Neurol Med Chir (Tokyo) 49, 402¿406, 2009

Intracranial Aneurysms in Patients With CREST Syndrome —Two Case Reports—

Ryuta NAKAE, Masaru IDEI,KiyoshiKUMANO, Shinji OKITA,andKanjiYAMANE

Department of Neurosurgery, Chugoku Rosai Hospital, Kure, Hiroshima

Abstract

CREST syndrome is a variant of characterized by , Raynaud's phenomenon, esophageal hypomotility, , and , and is a collagen vascular disease characterized by inflammation and fibrosis of multiple organs/tissues. Neurological and cerebrovascular abnormalities are uncommon in CREST syndrome. Here, we report two patients with CREST syndrome harboring intracranial aneurysms. A 53-year-old wo- man with a 6-month history of CREST syndrome had multiple intracranial aneurysms that arose from the right mid- dle cerebral artery, the left middle cerebral artery, the choroidal segment of the left internal carotid artery, and the left anterior cerebral artery. A 64-year-old woman with a 2-year history of CREST syndrome had a fusiform aneurysm located on the insular segment of the left middle cerebral artery. These patients were treated surgically and good outcome was achieved in both cases. The pathogenesis of cerebral aneurysms associated with collagen dis- eases, including CREST syndrome, remains unclear. Early treatment of CREST syndrome and other collagen dis- eases may prevent from progressing to affect the intracranial arteries and thus reduce the occurrence of aneurysms. The prognosis for patients with collagen diseases after rupture of cerebral aneurysm seems to be poor be- cause the multiplicity, atypical morphology, and atypical location of their aneurysms make treatment difficult. Thus, early detection and treatment are important to improve the prognosis.

Key words: intracranial aneurysm, CREST syndrome, scleroderma, collagen disease, cerebral arteritis

Introduction with transient weakness and numbness of her left upper extremity, as well as dysarthria. Six months earlier, she CREST syndrome is a member of the heterogeneous had noticed change in the color of her fingers and toes fol- scleroderma group of autoimmune diseases that cause lowing exposure to cold and subsequent rewarming (Ray- thickening, hardening, and tightening of the connective naud's phenomenon), and heartburn, , and tissue at various sites in the body, and may result in com- swelling of her fingers and toes had occurred from 3 plex disorders. CREST syndrome is characterized by the months before admission. Fiberoptic esophagogastroduo- coexistence of calcinosis, Raynaud's phenomenon, denoscopy revealed multiple proximal esophageal dilata- esophageal hypomotility, sclerodactyly, and telangiecta- tions. Antinuclear antibodies were detected and the an- sia. Usually only three of these five features are considered ticentromere antibody titer was greater than 1:1,280. necessary for the diagnosis of CREST syndrome. Anticen- Based on these clinical and serologic findings, the diagno- tromere antibodies are also frequently detected in patients sis was CREST syndrome. with CREST syndrome.4) Neurological and cerebrovascu- Magnetic resonance (MR) angiography demonstrated lar abnormalities are uncommon in CREST syndrome, un- multiple intracranial aneurysms. Digital subtraction an- like other collagen diseases such as systemic giography identified four aneurysms: An aneurysm 12 mm erythematosus or polyarteritis nodosa.38,56) Only two in diameter arising from the bifurcation of the right mid- patients with CREST syndrome have presented with in- dle cerebral artery (MCA), an aneurysm 16 mm in di- tracranial aneurysm.38,56) ameter arising from the bifurcation of the left MCA, an Here, we describe the clinical features of two patients aneurysm 4 mm in diameter located on the choroidal seg- with CREST syndrome associated with intracranial ment of the left internal carotid artery (ICA), and an aneurysms. aneurysm 2 mm in diameter on the left anterior cerebral artery (ACA) (Fig. 1). The intracranial arteries did not Case Reports demonstrate any irregularities indicative of . Surgical treatment was selected with the patient's in- Case 1: A 53-year-old woman was admitted to our hospital formed consent. The first operation treated the aneurysm of the right MCA because we strongly suspected that the Received February 19, 2009; Accepted April 3, 2009 patient's symptoms were caused by embolization of blood

402 Intracranial Aneurysms in Patients With CREST Syndrome 403 clots from this aneurysm. After right frontotemporal Cerebral angiography revealed a broad-necked craniotomy, a large aneurysm located at the bifurcation of aneurysm located on the insular segment of the left MCA the right MCA was identified, and its neck was closed (Fig. 2). The intracranial arteries did not demonstrate any with three clips. A second operation treated two of the irregularities indicative of vasculitis. Surgical treatment threeaneurysmsontheleftside26daysafterthefirst was selected with informed consent. After left frontotem- operation. After left frontotemporal craniotomy, the poral craniotomy, the aneurysm was identified on the in- aneurysms located on the choroidal segment of the left sular segment of the left MCA. Clipping of the aneurysm ICA and at the bifurcation of the left MCA were obliterat- was not feasible because of its fusiform shape, so wrap- ed with one clip and three clips, respectively. Surgical ping with autologous fascia and coating with fibrin glue treatment was not performed for the aneurysm located on were performed. The postoperative course was unevent- the left ACA because of its small size. The postoperative ful, and she was discharged 8 days after surgery without course was uneventful, and she was discharged 20 days af- neurological deficits. ter the second procedure without neurological deficits. Case 2: A 64-year-old woman was referred to our hospital Discussion for evaluation of an intracranial aneurysm that had been found incidentally during a medical check-up. She had a MR angiography has detected increasing numbers of history of CREST syndrome. Her symptoms included Ray- cerebral aneurysms in patients with collagen diseases, naud's phenomenon, arthritic pain, swelling of her fin- with a total of 48 cases reported up to September 2008, gers, and telangiectasia. Antinuclear antibodies were posi- including 25 patients with systemic lupus erythemato- tive and the anticentromere antibody titer was greater sus,1,10,11,14,18–20,22,25,27,30–33,37,42,43,52) 16 patients with polyar- than 1:1,280. The diagnosis of CREST syndrome had been teritis nodosa,2,8,9,24,28,29,35,36,41,44,45,49–51) 5 patients with scl- established 2 years earlier on the basis of the clinical and eroderma,3,17) and 2 patients with CREST syndrome.38,56) laboratoryfindings,andshehadbeentreatedwithoral To determine the specific features of cerebral aneurysm in steroids. patients with collagen diseases, we reviewed the 48 report- ed cases and identified the following four characteristics. First, multiple aneurysms are common in patients with collagen diseases. The incidence of multiple aneurysms (usually two or three lesions) ranges from 5.3% to 33.3%.13,15,21,26,39,47) Eight of 254 (3.1%) patients without collagen diseases had four aneurysms like our Case 1.54) In contrast, 19 of the 48 (39.6%) patients with collagen dis- eases had multiple aneurysms (Table 1), and 9 had five or more aneurysms. Second, there was a high frequency of fusiform Fig. 1. Case 1. A: Right internal carotid angiogram, an- aneurysms. The frequency of fusiform aneurysms is about teroposterior view, showing an aneurysm of the 1% in patients overall.55) However, fusiform aneurysms oc- right middle cerebral artery (MCA) (arrow). B, C: Left internal carotid angiograms, anteroposterior curred in 14 of the 48 (29.2%) reported patients with colla- view (B) and lateral view (C), showing aneurysms gen diseases (Table 1). A total of 102 cases of fusiform of the left MCA (large arrow), left internal carotid aneurysms arising from the MCA have been described, artery (small arrow), and left anterior cerebral ar- and only 20 patients (19.6%) had aneurysms located on the tery (arrowhead). insular segment like our Case 2.5) Third, aneurysms tended to occur on the distal parts of the arteries in patients with collagen diseases. A total of 14

Table 1 Profiles of reported cerebral aneurysms in patients with collagen diseases

No. of patients Type of collagen disease Multiple Fusiform Distal aneurysms aneurysm aneurysm

SLE 8 6 6 PN 7 6 7 SSc and CREST syndrome 4 2 1

Total (%) 19 (39.6) 14 (29.2) 14 (29.2)

Fig. 2 Case 2. Left internal carotid angiogram, 30 CREST: calcinosis, Raynaud's phenomenon, esophageal hy- degrees left anterior oblique view, showing an pomotility, sclerodactyly, and telangiectasia; PN: polyarteri- aneurysm of the left middle cerebral artery (ar- tis nodosa; SLE: systemic lupus erythematosus; SSc: systemic row). sclerosis.

Neurol Med Chir (Tokyo) 49, September, 2009 404 R. Nakae et al.

Table 2 Glasgow Outcome Scale (GOS) scores in previous cases of collagen disease in patients with rup- tured cerebral aneurysm

No. of patients

Type of collagen disease GOS GOS GOS scores scores score 4–5 2–3 1

SLE 5 0 12 PN 3 1 7 SSc and CREST syndrome 3 0 0

Total (%) 11 (35.5) 1 (3.2) 19 (61.3) Fig. 3 Case 2. Photomicrographs of the resected middle GOS score of 1 indicates death; 2, persistent vegetative state; meningeal artery branch showing fibrous change 3, severe disability; 4, moderate disability; and 5, good recov- of the adventitia (left, arrows) and the media (right, ery. CREST: calcinosis, Raynaud's phenomenon, esopha- arrows). Elastica van Gieson stain, original mag- geal hypomotility, sclerodactyly, and telangiectasia; PN: nification ×100 (left), ×200 (right). polyarteritis nodosa; SLE: systemic lupus erythematosus; SSc: systemic sclerosis. and capillaries.34) Only two cases of cerebral arteritis af- fecting medium to large vessels have been reported.16,19) A of the 48 (29.2%) patients had distal aneurysms (Table 1), patient with lupus erythematosus had focal necrosis and and 12 (85.7%) of these aneurysms were situated on the infiltration by polymorphonuclear cells in a segment of a posterior vessels. Cerebral arteritis is thought to be one of major branch of the MCA.16) Apatienthadafusiform the likely reasons for the formation of aneurysms associ- aneurysm arising from the posterior communicating ar- ated with collagen diseases,6,7,14,17,19,50,56) and vasculitis tery and adjacent posterior cerebral artery histologically usually involves small to medium-sized arteries.34) There- confirmed to be caused by transmural angiitis.19) Cerebral fore, aneurysms may tend to occur at atypical locations in vasculitis in patients with collagen diseases is often patients with collagen diseases. caused by end-organ failure or is associated with systemic Finally, the prognosis is worse after rupture of an vasculitis.12,23,48,53) Furthermore, progressive collagen dis- aneurysm in patients with collagen diseases compared to ease is usually treated by increasing steroid doses and the patients overall. The outcomes of 31 of 39 patients with duration of treatment is longer. Therefore, the vascular collagen disease and ruptured aneurysms were available. damage caused by arteritis and steroids in patients with Good outcome or moderate disability was achieved in 11 collagen disease is paralleled by the clinical severity of patients, but the mortality rate was extremely high, as 19 their disease. The prognosis of CREST syndrome is patients died (Table 2). The poor prognosis may be due to thought to be relatively good,40) suggesting that the rarity the increased frequency of multiple aneurysms with atypi- of cerebral aneurysms in patients with this syndrome is cal form and location, leading to difficulty in treatment. due to the low frequency of cerebral arteritis and long- Vasospasm is also very common after subarachnoid term steroid use. hemorrhage in patients with collagen diseases.46) Making In conclusion, early treatment of CREST syndrome and the prognosis even worse, some patients died of complica- other collagen diseases may prevent arteritis from tions associated with the underlying collagen disease, progressing to affect the intracranial arteries and thus such as infection, congestive , or acute renal reduce the occurrence of aneurysms. The prognosis for failure.9,19,20) patients with collagen diseases after rupture of cerebral The pathogenesis of cerebral aneurysms associated with aneurysm seems to be poor because the multiplicity, atypi- collagen diseases is still unknown, but is thought to be cal morphology, and atypical location of their aneurysms related to focal arteritis affecting small and medium-sized make treatment difficult. Thus, early detection and treat- cerebral vessels,6,7,14,17,19,50,56) as well as vascular fragility ment are important to improve the prognosis. caused by long-term steroid therapy.22) Intracranial vessels lack perivascular support, so are more vulnerable to such References changes,56) and chronic hemodynamic stress acting on the vessel wall may result in focal dilatation and aneurysm 1) Asai A, Matsutani M, Kohno T, Fujimaki T, Takakura K: formation.12) Excision of a branch of the middle meningeal Multiple saccular cerebral aneurysms associated with sys- artery for histological evaluation in our Case 2 revealed fi- temic lupus erythematosus — case report. Neurol Med Chir brous thickening of the media and adventitia indicative of (Tokyo) 29: 245–247, 1989 vasculitis (Fig. 3). This observation suggests that vasculitis 2) Beattie DK, Hellier WP, Powell MP: Stroke-induced cardiovascular changes: a rare cause of death from polyarte- involving the intracranial arteries was the cause of ritis nodosa. Br J Neurosurg 9: 223–226, 1995 aneurysm formation, although the middle meningeal ar- 3) Blaustein HS, Abed A, Leber R, Digiacinto G, Connery C, tery is not a cerebral artery. However, primary central ner- Anagnostopoulos CE: Synchronous intracranial aneurysm vous system involvement by collagen diseases is rare, and clipping and coronary artery bypass grafting in a scleroder- cerebral arteritis tends to mainly involve the small vessels

Neurol Med Chir (Tokyo) 49, September, 2009 Intracranial Aneurysms in Patients With CREST Syndrome 405

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