Cavernous Hemangioma of the Retina A Four-Generation Pedigree With Neurocutaneous Manifestations and an Example of Bilateral Retinal Involvement Richard E. Goldberg, MD; Thomas R. Pheasant, MD; Jerry A. Shields, MD \s=b\ Cavernous hemangioma of the retina is an unusual vascular hamartoma whose coexistence with vascular anomalies of the skin and central nervous system has been recognized recently. A 39-year-old woman, who had an acute palsy of the right third cranial nerve, had a history of seizures, cutaneous vascular anomalies, and a cavernous hemangioma of the retina of the right eye. One of her daughters demonstrated bilateral retinal cavernous hemangiomas, and another daughter, who developed seizures when febrile, displayed cutaneous vascular anomalies. A four-generation pedigree showed a number of cutaneous vascular anomalies, seizures, and stroke-related deaths. The pedigree suggests further support for considering this disorder an authentic oculoneurocutaneous triad. (Arch Ophthalmol 97:2321-2324, 1979) hemangioma of the reti¬ Cavernous lesion that has is rather na a rare been associated recently with vascular anomalies in the skin and central nervous system.14 This retinal hamar¬ toma may vary in appearance from a rather uncomplicated collection of elaborate, sessile, grape-like, thin-walled, often clus¬ aneurysms to an tered complex of red globules, at times projecting into the vitreous cavity with a three-dimensional quality. Gray-white material, the exact nature of which remains ill-defined, may Accepted for publication March 15, 1979. From the Vascular Unit (Drs Goldberg and Pheasant) and the Oncology Unit (Dr Shields), Retina Service, Wills Eye Hospital, Philadelphia, and the Retina Service, Department of Surgery, Holy Redeemer Hospital, Meadowbrook, Pa (Dr Goldberg). Dr Pheasant is now with M. S. Hershey Medical Center Division of Ophthalmology, Hershey, Pa. Read in part before the Macula Society, Key Biscayne, Fla, Jan 21, 1978; ophthalmology section, American Medical Association annual meeting, St Louis, June 15, 1978; and the Retina Society, Houston, Nov 11, 1978. Reprint requests to Vascular Unit, Retina Service, Wills Eye Hospital, 1601 Spring Garden St, Philadelphia, PA 19130 (Dr Goldberg). participate in the structure of this lesion. Smaller aneurysms may be grouped near the major malforma¬ tion, and both the course and caliber of the afferent and efferent vessels appear unaltered. In contrast to retinal capillary hemangiomas and retinal telangiectasias, this lesion is not associated with appreciable exudation, and marked leakage of fluorescein is not considered to be a characteristic angiographie property. Spontaneous hemorrhage can occur, particularly from the larger lesions. These hamartomas are frequently multiple and capable of simultaneous involvement of multiple organ sys¬ tems. This article describes a fourgeneration pedigree in which the multisystem nature of cavernous he¬ mangioma is implied, and an unusual occurrence of bilateral retinal lesions is demonstrated. To the best of our knowledge, this is only the fourth bilateral case reported in the ophthal¬ mic literature. REPORT OF CASES The proband was a 39-year-old woman with a lifelong history of seizures (current¬ ly controlled by phenytoin and phénobarbi¬ tal), who, in July 1976, fell and struck her head with no concomitant loss of conscious¬ ness. One month later she awoke with diplopia and came to us with a total right third nerve paralysis. There was also a questionable paresis of the right fourth nerve. She reported no history of intra¬ craneal noises, the conjunctival vessels were not engorged, no bruit was detected over the right orbit, and the corneal sensi¬ tivity in the right eye was considered within normal limits. The visual acuity was 20/20 + 2 in the right eye and 20/15 in the left eye. The contributory fundus findings were limited to the superonasal quadrant of the right eye, where a linear, radially oriented formation of rather fine saccular altera¬ tions in the retinal angioarchitecture was noted (Fig 1). A representative selection from the angiographie sequence (Fig 2) Downloaded From: http://archopht.jamanetwork.com/ by a New York University User on 06/01/2015 demonstrated fluorescein-plasma/erythrocyte layering within these aneurysms, reflecting the stagnant blood flow. Physical examination revealed cuta¬ neous vascular anomalies of the capillary variety at the midline in the lumbar region that, by history, were unchanged since birth (Fig 3). Appropriate neurosurgical consultation, well as skull x-ray films, a brain scan, and computerized axial tomography (CT scan) were obtained. The CT scan showed a small, deep-seated left posterior temporal lobe calcification with no signs of a mass lesion around it. The EEC showed a possi¬ ble left frontal focus of seizure activity. as Arteriograms disclosed a slight straighten¬ ing and elevation of the left posterior cerebral artery, but even with bonesubtraction studies, a vascular tumor could not be detected. A pneumoencephalogram was normal. Ultrasonography of both globes and orbits was normal. There was a familial history of diabetes (proband's father) and a five-hour glucose tolerance test was obtained. Results at fasting were 88 mg/dL; 115 mg/dL at 30 minutes; 120 mg/dL at one hour; 89 mg/dL at two hours; 61 mg/dL at three hours; 70 mg/dL at four hours and at five hours; urine results, negative at fasting, 30 minutes, and five hours; + 4 at one and two hours; +2 at three hours; and "trace" at four hours. Visual fields (tangent screen) in Novem¬ ber 1976 were normal, and by December the diplopia had cleared. In September 1977, this patient had a migraine headache, and she was examined by her neurosurgeon for frequent head¬ aches and transient episodes of diplopia. In November 1977, the patient experienced another episode of ptosis (right eye) and diplopia, but she was unavailable for our subsequent examination. In March 1978, the neurosurgeon record¬ ed that the proband's right pupil was dilated and fixed, but that the diplopia had responded to methylprednisolone (Medrol), 4 mg four times a day. This patient's 10-year-old daughter had a visual acuity of 20/20— bilaterally. Oph¬ thalmoscopy showed a cavernous heman¬ gioma of the retina involving the inferonasal quadrant of the right eye (Fig 4, top) and a somewhat smaller lesion in the su- Fig 1.—Cavernous hemangioma of retina in right eye of proband. Note radially oriented configuration of aneurysms in superior nasal quadrant. Fig 2—Representative selection from an¬ giographie sequence of hamartoma in proband's right eye demonstrates fluoresceln-plasma/erythrocyte layering within saccules. Fig 3.—Cutaneous vascular anomaly of capillary variety in midline of lumbar region of proband. Fig 4.—Top, Ten-year-old girl with sessile cavernous hemangioma of retina in inferi¬ quadrant of right eye. Bottom, Left eye of same child demonstrates cavernous hemangioma of retina in superior temporal or nasal quadrant. hands, defective gross motor coordination, impaired speech, and, by history, febrile grand mal seizures. Findings on her karyotype and amino acid studies were within Fig 5.—Left, Angiographie field in 10-year-old child's right eye demonstrates plasmaerythrocyte layering within aneurysms and some diffusion of dye into overlying vitreous. Right, Fluorescein sequence of left eye demonstrates plasma-erythrocyte separation. perotemporal quadrant of the left eye (Fig 4, bottom). Fluoroangiography of the right eye revealed plasma-erythrocytic layering within the ovoid aneurysms and, late in the sequence, some diffusion of dye into the overlying vitreous (Fig 5, left). Perfusion of the hamartoma was incomplete. In the left eye the angiogram also demonstrated plasma-erythrocyte separation within the vascular lesion (Fig 5, right). The proband had another daughter who underwent a neurologic evaluation when she was 3 years of age. At that time she displayed multiple congenital abnormali¬ ties, including poor configuration of the Downloaded From: http://archopht.jamanetwork.com/ by a New York University User on 06/01/2015 normal limits. Skull x-ray films were normal, with the exception of possible hypertelorism. Roentgenograms of the hands revealed mild incurvation of the little fingers. The distal phalanges of both fingers and thumbs were hypoplastic with multiple ossification centers that caused several of them to be somewhat elongated. The EEG was reported as normal. When seen at age 7 years, this daughter's visual acuity was 20/20 in both eyes. The fundi were normal, but she demonstrated cuta¬ neous hemangiomas of the lower part of the back similar to those of her mother. F4 F3 F2 FI HHBQ Ortgéjigsô 6 OCXI ¿ E Sèi Òjtóoi sui X EXAMINED o NORMAL ® RETINAL CAVERNOUS HEMANGIOMA SEIZURES CUTANEOUS VASCULAR LESIONS SEIZURES, CUTANEOUS LESIONS © RETINAL CAVERNOUS HEMANGIOMA, SEIZURES RETINAL CAVERNOUS HEMANGIOMA, CUTANEOUS LESIONS O RETINAL CAVERNOUS HEMANGIOMA, SEIZURES, CUTANEOUS LESIONS Fig 6—Pedigree spanning four generations and consisting of 90 persons. Arrow indicates proband. Numbers indicate number of persons a given symbol represents. Circles are females, and squares are males. cavernous hemangioma of the retina A pedigree spanning four generations COMMENT was constructed, and this consisted of 90 (and/or optic nerve), cutaneous angio¬ The multisystem expression of this persons. We examined the proband, her ma, and cavernoma of the cerebrum three children, and 11 other persons listed disorder has been difficult to evaluate. and brainstem in the category of phain the pedigree. They received ocular Cutaneous vascular hamartomas occur komatoses. examinations as well as examination for in the normal population, In 1971, Gass presented evidence commonly cutaneous vascular lesions. They were also and their presence in patients with that cavernous hemangioma of the questioned for a history of either grand cavernous hemangioma of the retina retina and optic nerve head is a specif¬ mal or petit mal seizures (Fig 6). We did ic vascular hamartoma to be differen¬ may prove to be a chance occurrence.1 not examine and question the remaining the described tiated from other vascular malforma¬ Nevertheless, patient persons in this pedigree, but, where possi¬ here and the associated pedigree tions including retinal telangiectasis, ble, informal information was gained from other family members. suggest inclusion of the syndrome of angiomatosis retinae, and racemose Downloaded From: http://archopht.jamanetwork.com/ by a New York University User on 06/01/2015 ' He reviewed three cases and referred to reports of nine addi¬ tional patients with ophthalmoscopic lesions suggestive of a similar disor¬ der. Two additional cases are cited in his addendum.2 In their review of this subject, Lewis et al related the details of three cases of cavernous hemangioma of the retina and noted the presence of 34 previously reported cases of this rare malformation. They also mentioned an additional case in their adden¬ dum.1 The proband's retinal vascular mal¬ formation consisted of a linear collec¬ tion of aneurysms. Her daughter's retinal hamartomas consisted of rath¬ er localized, sessile retinal vascular malformations composed of clusters of saccular aneurysms filled with blood of variable color. In this child, the thin-walled globules appeared to arise from a retinal vein, and isolated clumps of aneurysms surrounded the body of the lesion. The course and diameter of the afferent and efferent retinal vessels were generally unaf¬ fected. Although most cavernous he¬ mangiomas of the retina show no appreciable leakage of fluorescein, one of our patients showed some late diffusion of dye into the overlying vitreous. Fluorescein-plasma/erythrocyte layering within the saccular aneurysms suggested delayed perfu¬ sion (Fig 2). A gray-white substance suggesting fibrous tissue and partial¬ ly obscuring the underlying angioarchitecture was evident in one malfor¬ mation (Fig 4, left). The above description of our pa¬ tients concurs with the accounts of Gass and Lewis et al, who reviewed the history, fundus features, fluores¬ cein angiography, course, manage¬ ment, histoiogic characteristics, and differential diagnosis of this rare entity in detail.13 Involvement of the retina and central nervous system by a cavernous hemangioma was described by Weskamp and Cotlier in 1940. Their patient, a 17-year-old girl, had two capillary malformations of the occipi¬ tal scalp and convulsions at the age of 12 years. Radiologie evidence of intracranial calcification was obtained, and a cavernous hemangioma was extir¬ pated from the pre-Rolandic region. Gass described a patient with sei¬ zures, hemangioma of the retina, and cutaneous angiomas.2 This patient's father had had epilepsy and died of an intracranial hemorrhage. Cavernous hemangioma of the midbrain, pons, and cerebellum were noted at necrop¬ sy. angioma.- ' It has been exceedingly difficult to establish a definitive diagnosis of intracranial cavernous hemangiomas ante mortem. As recently as 1974, Roberson et al described the "cryptic" nature of these lesions. These authors concluded that autopsy-proved cav¬ ernous hemangiomas had eluded an¬ giographie demonstration ante mor¬ tem. As with our patient, even bone subtraction studies were of little benefit. In our pedigree, the proband uniquely had a total right third nerve palsy, but further statements regard¬ ing this ophthalmoplegia would be speculative. It may have been unre¬ lated to the retinal hamartoma. The left temporoparietal findings were inconclusive and could represent a second lesion. Colvard et al recently described retinal cavernous hemangioma in two patients.8 One individual was a 48year-old man with cutaneous angiomas, cavernous hemangioma of the right retina, and paresthesias in the right arm and leg, as well as paresis of the left sixth and seventh cranial nerves. The intracranial process was localized to the left pons and the lemniscus medialis. A second patient was-a 19-year-old man with congenital cardiovascular anomalies. In this sec¬ ond patient, the cavernous hemangi¬ oma of the retina was observed over a five-year period, and sclerosis of some of the larger saccules as well as mini¬ mal extravasation of fluorescein from the hamartoma were among the nota¬ ble features. A variety of cutaneous lesions have been described in association with retinal cavernous hemangioma. Mildner described a 14-year-old girl with cavernous hemangioma of the retina.7 She had a cavernous heman¬ gioma removed from her chest early in life. Gass relates that small cuta¬ neous angiomatous hamartomas are rather common, and thus, their pres¬ ence in patients with cavernous hemangioma of the retina may be a chance finding.' Retinal cavernous hemangiomas have also been asso¬ ciated with angioma serpiginosum, a dermatologie entity demonstrating progressive, widespread dilation of the subpapillary venous plexuses.8 These skin lesions are progressive from the first year of life throughout adolescence and are associated with motor and sensory loss due to vascular involvement of peripheral nerves. This entity further emphasizes the wide spectrum of cutaneous abnor¬ malities that may be associated with retinovascular hamartomas. To the best of our knowledge, this Downloaded From: http://archopht.jamanetwork.com/ by a New York University User on 06/01/2015 article contains only the fourth by cavernous hemangioma of the retina. The pedigree suggests a hereditary syndrome with highly variable penetrance and expressivity. The phakomatoses are a group of multisystem hamartomas with the potential for ocular involvement. Sturge-Weber syndrome and von Hippel-Lindau disease also involve struc¬ tures of mesodermal origin. In the former, cavernous hemangiomas of account of bilateral involvement the choroid are associated with telan- giectasias of the skin in the distribu¬ tion of the trigeminal nerve, as well as pial hemangiomas. In the latter, cere¬ bellar hemangiomas are associated with retinal capillary hemangiomas. These hemangiomas demonstrate that multisystem hamartomas need not be of the same cell type although they arise from the same embryologie cell layer. Evidence is accumulating for the association of retinal cavernous he¬ mangiomas with intracranial cavern¬ ous hemangiomas and cutaneous vas¬ cular hamartomas of a somewhat vari¬ able nature. This pedigree prompts careful continued examination of all family members, and while the prog¬ nosis for the affected eye appears to be generally good, the clinician should be aware that the patient or a member of the patient's family may harbor a threatening intracranial vascular le¬ sion. This investigation was supported in part by the Retina Research and Development Fund and by the Pennsylvania Lions Sight Conservation and Eye Research Foundation Inc. Miriam Creedon and Elaine DiMicco assisted in the preparation of this manuscript. References 1. Lewis RA, Cohen MH, Wise GN: Cavernous haemangioma of the retina and optic disc. Br J Ophthalmol 59:422-434, 1975. 2. Gass JDM: Cavernous hemangioma of the retina, a neuro-oculo-cutaneous syndrome. Am J Ophthalmol 71:799-814, 1971. 3. Gass JDM: Cavernous Hemangioma of the Retina: Differential Diagnosis of Intraocular Tumors. St Louis, CV Mosby Co, 1974, pp 294\x=req-\ 295. 4. Weskamp C, Cotlier I: Angioma del derebro y de la retina con malformaciones capilares de la prel. Arch Oftalmol Buenos Aires 15:1-10, 1940. 5. Roberson GH, Kase CS, Wolpow ER: Telangiectasis and cavernous angiomas of the brainstem: "Cryptic" vascular malformations: Report of a case. Neuroradiology 8:83-89, 1974. 6. Colvard DM, Robertson DM, Trautmann JC: Cavernous hemangioma of the retina. Arch Ophthalmol 96:2042-2044, 1978. 7. Mildner I: Kavernose hamangiome der retina als symptom einer phakomatose. Ber Dtsch Ophthalmol Ges 71:610-612, 1971. 8. Gauter-Smith PC, Sanders MD, Sanderson KV: Ocular and nervous system involvement in angioma serpiginosum. Br J Ophthalmol 55:433\x=req-\ 443, 1971.