FUTURE DEVELOPMENTS

An extension of conformal fixed beam technique is the use of the mMLC for intensity-modulated radiotherapy (IMRT). In IMRT, the movements of the Tungsten leaves into the beam’s path modulate the photon fluence of the beam during irradiation. Therefore, if a critical structure resides within a beam’s path and cannot be avoided, the application of IMRT can decrease the dose delivered in the portion of the field where the critical structure is located. The other fields then supplement additional dose to that portion of the tumor. Because of the complexity of IMRT planning, an inverse planning algorithm is used. This requires that the minimal dose to the tumor volume and maximum doses to the critical structures are first defined. Then, through multiple iterations, the planning algorithm deduces the optimal beam arrangements and intensity modulation within each field. As the dose prescription for the treatment of optic nerve neoplasms is relatively modest, it is unclear whether IMRT confers an advantage over the other non-IMRT conformal techniques discussed.

SUMMARY

Optic nerve neoplasm is ideally treated with SRT. With the advent of the mMLC, multiple conformal fixed beams and dynamic arc technique have become a reality for routine clinical treatment. The potential benefit of IMRT in the treatment of optic nerve neoplasms is promising and warrants research.

fibroblasts. Although there is substantial evidence for an autoimmune process being responsible for Graves’ ophthalmopathy, the case remains unproven and there is weak evidence in favor of an infectious etiology.

INTRODUCTION

All of the clinically significant eye symptoms and findings among patients with Graves’ ophthalmopathy can be traced to one of two phenomena, swelling in the retrobulbar space or restriction of extraocular muscle motion (1). The former is due to retrobulbar deposition of glycosaminoglycans (GAG), which strongly bind water in both orbital muscle and connective tissue (2). The latter is due to swelling and later fibrosis of the extraocular muscles (3). These observations are no longer controversial and scientists are now preoccupied with the more fundamental questions of why GAG selectively accumulate in orbital tissue and why extraocular muscle fibrosis takes place (3–6). While we recognize some of the mechanisms that may contribute to these processes, a comprehensive awareness and understanding of the initiating factors remains elusive.

This paper will describe how GAG deposition and extraocular muscle fibrosis bring about the clinical features of Graves’ ophthalmopathy. We will discuss how our knowledge of pathogenesis should inform our choice of measurements of change in Graves’ ophthalmopathy (7), and we will briefly review some of the more fundamental but still unproven theories of pathogenesis.

HOW ARE THE CLINICAL FEATURES OF

GRAVES’ OPHTHALMOPATHY EVOKED?

Patients with Graves’ eye disease typically complain of orbital or corneal pain, lacrimation, photophobia, blurring of vision, double vision, or impaired perception of color. On examination, they exhibit orbital congestion, proptosis, optic neuropathy, restricted gaze, divergent visual axes, corneal exposure, lid retraction, and periorbital edema. Early in the illness

congestive features may predominate. Later, extraocular muscle fibrosis and restrictions of gaze are dominant (8).

Orbital congestive changes closely mimic the changes seen with inflammation. It is, therefore, difficult to define the extent to which redness, swelling, and pain are due to inflammation vs. congestion. The rapidity with which redness, swelling, and pain disappear after effective orbital decompression suggests that congestion is an important component in many patients (9).

CONSEQUENCES OF SWELLING IN THE

RETROBULBAR SPACE

The bony orbit is shaped like a horizontally positioned cone with the globe occluding the anterior opening. The walls of the cone are relatively nondistensible. If soft tissues swell due to GAG deposition and water binding, then the globe is inevitably forced forward beyond the protective coverage of the eyelids. Patients will experience a sense of retrobulbar pressure. They will note a staring expression. The uncovered corneal surface is at risk of injury and offers a larger evaporative surface leading to dry eye complaints.

Increasing pressure in the retrobulbar space leads to impaired venous drainage, chemosis, and periorbital edema. Further pressure increase will impair optic nerve function with consequent loss of color vision, field defects, and reduced visual acuity. The complaint of visual blurring may be due to early diplopia, optic nerve pressure, or corneal changes (10,11).

CONSEQUENCES OF RESTRICTED

EXTRAOCULAR MUSCLE MOTION

The motion of extraocular muscles may be restricted from engorgement alone or because over time they have become fibrosed. When the muscles that attach to the globe are involved, the consequence is restricted upward gaze with or without diplopia. When the eyelid retractors are affected, lid retraction is the result. Fibrosis or swelling of extraocular muscles is frequently asymmetric (12).

Fibrosis is often represented as the inactive or ‘‘burnt out’’ stage of Graves’ ophthalmopathy. It should not be forgotten, however, that in another postulated autoimmune disease involving the thyroid, namely Riedel’s thyroiditis, fibrosis is the visible indication of activity. Riedel’s antibodies are presumed to induce fibrosis in the thyroid and many other tissues (13). Thus, the fibrotic stage of Graves’ ophthalmopathy may indicate a shift in antibody type rather than the disappearance of antibodies or the lessening of an autoimmune process.

WHAT MEASUREMENTS REFLECT THE

UNDERLYING PATHOLOGY IN GRAVES’

OPHTHALMOPATHY?

Although most studies of Graves’ ophthalmopathy in the past have relied on attempts to measure either patients’ symptoms or the external consequences of the underlying processes, modem technology allows us to directly measure volume of extraocular muscles and retrobulbar fat on computerized tomographic scans and magnetic resonance images (1). Range of extraocular muscle motion can be reliably measured on a Goldman perimeter. Lid retraction is reflected in widening of the lid fissures, which can be recorded directly or on patient photographs. It is no longer necessary to aggregate largely subjective assessments of secondary external eye findings into clinical indices (14). All of the clinically significant expressions of Graves’ ophthalmopathy can be measured objectively by determining volume of retrobulbar muscles and fat, defining range of motion and diplopia fields, and measuring lid fissure width and proptosis. From these primary changes, secondary consequences include corneal changes, periorbital edema, and optic nerve involvement.

WHY DO GAGS ACCUMULATE IN THE ORBIT

IN GRAVES’ DISEASE?

Glycosaminoglycan molecules are intensely hydrophilic and strongly bind water in the retrobulbar space. Orbital

fibroblasts in culture secrete GAG (15), and the production of GAG is upregulated by a variety of cytokines, including leukoregulin, TGF Beta, and Interferon alpha (15,16). The same immunomodulatory molecules can be detected in fresh human orbital tissue removed during decompression for Graves’ ophthalmopathy (17,18).

IS GRAVES’ OPHTHALMOPATHY DEFINITELY

AN AUTOIMMUNE DISEASE?

Bahn (6) has authoritatively reviewed this question. In brief, Witebsky et al. (19) defined criteria for showing that a particular human disease is autoimmune in nature. The criteria included: (1) demonstration of circulating or cell bound antibodies, (2) identification of the specific antigen against which the antibody is directed, (3) production of antibodies against the same antigen in experimental animals, and (4) reproduction of similar pathology in an actively sensitized experimental animal. According to these criteria, we cannot claim to have proven that Graves’ ophthalmopathy is an autoimmune disease, since neither the autoantigen nor specific pathogenic antibodies have been definitively identified nor as yet an experimental animal exists that fully satisfies the postulates.

Recently, Rose and Bona (20) revised the criteria for autoimmune disease. They suggest that evidence that is direct, indirect, or circumstantial may be drawn upon to support the contention that a disease is autoimmune in nature. If the disease can be induced by passive transfer of pathogenic antibodies to a normal human being or an experimental animal, it would constitute direct evidence for autoimmunity. In accordance with these criteria, thyrotoxic Graves’ disease fulfils the definition of an autoimmune process. Graves’ ophthalmopathy does not so readily conform to the direct diagnostic requirements for autoimmunity.

Indirect evidence includes identification of the autoantigen and showing its immunogenic properties in vitro or in an experimental animal (20). This may have been accomplished in ophthalmopathy. One report exists of orbital changes

consistent with active autoimmunity in mice genetically immunized with the TSH receptor. Splenocytes from the immunized mice were transferred to naive BALB=c mice, and 17=25 of the recipients showed lymphocytic and mast cell infiltration in the orbits together with adipose tissue accumulation and edema (21). This report has not yet been confirmed.

Finally, circumstantial evidence such as association with other autoimmune diseases or the demonstration of lymphocytes in the affected tissue or organ may be taken as suggestive of an autoimmune process (20). Graves’ orbital tissue does contain lymphocytes, including retrobulbar T-cells that are CD8-positive and that specifically recognize autologous fibroblasts (22). Inflammatory cytokines are present (23). Immunohistochemical studies suggest the presence of a local autoimmune process (24).

The presence of the TSH receptor in orbital tissue suggests that it may be a significant orbital autoantigen (25). However, the clinical correlations between severity of Graves’ ophthalmopathy and levels of the TSH receptor stimulating immunoglobulins are very weak in our own experience (30). Others have reported an association between TSI and the clinical activity score (26).

In summary, even with the more inclusive criteria offered by Rose and Bona (20), the case for autoimmunity as the cause of Graves’ ophthalmopathy remains unproved although it remains a highly probable hypothesis.

COULD GRAVES’ ORBITOPATHY BE AN

INFECTIOUS DISEASE?

Involvement of the extraocular muscles in Graves’ ophthalmopathy is frequently asymmetric. The inferior and medial recti are most frequently involved clinically. These are the muscles closest to the nasal sinuses, and the bone that separates them from the sinuses is porous. One might speculate that an as yet unidentified pathogen could infiltrate the orbit from the nasal sinuses. Some known pathogens carry TSH

receptors on their surface (27–29). Antibodies to these bacteria or viruses could cross react with TSH receptors on orbital fibroblasts and then escape into the circulation to react with the thyroid TSH receptor and evoke Graves’ hyperthyroidism. There is only weak supporting evidence for this hypothesis at present. While it would help to explain the asymmetry in extraocular muscle involvement and the preferential involvement of inferior and medial recti, the hypothesis lacks support in critical dimensions. Specifically, no such pathogens have been recognized or recovered from orbital tissues.

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