Journal of Neuro-Ophthalmology, December 1991, Volume 11, Issue 4

CREST-associated multiple intracranial aneurysms and bilateral optic neuropathies.

A patient with a clinical and serological diagnosis of CREST syndrome (calcinosis, Raynaud's phenomenon, esophageal motility abnormalities, sclerodactyly, telangiectatic lesions), a variant of PSS (progressive systemic sclerosis), was found to have multiple intracranial aneurysms. She subsequently developed bilateral optic neuropathies. Ischemic and compressive etiologies are proposed and related to the histopathology of the patient's underlying systemic disease.

! oUTnQI of Clinical NeurD- ophthalmology 11( 4): 233- 240, 1991. CREST- Associated Multiple Intracranial Aneurysms and Bilateral Optic Neuropathies Julio R. Ortiz, M. D., Nancy J. Newman, M. D., and Daniel L. Barrow, M. D. © 1991 Raven Press, Ltd., New York A patient with a clinical and serological diagnosis of CREST syndrome ( calcinosis, Raynaud's phenomenon, esophageal motility abnormalities, sclerodactyly, telan­giectatic lesions), a variant of PSS ( progressive systemic sclerosis), was found to have multiple intracranial aneu­rysms. She subsequently developed bilateral optic neu­ropathies. Ischemic and compressive etiologies are pro­posed and related to the histopathology of the patient's underlying systemic disease. Key Words: CREST syndrome- Optic neuropathy­Progressive systemic sclerosis ( PSS)- Intracranial aneu­rysms. From the Departments of Ophthalmology a · R. O., N. J. N.), Neurology ( N. J. N.), and Surgery ( Neurosurgery) ( D. L. B.), Em­ory University School of Medicine, Atlanta, Georgta, U. S. A. Address correspondence and reprint requests to Dr. Nancy J. Newman at Neuro- ophthalmology Unit, Emory Eye Center, 1327 Clifton Rd., N. E., Atlanta, GA 30322, U. S. A. 233 CREST syndrome, a clinical variant of progres­sive systemic sclerosis ( PSS), is typically character­ized by the development of subcutaneous calcific nodules, Raynaud's phenomenon, esophageal motility abnormalities, sclerodactyly, and telan­giectatic lesions of the skin and mucous mem­branes. As in many of the collagen- vascular dis­eases, degenerative and inflammatory lesions of the vascular system commonly occur. Because of the unique morphology and lack of perivascular support of the intracranial cerebral vessels, vascu­litic involvement may lead to vascular wall isch­emia, weakening, and aneurysmal dilatation. We present the first case ( to our knowledge), of CREST- associated multiple intracranial aneu­rysms. Aneurysmal compression and CREST­related vasculopathy may have combined to pro­duce bilateral optic neuropathies in this patient. CASE HISTORY A 66- year- old black woman was referred to the Emory Eye Center with bilateral visual loss. The patient complained of slowly progressive, painless loss of vision in both eyes. Ophthalmic examina­tion revealed visual acuities of 20/ 60, bilateral nu­clear sclerotic cataracts, and normal- appearing op­tic discs. Her past medical history included an acute sub­arachnoid hemorrhage at the age of 40. Cerebral angiography at that time revealed multiple intra­cranial aneurysms. She was managed at another hospital where surgical intervention was consid­ered too hazardous. No surgery was performed. Her past medical history was also notable for Raynaud's phenomenon, arthritic pain and swell­ing of her hands and knees, recurrent bouts of 234 J. R. ORTIZ ET AI. pneumonia with baseline dyspnea on exertion, dysphagia, a recurrent urticarial rash of the face and upper body, a single subcutaneous calcific nodule, and recurrent episodes of lower extremity thrombophlebitis. She had elevated serum globu­lins ( 3.5 g/ dl) with an electrophoretic pattern con­sistent with the presence of circulating immune complexes. Rheumatoid factor was positive; anti­nuclear antibodies were detected in a high titered homogeneous pattern; and anticentromere anti­bodies were elevated. Based on her clinical and serologic profile, the diagnosis of CREST syn­drome was made. One month after presentation, the patient had a left extracapsular cataract extraction with a poste­rior chamber intraocular lens implant. Immedi­ately after surgery, the patient complained of se­vere pain and visual loss in the left eye. Vision in that eye was limited to light perception; there was an afferent pupillary defect; and the intraocular pressure was elevated at 48 mm Hg. Two and one­half hours of aggressive therapy brought the intra­ocular pressure under control, but visual acuity did not improve to better than recognition of hand motions. Ischemic optic neuropathy was sus­pected, although disc edema was not appreciated. During the next 3 weeks, the patient noted a gradual decline in the vision of her right eye, and she was referred to the Neuro- ophthalmology Unit. Visual acuity was 20/ 300 in the right eye and hand motions in the left. There was a left relative afferent pupillary defect. Motility was full. Intra­ocular pressures were normal, and slit lamp exam­ination unremarkable. Ophthalmoscopic examina­tion revealed a normal- appearing disc in the right eye and temporal pallor in the left. Visual fields showed a superior altitudinal defect involving fix­ation on the right and an inferotemporal island of remaining vision on the left ( Fig. 1). Findings were diagnostic of bilateral optic neuropathies. A contrast- enhanced computed tomography ( CT) scan of the brain and orbits showed multiple enhancing soft tissue masses with rim calcifica­tions in the region of the circle of Willis, abutting the anterior visual pathways bilaterally ( Fig. 2). Four- vessel cerebral arteriogram revealed multiple aneurysms ( Figs. 3 and 4): ( a) an aneurysm of the right supraclinoid carotid at the origin of the supe­rior hypophyseal artery ( 0.3 cm); ( b) a bilobed, in­tracavernous aneurysm of the right internal carotid artery ( 1.2 cm); ( c) a bilobed aneurysm of the left ophthalmic artery at its origin ( 0.8 cm); ( d) an an­eurysm at the bifurcation of the right middle cere­bral artery ( 1.0 cm); ( e) an aneurysm of the left superior hypophyseal artery ( 0.8 cm); ( f) an aneu­rysm of the left anterior choroidal artery ( 1.6 cm). Given the progressive visual loss in the right eye and a normal- appearing optic nerve head, recent aneurysmal compression of the right optic nerve was suspected. The patient was referred for neu­rosurgical intervention and underwent a right frontotemporal craniotomy. The right side was 210 LEFT RIGHT ~ IG. 1. Pre- operative Goldmann visual fields. Inferotemporal island of vision, left eye. "' y'r- lr! or Clltltudlnal defect involving fixation, right eye. 1elin Neuro- ophthalmol. VA/. 11, ,,",, CREST- ASSOCIATED OPTIC NEUROPATHIES 235 A a FIG. 2. Contrast- enhanced coronal ( A) and axial ( B) CT scan demonstrates multiple soft tissue masses in the region of the anterior circle of Willis, bilaterally. A chosen to provide the best exposure of the right optic nerve, which had the most preserved vision. The right middle cerebral artery aneurysm was clipped without difficulty. The right supraclinoid carotid artery aneurysm arising from the region of the superior hypophyseal artery was pointing me­dially, indenting the right optic nerve, and was also clip- ligated. A bilobed aneurysm of the distal right intracavernous carotid artery was not com­pressing the visual apparatus and was reinforced with muslin. The left optic nerve was markedly deviated to the right and lay beneath the right optic nerve. This deviation was caused by a medially directed B FIG. 3. A: Right internal carotid arteriogram, anteroposterior view, shows right mid­dle cerebral artery ( arrowhead) intracavernous ( large arrow), and superior hypophy­seal ( small arrow) artery aneurysms. B: Left internal carotid injection shows left an­terior choroidal ( large arrow) and ophthalmic artery ( small arrow) aneurysms. J Clin Neuro- ophthalmol, Vol, II, No, 4, 1991 236 J. R. ORTIZ ET AL. A B FIG. 4. Right internal carotid arteriogram, lateral views. A: Right middle cerebral ( large arrowhead) and intracavernous ( large arrow) artery aneurysms are shown. B: Left anterior choroidal ( large arrow) and ophthalmic ( small arrow) artery aneurysms are seen. aneurysm arising from the region of the left supe­rior hypophyseal artery. It was felt that this lesion and the other two left- sided aneurysms could most safely be addressed from a left frontotemporal ap­proach. Postoperatively, the patient had a transient su­perior division third nerve paralysis. Vision in both eyes was limited to counting fingers. The vi­sual field on the right was notable for restoration of some peripheral vision temporally and superiorly, with further field loss centrally ( Fig. 5). At 5- month follow- up, her vision was 20/ 40 in the right eye and 20/ 100 in the left. Visual fields were remarkably improved, with only a central de­fect nasally in the right eye and some expansion of isopters in the left eye, which involved some fixa­tion inferiorly ( Fig. 6). An elective left- sided neu­rosurgical procedure to address the remaining an­eurysms is planned. DISCUSSION PSS and CREST Progressive systemic sclerosis is a generalized disorder of connective tissue characterized by de­(', · n"' r~~;' · · -"-,.- 1 _,. 1 ' m'lnJurv ch, lngt" s. Eventually "' li\.. rial leads / Gin NeuTo- ophthalmol. Vol. 11. No I. 1~~" 1 to severe fibrosis. Progressive systemic sclerosis manifests clinically by diffuse induration of the skin and dysfunction of visceral structures, partic­ularly the gastrointestinal tract, kidneys, heart, and lungs. Manifestations of this disorder are of­ten based on the functional and structural vascular compromises that occur after repeated vascular in­sults, subsequent healing, and proliferative vascu­lar response ( 1). The cause of vascular injury in PSS remains unknown. The leading hypothesis suggests that there exists an underlying systemic abnormality of collagen metabolism that specifi­cally affects the small vessels and capillaries ( 2). Histopathology Histopathologically, the vascular lesions are characterized by subintimal proliferation of con­nective tissue, subendothelial fibrin deposits, basement membrane thickening, and fragmenta­tion of elastic tissue ( 3,4). Devascularization of tissues is a generalized phenomenon in PSS, and it has been proposed that arteriolar and capillary endothelia may be the primary target cell population. Kaheleh and col­leagues noted that the sera of 31 of 52 patients with PSS contained cytotoxic activity specific for endo­thelial cells ( 1). In addition, immune complex de- CREST- ASSOCIATED OPTIC NEUROPATHIES 210 LEfT RIGHT FIG. 5. Postoperative visual fields. Visual field unchanged, left eye. Restoration of some field temporally and superiorly, with further loss centrally, right eye. 237 position has been known to induce endothelial damage in this disease ( 5). The coagulation cas­cade may be triggered by the intimal lesion, lead­ing to fibrin deposition, decreased blood flow, and local ischemia. Exposed subendothelium will also induce platelet adherence and aggregation at the site of injury. If this process involves vasa vaso-rum, it may theoretically lead to weakening and generalized dilatation of larger vascular structures. Although extremely rare, large blood vessel in­volvement occasionally gives rise to major symp­toms. Chaithiraphan and associates have de­scribed the devascularization of a coronary arterial wall leading to the development of three aneurys- 210 LEfT RIGHT FIG. 6. Visual fields at 5- month follow- up. Expansion of the visual field involves some fixation inferiorly, left eye. Normalization of the field with the exception of a central defect nasally, right eye. I Clin Neuro- ophthalmoi, Vol. 11, No. 4, 1991 238 ]. R. ORTIZ ET AL. mal bulges and anginal chest pain in a young pa­tient with PSS ( 6). Clinical Manifestations CREST syndrome, a clinical variant of PSS, is characterized by at least three of the following fea­tures: calcinosis, Raynaud's phenomenon, esoph­ageal motility abnormalities, sclerodactyly, and telangiectatic lesions of the skin and mucosal sur­faces. The majority of patients (> 85%) present with Raynaud's phenomenon, which may ante­date further manifestations of the disease by sev­eral years. The interval from the onset of symp­toms to a final diagnosis often exceeds 1~ 15 years ( 7). Patients with PSS and CREST have remarkably normal results on routine laboratory tests ( 8). The erythrocyte sedimentation rate tends to be normal or only slightly elevated. However, various au­toantibodies have been found in these syndromes. Approximately 30% of patients are rheumatoid fac­tor positive. Antibodies to collagen ( 9) and antinu­clear antibodies are very common. Anticentromere antibodies are found in 5~ 98% of patients with CREST and 3- 18% of patients with PSS, yet are rarely found in systemic lupus erythematosus ( 2%) and mixed connective tissue disease ( 6%) ( 7, 1~ 15). Anticentromere antibodies may be detected in a patient's serum prior to the development of the full CREST clinical syndrome. Autoantibodies found in other connective tissue diseases ( e. g., anti- DNA, anti- RNP, anti- Sjogren's syndrome an­tigen B) are not found in CREST patients. Neurologic and cerebrovascular abnormalities are uncommon in PSS and CREST syndrome, un­like related diseases such as systemic lupus erythe­matosus and polyarteritis nodosa. Gordon and Sil­verstein suggested that neurological complications of PSS are a result of concurrent drug therapy, involvement of other internal organs with second­ary neurologic sequelae ( i. e., hypertensive cere­brovascular disease from renal involvement, tet­any from gastrointestinal malabsorption syn­dromes, or confusion from pulmonary damage and hypoxia), or simply coincidental ( 16). The in­frequency of primary neurologic disease may re­flect the lack of collagenous connective tissue in the central nervous system. Cerebral blood vessels are only rarely involved by the disease process ( 16). Lee and Haynes described an unusual patient with PSS who died of a massive left cerebral in­Ln.~ ti(> T-' "~' 1JI",,~ to C\ l... Ct internal carotid arteritis ( 5). . .!;,- kening of the 1 Clin Neuro- ophlhalmol. Vol. 11. Nu. 4. lY~; carotid vessel wall and vasculitis of the vasa vaso­rum surrounding the internal carotid and anterior and middle cerebral arteries. No sclerodermatous fibrous thickening was seen in the anterior and middle cerebral arteries. Ophthalmologic manifestations of PSS are rare, but include keratitis ( 17,18) and keratoconus ( 19), shallow conjunctival fornices ( 20), keratoconjunc­tivitis sicca ( 21), eyelid tightness ( 19), and lid tel­angiectasia ( 20). Arnett and Michaels described a single case of inflammatory ocular myopathy ( 22). Gass presented a patient with multiple focal exu­dative and hemorrhagic retinal detachments ( 23). Multiple retinal vascular abnormalities have been described in association with PSS, including branch retinal vein occlusion ( 24), central vein oc­clusions ( 25), and branch ( 26) and central retinal arterial occlusions ( 27). Cases with optic nerve head edema ( 17), cotton wool spots ( 28), intraret­inaI edema, exudates and hemorrhages ( 17,26,29), and fibrinoid necrosis of choroidal vasculature ( 27) have been reported. We could find no reports of ischemic or compressive optic neuropathies docu­mented in the literature. Intracranial Aneurysms Intracranial aneurysms are discovered predomi­nantly in patients between 40 and 70 years of age, often presenting with catastrophic subarachnoid hemorrhage. Rarely do they present with an insid­ious, painless, and slowly progressive visual loss secondary to retrobulbar optic nerve compression. Optic disc swelling or associated neurologic signs are typically absent. Central, cecocentral, paracen­tral, arcuate, altitudinal, nasal, and temporal hemi­anopic visual field defects have been described ( 3~ 32). Visual loss associated with intracranial an­eurysms has been ascribed to vascular insuffi­ciency and/ or mechanical blockage of axonal trans­port ( 33,34). Acute monocular visual loss can occur, presumably on the basis of sudden inter­ruption of the vascular supply to the optic nerve ( 35). The reported frequency of multiple aneurysms varies widely. Bigelow found more than one aneu­rysm in 10.2% of 2,237 cases of intracranial aneu­rysms collected from the literature ( 36). Stehbens reported multiplicity in 30.3% of 122 brains found to harbor aneurysms on autopsy ( 37). Wilson and associates found that 45% of 254 aneurysm pa­tients studied had multiple aneurysms, and of these 68% had 2 aneurysms, 24% had 3 aneu­rysms, 8% had 4 aneurysms, and only 1 case had 5 CREST- ASSOCIATED OPTIC NEUROPATHIES 239 aneurysms ( 38). Rarely are more than three aneu­rysms found in anyone brain. When large num­bers of aneurysms are discovered, an arteritic pro­cess or connective tissue disease should be sus­pected ( 39). Intracrania~ aneurysms of inflammatory origin occur sporadIcally and may be infectious in etiol­ogy or noninfectious arteritis- related. Although ~ are, no~ infectiousaneurysms have been reported m a vanety of diseases. Polyarteritis nodosa has often been associated with splanchnic- mesenteric aneurysms. Cerebral vessels can be involved in as many as 20% of patients with this disease ( 40). An aneurysm ? n a s~ all branch of a vertebral artery wa~ found m a patient with Wegener's granuloma­tOSIS ( 41). A posterior communicating artery aneu­rysm pr: senting with subarachnoid hemorrhage was attributed to systemic lupus erythematosis in a 29- year- old woman ( 42). Multiple internal carotid artery aneurysms developed in a 34- month- old child with widespread giant cell arteritis of child­hood ( 43). Similarly, a small aneurysm of a cere­bellar pial artery was attributed to granulomatous angiitis in a 25- year- old man ( 44). Histologically, the intracranial cerebral arteries are muscular in type and have considerably thin­ner media and adventitia than extracranial arteries of similar size. They have a prominent internal elastic lamina and a few adventitial elastic fibrils. The media lacks elastica, and the external elastic lamina is notably absent. There are no vasa vaso­rum in the arterial walls of children and many young adults. As arterial walls age and develop atherosclerotic thickening, the vasa vasorum may become more prominent. Although intracranial vessel wall injury and aneurysm formation has been attributed to involvement of vasa vasorum, anatomical studies have shown a generalized ab­sence of vasa vasorum from the affected portions of the cerebral vasculature ( 45- 48). Rather, endo­thelial injury, followed by the adhesion of platelets and leukocytes and their activation, playa primary role in aneurysm formation. These events could lead to complement activation, release of lysosom­al enzymes and prostaglandins, with further me­chanical disruption of the vessel wall ( 49). Chronic hemodynamic stress at sites of vessel wall injury, with fragmentation of the elastic lamina and atro­phy of the media, may result in focal wall dilata­tion and frank aneurysm formation. Because of the architectural peculiarities and the lack of strong perivascular support of the cerebral arterial walls, chronic inflammation may lead to degenerative changes, ischemia, weakening of the arterial wall, and aneurysmal dilatation. Conclusions . Our patient had a clinical and serologic diagno­SIS of PSS and CREST syndrome, characterized by the presence of calcinosis, a long history of Raynaud's phenomenon, dysphagia, arthritis, re­current ~ hrombophlebitis, skin rashes, mild pul­monary mvolvement, positive rheumatoid factor, and elevated antinuclear and anticentromere anti­bodies. The sudden and profound visual loss in her left eye after cataract extraction may have been secondary to ischemia to the optic nerve ( 50). A short period of raised intraocular pressure may have changed ocular hemodynamics in an already compromised arteritic circulation. Furthermore, it is likely that both optic nerves were already com­p. romised by the effects of aneurysmal compres­SIOn. 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