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Ocular Manifestations in Hereditary Hemorrhagic Telangiectasia (Rendu-Osler-Weber Disease)
Ocular Manifestations in Hereditary Hemorrhagic Telangiectasia (Rendu-Osler-Weber Disease) Arthur M. Brant, Ph.D., Andrew P. Schachat, M.D., and Robert I. White, M.D.
Although hereditary hemorrhagic telangiectasia is a cause of bloody tears from the conjunctival telangiectasias, visual loss from intraocular vascular malformations is a rare complication. We examined 20 patients with hereditary hemorrhagic telangiectasia to determine the prevalence of ocular abnormalities in this disease. Seven patients (35%) had conjunctival telangiectasias and two (10%) had retinal vascular malformations. HEREOIT ARY HEMORRHAGIC TELANGIECTASIA is an autosomal dominant disease that is characterized by telangiectasias throughout various vascular beds in the body. Although Sutton! probably first described this disease in the 19th century, it was not until the late 1800s and early 1900s that Rendu.! Osler," and Weber 4 described many families with this condition. Since that time it has been referred to as RenduOsler-Weber disease. Subsequently, Hanes" described eight patients with this disease and suggested the descriptive name hereditary hemorrhagic telangiectasia based on the diagnostic triad of family history, hemorrhages, and multiple telangiectases. Although other names have been proposed' (for example, heredofamilial angiomatosis, familial hemorrhagic angiomatosis, and Osler's disease), hereditary hemorrhagic telangiectasia seems to be the most appropriate. It is also the most widely used. Ocular abnormalities have been reported in
Accepted for publication March 3, 1989. From the Ocular Oncology Service, Wilmer Ophthalmological Institute, Johns Hopkins Hospital, Baltimore, Maryland (Drs. Brant and Schachat) and the Department of Diagnostic and Radiological Imaging, Yale-New Haven Hospital, New Haven, Connecticut (Dr. White). Reprint requests to Andrew P. Schachat, M.D., 200 Wilmer Institute, Johns Hopkins Hospital, Baltimore, MD 21205.
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patients with hereditary hemorrhagic telangiectasia. However, many of these reports are not in the ophthalmic literature, and, therefore, only casually mention the ocular involvement as an incidental finding. For the most part, the ocular abnormalities consist solely of conjunctival telangiectasias, with only a few reported cases of intraocular involvement. Several studies have been undertaken to determine the frequency of ocular lesions in patients with hereditary hemorrhagic telangiectasia outside the United States. There are reports by Landau, Nelken, and Davis? in the British, Calmettes, Deodati, and Bee" in the French, and Vase and Vase" in the Scandinavian literature. We examined a group of patients with documented hereditary hemorrhagic telangiectasia in the United States.
Material and Methods We identified 80 patients with hereditary hemorrhagic telangiectasia through patient files of the Interventional Radiology Division of the Department of Radiology at Johns Hopkins Hospital. The patients were contacted by mail and offered a comprehensive ocular examination. Twenty patients from 15 families were examined. Most of the patients do not live in our area and chose not to travel back to Baltimore for the examination. The diagnosis of hereditary hemorrhagic telangiectasia was based on family history, epistaxis, and cutaneous telangiectasias. Additionally, since these patients were identified through a radiology database, many had pulmonary arteriovenous malformations. The examinations were performed by an ophthalmologist (A.P.S.) and consisted of an ophthalmic history, determination of the visual acuity with and without pinhole, external and slit-lamp examinations, intraocular pressure determination, direct and indirect ophthalmos-
©AMERICAN JOURNAL OF OPHTHALMOLOGY
107:642--646, JUNE, 1989
Hereditary Hemorrhagic Telangiectasia
Vol. 107, No.6
copy through a dilated pupil, and slit-lamp fundus biomicroscopy. Color fundus photography was performed routinely but fluorescein angiography was obtained only when an abnormality was detected.
Results
Twenty patients were examined; seven were male and 13 were female. The mean age was 39 years (range, 11 to 68 years). The most frequent systemic symptoms that patients reported related to hereditary hemorrhagic telangiectasia were epistaxis, dyspnea on exertion, and gastrointestinal bleeding. Symptoms related to the eyes were rare, and ranged from bloody tears to acute external hemorrhage. Three patients (15%) reported a history of bloody tears and one patient (5%) gave a history of frank hemorrhage from the eye. In this patient, a telangiectasia located on the conjunctival surface of the upper eyelid had previously undergone spontaneous hemorrhage on several occasions, necessitating thermal cautery of the lesion. Visual acuity was 20/25 or better in all patients. Conjunctival telangiectasias were noted in seven of the 20 patients (35%) (Fig. 1). These lesions were located on both the superior and inferior palpebral conjunctiva but none were observed on the bulbar conjunctiva. Examination of the fundi showed retinal vascular abnormalities in two patients (10%). One patient had a network of telangiectatic vessels in the right eye located adjacent to the optic disk that extended for approximately 2 disk
Fig. 1 (Brant, Schachat, and White). Spider-like angiomatous malformation on superior palpebral conjunctiva.
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diameters inferiorly along the temporal arcade (Fig. 2, left). The fluorescein angiogram demonstrated patent vessels without early or late leakage. The left eye also contained numerous telangiectatic vessels distributed throughout the papillomacular bundle (Fig. 2, right). This particular patient has been followed up for over one year; repeat fluorescein angiography has shown no change from the original examination. The other patient with intraocular involvement had multiple foci of fine telangiectasias throughout the retina. In another patient, marked tortuosity of the retinal vasculature was noted. However, this change can be a normal variant and is not necessarily related to hereditary hemorrhagic telangiectasia.
Discussion
Hereditary hemorrhagic telangiectasia is a rare, autosomal dominant disease characterized by vascular abnormalities in a multitude of organ systems. These vascular anomalies are composed of multiple dilatations of capillaries and venules that frequently have thinned vessel walls, which makes them friable and more prone to hemorrhage. The most common systemic symptoms are epistaxis, dyspnea on exertion, and gastrointestinal bleeding related either to hemorrhage from, or shunting through, abnormal vessels in the nasal mucosa, lung, and gastrointestinal tract. Hemorrhages from other sites also occur (for example, hemoptysis, hematuria), but are usually less common and present later in life. Frequently, patients with hereditary hemorrhagic telangiectasia are not aware of having the disease unless it has been previously diagnosed in their family. Presumably this is because the parents and siblings were only minimally symptomatic. 10 The most serious consequence of hereditary hemorrhagic telangiectasia is the potential for paradoxical embolization and stroke. This occurs when venous thrombi, originating in deep veins in the leg or pelvis, pass through arteriovenous malformations in the lung and lodge in the brain. Embolotherapy of pulmonary arteriovenous malformations to minimize the risk of stroke has been developed and refined by White and associates." A wide range of ocular vascular lesions have been reported in patients with hereditary hem-
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Fig. 2 (Brant, Schachat, and White). Left, Red-free photograph of retinal telangiectasia on inferior temporal arcade in the right eye. Right, There are mild telangiectatic vessels in the macular area of the left eye.
orrhagic telangiectasia. Miles" cited the earliest cases of conjunctival telangiectasias reported by Weber 4 in 1907, followed by Hanes," Schwartz," Schoen;" Stock," Reed," and New and Anderson." However, these reports were not published in the ophthalmic literature and often consisted only of incidental mentions of conjunctival lesions, with no information as to whether they were complicated by hemorrhage. It is doubtful that all patients were examined by an ophthalmologist. Reports by Miles," Cuendet and Magnenat," and Landau, Nelken, and Davis? have been published in the ophthalmic literature, and in their patients, spontaneous hemorrhages were not reported. According to Garner and Crossman," conjunctival telangiectasias with a history of associated hemorrhaging were first reported by Cjessing" in 1916 and subsequently by others. 21-25 Although Cjessing" described hemorrhagic retinopathy in a patient with hereditary hemorrhagic telangiectasia, no mention was made of retinal vascular disease and alternative diagnoses are possible. According to Davis and Smith, Francois first described intraocular involvement in hereditary hemorrhagic telangiectasia in 1938. 21,26 A 74-year-old hypertensive woman who had retinal vascular changes in the right eye that were consistent with hypertensive retinopathy was described. Further investigation was advised. Subsequent reports included that of Cuendet and Magnenat" who in a 1953 review reported that only the case of
Prancois," out of all reported cases of retinal manifestations in hereditary hemorrhagic telangiectasia, demonstrated a documented retinal vascular malformation. Landau, Nelken, and Davis? examined 29 members within four generations of a family with hereditary hemorrhagic telangiectasia and found ectatic formations resembling varices in the retinal veins of two sisters. Their drawings of tortuous vessels could represent a change related to the diagnosis of hereditary hemorrhagic telangiectasia, but vascular tortuosity is a common finding in healthy patients and need not indicate a true association. Roubin" described a patient with new vessels on the optic disk. It is unclear whether these vessels represented arteriovenous malformations, shunt vessels, or true disk neovascularization. Calmettes, Deodati, and Bec8 examined 15 patients with hereditary hemorrhagic telangiectasia and found only one with retinal involvement. In this patient, the retinal hemorrhages regressed after correction of the anemia, at which point there was no evidence of any retinal involvement. The retinal abnormality in this patient was more likely attributable to the anemia than to hereditary hemorrhagic telangiectasia directly. Forker and Bean" described a patient with a retinal arteriovenous malformation and included fundus photographs. Massa, de Vloo, and [amotton" described a small number of patients with intraocular disease. The only photographs
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provided were those of a patient with a choroidal rupture that almost certainly was not related to the underlying diagnosis of hereditary hemorrhagic telangiectasia. Meyer-Schwickerath and von Barsewisch" described a retinal telangiectasia in a patient with hereditary hemorrhagic telangiectasia that was documented by fundus photography. In 1971 Davis and Smith" reviewed the literature and reported an additional case of retinal involvement in a patient with hereditary hemorrhagic telangiectasia. However, it is possible that their patient actually had Eales' disease, some other obliterative vasculitis, or simply multiple old branch retinal vein occlusions. Vase and Vase" examined 47 patients in Denmark with hereditary hemorrhagic telangiectasia and found one case with a retinal abnormality. This patient had a clear arteriovenous malformation in the retina that was well documented by fluorescein angiography. Although hereditary hemorrhagic telangiectasia is a relatively rare disease, ocular involvement is common in these patients. In the three studies outside the United States, involvement of the eye was seen in between 45% and 65% of patients, with the most common lesions being conjunctival telangiectasias. Review of the previously reported cases of intraocular involvement in hereditary hemorrhagic telangiectasia raises the question of whether the reports by Francois," Landau, Nelken, and Davis.' Calmetres. Deodati, and Bee," Massa, de Vloo, and [amotton." and Davis and Smith" actually reflect manifestations of hereditary hemorrhagic telangiectasia. The findings may be associated with another disease process or simply reports of nonspecific findings. The cases by Roubin," Meyer-Schwickerath and von Barsewisch," Forker and Bean." and Vase and Vase? probably do accurately depict ocular abnormalities that are a result of the disease process in hereditary hemorrhagic telangiectasia. As part of this study, we examined 20 patients with hereditary hemorrhagic telangiectasia and found ocular vascular anomalies believed to be related to the disease in nine (45%) of the patients. Seven patients (35%) had conjunctival telangiectasias and the other two (10%) had intraocular lesions. The prevalence of conjunctival telangiectasias is consistent with that previously reported. Comparison of the prevalence of retinal lesions is less meaningful since the numbers are small, and there have only been four such reports, only one of which was part of a prevalence study.
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The 45% prevalence rate of ocular abnormalities seen in our patients may not be accurate. Ascertainment bias may be present. Our referral practice may not reflect the normal nationwide distribution of patients with hereditary hemorrhagic telangiectasia. Additionally, patients with previously diagnosed ocular disease may have been more likely to respond to our offer for a free examination. Conversely, we did not perform fluorescein angiography on all patients and subtle disease may have been overlooked. Bleeding from the conjunctiva is uncommon and is limited to a few rare conditions. A listing by Duke-Elder" of conditions in which hemorrhage from the conjunctiva can be seen includes hereditary hemorrhagic telangiectasia, hemophilia, vicarious menstruation, hysteria, conjunctivitis, jaundice, vascular tumors, after ocular manipulation, granulomas, advanced atheromas, after silver nitrate therapy, regurgitant flow of blood through the nasolacrimal duct, and in normal individuals it is associated with strenuous effort. We have treated patients with lacrimal tumors and intraocular melanomas who also have had bloody tears. The differential diagnosis of the intraocular lesions seen in hereditary hemorrhagic telangiectasia is lengthy. The typical vascular lesion is a small arteriovenous malformation. Hemorrhage and lipid are absent, and the angiogram fails to demonstrate nonperfusion or leakage. When some of these other features are present, alternative diagnoses such as hypertensive retinopathy, branch retinal vein occlusion, diabetic retinopathy, Coats' disease, Eales' disease, the vascular changes seen in patients with ataxia telangiectasia, and the phakornatoses" should be considered. Patients with hereditary hemorrhagic telangiectasia should be made aware of the ocular symptoms associated with this disease. Bloody tears caused by hemorrhage from conjunctival telangiectasias are a frightening symptom. Fortunately, the bleeding is rarely severe and if recurrent, the telangiectasias may respond to cautery.":" There have been a number of reports of fundus abnormalities in patients with hereditary hemorrhagic telangiectasia. Tortuosity and dilatation of retinal vessels is common and may be seen in normal patients. Similarly, there are many causes of retinal and disk neovascularization and these findings are not likely to be causally related to hereditary hemorrhagic telangiectasia. The retinal vascular lesion illustrated in Figure 2 and described by
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both Vase and Vase" and Forker and Bean" is a rare finding in otherwise normal patients and is likely related to the systemic diagnosis. In general, the retinal lesions seen in patients with hereditary hemorrhagic telangiectasia are stable and seldom cause symptoms. Treatment is rarely required.
References 1. Sutton, H.: Epistaxis as an indication of impaired nutrition and of degeneration of the vascular system. Med. Mirror 1:769, 1864. 2. Rendu, M.: Epistaxis repetees chez un sujet Pasteur de petits angiomes cutanes et muceux. Bull. Mem. Soc. Med. Hop. 13:731, 1896. 3. Osler, W.: On a family form of recurring epistaxis associated with multiple telangiectases of the skin and mucous membranes. Bull. Johns Hopkins Hosp. 12:333, 1901. 4. Weber, F.: Multiple hereditary developmental angiomata of the skin and the mucous membranes associated with recurring haemorrhages. Lancet 2:160,1907. 5. Hanes, F.: Multiple hereditary telangiectases causing hemorrhage (hereditary hemorrhagic telangiectasia). Bull. Johns Hopkins Hosp. 20:63, 1909. 6. Goldstein, H.: Goldstein's heredofamilial angiomatosis with recurring familial hemorrhages. Arch. Intern. Med. 48:836, 1931. 7. Landau, J., Nelken, E., and Davis, E.: Hereditary hemorrhagic telangiectasia with retinal and conjunctival lesions. Lancet 2:230, 1956. 8. Calmettes, M., Deodati, F., and Bee, P.: Les hernorragies retiniermes dans la maladie de RenduOsler. Bull. Soc. Ophtalmol. Fr. 58:482, 1958. 9. Vase, I., and Vase, P.: Ocular lesions in hereditary haemorrhagic telangiectasia. Acta Ophthalmol. 57:1084,1979. 10. Hodgson, C. H., Burchell, H. B., Good, C. A., and Clagett, O. T.: Hereditary hemorrhagic telangiectasia and pulmonary arteriovenous fistula. Survey of a large family. N. Engl. J. Med. 261:625, 1959. 11. White, R. I., Lynch-Nyhan, A., Terry, P., Buescher, P. C.; Farmlett, E., Charnas, L., Shuman, K., Kim, W., Kinnison, M., and Mitchell, S.: Pulmonary arteriovenous malformations. Techniques and long-term outcome of embolotherapy. Radiology 169:663, 1988. 12. Miles, N. E.: Hereditary hemorrhagic telangiectasia. Report of a case. Am. J. Ophthalmol. 35:543, 1952. 13. Schwartz, J.: Hereditary hemorrhagic telangiectasis. Minn. Med. J. 8:551, 1925.
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14. Schoen, R.: Farniliare Teleangiektasie mit habituellem Nasenbluten (Teleangiectasia hereditaria haemorrhagica Osler). Dtsch. Arch. Klin. Med. 167:156, 1930. 15. Stock, M.: Hereditary hemorrhagic telangiectasis. Arch. Otolaryngol. 40:108, 1944. 16. Reed, H.: Hereditary haemorrhagic telangiectasia with conjunctival lesions. Proc. R. Soc. Med. 51:67, 1948. 17. New, W., and Anderson, G.: Hereditary hemorrhagic telangiectasis. Arch. Dermatol. Syphilol. 67:229, 1953. J. F., and Magnenat P.: 18. Cuendet, Symptomatologie oculaire de la maladie de RenduOsler. Schweiz. Med. Wochenschr. 83:1531, 1953. 19. Garner, L. L., and Grossman, E. E.: Hereditary hemorrhagic telangiectasis with beta irradiation of a conjunctival lesion. Am. J. Ophthalmol. 41:672, 1956. 20. Gjessing, E.: Telangiectasia hereditaria haemorrhagica (Osler). Dermatol. Z. 23:193, 1916. 21. Francois, J.: L'angiomatose hernorragique familiale et ses complications oculaires. Arch. Ophtalmol. 2:425, 1938. 22. Pitter, J.: Rare localization of Osler's disease beneath the conjunctiva. Klin. Monatsbl. Augenheildk. 107:76, 1941. 23. Von Witmer, R.: Conjunctivalveriinderungen beim Morbus Osler. Ophthalmologica 121:158, 1951. 24. Wolper, J., and Laibson, P.: Hereditary hemorrhagic telangiectasis (Rendu-Osler-Weber disease) with filamentary keratitis. Arch. Ophthalmol. 81:272,1969. 25. Pandolfi, M., and Ehinger, B.: Conjunctival bleeding in Osler's disease with associated platelet dysfunction. A case report. Acta Ophthalmol. 56:75, 1978. 26. Davis, D., and Smith, L.: Retinal involvement in hereditary hemorrhagic telangiectasia. Arch. Ophthalmol. 85:618, 1971. 27. Roubin, I.: Telangiectasia of the disc in Osler's disease. Vestn. Oftalmol. 3:29, 1957. 28. Forker, E., and Bean, W.: Retinal arteriovenous aneurysm in hereditary hemorrhagic telangiectasia. Arch. Intern. Med. 111:778, 1963. 29. Massa, J., de Vloo, N., and jarnotton, L.: Les manifestations oculaires des hemopathies. Bull. Soc. Beige Ophtalmol. 142:317, 1966. 30. Meyer-Schwickerath, G., and von Barsewisch, B.: Gefiissveriinderungen an haut und retina. Ber. Dtsch. Ophthalmol. Ges. 68:525, 1968. 31. Duke-Elder, S.: Diseases of the Outer Eye. Conjunctiva. In System of Ophthalmology, vol. 8, pt. 1. St. Louis, C. V. Mosby, 1965, pp. 37-39. 32. Shields, J.: The systemic hamartomatoses (phakomatoses). In Shields, J. A. (ed.): Diagnosis and Management of Intraocular Tumors. St. Louis, C. V. Mosby, 1983, pp. 649-684.
Although hereditary hemorrhagic telangiectasia is a cause of bloody tears from the conjunctival telangiectasias, visual loss from intraocular vascular malformations is a rare complication. We examined 20 patients with hereditary hemorrhagic telangiectasia to determine the prevalence of ocular abnormalities in this disease. Seven patients (35%) had conjunctival telangiectasias and two (10%) had retinal vascular malformations. HEREOIT ARY HEMORRHAGIC TELANGIECTASIA is an autosomal dominant disease that is characterized by telangiectasias throughout various vascular beds in the body. Although Sutton! probably first described this disease in the 19th century, it was not until the late 1800s and early 1900s that Rendu.! Osler," and Weber 4 described many families with this condition. Since that time it has been referred to as RenduOsler-Weber disease. Subsequently, Hanes" described eight patients with this disease and suggested the descriptive name hereditary hemorrhagic telangiectasia based on the diagnostic triad of family history, hemorrhages, and multiple telangiectases. Although other names have been proposed' (for example, heredofamilial angiomatosis, familial hemorrhagic angiomatosis, and Osler's disease), hereditary hemorrhagic telangiectasia seems to be the most appropriate. It is also the most widely used. Ocular abnormalities have been reported in
Accepted for publication March 3, 1989. From the Ocular Oncology Service, Wilmer Ophthalmological Institute, Johns Hopkins Hospital, Baltimore, Maryland (Drs. Brant and Schachat) and the Department of Diagnostic and Radiological Imaging, Yale-New Haven Hospital, New Haven, Connecticut (Dr. White). Reprint requests to Andrew P. Schachat, M.D., 200 Wilmer Institute, Johns Hopkins Hospital, Baltimore, MD 21205.
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patients with hereditary hemorrhagic telangiectasia. However, many of these reports are not in the ophthalmic literature, and, therefore, only casually mention the ocular involvement as an incidental finding. For the most part, the ocular abnormalities consist solely of conjunctival telangiectasias, with only a few reported cases of intraocular involvement. Several studies have been undertaken to determine the frequency of ocular lesions in patients with hereditary hemorrhagic telangiectasia outside the United States. There are reports by Landau, Nelken, and Davis? in the British, Calmettes, Deodati, and Bee" in the French, and Vase and Vase" in the Scandinavian literature. We examined a group of patients with documented hereditary hemorrhagic telangiectasia in the United States.
Material and Methods We identified 80 patients with hereditary hemorrhagic telangiectasia through patient files of the Interventional Radiology Division of the Department of Radiology at Johns Hopkins Hospital. The patients were contacted by mail and offered a comprehensive ocular examination. Twenty patients from 15 families were examined. Most of the patients do not live in our area and chose not to travel back to Baltimore for the examination. The diagnosis of hereditary hemorrhagic telangiectasia was based on family history, epistaxis, and cutaneous telangiectasias. Additionally, since these patients were identified through a radiology database, many had pulmonary arteriovenous malformations. The examinations were performed by an ophthalmologist (A.P.S.) and consisted of an ophthalmic history, determination of the visual acuity with and without pinhole, external and slit-lamp examinations, intraocular pressure determination, direct and indirect ophthalmos-
©AMERICAN JOURNAL OF OPHTHALMOLOGY
107:642--646, JUNE, 1989
Hereditary Hemorrhagic Telangiectasia
Vol. 107, No.6
copy through a dilated pupil, and slit-lamp fundus biomicroscopy. Color fundus photography was performed routinely but fluorescein angiography was obtained only when an abnormality was detected.
Results
Twenty patients were examined; seven were male and 13 were female. The mean age was 39 years (range, 11 to 68 years). The most frequent systemic symptoms that patients reported related to hereditary hemorrhagic telangiectasia were epistaxis, dyspnea on exertion, and gastrointestinal bleeding. Symptoms related to the eyes were rare, and ranged from bloody tears to acute external hemorrhage. Three patients (15%) reported a history of bloody tears and one patient (5%) gave a history of frank hemorrhage from the eye. In this patient, a telangiectasia located on the conjunctival surface of the upper eyelid had previously undergone spontaneous hemorrhage on several occasions, necessitating thermal cautery of the lesion. Visual acuity was 20/25 or better in all patients. Conjunctival telangiectasias were noted in seven of the 20 patients (35%) (Fig. 1). These lesions were located on both the superior and inferior palpebral conjunctiva but none were observed on the bulbar conjunctiva. Examination of the fundi showed retinal vascular abnormalities in two patients (10%). One patient had a network of telangiectatic vessels in the right eye located adjacent to the optic disk that extended for approximately 2 disk
Fig. 1 (Brant, Schachat, and White). Spider-like angiomatous malformation on superior palpebral conjunctiva.
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diameters inferiorly along the temporal arcade (Fig. 2, left). The fluorescein angiogram demonstrated patent vessels without early or late leakage. The left eye also contained numerous telangiectatic vessels distributed throughout the papillomacular bundle (Fig. 2, right). This particular patient has been followed up for over one year; repeat fluorescein angiography has shown no change from the original examination. The other patient with intraocular involvement had multiple foci of fine telangiectasias throughout the retina. In another patient, marked tortuosity of the retinal vasculature was noted. However, this change can be a normal variant and is not necessarily related to hereditary hemorrhagic telangiectasia.
Discussion
Hereditary hemorrhagic telangiectasia is a rare, autosomal dominant disease characterized by vascular abnormalities in a multitude of organ systems. These vascular anomalies are composed of multiple dilatations of capillaries and venules that frequently have thinned vessel walls, which makes them friable and more prone to hemorrhage. The most common systemic symptoms are epistaxis, dyspnea on exertion, and gastrointestinal bleeding related either to hemorrhage from, or shunting through, abnormal vessels in the nasal mucosa, lung, and gastrointestinal tract. Hemorrhages from other sites also occur (for example, hemoptysis, hematuria), but are usually less common and present later in life. Frequently, patients with hereditary hemorrhagic telangiectasia are not aware of having the disease unless it has been previously diagnosed in their family. Presumably this is because the parents and siblings were only minimally symptomatic. 10 The most serious consequence of hereditary hemorrhagic telangiectasia is the potential for paradoxical embolization and stroke. This occurs when venous thrombi, originating in deep veins in the leg or pelvis, pass through arteriovenous malformations in the lung and lodge in the brain. Embolotherapy of pulmonary arteriovenous malformations to minimize the risk of stroke has been developed and refined by White and associates." A wide range of ocular vascular lesions have been reported in patients with hereditary hem-
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Fig. 2 (Brant, Schachat, and White). Left, Red-free photograph of retinal telangiectasia on inferior temporal arcade in the right eye. Right, There are mild telangiectatic vessels in the macular area of the left eye.
orrhagic telangiectasia. Miles" cited the earliest cases of conjunctival telangiectasias reported by Weber 4 in 1907, followed by Hanes," Schwartz," Schoen;" Stock," Reed," and New and Anderson." However, these reports were not published in the ophthalmic literature and often consisted only of incidental mentions of conjunctival lesions, with no information as to whether they were complicated by hemorrhage. It is doubtful that all patients were examined by an ophthalmologist. Reports by Miles," Cuendet and Magnenat," and Landau, Nelken, and Davis? have been published in the ophthalmic literature, and in their patients, spontaneous hemorrhages were not reported. According to Garner and Crossman," conjunctival telangiectasias with a history of associated hemorrhaging were first reported by Cjessing" in 1916 and subsequently by others. 21-25 Although Cjessing" described hemorrhagic retinopathy in a patient with hereditary hemorrhagic telangiectasia, no mention was made of retinal vascular disease and alternative diagnoses are possible. According to Davis and Smith, Francois first described intraocular involvement in hereditary hemorrhagic telangiectasia in 1938. 21,26 A 74-year-old hypertensive woman who had retinal vascular changes in the right eye that were consistent with hypertensive retinopathy was described. Further investigation was advised. Subsequent reports included that of Cuendet and Magnenat" who in a 1953 review reported that only the case of
Prancois," out of all reported cases of retinal manifestations in hereditary hemorrhagic telangiectasia, demonstrated a documented retinal vascular malformation. Landau, Nelken, and Davis? examined 29 members within four generations of a family with hereditary hemorrhagic telangiectasia and found ectatic formations resembling varices in the retinal veins of two sisters. Their drawings of tortuous vessels could represent a change related to the diagnosis of hereditary hemorrhagic telangiectasia, but vascular tortuosity is a common finding in healthy patients and need not indicate a true association. Roubin" described a patient with new vessels on the optic disk. It is unclear whether these vessels represented arteriovenous malformations, shunt vessels, or true disk neovascularization. Calmettes, Deodati, and Bec8 examined 15 patients with hereditary hemorrhagic telangiectasia and found only one with retinal involvement. In this patient, the retinal hemorrhages regressed after correction of the anemia, at which point there was no evidence of any retinal involvement. The retinal abnormality in this patient was more likely attributable to the anemia than to hereditary hemorrhagic telangiectasia directly. Forker and Bean" described a patient with a retinal arteriovenous malformation and included fundus photographs. Massa, de Vloo, and [amotton" described a small number of patients with intraocular disease. The only photographs
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Hereditary Hemorrhagic Telangiectasia
provided were those of a patient with a choroidal rupture that almost certainly was not related to the underlying diagnosis of hereditary hemorrhagic telangiectasia. Meyer-Schwickerath and von Barsewisch" described a retinal telangiectasia in a patient with hereditary hemorrhagic telangiectasia that was documented by fundus photography. In 1971 Davis and Smith" reviewed the literature and reported an additional case of retinal involvement in a patient with hereditary hemorrhagic telangiectasia. However, it is possible that their patient actually had Eales' disease, some other obliterative vasculitis, or simply multiple old branch retinal vein occlusions. Vase and Vase" examined 47 patients in Denmark with hereditary hemorrhagic telangiectasia and found one case with a retinal abnormality. This patient had a clear arteriovenous malformation in the retina that was well documented by fluorescein angiography. Although hereditary hemorrhagic telangiectasia is a relatively rare disease, ocular involvement is common in these patients. In the three studies outside the United States, involvement of the eye was seen in between 45% and 65% of patients, with the most common lesions being conjunctival telangiectasias. Review of the previously reported cases of intraocular involvement in hereditary hemorrhagic telangiectasia raises the question of whether the reports by Francois," Landau, Nelken, and Davis.' Calmetres. Deodati, and Bee," Massa, de Vloo, and [amotton." and Davis and Smith" actually reflect manifestations of hereditary hemorrhagic telangiectasia. The findings may be associated with another disease process or simply reports of nonspecific findings. The cases by Roubin," Meyer-Schwickerath and von Barsewisch," Forker and Bean." and Vase and Vase? probably do accurately depict ocular abnormalities that are a result of the disease process in hereditary hemorrhagic telangiectasia. As part of this study, we examined 20 patients with hereditary hemorrhagic telangiectasia and found ocular vascular anomalies believed to be related to the disease in nine (45%) of the patients. Seven patients (35%) had conjunctival telangiectasias and the other two (10%) had intraocular lesions. The prevalence of conjunctival telangiectasias is consistent with that previously reported. Comparison of the prevalence of retinal lesions is less meaningful since the numbers are small, and there have only been four such reports, only one of which was part of a prevalence study.
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The 45% prevalence rate of ocular abnormalities seen in our patients may not be accurate. Ascertainment bias may be present. Our referral practice may not reflect the normal nationwide distribution of patients with hereditary hemorrhagic telangiectasia. Additionally, patients with previously diagnosed ocular disease may have been more likely to respond to our offer for a free examination. Conversely, we did not perform fluorescein angiography on all patients and subtle disease may have been overlooked. Bleeding from the conjunctiva is uncommon and is limited to a few rare conditions. A listing by Duke-Elder" of conditions in which hemorrhage from the conjunctiva can be seen includes hereditary hemorrhagic telangiectasia, hemophilia, vicarious menstruation, hysteria, conjunctivitis, jaundice, vascular tumors, after ocular manipulation, granulomas, advanced atheromas, after silver nitrate therapy, regurgitant flow of blood through the nasolacrimal duct, and in normal individuals it is associated with strenuous effort. We have treated patients with lacrimal tumors and intraocular melanomas who also have had bloody tears. The differential diagnosis of the intraocular lesions seen in hereditary hemorrhagic telangiectasia is lengthy. The typical vascular lesion is a small arteriovenous malformation. Hemorrhage and lipid are absent, and the angiogram fails to demonstrate nonperfusion or leakage. When some of these other features are present, alternative diagnoses such as hypertensive retinopathy, branch retinal vein occlusion, diabetic retinopathy, Coats' disease, Eales' disease, the vascular changes seen in patients with ataxia telangiectasia, and the phakornatoses" should be considered. Patients with hereditary hemorrhagic telangiectasia should be made aware of the ocular symptoms associated with this disease. Bloody tears caused by hemorrhage from conjunctival telangiectasias are a frightening symptom. Fortunately, the bleeding is rarely severe and if recurrent, the telangiectasias may respond to cautery.":" There have been a number of reports of fundus abnormalities in patients with hereditary hemorrhagic telangiectasia. Tortuosity and dilatation of retinal vessels is common and may be seen in normal patients. Similarly, there are many causes of retinal and disk neovascularization and these findings are not likely to be causally related to hereditary hemorrhagic telangiectasia. The retinal vascular lesion illustrated in Figure 2 and described by
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both Vase and Vase" and Forker and Bean" is a rare finding in otherwise normal patients and is likely related to the systemic diagnosis. In general, the retinal lesions seen in patients with hereditary hemorrhagic telangiectasia are stable and seldom cause symptoms. Treatment is rarely required.
References 1. Sutton, H.: Epistaxis as an indication of impaired nutrition and of degeneration of the vascular system. Med. Mirror 1:769, 1864. 2. Rendu, M.: Epistaxis repetees chez un sujet Pasteur de petits angiomes cutanes et muceux. Bull. Mem. Soc. Med. Hop. 13:731, 1896. 3. Osler, W.: On a family form of recurring epistaxis associated with multiple telangiectases of the skin and mucous membranes. Bull. Johns Hopkins Hosp. 12:333, 1901. 4. Weber, F.: Multiple hereditary developmental angiomata of the skin and the mucous membranes associated with recurring haemorrhages. Lancet 2:160,1907. 5. Hanes, F.: Multiple hereditary telangiectases causing hemorrhage (hereditary hemorrhagic telangiectasia). Bull. Johns Hopkins Hosp. 20:63, 1909. 6. Goldstein, H.: Goldstein's heredofamilial angiomatosis with recurring familial hemorrhages. Arch. Intern. Med. 48:836, 1931. 7. Landau, J., Nelken, E., and Davis, E.: Hereditary hemorrhagic telangiectasia with retinal and conjunctival lesions. Lancet 2:230, 1956. 8. Calmettes, M., Deodati, F., and Bee, P.: Les hernorragies retiniermes dans la maladie de RenduOsler. Bull. Soc. Ophtalmol. Fr. 58:482, 1958. 9. Vase, I., and Vase, P.: Ocular lesions in hereditary haemorrhagic telangiectasia. Acta Ophthalmol. 57:1084,1979. 10. Hodgson, C. H., Burchell, H. B., Good, C. A., and Clagett, O. T.: Hereditary hemorrhagic telangiectasia and pulmonary arteriovenous fistula. Survey of a large family. N. Engl. J. Med. 261:625, 1959. 11. White, R. I., Lynch-Nyhan, A., Terry, P., Buescher, P. C.; Farmlett, E., Charnas, L., Shuman, K., Kim, W., Kinnison, M., and Mitchell, S.: Pulmonary arteriovenous malformations. Techniques and long-term outcome of embolotherapy. Radiology 169:663, 1988. 12. Miles, N. E.: Hereditary hemorrhagic telangiectasia. Report of a case. Am. J. Ophthalmol. 35:543, 1952. 13. Schwartz, J.: Hereditary hemorrhagic telangiectasis. Minn. Med. J. 8:551, 1925.
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14. Schoen, R.: Farniliare Teleangiektasie mit habituellem Nasenbluten (Teleangiectasia hereditaria haemorrhagica Osler). Dtsch. Arch. Klin. Med. 167:156, 1930. 15. Stock, M.: Hereditary hemorrhagic telangiectasis. Arch. Otolaryngol. 40:108, 1944. 16. Reed, H.: Hereditary haemorrhagic telangiectasia with conjunctival lesions. Proc. R. Soc. Med. 51:67, 1948. 17. New, W., and Anderson, G.: Hereditary hemorrhagic telangiectasis. Arch. Dermatol. Syphilol. 67:229, 1953. J. F., and Magnenat P.: 18. Cuendet, Symptomatologie oculaire de la maladie de RenduOsler. Schweiz. Med. Wochenschr. 83:1531, 1953. 19. Garner, L. L., and Grossman, E. E.: Hereditary hemorrhagic telangiectasis with beta irradiation of a conjunctival lesion. Am. J. Ophthalmol. 41:672, 1956. 20. Gjessing, E.: Telangiectasia hereditaria haemorrhagica (Osler). Dermatol. Z. 23:193, 1916. 21. Francois, J.: L'angiomatose hernorragique familiale et ses complications oculaires. Arch. Ophtalmol. 2:425, 1938. 22. Pitter, J.: Rare localization of Osler's disease beneath the conjunctiva. Klin. Monatsbl. Augenheildk. 107:76, 1941. 23. Von Witmer, R.: Conjunctivalveriinderungen beim Morbus Osler. Ophthalmologica 121:158, 1951. 24. Wolper, J., and Laibson, P.: Hereditary hemorrhagic telangiectasis (Rendu-Osler-Weber disease) with filamentary keratitis. Arch. Ophthalmol. 81:272,1969. 25. Pandolfi, M., and Ehinger, B.: Conjunctival bleeding in Osler's disease with associated platelet dysfunction. A case report. Acta Ophthalmol. 56:75, 1978. 26. Davis, D., and Smith, L.: Retinal involvement in hereditary hemorrhagic telangiectasia. Arch. Ophthalmol. 85:618, 1971. 27. Roubin, I.: Telangiectasia of the disc in Osler's disease. Vestn. Oftalmol. 3:29, 1957. 28. Forker, E., and Bean, W.: Retinal arteriovenous aneurysm in hereditary hemorrhagic telangiectasia. Arch. Intern. Med. 111:778, 1963. 29. Massa, J., de Vloo, N., and jarnotton, L.: Les manifestations oculaires des hemopathies. Bull. Soc. Beige Ophtalmol. 142:317, 1966. 30. Meyer-Schwickerath, G., and von Barsewisch, B.: Gefiissveriinderungen an haut und retina. Ber. Dtsch. Ophthalmol. Ges. 68:525, 1968. 31. Duke-Elder, S.: Diseases of the Outer Eye. Conjunctiva. In System of Ophthalmology, vol. 8, pt. 1. St. Louis, C. V. Mosby, 1965, pp. 37-39. 32. Shields, J.: The systemic hamartomatoses (phakomatoses). In Shields, J. A. (ed.): Diagnosis and Management of Intraocular Tumors. St. Louis, C. V. Mosby, 1983, pp. 649-684.