Graves' ophthalmopathy

The endocrine ophthalmopathy (from Latin: orbis = circle and Greek:. . Πάθος, páthos = passion, addiction endocrine = " tampering inward " Synonyms: endocrine ophthalmopathy, EO ) is a disease of the eye socket (orbit ). It is one of the organ-specific autoimmune disease and usually occurs together with a thyroid malfunction ( endocrine ), with women being affected much more frequently than men.

Clinically, it manifests itself with a distinct protrusion of the eyes ( exophthalmos ) and an associated enlargement of the palpebral fissures. Trigger for this striking symptoms are structural and image size changes behind the eyeball ( retrobulbar ) lying muscle, fat and connective tissue.

Along with heart rate (tachycardia ) and an enlargement of the thyroid gland ( goiter) forms of exophthalmos, the so-called Merseburg triad, a three-piece ( Triassic) symptom complex. This is one of the classic, but not compelling clinical signs of Graves' disease and was described in 1840 by Carl Adolph von Basedow, who was then active in Merseburg.

The disease has different severity and activity levels. Because of the eye-catching cosmetic appearance can be the organic and functional problems also joined by strong psychosocial stress under which sufferers have to suffer. Although there are a number of symptomatic treatment measures, however, the causes repairable ( causal) therapy is not yet known.

• 4.1 Conservative treatment 4.1.1 drugs
• 4.1.2 Combination options
• 4.1.3 Experimental treatment approaches
• 4.1.4 Prevention in radioiodine therapy
• 4.1.5 irradiation
• 4.1.6 botulinum toxin

• 4.2.1 Orbita
• 4.2.2 eye muscles
• 4.2.3 lids

Cause and Frequency

The cause of Graves' ophthalmopathy is unknown. As probably applies an inherited autoimmune disorder that is responsible for the formation of autoantibodies against TSH receptors. These receptors are also found in the tissue of the eye socket.

The thyroid eye disease occurs in 10% of all thyroid patients before and occurs in up over 90 % of the cases at the same time in the context of Graves' disease, while 60 % in conjunction with an overactive thyroid (hyperthyroidism) on. For the frequency ( prevalence) of Graves' disease in Germany but there is no precise information. In areas with sufficient iodine this is indicated in women with 2 to 3% and in men with about a tenth of that. The annual rate of new cases of Graves' disease is 1 per 1,000 inhabitants.

However, the thyroid eye disease can also develop in time before or years after the onset of thyroid disorders. The endocrine ophthalmopathy is therefore interpreted as outside the thyroid ( extrathyreoidal ) situated the manifestation of Graves' disease underlying autoimmune processes. Thus, the same causes will be accepted. This genetic predisposition, environmental influences, their meanings are not yet clear, and a complex immunological process play a role. Even under radioiodine therapy may be a hitherto little or clinically inapparent ( inconspicuous ) form endocrine ophthalmopathy or deteriorate significantly.

They rarely but can be found in a Hashimoto's disease or entirely without evidence of thyroid involvement. Excessive consumption of nicotine ( nicotine ) can adversely affect the course and severity of the disease. The thyroid eye disease occurs in women six times more frequently than men, with the serious cases obviously predominate in men. Thyrotropin receptor autoantibodies ( TSH receptor antibody ) correlate (at least for whites) with the activity of the disease and help to assess the prognosis of Graves' ophthalmopathy.

Although the endocrine ophthalmopathy in most cases associated with thyroid disease, a causal relationship has not been proven, which is why it is considered as an independent autoimmune disease.

The common in the Anglo- American language and used as a synonym term Graves ophthalmopathy already provides a direct link between the increased incidence of eye disease and Graves 'disease (English: Graves ' disease ) ago. The Irish physician Robert James Graves described in 1835 a case of pathological thyroid enlargement ( goiter) in combination with a proptosis.

Pathogenesis

The occurrence of endocrine ophthalmopathy is the result of complex defense mechanisms of the body against its own tissues ( autoimmune processes) that are triggered by certain blood cells called B and autoreactive T lymphocytes, and with an increased formation of antibodies ( thyroid-stimulating hormone receptor autoantibodies, TRAK ) go hand in hand. There are indications that TRAK with stimulant properties ( thyroid stimulating antibodies, TSAb ) favor the formation of endocrine ophthalmopathy particularly, but the exact mechanism is not yet known. Other receptor antibodies (for example, insulin-like growth factors) may play a role.

In comparison to other areas of the body respond specific connective tissue cells, called fibroblasts, in the retrobulbar tissue particularly sensitive to inflammatory stimuli like, and in particular stimulation of specific antigens, so-called CD40 proteins, resulting in the formation of new fat cells. Also favoring effect a genetic predisposition as well as tobacco use.

The so- induced immunological inflammation leads in the eye socket to the swelling of the muscle, fat and connective tissue, widened the gap between orbital and eyeball and thus leads to both a protrusion of the eye ( exophthalmos ), and loss of elasticity of the eye muscles with movement restrictions and double vision. The main reason for this process are penetrations of the tissue with lymphocytes ( lymphocytic infiltration ) and an increase in fibroblasts. In addition, it comes to the proliferation of a Bindegewebsbaustoffes, the collagen, with a simultaneous increase further of stored glycosaminoglycans and an excessive accumulation of water in the tissue. A typical appearance of the eye muscles and less frequently of the optic nerve is also a diffuse Fettgewebswachstum, a so-called lipomatosis.

Clinical manifestations

The endocrine ophthalmopathy occurs one or both sides, but then often less pronounced. Other sources point to a rather bilaterally symmetrical disease. It has a number of dynamically changing clinical features, which generally due to inflammation, structural change and an increase in volume from behind the eye gelegenem, orbital fat, - caused connective and muscle tissue (see also: periorbita ). Is endocrine ophthalmopathy so pronounced that a complete eyelid closure is no longer possible ( lagophthalmos ) and therefore corneal ulcers occur, it is called malignant exophthalmos.

Like other diseases, the thyroid eye disease sufferers burden mentally strong. In addition to general discomfort, the functional limitations of diplopia and head postures that may pose significant obstacles in many areas of life in general, the cosmetic- aesthetic aspect can lead to social withdrawal.

Eye socket (orbit )

The exophthalmos, the emergence of one or both eyes from the orbit, is the classic symptom of Graves' ophthalmopathy and result of a painful spread of retrobulbar tissue that can bulge into the eyelids. In 3% of cases, in addition to soft tissue swelling in the orbital apex (eg edema) and in consequence to a compression and thus damage of the optic nerve with deterioration of visual acuity and corresponding visual field loss.

The degree of proptosis can be with a ophthalmologic examination device, the Exophthalmometer, quantify so-called, and thus allows for the documentation of progress and status. Space-occupying processes and space in the orbit can be represented by imaging techniques (ultrasound, CT, NMR). An investigation of visual field and visual acuity by means of perimetry and eye tests.

Eye muscles

Movement disorders caused by swelling, infiltration or pathological tissue proliferation ( fibrosis ) of the eye muscles, with a magnification up to ten times their normal volume is possible. As a result there is a loss of elasticity with partly clear reduced ductility, often accompanied by pain when looking twists. The movement restrictions do not occur in Muskelzugrichtung as an expression of reduced muscle power on, but in the opposite direction, which is almost as apparent paralysis ( paresis pseudo ) of the equilateral muscular opponent ( antagonist) represents. Clinical signs, for example, the restriction of the monocular fields of view, strabismus and diplopia with compensatory head postures. Another typical symptom is the so-called Möbius sign, a partly distinct inability to move both eyes simultaneously toward the nose ( convergence weakness).

Different Motilitätsuntersuchungen and determining the areas in which double image free is simply seen with both eyes (fusion fields of view ), are carried out in the rule of apparatus to a so-called Synoptometer or in free space to the tangent panel ( Harms ). To determine the maximum movement ability of the right and left eye ( monocular excursion routes ) can also be an examination of the pursuit movements on the Goldmann perimeter are performed. A Pinzettenzugtest provides information on the passive range of motion of the eye. Since there is an increase in intraocular pressure in the short term while looking opposite to the direction of pull of a fibrotic muscle, the implementation of intraocular pressure measurements in different viewing directions ( Blickrichtungstonometrie ) may be useful. Muscle structures and dimensions can be represented by imaging methods.

Lider

In most cases the upper lid is retracted ( retraction ), which gives the impression of a rigid gaze (cooker symbol). It is often the sclera ( sclera ) above the transition ( limbus ) of the cornea visible ( Dalrymple 's sign), and the upper eyelid remains at infraduction back ( Graefe 's sign). A rare eyelid ( Stellwag characters) often leads to wetting of corneal disorders as well as to dehydration and chemosis of the conjunctiva.

Can be used for documentation of progress and status take place ( space between upper and lower eyelid ) and agility with a simple ruler to assess the palpebral fissure and is expressed in millimeters. The frequency of the blink is expressed in number of per minute.

Other clinical signs

Further symptoms of Graves' ophthalmopathy upper eyelid edema ( Enroth 's sign), difficulty ectropionization ( Gifford- characters), abnormal Oberlidpigmentierung ( Jellinek 's sign), horizontal Lidfurche apply ( Pocher characters), lack frown when looking uplift ( Joffroy characters) and Lidzittern with closed lids ( Rodenbach characters).

Diagnostics

The diagnosis is primarily clinical. In the classical case of exophthalmos occurs as part of the so-called Merseburg triad on together with thyroid enlargement and rapid heartbeat in the course of Graves' disease.

Other diagnostic measures are primarily used to detect the severity and degree of activity of the disease, as well as threatening complications. In particular for the assessment of the inflammatory activity of the investigation is by means of nuclear magnetic resonance spectroscopy (NMR).

The differential diagnosis and the clinical picture of ocular myositis is using various imaging techniques (computed tomography, NMR ) next to a tumor located behind the eye excluded. Be difficult to distinguish from the endocrine ophthalmopathy (Graves ophthalmopathy ) are the ones so far poorly understood, Idiopathic orbital inflammation and the isolated immunogenic ophthalmopathy. Both are ultimately exclusion diagnoses in the absence of evidence of endocrine involvement.

For the classification of disease and stage, there are various schemes, of which, however, has so far none definitively established as the standard. Since 1969 is the so-called NOSPECS schema application, a classification of the American Thyroid Association. The letter sequence is a special abbreviation ( acronym) for the English names of the queried symptoms. It is also the name of its developer, the U.S. American physician Sidney C. Werner, known as Werner classification. Within this classification, there is a further classification according to the grades 0, A, B and C, with which a specific point value can be determined. Together with another parameter for disease activity, the so-called CAS score (after Mourits ), the entire course of the disease is evaluated

As an extension of NOSPECS scheme, the so-called LEMO classification has been established, which will involve a more reasonable and practicable division and was first proposed by Boergen and Pickardt 1991. This is a so-called faceted classification. The classification is in each case, prefixed with the letter and a following digit. L1E2M0O2 is, for example " only eyelid edema, conjunctival irritation in the morning, lack of muscle changes and peripheral visual field defects ."

These schemes are before and can be an important aid, the progression, or even a treatment-related improvement of clinical estimated useful during treatment. In addition, they give a clear overview of the significance of important symptoms.

Treatment and prognosis

A causes repairable ( causal) therapy is not yet known. However, it is possible in many cases to treat the symptoms. Cortisone preparations are assumed to be the first choice. In cases where its effect is not satisfactory, additional measures can be taken, their use, however, because of outstanding scientific studies not based on empirically proven effectiveness ( evidence- based) takes place. The effectiveness of therapy can by the cooperation of several medical specialties - are improved (interdisciplinary internal medicine, radiation therapy, ophthalmology and specialized surgeon ). In the event of extreme psychological stress due to the disease can be helpful by psychologists support. Despite professionally therapy occurs only in 30% of patients experienced an improvement in 60 % there is no change, and 10% if a deterioration.

Conservative treatment

Conservative treatment measures will generally be related to the severity and activity of the disease and have in the first respect, the goal is to inhibit inflammation or to lessen. Information on the direct improvement of ocular motility by conservative treatments have made ​​little so far in the literature. The bridging treatment of the double images special prism glasses, when the squint angle is not too large, may be used.

In about half of all patients with severe thyroid eye disease psychosomatic care is indicated. The basic goal of treatment is to achieve in addition to improving the organic and functional situation the best possible restoration of the external appearance of the patient and a reintegration into their professional and personal environment.

Drugs

In mild forms, associated only with dryness of the eyes or slight conjunctival irritation, topical treatment with artificial tears or ointments may be sufficient.

In moderate to severe cases where an existing or imminent deterioration of eyesight is, apply cortisone preparations, usually administered intravenously, as a drug of first choice. Concomitant treatment of thyroid dysfunction is of course necessary. Cortisone preparations have proven themselves in active inflammatory process because of their fast effectiveness on swelling. In severe disease, intravenous, high-dose treatment may be recommended. However, there are a number of side effects ( weight gain, mood swings, stomach discomfort ) and contraindications ( diabetes mellitus, infectious diseases, psychosis, peptic ulcers, osteoporosis).

Possible combinations

In cases where the primary fails introduced cortisone therapy, there is currently no consensus about the way the optimal follow-up treatment. However, the application of a second cortisone treatment with irradiation or cyclosporine appears promising. The selection of additional procedures, however, depends on the experience of the treating physicians, since in this range of evidence-based recommendations are still lacking.

Experimental treatment approaches

Further methods in the experimental stage biotechnology products apply ( biologics ), especially the drug rituximab.

Prevention in radioiodine therapy

Preventive administration of prednisolone is recommended when performing a Radiojodtheapie. It is, however, controversial, which is an optimal dosage.

Radiotherapy

Irradiation is a supplement together with another cortisone thrust recommended if the first does not provide sufficient success has brought. However, evidence-based recommendations are still lacking. She will be conducted in the form of a Orbitaspitzenbestrahlung with a diagnosis- dependent dose of 2-16 Gy. This has the advantage that in contrast to the much less of cortisone side effects. However, the effect is generally lower and their entry will be longer. Recent studies have shown that lower doses (1 Gy / week) can be just as effective over a longer treatment period ( 10-20 weeks) scaled as the use of higher doses over shorter periods (4 times / week 2 Gy up to 12 Gy total dose ).

Botulinum toxin

As treatment with limited duration of action can be used to reduce double vision or a Oberlidretraktion the neurotoxin botulinum toxin into the affected extraocular muscle, or musculus tarsalis (Müller shear muscle - levator ) and injected as a temporary relaxation of these muscles can be achieved. Here, however, no permanent damage to the structures may have occurred by fibrosis.

Operations

Surgical procedures are performed only in the inactive, chronic fibrotic phase of the disease and has passed after a constant finding for a period of at least six months. The order of the measures according to the surgically treated first the orbit, the extraocular muscles and finally the eyelids is observed. Between the individual operations in each case a few months should be.

Orbita

Operations on the eye socket are performed as a relief measure to treat the one hand, the threat of or actual strangulation of the optic nerve. They come in an option when all conservative treatment options have been exhausted, or as an emergency supply in case of acute optic nerve contusion. On the other hand, they also be performed from cosmetic-aesthetic reasons to treat an abnormal proptosis and to position the eyeball back into the orbit. Here, however, the disease has about six months a stable course without further progression have taken and be without acute inflammatory processes.

There are various methods of pressure relief (decompression). Either it directly adipose tissue is removed, or you just by removing the lateral or lower bony Orbitabegrenzungen space into which the tissue can spread. This fixes the Orbitadecke are rare because of the close proximity to the skull inside. Depending on the access road to the area of ​​operations and technology for the processes employed are in surgical interventions for an eye and / or ENT surgery, so it can represent an interdisciplinary treatment strategy.

Like other operations are also interventions for orbital decompression is not without risk. In some cases, it can lead to complications with sensory disturbances in the face or to an increased squint of the eyes. In very rare cases, injuries to the eye can occur.

Eye muscles

The goal of eye muscle surgery at a Graves' ophthalmopathy is to achieve a normalization of eye movement with the largest possible field binocular single vision, and this without taking a compensatory head posture. The success rate is between about 60-80 % of a double image of freedom in the normal use of vision. Since Schiel positions and movement restrictions are due to a lack of extensibility and structural changes of the muscles, the process fundamentals and dosage guidelines normal strabismus surgery may be used only very limited in such operations. Which muscles with which technology ultimately, surgical, depends on the individual clinical picture and the respective findings. Careful dosage is necessary in particular to avoid overcorrection. For this reason, if appropriate several operations, including both eyes, to be entirely displayed.

Usually a rear bearing of the fibrotic muscle is performed. This can be done with and without a solid reattachment ( reattachment ) of the muscle on the globe. In the second case it is possible to influence the operation effect of readjusting the threads to the first postoperative day, yet. As dosage Directive has been proposed in the operation of the vertical rectus muscles squint angle reduction of 2 ° per millimeter of muscle return transfer to be based, in the operation of horizontal recti 1.7 ° per millimeter rear storage track. The recommendation pure rear bearings does not apply to very large squint angles.

Lider

Eyelid operations are in the line of surgical therapy measures of endocrine ophthalmopathy chronologically last. You can come into question if this seems useful for a permanent retraction of the upper eyelid, especially when looking down from cosmetic-aesthetic grounds, or where there is a risk of corneal dehydration due to an incomplete Lidschlusses.

In general, a debilitating intervention on the levator, the levator palpebrae superioris performed. Another method is the top and side, and Unterlidverlängerung Lidspaltenverkleinerung.

Health economic aspects

Although specifically related to the endocrine ophthalmopathy, not yet available health economic data, it is believed that it causes very high direct and indirect costs. These are, firstly, due to the complex and multidisciplinary therapeutic measures, the potentially very long or even drug-resistant disease processes, as well as a correspondingly intensive aftercare. Secondly, it can lead to permanent disability due to sick leave long absence from work through. The establishment of specialized centers, as well as increased research, especially in the genetic field, as an approach is seen to develop focused and effective treatment measures and thus ensure a reduction in costs, without counteracting the primary goal of optimal patient care.