Familial Cavernous Angiomas Joseph M. Bicknell, MD; Thomas J. Carlow, MD; Mario Kornfeld, MD; Jorgen Stovring, MD; Paul Turner, MD \s=b\ Cavernous angiomas are rare, surgically remediable vascular malformations of the CNS that may be characterized by hemorrhage, seizures, or focal neurologic deficits. Three families with cavernous angiomas have been described, and we report two more. In the first, the mother died suddenly with headache. A pontine cavernous angioma was found at autopsy in one son. His brother has similar pontine signs and a radiographically proved pontine mass. The brother's son has seizures and a calcified cerebral lesion. In the second family, the father had a cavernous angioma excised from the caudate. One of his daughters had a hemorrhagic mass removed from the spinal cord. Another daughter has seizures and a temporal lobe vascular lesion proved angiographi- cally. Awareness of the possibility of familial involvement may aid in diagnosis of angioma. (Arch Neurol 35:746-749, 1978) cavernous Cavernous angiomas partrelatively are vascular malforma¬ tions that may involve any of the CNS. Some are clinically quiescent, but others cause seizures, hemor¬ rhage, or focal neurologic deficit. Identification of these malformations is clinically important, since surgical removal of accessible lesions is rela¬ tively easy. Cavernous angiomas may be shown radiographically, especially by computerized axial tomography (CT); at times, there are supporting findings on cerebral angiography, and occasionally calcifications in the an¬ gioma are seen on plain skull roent¬ genograms. They should be suspected clinically when focal neurologic prob¬ lems affect more than one family member. Three such instances of uncommon familial involvement have been re¬ ported in the past.13 We studied two additional families showing patholog¬ ic, radiographie, or clinical evidence of cavernous angioma. REPORT OF CASES Case 1.—A 35-year-old man was well until the age of 8 years, when suddenly strabismus, right facial paralysis, and left hemianesthesia developed. Neurologic ex¬ amination performed when he was 26 years of age disclosed bilateral horizontal gaze pareses, right abducens paralysis, and palatal myoclonus in synchrony with a dissociated pendular vertical nystagmus. No ocular movement was noted in response to caloric or optokinetic stimuli. The masseter muscle on the right was weak, atrophie, and fasciculating. Right facial muscles were totally paralyzed. Hearing was impaired, mildly on the left and severely on the right. Hemiparesis, hemi¬ anesthesia, and ataxia were present on the left, and sweating was decreased on the entire right side of the body. Carotid and vertebral angiograms, pneumoencephalogram, and CSF examination showed no abnormality. He died suddenly at 35 years of age with a blood alcohol level of 519 mg/ dl. Bulging of the central pons, thinning of the right abducens and facial nerves, and atrophy of the right cerebellar hemisphere and vermis were evident on examination of the brain. Brain stem sections showed a brownish-red tegmental mass from the upper medulla to the inferior colliculus that extended through the brachium pontis into the right cerebellar hemisphere (Fig 1). Histologically, the pontine lesion was a cavernous angioma composed of closely packed, irregular vascular channels. The channels had fibrous walls devoid of elastic fibers and smooth muscle; they were lined by a single layer of endothelium. Some contained thrombi in various stages of organization. Areas of calcification and metaplastic bone were present in several portions of the lesion. The surrounding parenchyma was rarified in some places, heavily gliotic in others, and contained numerous hemosiderin-laden macrophages (Fig 2). A second malformation, a minute telangiectasis, was seen in the right lingual gyrus. Case 2.—The older brother of patient 1 was in good health until he was 38 years old, when he abruptly experienced vertigo, tinnitus, hearing loss on the right side, and occipital headache. Within a week he became anesthetic on his entire left side. examination Neuro-ophthalmologic showed a horizontal gaze paresis on the Fig 1.—Large, dark red, lobulated lesion in pontine tegmentum (case 1). It includes rounded space with calcified wall (midline, between base and tegmentum) and scattered white specks of calcium. Accepted for publication Jan 4, 1978. From the Departments of Neurology (Drs Bicknell and Carlow), Pathology (Dr Kornfeld), and Radiology (Dr Stovring), and the Division of Neurosurgery (Dr Turner), University of New Mexico School of Medicine and Veterans Administration Hospital, Albuquerque, NM. Reprint requests to Department of Neurology, University of New Mexico School of Medicine, 2211 Lomas Blvd NE, Albuquerque, NM 87131 (Dr Bicknell). Downloaded From: http://archneur.jamanetwork.com/ by a University of Pennsylvania User on 06/14/2015 Fig 2.—Lesion is composed of tightly packed vascular channels of variable sizes (case 1). Walls consist of connective Fig 3.—Case 3. Circumscribed area of small stippled calcifications in right posterior temporal area (arrows). tissue lined with endothelium. There is no elastica nor media. Dark precipitates are calcium (Verhoeff-von Gieson, 4.5). right side, bilateral abducens paresis, hori¬ zontal gaze-evoked nystagmus on right and left lateral gaze, rotary nystagmus on upward gaze, and saccadic pursuit when following targets to the right. Corneal reflex, facial sensation, and jaw strength were reduced on the right. There was a right peripheral facial paresis with myoky¬ mia. Hearing was impaired bilaterally (more on the right than the left), with features of retrocochlear involvement on audiometry. A subtle left hemiparesis and ataxia were evident. Carotid and vertebral angiography were normal; pneumoencephalography, howev¬ er, showing enlargement of the right side of the pons. He was felt to have a pontine glioma (the nature of his brother's illness had not yet been determined), and he was treated by irradiation and chemotherapy. His symptoms have remained stable for three years. Contrast-enhancing lesions in the right side of the pons and left cerebel¬ lar hemisphere consistent with cavernous angiomas have been proved subsequently by CT scan. Case 3.-The 19-year-old son of patient 2 had seizures when he was 9 years old, some beginning focally in the left arm and others displaying a psychomotor pattern. His neurologic examination was normal, but EEG showed spike discharges and a slow wave focus in the right posterior temporal region. A 3-cm spherical area of finely granular calcification was seen in the same area in roentgenograms of the Fig 4.—Case 5. a, Precontrast CT scan showing calcium-containing, well-circumscribed lesion in right caudate nucleus and internal capsule (arrow); no mass effect, b, Enhancement of lesion after contrast (arrow). skull (Fig 3). The mass appeared avascular angiographically, and a biopsy was at¬ tempted. Examination of the excised tissue, how¬ ever, showed only glial proliferation, globose eosinophilic bodies, and hemosiderin-containing macrophages, consistent with tissue from the periphery of a lesion that had bled at some time in the past. In the ensuing ten years, despite school and behavioral problems and unreliable use of anticonvulsants, he has remained neurolog¬ ically normal with infrequent seizures. Computerized axial tomographs showed angioma. cavernous Case 4.—A woman, the mother of patients 1 and 3 and the grandmother of patient 3, was not seen. She was said to have "died suddenly with a severe head¬ ache at an early age." Case 5.—A 56-year-old man had lifelong weakness and wasting of the left arm. Despite two years of college education, he had always held menial jobs and had been a chronic alcoholic for many years. His memory and equilibrium had been poor for Downloaded From: http://archneur.jamanetwork.com/ by a University of Pennsylvania User on 06/14/2015 Fig 5.—Case 7. Precontrast CT scan with calcification in left posterior temporal region (arrow). five years, and he was hospitalized for evaluation of dementia. On examination, although alert and oriented, he could not remember three items for two minutes. Cranial nerve testing showed only mild dysarthria. The left arm and hand were small, weak, and spastic, with a flexed posture and choreoathetotic movements. The gait was broad-based. Reflexes were hyperactive on the left. Sensory function was normal. The CT scan showed slight ventricular enlargement, and a 3.5-cm, contrastenhancing mass was present in the head of the right caudate nucleus (Fig 4). Right internal carotid angiography showed no abnormality. The lesion was excised with¬ out difficulty, and the patient was discharged unchanged. On gross examination, the excised mass was firm and its cut surface had a spongy appearance due to the presence of multiple cystic spaces. Microscopically, it was a cavernous angioma consisting of a plexus of clustered vascular channels of varying size. The vessel walls were composed exclu¬ sively of connective tissue that often displayed irregular hyalin thickening; the vascular channels were lined by a single endothelial layer. There were areas of thrombosis and focal calcification, and the surrounding tissues showed gliosis and hemosiderin-laden macrophages. Case 6.-The 32-year-old daughter of patient 5 was well until she was 20 years of age, when she noted sensory loss in her left toes. This gradually ascended to the iliac crest and then extended to the right leg. At 21 years, when she experienced dysesthetic shock-like pains in the left leg, myelography was normal. However, myelography performed when she was 24 years, after she had become weak in the left leg and was unable to void, showed enlargement of Fig 6—Case 7. Late venous phase of left carotid arteriogram shows persistent opacification of irregular sinusoidal channels in angioma of left posterior temporal region (arrows). the spinal cord, with a partial block of the spinal canal at the T6-T7 level. A multilobulated, intramedullary lesion was excised from the cord. Grossly, it included liquid hematoma, three solid blood clots, and grayish surrounding tissue. Microscopic examination showed clotted blood, small fragments of cord parenchyma stained with blood pigment, and large vascular spaces described as "very dilated capillary-type structures resembling a hygroma or vascular malformation." Postop¬ eratively, her legs remained weak and painful, and she continued to have trouble voiding. Her dysesthetic leg pain became increasingly severe despite treatment with phenytoin sodium and carbamazepine. When she was 27 years of age, a myelogram showed enlargement of the spinal cord from T5 to T7. A second laminectomy showed numerous dilated vascular chan¬ nels entering an unresectable intramedul¬ lary mass of vessels. Her symptoms worsened slowly over the next three years. Selective spinal cord angiography failed to show abnormal vessels, and she remains paraparetic with a T6 sensory level. Case 7.-A 28-year-old woman, the sister of patient 6, had had psychomotor seizures since she was 15 years old. This was controlled with carbamazepine, 200 mg twice daily. Results of neurologic examina¬ tion were normal. At 28 years of age, her EEG showed left temporal spikes and slow high-density posterior temporal region waves. A CT scan indicated a mass in the left (Fig 5). Left carotid angiography was carried injection of 6 ml of 60% iothalamate meglumine per second for 2lk s (a total of 15 ml of contrast medium). The filming sequence was extended over 16 s, and irregular sinusoidal channels were seen in the left posterior temporal region, with opacification persisting after contrast had disappeared from all other intracranial veins (Fig 6). The diagnosis of cavernous angioma was suspected, but because of the left temporal location and the patient's good response to medication, surgery was deferred. out with the Vascular COMMENT malformations of the system are typically divided into at least three major categories: (1) capillary telangiectasis, (2) caver¬ nous angioma, and (3) venous and nervous arteriovenous malformation.45 Each has characteristic features pathologi¬ cally, clinically, and radiograpliically. Grossly, the cavernous angiomas range in size from one millimeter to several centimeters. They may be single or multiple, may be accompa¬ nied by cavernous angiomas in other organ systems, and may appear in association with telangiectases. Often Downloaded From: http://archneur.jamanetwork.com/ by a University of Pennsylvania User on 06/14/2015 they are circumscribed or encapsu¬ lated multilobular. Hemorrhage, thrombosis, calcifica¬ tion, or ossification may be seen.5·6 Microscopically, they are composed of closely packed, irregular, thin-walled channels with no elastica, no muscularis, and no intervening neural tissue.4 The vessel walls may be hyalinized, and hemosiderin staining and gliosis of adjacent tissue may reflect minor hemorrhages.5 Clinically, the cavernous angioma may be quiescent, coming to light only at and may be autopsy. Symptomatic patients may have seizures, hemorrhage, or focal deficits, and the evolution may be ictal or progressive.67 The cere¬ brum and pons are the commonest sites, but the midbrain, cerebellum, medulla, or spinal cord may also be involved.4·6·8 Radiographically, gioma may be seen as (1) a circum¬ scribed area of small, stippled calcifi¬ cation in plain skull films; (2) an area of increased uptake on radionuclide brain scan9; (3) a nonspecific mass in pneumoencephalography; (4) an area of increased density in CT scan10; or (5) an area of abnormal vascularity in angiography. Computerized axial tomographic scanning is more sensitive than ordi¬ nary roentgenography in detecting calcifications, which are typically clus¬ a cavernous an¬ tered in a well-demarcated area. Blood in the cavernous vascular spaces also appears as increased density and may show enhancement after intravenous contrast administration. There is little or no mass effect unless recent hemor¬ rhage has occurred. Angiography has been done in approximately 20 reported cases of cavernous angioma. Many patients have shown no abnormality or at most an avascular mass.1112 Enlarged feed¬ ing arteries are never seen, but irreg¬ ular neovascularity in the early arteri¬ al phase was described in one case.13 Recently, with improved angiographie techniques, capillary blush and promi¬ nent draining veins have been seen in several cases.9·14 Increased volumes of contrast medium and prolonged film¬ ing may be necessary, and contrast may persist in the angioma longer than in other venous structures.15 Kufs,1 in 1928, described multiple "telangiectatic nodules" of the brain in a man of 81 years, his 45-year-old daughter had suddenly experienced a pontine syndrome at the age of 20 years. A family reported in 1936 by Michael and Levin had five affected members.'2 The mother had seizures for three years and "died of epilepsy," and her brother had seizures as well. A daughter with intermittent left hemiplegia, focal convulsions, and calcifica¬ tions visible in plain skull roentgeno¬ grams died in status epilepticus. Postmortem examination showed cav¬ ernous angiomas of the right frontal, temporal, and parietal lobes, the left hippocampus, and the right cerebellar hemisphere. Her younger sister also had focal seizures and calcifications, and her older sister had migraine-like episodes, with transient sensory loss on the left side followed by head¬ aches. Two patients with pathologically verified cavernous angiomas were described by Clark in 1970.3 In a 27year-old man with headaches, psycho¬ motor seizures, and a midbrain mass, hydrocephalus developed and he died after surgical exploration and shunt¬ ing. He had cavernous angiomas in the left frontal and temporal lobe and the posterior half of the midbrain. His daughter died in coma at the age of 28 years after one year of headaches; autopsy disclosed a right temporal cavernous angioma with evidence of both old and recent hemorrhage. Of these nine cases, four were confirmed pathologically and five were diagnosed on clinical and radiographic grounds. Of our seven patients, one from each family (patients 1 and 5) showed the classical pathological findings of cavernous angioma, while another from each family (patients 3 and 6) showed compatible, but less conclu¬ sive, histologie changes. The tissue in case 3 resembled that seen adjacent to a vascular malformation, and that in case 6 was typical of the cryptic angio¬ ma in which hemorrhage obliterates much of the original vascular malfor¬ mation. One case from each family (case 2 and 7) had no pathologic confir¬ mation, but radiographie findings were ma. quite typical of cavernous angio¬ In only one patient (case 4) was the diagnosis made solely on the clini¬ cal history. With 16 cases in five families now described, familial occurrence appears to be an important clinical character¬ istic of cavernous angioma. The ease of identifying cavernous angiomas by CT scan and perhaps by modern angiographie technique and the feasi¬ bility of surgical excision12 makes identification of these cases increas¬ ingly important. A positive family history may be a valuable aid to the early diagnosis and treatment of cavernous angioma. References 1. Kufs H: Ueber Heredofamiliare Angioma- tose des Gehirns und der Retina, ihre Beziehung- en zueinander und zur Angiomatose der Haut. Z Neurol Psychiatry 113:651-686, 1928. 2. Michael JC, Levin PM: Multiple telangiectases of brain: A discussion of hereditary factors in their development. Arch Neurol Psychiatry 36:514-539, 1936. 3. Clark JV: Familial occurrence of cavernous angiomata of the brain. J Neurol Neurosurg Psychiatry 33:871-876, 1970. 4. Russell DS, Rubinstein LF: Tumours and hamartomas of the blood vessels, in Pathology of Tumours of the Nervous System. Baltimore, Williams &Wilkins Co, 1972, pp 85-108. 5. McCormick WF: The pathology of vascular ("arteriovenous") malformations. J Neurosurg 24:807-816, 1966. 6. Roberson GH, Kase CS, Wolpaw ER: Telangiectases and cavernous angiomas of the brainstem\p=m-\"cryptic"vascular malformations: Report of a case. Neuroradiology 8:83-89, 1974. 7. Zeller RS, Chutorian AM: Vascular malformation of the pons in children. Neurology 25:776\x=req-\ 780, 1975. 8. McCormick WF, Hardman JM, Boulter TR: Vascular malformations ("angiomas") of the brain, with special reference to those occurring in the posterior fossa. J Neurosurg 28:241-251, 1968. 9. Bartlett JE, Kishore PR: Intracranial cavernous angioma. Am J Roentgenol Radium Ther Nucl Med 128:653-656, 1977. 10. Kendall BE, Claveria LE: The use of computed axial tomography (CAT) for the diagnosis and management of intracranial angiomas. Neuroradiology 12:141-160, 1976. 11. Kamrin RB, Buchsbaum HW: Large vascular malformations of the brain not visualized by serial angiography. Arch Neurol 13:413-420, 1965. 12. Schneider RC, Liss L: Cavernous hemangiomas of the cerebral hemispheres. J Neurosurg 15:392-399, 1958. 13. Jonutis AF, Sondheimer FK, Klein HZ, et al: Intracerebral cavernous hemangioma with angiographically demonstrated pathologic vasculature. Neuroradiology 3:57-63, 1971. 14. Liliequist B: Angiography in intracerebral cavernous hemangioma. Neuroradiology 9:69-72, 1975. 15. Bogren H, Svalander C, Wickbom I: Angiography in intracranial cavernous angiomas. Acta Radiol 10:81-89, 1970. Downloaded From: http://archneur.jamanetwork.com/ by a University of Pennsylvania User on 06/14/2015