating hormone releasing hormone (TRH) stimulation of TSH and the negative feedback of T3 down-regulating TSH. Autoantibodies against autoantigens, such as autoantibodies against TSHR, thyroid peroxidase (TPO), and Tg, of which autoantibodies against TSHR are most important, The fact that many, thyroid stimulating antibodies (of TSAb) binding of this receptor on thyroid cell membrane, can cause excessive secretion of thyroid hormones.

TSHR is also present in the connective tissue and extraocular muscles of the eyelids of patients with thyroid-associated ophthalmopathy. The PCR method confirmed that the patient's eyelid tissue contains mRNA encoding TSHR, and some patients have TSHR antibodies in peripheral blood. It is speculated that a subunit of TSH is a tumor. The substance of the eye, which reacts with abnormal immunoglobulins bound to the extraocular muscles, leading to the occurrence of thyroid-related eye diseases, but the antibodies of TSHR are not only present in the peripheral blood of patients with ocular diseases, but also in the blood of patients with hyperthyroidism without eye disease. There is no significant difference in antibody titers between the two groups. There is no experimental evidence that anti-TSHR antibodies can cause orbital fibroblasts to proliferate or damage the extraocular muscles. If TSH is the common antigen we are looking for, it is difficult to explain patients with ocular Graves' ophthalmopathy. The thyroid is not affected.

(2) thyroglobulin (Tg): thyroglobulin (Tg) is also found in the orbital tissue of patients with thyroid-associated ophthalmopathy. These thyroglobulins extracted from the orbital tissue can combine with rabbit anti-thyroglobulin antibodies to form an immune complex. It can also capture anti-T4 antibodies, indicating that they contain fragments of thyroid hormones, presumably derived from the thyroid gland and maintain the original structure, reaching the eyelids through the lymphatic circulation, triggering an autoimmune response in susceptible individuals, and no Tg found in the orbital tissue. Anti-Tg immune complexes indicate that Tg is a cellular immune response mediated by the eyelids.

(3) Other suspicious common antigens: including thyroid peroxidase, acetylcholinesterase and growth-promoting factor C. Anti-acetylcholine receptor antibodies were also found in a small number of patients with thyroid-associated ophthalmopathy.

2. Extraocular sarcolemmal antigens The soluble antigens and membrane antigens of some extraocular muscles and orbital tissues may also act as common antigens, including 55kDa, 64kDa, 95kDa proteins, etc. The blood of thyroid-associated ophthalmopathy patients contains various antibodies against the orbital antigen. The extraocular muscle endometrium and the epithelium have IgA and IgE staining positive. Atkinson reacts the peripheral blood of the patient with the crude muscle of the pig's extraocular muscle. The homogenate cross-reacts with the human eyelid antigen and finds 64% of active patients showed higher titer antibody titers, only 25% of active patients after treatment expressed antibodies, the positive rate of inactive patients was 17%, and the normal control was 3%. Anti-thyroid and orbital cross-antigen antibodies can be expressed in the presence or absence of ocular diseases. About 70% of patients with thyroid-associated ocular diseases express antibodies against human extraocular sarcolemmal antigen. Antibody titer is closely related to the clinical activity and course of eye disease. In other similar studies, 30% of normal people and 70% of patients with myasthenia gravis were also positive. The 64kDa protein is one of the extraocular sarcolemmal antigens, which is associated with a certain thyroid antigen. Homology, thyroid-associated ophthalmopathy patients can detect anti-64kDa protein antibodies in the blood, using human extraocular muscle antigen as an immunogen to make mouse monoclonal antibodies for the isolation and identification of ocular muscle antigens, most antibodies are directed to cytosol components Not a membrane, in which an antibody cross-reacts with thyroid microsomes.

Autoantibodies cause pathological damage mainly through the following mechanisms:

(1) Antibody-mediated cytotoxicity: autoantibodies (mainly IgGs) bind to autoantigens on the cell membrane surface and then kill target cells by different means: 1 immobilization and activation of complement, C1q is a soluble Fc receptor, It can bind to the Fc segment of IgG or IgM, leading to the cascade reaction of the complement system. Eventually, the cells undergo irreversible destruction. 100 nm pores are found on the surface of the membrane, and the contents of the cells leak out and the cells dissolve. 2 By immunomodulation, target cells adhere to the surface of phagocytic cells (macrophages, neutrophils) and are then phagocytosed.

(2) Antibody-stimulated target cells: characterized in that the autoantibodies bind to the target antigen on the surface of the cell membrane, do not bind to complement, and the cells are not damaged, but are stimulated to cause hyperfunction. Some patients with hyperthyroidism have long serum. Thyroid stimulating hormone (LATS), an anti-thyroid tissue antigen, lgG-type antibody, can play the same role through the placenta into the fetus, electron microscopy to see LATS binding to thyroid cell surface antigen, increased intracellular protein synthesis, Golgi As the complex increases, LATS promotes increased thyroid secretion, causing hyperthyroidism.

(3) Antibody neutralization: The antibody binds to an antigenic substance or receptor having an important physiological activity in the body, causing it to be inactivated and lose its function, thereby causing a corresponding disorder.

(4) Damage effect of antibody-antigen forming immune complex: no immune complex was found to be involved in the occurrence of thyroid-associated eye disease.

3. Cellular immunity: There are many studies on cellular immune responses to thyroid-associated ophthalmopathy, abnormal cellular immunity, imbalance of lymphocyte subsets, excessive enhancement of B cell activity, and decreased T cell function, decreased CD8 cells, and increased CD8/CD4 ratio.

Patients with T cell subsets and natural killer cells produced non-specific changes, antibody-dependent cytotoxicity (ADCC) for extraocular muscle antigens, cross-immunity reaction of eyelids and thyroids, and in vitro experiments confirmed the presence of thyroid antigens in patients with thyroid-associated ophthalmopathy The cellular response, when the decompressive extracorporeal muscle specimen is obtained by reacting with the thyroid and orbital antigen, the mobile inhibitory factor is positive. If the normal human and the patient's peripheral blood lymphocytes are respectively reacted with the eye muscle tissue, the patient group lymphocyte It has a cytotoxic effect on normal eye muscles, and the addition of thyroxine does not make this reaction disappear.

4. Cytokines: In recent years, some progress has been made in the study of the pathogenesis of thyroid-associated ophthalmopathy from the level of cytokines. Cytokines are a group of immune cells or non-immune cells produced in vivo during the process of inflammation and immune response. Biologically active heterogeneous peptide regulators, which are letters or symbols in biological regulatory languages. Mononuclear/macrophages, T cells, B cells, bone marrow stromal cells, white blood cells, fibroblasts, etc. can produce cytokines. There are many types of cytokines. Currently known important cytokines are roughly classified into five categories: interferon group (IFNs), interleukin group (ILs), clone stimulating factor group (CSFs), transforming growth factor group. (TGFs) and tumor necrosis factor group (TNFs), cytokines as intercellular soluble signals, promote T cell activation, B cell activation and other immune responses, and can directly act on target organs in autoimmune response It plays an important role.

The first cytokines that attracted attention were migration inhibitory factor (MIF), transforming growth factor (TGF) and insulin-like growth factor (IGF-1), which were discovered in experimental exophthalmic studies in the 1930s and 1940s. The crude extract of the pituitary gland can cause pathological changes of the eyelids in the rodent like Graves' eye disease. At that time, it was thought that the TSH in the pituitary was working. Later, it was found that TSH was inhibited in thyrotoxicosis, and later it was thought that it was because of the pituitary gland. Enriched with various cytokines, especially TGF, IGF-1, and confirmed that they can stimulate fibro-blast (Fb) proliferation and secretion of GAG, the extraocular muscle is a rich source of IGF and TGF, fibroblasts and Lymphocytes can also produce a variety of cytokines.

Adhesion molecules are glycoproteins that are present on the surface of cell membranes and mediate contact between cells and cells or between cells and extracellular matrices. With extensive research on adhesion molecules, some foreign studies have found that adhesion molecules are in Graves' ophthalmopathy. It plays an important role in the process of occurrence. There are many kinds of adhesion molecules and they are widely distributed. They are mainly attributed to five major families, such as immunoglobulin superfamily, integrin family, selectin family, calcium-dependent family and unclassified adhesion molecules. Adhesion molecules are widely expressed in the sacral tissue. Intercellular adhesion molecule (ICAM-1) is involved in vascular endothelial cells, interstitial and sarcolemmal connective tissue surrounding the extraocular muscles, connective tissue after the ball, and fibroblasts. Cells and a large number of monocytes are expressed, and vascular endothelial cells express ELAM-1 and vascular cell adhesion molecule (VCAM-1). Some monocytes express 2 integrin, and some cytokines such as IL-la and IFN-r can induce post-balloon fibroblasts to express active ICAM-1. High levels of soluble adhesion molecules are also detected in serum of patients with thyroid-associated ophthalmopathy.

5. Eyelid target cells: Another hot topic in the pathogenesis of thyroid-related eye diseases is which tissue in the eyelid is the target cell for the initiation of the immune response. Some scholars believe that it is the orbital fibroblast, and the other part supports the extraocular muscle. organization.

Histocompatibility antigen DR (HLA-DR) and heat shock protein (HSP-70) are expressed in fibroblasts, vascular endothelial cells and infiltrating lymphocytes of extraocular muscles, and the sputum tissue of untreated patients is Obviously; HSP-70 is expressed in muscle cells and fibroblasts, and the expression of patients with short course of disease is enhanced, suggesting that extraocular muscle cells and fibroblasts may be important target cells of TAO autoimmune response, infiltrative exophthalmos extraocular muscle super Microstructural studies showed that each extraocular muscle cell had different degrees of damage. In the early stage, some Z-ray disorders of myofibril were observed and disappeared. In the middle and late stages, different degrees of muscle cell sarcoplasmic reticulum expansion and partial destruction of myofibril were observed. , forming vacuoles, visible secondary lysosomes and residual bodies, severely damaged muscle cells, phagocytosis by phagocytic cells, fibrosis, and visible fibroblasts, extraocular muscles may be the main target tissue of thyroid-related eye diseases In a sense, this problem is not very important at present, because the symptoms and signs of thyroid-related eye disease in clinical are caused by damage of extraocular muscles, thyroid-related eye diseases to muscles. The damage is either directly or in the vicinity of the tissue, or is due to fibroblast damage, which does not change the nature of the damage. The important point of this problem is that if these two One of the seed cells is the origin of the autoimmune reaction, and gene therapy can be used to avoid autoimmunity, but this is not possible at present.

In summary, the characteristics of the disease have the following four points:

1 Thyroid-related eye disease is part of thyroid disease.

2 Thyroid-related eye disease is an organ-specific autoimmune disease, not caused by thyroid disease, but the immune system's own stable mechanism of disorder causes abnormal T cells to respond to the thyroid and extraocular muscles.

3 thyroid stimulating hormone and abnormal immunoglobulin interactions localized in the extraocular muscles, causing eyeball protrusion.

4 The thyroglobulin bound on the extraocular sarcolemma reacts with the common antigen of the eye and the thyroid to cause the disease. Clinical manifestations: Clinical manifestations: Thyroid-related eye disease is a complex group of eyelid diseases, and its typical clinical symptoms are: Light, tearing, foreign body sensation, vision loss and double vision, etc., including: eyelid retraction, delayed upper eyelid, conjunctival hyperemia, periorbital tissue edema, prominent eyeball, extraocular muscle hypertrophy, orbital insufficiency, exposed keratitis and Compression optic neuropathy, such as double eyeballs with retraction of the eyelids, gaze and goiter are typical endocrine and exophthalmia symptoms. For a long time, many scholars have conducted in-depth research and description of eye signs.

The signs of thyroid-associated ophthalmopathy are also due to the acute or chronic phase of thyroid-associated ophthalmopathy. The severity of the disease, the lesions are active or stable, and the parts of the eye tissue are different, and so on. The appearance of the signs is not exactly the same, some eye signs are relatively unique for thyroid-related eye diseases, such as eyeballs plus sputum delay or gaze, eyeballs plus restrictive extraocular muscle disease, and hypertrophic extraocular muscles at the tip of the eye At the optic nerve, the vasodilatation at the end of the medial and lateral rectus, conjunctival, periorbital edema and exposed keratitis are common in thyroid-associated ophthalmopathy, but can also be seen in other eye diseases, any thyroid disease (hyperthyroidism, hypothyroidism) The eye signs of eye disease caused by Hashimoto's thyroiditis and thyroid cancer are completely similar, so thyroid disease cannot be determined from the eye.

1. Eyelid retraction and lag Eyelid retraction and lag In patients with thyroid-related eye disease, the eyelid stagnation is the upper eyelid retraction, and the drop in the fall has diagnostic value (diagnostic eye). The width of normal cleft palate is related to ethnicity, heredity, etc. The middle part of the upper temporal margin is located between the upper limbus and the upper pupillary edge, or the upper temporal margin covers 2 mm below the upper corner of the limbus, and the middle part of the lower temporal margin is the lower lower corner of the scleral margin. If the upper and lower temporal margins leave the above normal position Usually, the eyelids are retracted or the ptosis is drooping. In thyroid-related eye diseases, the eyelids are usually retracted, that is, the upper temporal margin is elevated, even above the upper corner of the limbus, and the lower iliac margin is below the lower angleal limbus, so that the upper canopy or The lower sclera is exposed (white). In the retraction of the eyelid, the upper eyelid retracts more often (Fig. 1). When the eyeball looks down, the upper eyelid of the normal person moves down. When the thyroid-related eye disease patient looks down, the upper eye is retracted. You can't move down or fall slowly as the eyeball turns down. It is called the late sputum. It is affected by the Müller muscle and the upper iliac muscle, which makes the retraction, the drop function is poor, and the swelling of the eyelid affects the orbicularis muscle to close the eyelid. With, so patients blink reflex reduction, it was staring state, which is a more particular symptoms, often seen in patients with thyroid-associated ophthalmopathy.

35% to 60% of patients with thyroid-associated ophthalmopathy have eyelid retraction, which causes the retraction of the upper eyelid:

1Müller muscle hyperactivity (sympathetic overactivity).

2 Lifting the diaphragm and adhesion to the surrounding tissue.

3 The constrictor muscles adhere to the surrounding tissue.

Small study of normal people and 10 patients with thyroid-associated ophthalmopathy put the diaphragm muscles. The biopsy showed that the muscle fibers of the patients were significantly enlarged. In some patients, the tendons were slightly thickened, and the gap between the muscle fibers and the muscle bundles was widened, and the fibrosis between the muscle fibers was mild. There are mucopolysaccharide deposition in the muscle space, mild focal inflammation and fat infiltration. The above is the pathological basis of the upper jaw retraction, delay and swelling.

2. Soft-tissue involvement In patients with thyroid-associated ophthalmopathy, inflammatory cell infiltration, vascular congestion and expansion, increased permeability, increased interstitial fluid, but mainly increased deposition of mucopolysaccharides in the interstitial space. The tissue absorbs a large amount of water. These two factors add up to the eyelids, conjunctival hyperemia, redness, eyelids, conjunctiva, lacrimal gland, orbital soft tissue swelling, acute thyroid-associated ophthalmopathy or infiltrating exudate eye soft tissue involvement is most obvious.

(1) Congestion of eyelids: swelling of the eyelids, swelling of the eyelids, redness, fullness and thickening, disappearance of the upper sulcus, swelling of the upper eyelids, and it is divided into mild, moderate or severe, severe eyelid congestion and swelling leading to eye movement The degree of difference, the eyelids can not be closed, which is the main cause of exposed keratitis.

(2) conjunctival congestion and edema: local conjunctival hyperemia is mostly inside, the vascular dilatation of the external rectus muscle attachment (Fig. 3A), has a certain diagnostic significance, usually conjunctival congestion and edema occurs on the temporal side or below, can also Occurred on the nasal side, relatively rare on the upper side, the conjunctiva became red due to severe congestion, swelling and rising, and protruding beyond the cleft palate is another cause of exposure to membranous inflammation.

(3) tears involved: tears can be due to congestion, edema and uplift, lacrimal gland can be swollen due to congestion, edema, clinical can lift the upper side of the upper eyelid, visible supracondylar humeral enlargement and prominent lacrimal gland, some cases in the sputum The upper part can be swollen and swollen lacrimal gland, and more is the CT scan of the eyelid showing lacrimal gland enlargement (Fig. 4). The lacrimal gland is involved in thyroid-associated ophthalmopathy. The cause is still unknown. Histopathological examination revealed mild mononuclear cell infiltration and interstitial Edema, no extensive fibrosis, Khalid et al. used high performance liquid chromatography to determine the tears of 50 patients with thyroid-associated ophthalmopathy, and compared with healthy people, found that about 1 / 6 patients (8 / 50) Example: IgA levels in the tears increased, no abnormalities were found in the control group, and 10 cases of globulin increased, suggesting a change in the lacrimal gland protein composition.

(4) Orbital soft tissue swelling: The content of sputum is mainly composed of sputum fat and extraocular muscle. In patients with acute thyroid-associated ophthalmopathy, the sputum fat space is widened due to edema and congestion, and the extraocular muscle is hypertrophic due to edema and congestion. In general, there are inflammatory cells, especially lymphocytes infiltration, vasodilation, aggravation of eyelid tissue swelling, a large increase in sputum content, increased sputum pressure, obstruction of ocular venous return, more fluid accumulation in soft tissue, more severe eyelid soft tissue swelling The eyeball is protuberance and the activity is limited. When the high-resolution CT examination is performed, the fat density of the ankle is increased, and the vein on the eye is thickened.

Patients with ocular soft tissue involvement often have associated symptoms such as eye discomfort, dry eyes, eye pain, foreign body sensation, photophobia, tearing, diplopia, and decreased vision.

3. Exophthalmos (exophthalmos) In addition to the special eyelid syndrome with diagnostic significance, eyeball protrusion is also a common sign. Simple eyeball protrusion does not have diagnostic significance, but simple eyeball protrusion is rare in thyroid-associated eye disease. All are accompanied by some special eye changes. If only simple eyeballs are prominent, other eyelid diseases should be considered, especially eyelid tumors. The cause of eyeballs is extraocular muscle hypertrophy, increased fat, and increased sputum content in bony eyelids. Moving forward and forward, pushing the eyeball forward, the eyeball of the thyroid-associated eye disease is the most common sign. The degree of protrusion can be mild, moderate and severe. The ocular protrusion of the thyroid-related eye disease is relatively symmetrical, 58% In case of case, the difference in binocular protrusion is less than 5mm. In 89% of cases, the difference in binocular protrusion is less than 7mm. In short, the difference in binocular protrusion is not more than 10.9mm. If this value is not exceeded, it is obvious that there may be a tumor in the sputum. The eyeball protrusion of patients with related eye diseases is generally increased by 3 mm compared with normal people.

4. Global subluxation Incomplete ocular dislocation can occur in progressive thyroid-associated eyelid disease, but it is rare because the fat volume in the eyelid increases rapidly, causing the eyeball to shift forward, and the equator of the eyeball reaches the rim. In the department, the eyelids can be retracted (Fig. 6). All patients with incomplete dislocation of the eyeball showed an increase in the fat content in the sputum, while the extraocular muscles did not expand significantly and there was no history of diplopia.

Nunery reports that there are two subtypes of thyroid-associated ophthalmopathy: type I is normal eye movement or only limited after extreme steering, with varying degrees of symmetrical prominence, no eyelid inflammation, occurring in young women, average 36 years old Most women, female: male 8:1, CT scan of the eyelid showed increased fat content (volume) in the sputum, with or without extraocular muscle enlargement, type II is restrictive muscle disease, eyeball in situ within 20 ° double vision The degree of eye asymmetry is asymmetrical, the average age is 52 years old, female: male is 2:1. CT scan shows that the axons of the extraocular muscles are enlarged, and the patients with incomplete lens dislocation are mostly type I.

5. Extraocular muscle involvement thyroid-associated eye disease often has restrictive extraocular muscle lesions, also known as thyroid extraocular muscle disease, which is characterized by enlargement of the muscles of the extraocular muscles, normal muscle attachment, and mild involvement. Clinically difficult to determine, ultrasound, CT or MRI examination can show that severe thyroid extraocular muscle disease in addition to the eyeball protrusion, displacement affects the patient's appearance, the greater impact is double vision, causing headache, eye swelling, life, study and work Extremely difficult (Figure 7), the second effect is the reduction of the function of the eyes, the near or reading can not last, after a long time the patient feels pain, dizziness, similar to the clinical manifestations of glaucoma.

Extraocular muscle lesions are usually bilateral, multimuscular, vertical muscle involvement is more common than horizontal muscle, the most common inferior rectus muscle involvement, accounting for 60%, followed by the medial rectus muscle 50%, the superior rectus muscle 40% and the lateral rectus muscle 29 %, CT scan (horizontal and coronal) showed that the muscle abdomen was spindle-shaped, the boundary was clear, and the tendon did not grow up (Fig. 8A). The thyroid-associated eye disease can be viewed according to the patient's double vision, limited eye movement, or eyeball shift. Considering the extraocular muscle involvement, it usually accounts for 60%, but the CT scan of the eyelids proves that the extraocular muscle hypertrophy accounts for 93%. The CT scan of the thyroid-associated eye disease can not only be done horizontally, otherwise it is easy to mistake the monocular rectus muscle hypertrophy. In the internal tumor, a coronary scan can be used to obtain a correct diagnosis.

6. Corneal involvement Corneal involvement is a common complication of thyroid-associated eye disease. There are several types, the severity of which is different, the most serious is corneal ulcer with secondary infection.

(1) superficial punctate keratitis (SPK): corneal epithelial scattered or diffuse punctate, located in the center of the cornea or other parts, stained with fluorescein or rose red as point green or red, incidence Accounted for 8.3% of thyroid-related eye diseases.

(2) superior limbic keratoconjuntivitis (SLK): occurs mostly in young women, can be unilateral or bilateral disease, SLK accounted for 0.9% of thyroid-related eye disease, some patients can appear at the same time, There are also cases of hyperthyroidism after several years of SLK, clinical manifestations can be photophobic, foreign body sensation, recurrent episodes, diffuse conjunctival hyperemia, upper conjunctival hyperemia, range of 10 to 2 o'clock, mild to severe, upper limbus Gray-white infiltration, thickening and connected cornea often form a "ditch-like", the upper cornea can be a bit epithelial shedding, fluorescein staining is green, and can be accompanied by filamentous keratitis, not flipping the upper jaw is often mistaken for chronic conjunctivitis, shallow Scleritis.

(3) Exposure keratitis or ulceration (exposure keratitis or ulceration): its clinical manifestations are corneal exposure dry, epithelial shedding, severe secondary infection, corneal gray, inflammatory infiltration, necrosis ulceration, may be associated with prophase Pus or suppurative endophthalmitis (Figure 10), which is the most serious corneal complication of thyroid-associated eye disease. If the eye is blind, the pain is unbearable, and the eyeball is eventually removed, causing exposure keratitis:

1 The eyeball is severely prominent and the eyelids are incompletely closed.

2 eyelid swelling, orbital diaphragm muscle function is low, difficult to close.

3 ball conjunctiva was severely congested and edema, prominent in the cleft palate, and the eyelid closure was blocked.

4 Extraocular muscle involvement, dysfunction, Bell phenomenon that protects the cornea disappears.

7. Optic neuropathy optic neuropathy is mainly caused by hypertrophic extraocular muscles that oppress the optic nerve at the tip of the sac, causing blood supply disorders, nerve fiber swelling, degeneration or degeneration, late optic atrophy, and other causes of optic neuropathy. In the acute phase of thyroid-associated eye disease, the content of sputum increased sharply, the pressure increased, and the optic nerve was directly compressed; the acute sputum tissue was inflamed, the toxin harmed the optic nerve, and the incidence of thyroid-associated ophthalmopathy with optic neuropathy was 8.6%. CT scan of the optic neuropathy showed The extraocular muscles of the abdomen were significantly enlarged. The moderate to severe occlusion was 79.2%. The optic nerve was flattened at the tip of the sacral or proximal iliac crest or 56.9% was enlarged by the enlarged extraocular muscle. The upper venous dilatation was 33.3. %, the eyeball protrudes 95%, the lacrimal gland shifts forward to the forehead condyle 64%, and in a few cases the ethmoid cardboard is convex.

Oppressive optic neuropathy is a potentially serious complication. The patient is older, the eyeball is mild to moderate, the vision is decreased and the visual field defect is concealed. In the initial stage, the optic disc is not changed. As the disease progresses, the optic disc appears. Edema or atrophy, the retina may have wrinkles, the patient appears to be blurred vision, vision loss can not be corrected with the lens, and finally vision loss.

8. Increasing intraocular tension Wessely first reported that patients with thyroid-associated eye disease have elevated intraocular pressure, but generally do not use intraocular pressure measurement as a routine examination of the disease, thyroid-related eye disease with elevated intraocular pressure or subsequent Glaucoma may be related to the following factors:

1 The eyelid is congested, and the venous pressure on the surface of the sclera is increased due to the expansion of the vein on the eye (resistance of reflux).

2 When the eyeball rotates in the opposite direction of the restrictive extraocular muscle, the hypertrophic extraocular muscle presses the eyeball.

3 trabecular meshwork has mucopolysaccharide, thyroid toxicity and/or genetically related susceptibility (a family history of glaucoma).

Intraocular pressure is measured in patients with thyroid-associated ophthalmopathy, which can be measured in the in situ of the eye. Peele Cockerham et al. found that the intraocular pressure increased by 24%, but the Spicerer study measured intraocular pressure when the eyeball was rotated 15° to 20°. The height is more significant, and it is suggested that the average patient should measure at least once every 6 months. For patients with active period, the interval should be shorter. The increase of intraocular pressure is more than 22mmHg for 2 measurements. The diagnosis of thyroid-related eye disease with glaucoma is based on Increased intraocular pressure, progressive increase in cup (disc) and characteristic visual field changes, attention to whether there is elevated intraocular pressure and glaucoma treatment before thyroid-related eye disease, and hormonal glaucoma caused by long-term hormone therapy The difference, Karadimas et al studied 100 patients with hypothyroidism, no increase in intraocular pressure.

According to the ocular signs of thyroid disease, Werner proposed the classification of ocular changes in thyroid-related eye diseases in the United States Thyroid Agreement in 1969. It was revised in 1977. In 1981, Van Dyke abbreviated the first English letter for convenience. NOSPECS (Table 1), grade 0 and 1 ocular clinical manifestations are mild, non-infiltration (NO, non-infiltration), grade 2 to 6 with more severe eye invasion, invasive (SPECS, infiltration) .

Werner divides each level into none (o), mild (a), moderate (b), and severe (c). Some patients with thyroid-associated eye disease have a full course of disease, and some patients do not necessarily go through each disease course. In a classification, van Dyke et al proposed a RELIEF classification focusing on soft tissue, R represents the resistance of the eyeball to the posterior pressure, E represents the lacrimal duct, conjunctival edema, L represents the growth of the lacrimal gland, I represents conjunctival hyperemia, E represents the orbital edema, and F represents The eyelids are full, and each level is divided into lack, mild, moderate and severe. This classification method is not comprehensive. Some authors divide the eye changes of thyroid-related eye diseases into non-invasive lesions and invasive lesions, non-invasive. Lesions, mainly non-inflammatory lesions in the eye, such as eyelid retraction, scleral whiteness, sluggish drop, gaze, if there is eyeball protrusion, but no restrictive extraocular muscle lesions and optic nerve damage, invasive lesions, mainly inflammatory in the eye Infiltration, such as ocular soft tissue involvement, damage to the extraocular muscles and optic nerve, this classification is conducive to clinicians to choose treatment options, there are other classification methods, but rarely used in ophthalmology.

The Werner classification method is the most widely used. Donaldson et al. quantified and quantified o, a, b, and c in the classification method. The lack, mild, moderate, and severe are represented by 0, 1, 2, and 3, respectively. With a maximum score of 15 points, this grading system is used by some clinicians to monitor and evaluate clinical outcomes.

Thyroid-related eye disease prevention

1, actively adjust the level of thyroid hormone, maintain in the normal range, avoid sudden reduction or increase in the amount of drugs.

2, to avoid spicy spicy food, quit smoking, to prevent eye fatigue, in the case of strong light, wear sunglasses, to avoid emotional excitement. When you are sleeping, your head is high, and those with cleft palate should be covered with eye ointment or wet room protection.

Thyroid-related eye disease complications Complications, corneal disease, optic neuropathy

Corneal lesions and optic neuropathy.

Thyroid-related eye disease symptoms Common symptoms Inflammatory eye swelling, lacrimal keratitis, visual field defect, conjunctival hyperemia, ptosis, soft tissue swelling, rhombus - phenomenon, lacrimal gland enlargement

Thyroid-related eye disease is a complex group of eyelid diseases. Its typical clinical symptoms are: photophobia, tearing, foreign body sensation, vision loss and diplopia. The signs include: eyelid retraction, delayed upper eyelid, conjunctival hyperemia, periorbital tissue Edema, eyeballs, extraocular muscle hypertrophy, eyelid regurgitation, exposed keratitis and optic optic neuropathy, double eyeballs with orbital retraction, gaze and goiter are typical endocrine and exophthalmia symptoms. For a long time, many scholars The eye signs have been deeply studied and described. The signs of thyroid-related eye diseases are due to the acute or chronic phase of the patients with thyroid-related eye diseases. The severity of the disease is active or stable, and the affected parts of the eye tissue are different. The various factors vary, so the signs appearing in each patient are not exactly the same. Some eye signs are relatively unique for thyroid-related eye diseases, such as eyeballs plus stagnation or gaze, eyeballs and restrictive eyes. Myopathy, and the hypertrophic extraocular muscle compresses the optic nerve at the tip of the ankle, and the vasodilatation at the end of the inner and outer rectus muscles, the conjunctiva, Peripheral edema and exposed keratitis are common in thyroid-associated ophthalmopathy, but it can also be seen in other eye diseases. Any thyroid disease (hyperthyroidism, hypothyroidism, Hashimoto's thyroiditis, thyroid cancer) causes eye diseases to be completely similar. Therefore, thyroid disease cannot be determined from the eye.

1. Eyelid retraction and lag Eyelid retraction and lag In patients with thyroid-related eye disease, the eyelid stagnation is the upper eyelid retraction, and the drop in the fall has diagnostic value (diagnostic eye). The width of normal cleft palate is related to ethnicity, heredity, etc. The middle part of the upper temporal margin is located between the upper limbus and the upper pupillary edge, or the upper temporal margin covers 2 mm below the upper corner of the limbus, and the middle part of the lower temporal margin is the lower lower corner of the scleral margin. If the upper and lower temporal margins leave the above normal position Usually, the eyelids are retracted or the ptosis is drooping. In thyroid-related eye diseases, the eyelids are usually retracted, that is, the upper temporal margin is elevated, even above the upper corner of the limbus, and the lower iliac margin is below the lower angleal limbus, so that the upper canopy or The lower sclera is exposed (white). In the eyelid retraction, the upper eyelid retracts more often. When the eyeball looks down, the normal person's upper eyelid moves down. When the thyroid-related eye disease patient looks down, the retracted upper eyelid cannot follow the eyeball. Down and down or slow down, called the late sputum, caused by Müller muscle and lifting the diaphragm, so that withdrawal, poor drop function, plus eyelid swelling affect the orbicularis muscle closure of the eyelids Therefore, the patient's blink reflex is reduced, showing a gaze state, which is also a special sign. It is often seen in patients with thyroid-associated ophthalmopathy. 35% to 60% of patients with thyroid-associated eye disease have retraction of the eyelid, which causes the retraction of the palate: 1Müller muscle hyperactivity (sympathetic overactivity). 2 Lifting the diaphragm and adhesion to the surrounding tissue. 3 The constrictor muscles adhered to the surrounding tissues, Small studied normal people and 10 patients with thyroid-related eye diseases. The muscles of the patients were significantly enlarged. The muscle fibers of some patients were slightly thickened, and the muscle fibers and muscle bundles were slightly thickened. The gap is widened, the fibrosis between the muscle fibers, the mucopolysaccharide deposition in the muscle space, mild focal inflammation and fat infiltration, the above is the pathological basis of the upper jaw retraction, delay and swelling.

2. Soft-tissue involvement In patients with thyroid-associated ophthalmopathy, inflammatory cell infiltration, vascular congestion and expansion, increased permeability, increased interstitial fluid, but mainly increased deposition of mucopolysaccharides in the interstitial space. The tissue absorbs a large amount of water. These two factors add up to the eyelids, conjunctival hyperemia, redness, eyelids, conjunctiva, lacrimal gland, orbital soft tissue swelling, acute thyroid-associated ophthalmopathy or infiltrating exudate eye soft tissue involvement is most obvious.

(1) Congestion of eyelids: swelling of the eyelids, swelling of the eyelids, redness, fullness and thickening, disappearance of the upper sulcus, swelling of the upper eyelids, and it is divided into mild, moderate or severe, severe eyelid congestion and swelling leading to eye movement The degree of difference, the eyelids can not be closed, which is the main cause of exposed keratitis. (2) conjunctival congestion and edema: local conjunctival hyperemia is mostly inside, the vascular dilatation of the external rectus muscle attachment (Fig. 3A), has a certain diagnostic significance, usually conjunctival congestion and edema occurs on the temporal side or below, can also Occurred on the nasal side, relatively rare on the upper side, the conjunctiva became red due to severe congestion, swelling and rising, and protruding beyond the cleft palate is another cause of exposure to membranous inflammation. (3) tears involved: tears can be due to congestion, edema and uplift, lacrimal gland can be swollen due to congestion, edema, clinical can lift the upper side of the upper eyelid, visible supracondylar humeral enlargement and prominent lacrimal gland, some cases in the sputum The upper part can be swollen and swollen lacrimal gland, more is the CT scan of the eyelid showing lacrimal gland enlargement, the lacrimal gland involvement of thyroid-associated ophthalmopathy patients, the cause is still unknown, histopathological examination revealed mild mononuclear cell infiltration and interstitial edema, no extensive Fibrosis, Khalid et al. High-performance liquid chromatography was used to measure the tears of 50 patients with thyroid-associated ophthalmopathy, and compared with healthy people, it was found that about 1 in 6 patients (8/50 patients) had tears. IgA levels were elevated, no abnormalities were found in the control group, and 10 globulins were increased, suggesting a change in lacrimal gland protein composition. (4) Orbital soft tissue swelling: The content of sputum is mainly composed of sputum fat and extraocular muscle. In patients with acute thyroid-associated ophthalmopathy, the sputum fat space is widened due to edema and congestion, and the extraocular muscle is hypertrophic due to edema and congestion. In general, there are inflammatory cells, especially lymphocytes infiltration, vasodilation, aggravation of eyelid tissue swelling, a large increase in sputum content, increased sputum pressure, obstruction of ocular venous return, more fluid accumulation in soft tissue, more severe eyelid soft tissue swelling The eyeball is protuberance and the activity is limited. When the high-resolution CT examination is performed, the fat density of the ankle is increased, and the vein on the eye is thickened. Patients with ocular soft tissue involvement often have associated symptoms such as eye discomfort, dry eyes, eye pain, foreign body sensation, photophobia, tearing, diplopia, and decreased vision.

3. Exophthalmos (exophthalmos) In addition to the special eyelid syndrome with diagnostic significance, eyeball protrusion is also a common sign. Simple eyeball protrusion does not have diagnostic significance, but simple eyeball protrusion is rare in thyroid-associated eye disease. All are accompanied by some special eye changes. If only simple eyeballs are prominent, other eyelid diseases should be considered, especially eyelid tumors. The cause of eyeballs is extraocular muscle hypertrophy, increased fat, and increased sputum content in bony eyelids. Moving forward and forward, pushing the eyeball forward, the eyeball of the thyroid-associated eye disease is the most common sign. The degree of protrusion can be mild, moderate and severe. The ocular protrusion of the thyroid-related eye disease is relatively symmetrical, 58% In case of case, the difference in binocular protrusion is less than 5mm. In 89% of cases, the difference in binocular protrusion is less than 7mm. In short, the difference in binocular protrusion is not more than 10.9mm. If this value is not exceeded, it is obvious that there may be a tumor in the sputum. The eyeball protrusion of patients with related eye diseases is generally increased by 3 mm compared with normal people.

4. Global subluxation Incomplete ocular dislocation can occur in progressive thyroid-associated eyelid disease, but it is rare because the fat volume in the eyelid increases rapidly, causing the eyeball to shift forward, and the equator of the eyeball reaches the rim. Department, eyelids can be retracted, all patients with incomplete dislocation of the eye, CT scans showed increased fat content in the sputum, while the extraocular muscles did not significantly expand, no history of diplopia. Nunery reports that there are two subtypes of thyroid-associated ophthalmopathy: type I is normal eye movement or only limited after extreme steering, with varying degrees of symmetrical prominence, no eyelid inflammation, occurring in young women, average 36 years old Most women, female: male 8:1, CT scan of the eyelid showed increased fat content (volume) in the sputum, with or without extraocular muscle enlargement, type II is restrictive muscle disease, eyeball in situ within 20 ° double vision The degree of eye asymmetry is asymmetrical, the average age is 52 years old, female: male is 2:1. CT scan shows that the axons of the extraocular muscles are enlarged, and the patients with incomplete lens dislocation are mostly type I.

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