Exp. Clin. Endocrino!. Vol. 97, No. 2/3, 1991, pp. 187-190
J. A. Barth, Leipzig
Mayo Clinic, Department of Internal Medicine, Division of Endocrinology
Some Unanswered Questions in Thyroid-Related Ophthalmopathy C. A. Goii,iAN, A. HEUFELDER and REBECCA S. BAHN
Autoimmune hyperthyroidism, when fully expressed, is characterized by thyrotoxicosis, ophthalmopathy, dermopathy, and acropachy. Since these expressions occur in decreasing order of frequency as listed, it is natural that the eforts of most investigators attempting to understand their pathogenesis should have focused on the most common and most obvious component of this illness, namely, thyrotoxicosis. We have gradually appreciated the central role of thyroid stimulating immunoglobulins in bringing about hyperthyroidism in this condition, but a comprehensive understanding of pathogenesis must also include explanations for the development of ophthalmopathy, dermopathy, and acropachy. These themes are now being addressed by increasing numbers of investigators and this symposium attests to interest in the wider field. If Dr. von Basedow, who was first to describe the dermopathic changes associated with toxic goiter (von Basedow, 1840), were present today, I think his penetrating intellect would find the present statusof our understanding to be improved in certain regards but notably lacking in others. We have a reasonably good understanding of the proximate mechanical problem in thyroid-related orbitopathy (Gorman and Bahn, 1989). There is a discrepancy between the volume of the swollen orbital tissues and the bony orbit in which they reside. Swelling takes place in both extraocular muscles and retrobulbar connective tissue and tends to displace the globe forward. The orbital septum and the extraocular muscles which are firmly attached to the annulus of Zinn resist the forward movement of the globe. Pressure rises in the retrobulbar space, venous drainage is impaired, and optic neuropathy may follow. Movement of the globe beyond the protective coverage of the eyelid results in lacrimation, photophobia, exposure keratitis, and sometimes corneal ulceration. Swelling of extraocular muscles, including the levators, is eventually followed by fibrosis and shortening. As a result, eyelids retract and worsen the exposure problems. Asymmetric shortening of extraocular muscles causes permanent diplopia. All available treatments are directed eithr toward shrinking the swollen retrobulbar tissues or expanding the space available for them to occupy. In general terms, efficacy can be assessed through examination of the degree to which proptosis regresses since proptosis is both consequence and indicator of the volume discrepancy (Bahn and Gorman, 1987).
Downloaded by: Collections and Technical Services Department. Copyrighted material.
(Head: C. A. Gorman), Rochester, Minnesota, U.S.A.
188
Exp. Clin. Endocrino!. 97 (1991) 2/3
Rather than dwelling on achievements in our understanding, we wish to emphasize in this presentation those areas where our understanding remains imperfect and our concepts unclear. It is to be hoped that during this symposium we will become enlightened on at least some of these points.
If thyroid orbitopathy is a consequence of some circulating humoral agent, it is difficult to explain the frequent asymmetry in its presentation. Occasionally, one orbit is extensively involved when minimally detectable change is present contralaterally. Further, the medial and inferior recti muscles are more commonly affected than other extraocular muscles (Dyer, 1984). In some patients, retro-ocular muscles are minimally affected but the retrobulbar connective tissue is notably expanded (Forbes et al., 1986). These variants in presentation are not easily accommodated within current theories. Because thyroidrelated ophthalmopathy is not a fatal disease, there have been relatively few modern and comprehensive histopathological examinations of the orbital tissues (Hufnagel et al., 1984; Daicker, 1979; Kroll et al., 1966). Existing reports indicate that the extraocular muscles are histologically intact. Edema and inflammatory cells infiltrate between muscle
fibers. Although qualitative histochemical studies suggest that increased amounts of glycosaminoglycan are present in the orbital muscles and connective tissue of patients with thyroid ophthalmopathy, quantitative studies are still lacking in this important area. Diagnosis When a patient has bilateral, symmetrical orbital disease with involvement of eyelids, cornea, extraocular muscles, retrobulbar connective tissue, and the optic nerve, in the set-
ting of hyperthyroidism with circulating thyroid stimulating immunoglobulins, the diagnosis of thyroid-related ophthalmopathy is not in doubt. As progressively fewer of these expressions are present, the diagnosis becomes less certain. What are the minimum diagnostic criteria for thyroid-related orbitopathy? Should mild symptoms or signs of eye irritation alone, in the setting of hyperthyroidism, be considered diagnostic? Is evidence of extraocular muscle involvement a requirement? Must there be eyelid retraction? Is evidence of clinical or radiologic bilaterality a requisite? How precisely can orbital myositis and thyroid-related opthalmopathy be distinguished from each other? What is the relationship to ocular myasthenia?
freatment Evaluation Criteria How shall we assess response to therapy? Diffeiences of opinion exist concerning the
relative efficacy of medical versus surgical forms of treatment of thyroid-associated ophthalmopathy. This uncertainty is, in part, ¡Jerived from the manner in which investigators have conducted their studies and expressed their results. Although there are
Downloaded by: Collections and Technical Services Department. Copyrighted material.
Histopathology
C. A. GORMAN et. al., Thyroid-Related Ophthalmopathy
189
many uncontrolled, anecdotal reports of efficacious treatments with one or another form of treatment, very few carefully controlled prospective clinical trials have been carried out. In addition, the time frames within which of the results of therapy were assessed have differed greatly between studies, and even within some studies. Improvement which
that treatment results can be defined in terms of quantitative changes in proptosis, visual acuity, visual field defects, palpebral fissure width, and extraocular muscle volume (Bahn et al., 1987). However, there is no general agreement on the specific indicators which reliably define improvement or regression in thyroid-related ophthalmopathy. In particular, use of numerical indices which rely heavily on periorbital soft tissue changes can be highly misleading because these tissue changes can vary considerably from day to day and their assessment is very subjective. Which Therapy Is Most Effective
Recent carefully controlled trials have helped to place the use of cyclosporin and corticosteroids in perspective (Prummel et al., 1989). The role of radiotherapy to the orbits remains highly controversial and as an isolated form of treatment, its efficacy has not been definitively established. It may enhance corticosteroid therapy (Bartalena et al., 1983). More controlled studies of plasmapheresis are needed (Kelly et al., 1983). The various approaches to orbital decompression are gradually becoming better defined in terms of their relative strengths and weaknesses, but consensus in regard to the optimal surgical approach for a particular patient has not been achieved and differs widely between institutions and across national boundaries (Garrity et al., 1989).
Pathdgenesis Perhaps less is known about the pathogenesis, than about any other aspect of thyroidrelated ophthalmopathy. It is not clear whether extraocular muscle cells or retro-ocular fibroblasts are the primary targets in this autoimmune disease. Our laboratory is studying the regulation of glycosaminoglycan synthesis by retro-ocular and pretibial fibroblasts (Smith et al., 1989; Bahn et al., 1989), as well as serum IgG binding to these cells (Bahn et al., 1987). Other investigators have focused on the role of serum antibodies, some of which are cytotoxic, directed against extraocular muscle membranes (Hiromatsu et al., 1987).
There is current interest in the role of infection in the development of thyrotoxicosis and ophthalmopathy. The demonstration that certain bacteria possess TSH receptors has led to the hypothesis that antibodies directed against TSH receptors in bacteria crossreact with and stimulate thyroid follicular TSH receptors. The recent cloning of the TSH receptor (Libert et al., 1989) will allow this hypothesis to be tested rigorously and related questions to be addressed. What is the exact nature of the TSH receptor in bacteria? Are TSH receptors also present in orbital cells? If so, on what cells do they reside and do they differ in structure from TSH receptors on thyroid follicular cells?
Downloaded by: Collections and Technical Services Department. Copyrighted material.
results months or years after a particular form of treatment cannot reasonably be attributed to that treatment. Likewise, good results following application of several simultaneous treatments cannot be attributed to any single modality. It is our perception
Exp. Clin. Endocrino!. 97 (1991) 2/3
190
References BAHN, R.; GoRMAN, C.: Choice of therapy and criteria for assessing treatment outcome in thyroidassociated ophthalmopathy. Endocrinol. and Metab. Clinics in North America 16(1987)391-407. BAHN, R.; SMITH, T. J.; GORMAN, C. A.: The centra! role of the fibroblast in the pathogenesis of ex-
trathyroidal manifestations of Graves' disease. Acta Endocrino!ogica 121 (1989) 75-81. BARTALENA, L.; MARcoccl, C.; CHIOVATO, L.; et al.: Orbital coba!t irradiation combined with systemic corticosteroids for Graves' oththalmopathy: Comparison with systemic corticosteroids alone. J. Clin. Endocrinol. Metab. 56 (1983) 1139. DAICKER, B.: Das gewebliche Subsstrat der verdickten äußeren Augenmuskeln bei der endokrinen Orbitopathie. K!in. Monatsbl. Augenheilkd. 174 (1979) 843. DYER, J. A.: Ocular muscle surgery, In: The eye and orbit in thyroid disease. Eds. Golu&AN, C.; WALLER, R.; DYER, J., New York: Raven Press 1984, pp. 253-261. [61 FORBES, G.; Goiu, C. A.; BRENNAN, M. D.; GEHRING, D. G.; IL5TRuP, D. M. EARNEST Iv, F.:
Ophthalmopathy of Graves' disease: computerized volume measurements of the orbita! fat and muscle. AJNR 7 (1986) 651-656. GARRITY, J. A.; McCiy, T. V.; GoRMAN, C. A.: Compression and decompression of orbita! contents in Graves' ophthalmopathy. Acta Endocrinologica (Copenh.) 121 (1989) 160-168. Go1uiAN, C.; BAHN, R.: Pathogenesis of Graves' ophthalmopathy, In: Dey. Ophthalmol. Eds. PICKARDT, C.; BOERGEN, K., Vol. 20, Basel: S. Karger 1989, pp. 1-7. HIROMATSU, Y.; FUKIZAWA, H.; How, J.; WALL, J. R.: Antibody-dependent cell-mediated cytotox-
icity against human eye muscle cells and orbital fibroblasts in Graves' ophthalmopathy - role of class II MHC antigen expression and gamma interferon action of effector and target cells. Clin. Exp. Immunol. 70 (1987) 593-603. HUFNAGEL, T. J.; HICKEY, W. E; COBBS, W. H.; JAXOBIEC, E A.; IwAHolo, T.; EAGLE, R. C.: Im-
munohistochemica! and ultrastructural studies on the exenterated orbital tissues of a patient with Graves' disease. Ophthalmology 91 (1984) 1411-1419. KELLY, W. E; LONOSON, D.; SMITHARD, D. et al.: An evaluation of plasma exchange for Graves'
ophthalmopathy. Clin. Endocrinol. 18 (1983) 485. [121 KROLL, A. J.; KuwARk, T.: Dysthyroid ocular myopathy: anatomy, histology, and electron microscopy. Arch. Ophthalmol. 76 (1966) 244-257. LIBERT, E; LEFORT, A.; GERARD, C.; PARMENTIER, M.; PERRET, J.; LUDGATE, M.; DUMONT, J. E.;
VASSART, G.: Cloning, sequencing and expression of the human thyrotropin (TSH) receptor:
evidence for binding of autoantibodies. Biochem. and Biophysiol. Res. Comm. 165 (1989) 1250-1255. VAN DER GG, R.; KRENNING, E. P.; MouRrrs, M. P.; BEROHOUT, A.; KOORNEEF, L.; WIERSINGA, W. M.: Prednisone and cyclosporine in the treatment of severe Graves' PRUMMEL, M. E;
ophthalmopathy. New Engl. J. Med. 321 (1989) 1353-1359. SMITH, T. J.; BA1iP, R. S.; GoRES , C. A.: Connective tissue, glycosaminoglycans, and diseases of the thyroid. Endocrine Reviews 10 (1989) 366-391. VON BASEDOW, K. A.: Exophthalmus durch Hypertrophie des Zellgewebes in der Augenhöhle. Wochenschr. ges. Heilk. Berlin 6 (1840) 197-220. Author's address: C. A. GORMAN, M.B., B. Ch., Mayo Clinic, Department of Internal Medicine, Div. of Endocrinology, Rochester, MN 55905, USA
Downloaded by: Collections and Technical Services Department. Copyrighted material.
Other current areas of investigation include examination of the roles of cell-mediated immunity, cytokines and "aberrant" HLA-DR expression in the initiation and propagation of retroocular and pretibial pathology. The roles of antithyroglobulin antibodies, TSH itself, and fragments of the TSH molecule need to be elucidated. We look forward with enthusiasm to the presentations in this symposium. They promise illumination of this enigmatic disease that was so clearly described in its clinical manifestations just 150 years ago by the person in whose honor this symposium is held.
J. A. Barth, Leipzig
Mayo Clinic, Department of Internal Medicine, Division of Endocrinology
Some Unanswered Questions in Thyroid-Related Ophthalmopathy C. A. Goii,iAN, A. HEUFELDER and REBECCA S. BAHN
Autoimmune hyperthyroidism, when fully expressed, is characterized by thyrotoxicosis, ophthalmopathy, dermopathy, and acropachy. Since these expressions occur in decreasing order of frequency as listed, it is natural that the eforts of most investigators attempting to understand their pathogenesis should have focused on the most common and most obvious component of this illness, namely, thyrotoxicosis. We have gradually appreciated the central role of thyroid stimulating immunoglobulins in bringing about hyperthyroidism in this condition, but a comprehensive understanding of pathogenesis must also include explanations for the development of ophthalmopathy, dermopathy, and acropachy. These themes are now being addressed by increasing numbers of investigators and this symposium attests to interest in the wider field. If Dr. von Basedow, who was first to describe the dermopathic changes associated with toxic goiter (von Basedow, 1840), were present today, I think his penetrating intellect would find the present statusof our understanding to be improved in certain regards but notably lacking in others. We have a reasonably good understanding of the proximate mechanical problem in thyroid-related orbitopathy (Gorman and Bahn, 1989). There is a discrepancy between the volume of the swollen orbital tissues and the bony orbit in which they reside. Swelling takes place in both extraocular muscles and retrobulbar connective tissue and tends to displace the globe forward. The orbital septum and the extraocular muscles which are firmly attached to the annulus of Zinn resist the forward movement of the globe. Pressure rises in the retrobulbar space, venous drainage is impaired, and optic neuropathy may follow. Movement of the globe beyond the protective coverage of the eyelid results in lacrimation, photophobia, exposure keratitis, and sometimes corneal ulceration. Swelling of extraocular muscles, including the levators, is eventually followed by fibrosis and shortening. As a result, eyelids retract and worsen the exposure problems. Asymmetric shortening of extraocular muscles causes permanent diplopia. All available treatments are directed eithr toward shrinking the swollen retrobulbar tissues or expanding the space available for them to occupy. In general terms, efficacy can be assessed through examination of the degree to which proptosis regresses since proptosis is both consequence and indicator of the volume discrepancy (Bahn and Gorman, 1987).
Downloaded by: Collections and Technical Services Department. Copyrighted material.
(Head: C. A. Gorman), Rochester, Minnesota, U.S.A.
188
Exp. Clin. Endocrino!. 97 (1991) 2/3
Rather than dwelling on achievements in our understanding, we wish to emphasize in this presentation those areas where our understanding remains imperfect and our concepts unclear. It is to be hoped that during this symposium we will become enlightened on at least some of these points.
If thyroid orbitopathy is a consequence of some circulating humoral agent, it is difficult to explain the frequent asymmetry in its presentation. Occasionally, one orbit is extensively involved when minimally detectable change is present contralaterally. Further, the medial and inferior recti muscles are more commonly affected than other extraocular muscles (Dyer, 1984). In some patients, retro-ocular muscles are minimally affected but the retrobulbar connective tissue is notably expanded (Forbes et al., 1986). These variants in presentation are not easily accommodated within current theories. Because thyroidrelated ophthalmopathy is not a fatal disease, there have been relatively few modern and comprehensive histopathological examinations of the orbital tissues (Hufnagel et al., 1984; Daicker, 1979; Kroll et al., 1966). Existing reports indicate that the extraocular muscles are histologically intact. Edema and inflammatory cells infiltrate between muscle
fibers. Although qualitative histochemical studies suggest that increased amounts of glycosaminoglycan are present in the orbital muscles and connective tissue of patients with thyroid ophthalmopathy, quantitative studies are still lacking in this important area. Diagnosis When a patient has bilateral, symmetrical orbital disease with involvement of eyelids, cornea, extraocular muscles, retrobulbar connective tissue, and the optic nerve, in the set-
ting of hyperthyroidism with circulating thyroid stimulating immunoglobulins, the diagnosis of thyroid-related ophthalmopathy is not in doubt. As progressively fewer of these expressions are present, the diagnosis becomes less certain. What are the minimum diagnostic criteria for thyroid-related orbitopathy? Should mild symptoms or signs of eye irritation alone, in the setting of hyperthyroidism, be considered diagnostic? Is evidence of extraocular muscle involvement a requirement? Must there be eyelid retraction? Is evidence of clinical or radiologic bilaterality a requisite? How precisely can orbital myositis and thyroid-related opthalmopathy be distinguished from each other? What is the relationship to ocular myasthenia?
freatment Evaluation Criteria How shall we assess response to therapy? Diffeiences of opinion exist concerning the
relative efficacy of medical versus surgical forms of treatment of thyroid-associated ophthalmopathy. This uncertainty is, in part, ¡Jerived from the manner in which investigators have conducted their studies and expressed their results. Although there are
Downloaded by: Collections and Technical Services Department. Copyrighted material.
Histopathology
C. A. GORMAN et. al., Thyroid-Related Ophthalmopathy
189
many uncontrolled, anecdotal reports of efficacious treatments with one or another form of treatment, very few carefully controlled prospective clinical trials have been carried out. In addition, the time frames within which of the results of therapy were assessed have differed greatly between studies, and even within some studies. Improvement which
that treatment results can be defined in terms of quantitative changes in proptosis, visual acuity, visual field defects, palpebral fissure width, and extraocular muscle volume (Bahn et al., 1987). However, there is no general agreement on the specific indicators which reliably define improvement or regression in thyroid-related ophthalmopathy. In particular, use of numerical indices which rely heavily on periorbital soft tissue changes can be highly misleading because these tissue changes can vary considerably from day to day and their assessment is very subjective. Which Therapy Is Most Effective
Recent carefully controlled trials have helped to place the use of cyclosporin and corticosteroids in perspective (Prummel et al., 1989). The role of radiotherapy to the orbits remains highly controversial and as an isolated form of treatment, its efficacy has not been definitively established. It may enhance corticosteroid therapy (Bartalena et al., 1983). More controlled studies of plasmapheresis are needed (Kelly et al., 1983). The various approaches to orbital decompression are gradually becoming better defined in terms of their relative strengths and weaknesses, but consensus in regard to the optimal surgical approach for a particular patient has not been achieved and differs widely between institutions and across national boundaries (Garrity et al., 1989).
Pathdgenesis Perhaps less is known about the pathogenesis, than about any other aspect of thyroidrelated ophthalmopathy. It is not clear whether extraocular muscle cells or retro-ocular fibroblasts are the primary targets in this autoimmune disease. Our laboratory is studying the regulation of glycosaminoglycan synthesis by retro-ocular and pretibial fibroblasts (Smith et al., 1989; Bahn et al., 1989), as well as serum IgG binding to these cells (Bahn et al., 1987). Other investigators have focused on the role of serum antibodies, some of which are cytotoxic, directed against extraocular muscle membranes (Hiromatsu et al., 1987).
There is current interest in the role of infection in the development of thyrotoxicosis and ophthalmopathy. The demonstration that certain bacteria possess TSH receptors has led to the hypothesis that antibodies directed against TSH receptors in bacteria crossreact with and stimulate thyroid follicular TSH receptors. The recent cloning of the TSH receptor (Libert et al., 1989) will allow this hypothesis to be tested rigorously and related questions to be addressed. What is the exact nature of the TSH receptor in bacteria? Are TSH receptors also present in orbital cells? If so, on what cells do they reside and do they differ in structure from TSH receptors on thyroid follicular cells?
Downloaded by: Collections and Technical Services Department. Copyrighted material.
results months or years after a particular form of treatment cannot reasonably be attributed to that treatment. Likewise, good results following application of several simultaneous treatments cannot be attributed to any single modality. It is our perception
Exp. Clin. Endocrino!. 97 (1991) 2/3
190
References BAHN, R.; GoRMAN, C.: Choice of therapy and criteria for assessing treatment outcome in thyroidassociated ophthalmopathy. Endocrinol. and Metab. Clinics in North America 16(1987)391-407. BAHN, R.; SMITH, T. J.; GORMAN, C. A.: The centra! role of the fibroblast in the pathogenesis of ex-
trathyroidal manifestations of Graves' disease. Acta Endocrino!ogica 121 (1989) 75-81. BARTALENA, L.; MARcoccl, C.; CHIOVATO, L.; et al.: Orbital coba!t irradiation combined with systemic corticosteroids for Graves' oththalmopathy: Comparison with systemic corticosteroids alone. J. Clin. Endocrinol. Metab. 56 (1983) 1139. DAICKER, B.: Das gewebliche Subsstrat der verdickten äußeren Augenmuskeln bei der endokrinen Orbitopathie. K!in. Monatsbl. Augenheilkd. 174 (1979) 843. DYER, J. A.: Ocular muscle surgery, In: The eye and orbit in thyroid disease. Eds. Golu&AN, C.; WALLER, R.; DYER, J., New York: Raven Press 1984, pp. 253-261. [61 FORBES, G.; Goiu, C. A.; BRENNAN, M. D.; GEHRING, D. G.; IL5TRuP, D. M. EARNEST Iv, F.:
Ophthalmopathy of Graves' disease: computerized volume measurements of the orbita! fat and muscle. AJNR 7 (1986) 651-656. GARRITY, J. A.; McCiy, T. V.; GoRMAN, C. A.: Compression and decompression of orbita! contents in Graves' ophthalmopathy. Acta Endocrinologica (Copenh.) 121 (1989) 160-168. Go1uiAN, C.; BAHN, R.: Pathogenesis of Graves' ophthalmopathy, In: Dey. Ophthalmol. Eds. PICKARDT, C.; BOERGEN, K., Vol. 20, Basel: S. Karger 1989, pp. 1-7. HIROMATSU, Y.; FUKIZAWA, H.; How, J.; WALL, J. R.: Antibody-dependent cell-mediated cytotox-
icity against human eye muscle cells and orbital fibroblasts in Graves' ophthalmopathy - role of class II MHC antigen expression and gamma interferon action of effector and target cells. Clin. Exp. Immunol. 70 (1987) 593-603. HUFNAGEL, T. J.; HICKEY, W. E; COBBS, W. H.; JAXOBIEC, E A.; IwAHolo, T.; EAGLE, R. C.: Im-
munohistochemica! and ultrastructural studies on the exenterated orbital tissues of a patient with Graves' disease. Ophthalmology 91 (1984) 1411-1419. KELLY, W. E; LONOSON, D.; SMITHARD, D. et al.: An evaluation of plasma exchange for Graves'
ophthalmopathy. Clin. Endocrinol. 18 (1983) 485. [121 KROLL, A. J.; KuwARk, T.: Dysthyroid ocular myopathy: anatomy, histology, and electron microscopy. Arch. Ophthalmol. 76 (1966) 244-257. LIBERT, E; LEFORT, A.; GERARD, C.; PARMENTIER, M.; PERRET, J.; LUDGATE, M.; DUMONT, J. E.;
VASSART, G.: Cloning, sequencing and expression of the human thyrotropin (TSH) receptor:
evidence for binding of autoantibodies. Biochem. and Biophysiol. Res. Comm. 165 (1989) 1250-1255. VAN DER GG, R.; KRENNING, E. P.; MouRrrs, M. P.; BEROHOUT, A.; KOORNEEF, L.; WIERSINGA, W. M.: Prednisone and cyclosporine in the treatment of severe Graves' PRUMMEL, M. E;
ophthalmopathy. New Engl. J. Med. 321 (1989) 1353-1359. SMITH, T. J.; BA1iP, R. S.; GoRES , C. A.: Connective tissue, glycosaminoglycans, and diseases of the thyroid. Endocrine Reviews 10 (1989) 366-391. VON BASEDOW, K. A.: Exophthalmus durch Hypertrophie des Zellgewebes in der Augenhöhle. Wochenschr. ges. Heilk. Berlin 6 (1840) 197-220. Author's address: C. A. GORMAN, M.B., B. Ch., Mayo Clinic, Department of Internal Medicine, Div. of Endocrinology, Rochester, MN 55905, USA
Downloaded by: Collections and Technical Services Department. Copyrighted material.
Other current areas of investigation include examination of the roles of cell-mediated immunity, cytokines and "aberrant" HLA-DR expression in the initiation and propagation of retroocular and pretibial pathology. The roles of antithyroglobulin antibodies, TSH itself, and fragments of the TSH molecule need to be elucidated. We look forward with enthusiasm to the presentations in this symposium. They promise illumination of this enigmatic disease that was so clearly described in its clinical manifestations just 150 years ago by the person in whose honor this symposium is held.
