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A 42-year-old woman with systemic lupus erythematosis (SLE), positive lupus anticoagulant, elevated titers of IgG and IgM anticardiolipin antibody and β2 glycoprotein antibodies, idiopathic thrombocytopenia, and hemolytic anemia presented with menorrhagia and anemia. She received both platelet and red cell transfusions and had an unrevealing endometrial biopsy. She was treated with intravenous immunoglobulin therapy for autoimmune-mediated thrombocytopenia and was taking hydroxychloroquine 200 mg twice daily that was a home medication. She was started on prednisone 60 mg daily. During her hospitalization, she developed a sudden, severe, sharp, and pounding occipital and nuchal headache with sharp shooting pains radiating down the back of the neck. She was alert and oriented with normal cranial nerve function, motor strength, and sensation. Her headache was unsuccessfully treated with fioricet and acetaminophen.
42歲，女性，系統性紅斑狼瘡，狼瘡抗凝物陽性，抗心磷脂抗體IgG、IgM和β2糖蛋白抗體效價增高，特發性血小板減少和溶血性貧血，主要症狀是月經增多和貧血。給予輸注血小板和紅細胞治療、並給予子宮內膜活檢，未見臨床意義。給予靜脈免疫球蛋白治療自身免疫介導的血小板減少症，出院後持續口服羥化氯喹200mg 2/日。開始口服強的松60mg 1/日。住院期間，患者出現突發的嚴重的枕部和頸背部尖銳的重擊樣疼痛伴向下放散至頸後部的銳利的放射痛。查體：神清，定向力正常，顱神經、肌力和感覺正常。口服fioricet（一種治療肌肉緊張性頭痛、收縮性頭痛、偏頭痛的藥。由布他比妥、撲熱息痛、咖啡因等合成。暫無準確中文譯名）和對乙醯氨基酚後頭痛無明顯緩解。
The day after headache onset, a noncontrast head computed tomography revealed a subarachnoid hemorrhage (SAH) extending from the interpeduncular fossa caudally to the cervicomedullary junction (Figure 1). Computed tomographic angiogram of the head and neck revealed a focal left vertebral artery stenosis with poststenotic aneurysmal dilation of the intradural (V4) segment. There were additional multifocal areas of beading and long tapered vessel narrowing involving the M2 division of the left middle cerebral artery and anterior cerebral arteries and M3 division of the right middle cerebral artery (Figure 1). Magnetic resonance brain demonstrated multifocal but posteriorly predominant T2 hyperintense lesions that resembled posterior reversible leukoencephalopathy syndrome (Figure 2). Conventional angiogram confirmed the global small and medium vessel vasculopathy with a left V4 vertebral artery fusiform aneurysm measuring 10.6 mm×5.5 mm distal to the origin of the left posterior inferior cerebellar artery (Figure 2).
第二天，行頭CT檢查提示蛛網膜下腔出血（SAH），從腳間窩向下直到頸延髓交界處（圖1）。頭頸CTA顯示左側椎動脈硬膜內段（V4）局限性狹窄及狹窄後動脈瘤樣擴張。另外左側大腦中動脈M2分支和大腦前動脈以及右側大腦中動脈M3分支有多灶性的串珠樣和長節段逐漸變細的血管狹窄區域（圖1）。頭MRI示多灶但以後部為主的T2高信號病灶類似可逆性後部白質腦病症候群（圖2）。常規的血管造影證實普遍的小血管和中等血管的血管病變，左側椎動脈V4段紡錘狀動脈瘤，大小10.6 mm×5.5 mm，在左側小腦後下動脈起始部的遠端（圖2）。
圖1.狼瘡相關的中樞神經系統血管炎和蛛網膜下腔出血（SAH） A，頭CT提示延髓周邊SAH（黑色箭頭）。B，CTA提示左側椎動脈顱內V4段局限性狹窄和狹窄後擴張（白色箭頭）。C，另外有右側M3分支局部狹窄（箭頭）和左側大腦中動脈M2分支（星號）逐漸變細。
圖2. 頭MRI和DSA提示狼瘡相關的中樞神經系統血管炎。A，FLAIR成像有後部明顯的可逆性後部白質腦病綜合症樣改變的高信號和蛛網膜下腔出血表現。B,普通血管造影顯示小血管長節段的狹窄和擴張（箭）和更遠端串珠樣表現（箭頭）。C，左側椎動脈動脈瘤和基底動脈不規則改變。
She was diagnosed with a lupus vasculitis and resultant aneurysmal dilation of the vertebral artery. The rupture of the vertebral artery aneurysm likely lead to the perimedullary and peripontine SAH. She was started on nimodipine 60 mg 4×daily to prevent vasospasm. Methylprednisolone at a dose of 125 mg was administered for 3 days and transitioned to prednisone 60 mg daily. She continued to have progressive symptoms with worsening headache and mild confusion. She was given 2 infusions of rituximab 1 g separated by 14 days to treat the underlying autoimmune condition. She underwent successful coil embolization of the left vertebral artery aneurysm with preservation of the left posterior inferior cerebellar artery ≈3 weeks after discovery of the SAH. Coiling was delayed to allow for some healing of the vessel and to prevent catheter-induced vasospasm that was apparent on initial conventional angiogram and required intra-arterial verapamil infusion. She had persistent mild to moderate back and neck pain that was alleviated by oxycodone and gabapentin.
診斷為狼瘡性血管炎和椎動脈動脈瘤樣擴張。可能是椎動脈動脈瘤的破裂導致延髓周圍和橋腦周圍的SAH。給予尼莫地平60mg一天四次預防血管痙攣。甲強龍125mg連用3天後改為強的松60mg1/日。患者症狀繼續進展，頭痛更嚴重，並有輕度的意識混亂。14天內分別給予2次利妥昔單抗1g治療基礎的自身免疫性疾病。發現SAH後3周患者成功接受了左側椎動脈動脈瘤彈簧圈栓塞術，保留了左側小腦後下動脈。彈簧圈延期置入可以使血管有所修復並且可以預防導管引起的血管痙攣，這在首次常規血管造影時很明顯，需要動脈內用維拉帕米解痙。患者持續的輕至中度後背和頸痛，羥考酮控釋片和加巴噴丁可以緩解。
Eleven days after coil embolization, she developed rapid onset bilateral iliopsoas, quadriceps, hamstring, and anterior tibialis muscle weakness with sensory loss of pinprick sensation up to the mid thoracic level and urinary retention. Urgent cervical and thoracic spine magnetic resonance imaging revealed the cause of her paraplegia. There was a T2 hyperintense lesion with an associated rim of susceptibility consistent with hemorrhage centered within the left anterior spinal canal at the T4 and T5 levels suggestive of a ruptured intraspinal arterial aneurysm with surrounding hematoma and cord compression. There was extensive abnormal T2 cord signal extending from C5 to the conus. Emergent conventional spinal angiogram demonstrated a radiculopial artery supplying the posterior spinal artery at the left T4 level with a small 1-mm aneurysm and active contrast extravasation into the thecal sac (Figure 3). She underwent emergent T3–T6 laminectomy with intradural exploration and debulking of the intradural hematoma. The left posterior spinal artery aneurysm was surgically obliterated using bipolar coagulation and excision. Repeat magnetic resonance imaging was performed ≈1 week and again 1 month after her SAH. Although she had some posterior circulation infarcts involving the cerebellum possibly related to the vertebral artery coil embolization, the fluid-attenuated inversion recovery hyperintense lesions and previously identified multifocal areas of stenosis were significantly improved. One month after her neurological injuries, she had persistent paraparesis. She was able to move her toes and had some trace. Aneurysmal quadriceps movement but remained wheelchair dependent. She also had debilitating neuropathic pain in the abdomen and legs and persistent fecal and urinary retention.
彈簧圈栓塞11天後，患者出現快速起病的雙側髂腰肌、股四頭肌、縫匠肌和脛前肌無力伴有上至中胸段的針刺覺感覺消失和尿儲留。急診頸胸脊髓磁共振成像揭示了患者截癱的原因。在T4、T5水平椎管左前部中間有個T2高信號病變邊緣與出血信號一致，提示椎管內動脈瘤破裂，周圍形成血腫和脊髓受壓。廣泛的T2異常信號從C5延伸到圓錐。急診脊髓血管造影提示在左側T4水平供應脊後動脈的一根動脈有個小的1mm的動脈瘤造影劑外漏到鞘膜囊（圖3）。立即急診行T3-T6椎體的椎板切除術，硬膜內探查和硬膜內血腫的清除。採用雙極電凝切除方法手術切除了左側脊後動脈動脈瘤。1周後和SAH 1月後複查了核磁共振。雖然患者出現累及小腦可能與椎動脈彈簧圈栓塞有關的後循環梗死，FLAIR上高信號病灶和以前確定的多發狹窄區域明顯改善。神經系統症狀出現1月後，患者持續有截癱。能夠動大腳趾，股四頭肌輕微運動，但仍需要輪椅。患者腹部和腿存在神經病理性疼痛，持續的尿便瀦留。
圖3. 狼瘡相關的脊動脈動脈瘤和脊髓損傷。A和B，頸胸脊髓高信號改變，T4-T5節段出血性病灶，C為正常的上段頸脊髓。D,脊髓常規血管造影提示為脊後動脈供血的根動脈上有個小動脈瘤並有活動性滲血。
The presentation and radiographic findings of this case are most consistent with a lupus vasculitis causing multifocal constriction of the cerebral vessels. There were focal areas of stenosis in the more proximal vessels and a beading of the distal smaller vessels. There were additional long regions of tapered vessel narrowing. The associated vertebral artery aneurysm was fusiform and distal to a longer segment of narrowing. The cause of the aneurysm was a presumed combination of vasculitic weakening of the vessel wall and poststenotic dilation of the vertebral artery. Although vasospasm related to SAH is possible, this is often seen several days after SAH unlike in this case where the vessel changes seemed coincident with the SAH. In addition, the cooccurrence of pronounced changes in the anterior circulation and posterior reversible leukoencephalopathy syndrome–like changes in the brain parenchyma were more suggestive of lupus vasculitis. The most debilitating event was the spinal hemorrhage related to a posterior spinal artery aneurysm found after she became paraplegic.
本患者的臨床表現和影像學結果非常符合狼瘡性血管炎引起的腦血管多灶性收縮。更近端的血管局灶性的狹窄遠端更細的血管串珠樣改變。還有長節段的逐漸變細的血管狹窄區域。伴發的椎動脈動脈瘤紡錘型位於很長的狹窄節段的遠端。動脈瘤形成的原因估計血管壁血管炎性削弱和椎動脈狹窄後擴張綜合作用的結果。雖然可能有SAH相關的血管痙攣，這種血管痙攣常在SAH後數天發生，不像本例血管的改變與SAH伴發的。而且前循環血管的明顯變化和腦實質可逆性後部白質腦病綜合症樣改變並存更提示狼瘡性血管炎。患者截癱後發現的脊後動脈動脈瘤引起的脊髓出血是患者病情最嚴重的罪魁禍首。
Central Nervous System Manifestations of SLE
SLE的中樞神經系統表現
SLE can affect the central nervous system producing heterogenous disorders of the brain and spinal cord. When combined with psychosis or mood disturbance, these central nervous system manifestations of lupus are often grouped into the broad and nondescript category of neuropsychiatric lupus. However, this grouping does not inform the variable nature of lupus-associated central nervous system pathology. SLE can present with seizures, encephalopathy, headache, psychosis, and focal neurological deficits related to cerebral infarction and transverse myelitis. Brain magnetic resonance imaging abnormalities associated with SLE vary but have been observed in 40% to 50% of patients with SLE. Small or punctate juxtacortical T2 fluid-attenuated inversion recovery hyperintense lesions and periventricular and subcortical white-matter lesions have been observed. SLE can present with more extensive white-matter lesions and posterior reversible leukoencephalopathy syndrome.1
SLE可影響中樞神經系統產生腦和脊髓的各種症狀。當與精神病或情緒障礙並存時，狼瘡的這些中樞神經系統表現通常會被劃歸到神經精神性狼瘡這一寬泛的無特徵的大類中。但這分類不能體現出狼瘡相關的中樞神經系統病理改變的各種特徵。SLE可以表現為癲癇、腦病、頭痛、神經症和腦梗死及橫貫性脊髓炎引起的局灶性神經功能缺損。SLE相關的腦磁共振異常表現多種多樣，見於40-50%的SLE患者。觀察到的有T2、FLAIR上小的或斑點狀近皮層的高信號病灶和腦室旁及皮層下白質的病變。SLE可表現為更廣泛的白質病變和可逆性後部白質腦病症候群。
SLE confers an increased risk of ischemic stroke. Embolic strokes may accompany elevated antiphospholipid antibodies or Libman–Sacks endocarditis. In addition, small vessel lacunar and large vessel atheromatous stroke subtypes have also been reported in SLE.2 However, the association between SLE and hemorrhagic stroke, including SAH, remains less defined. In 1 study, 5.6% of patients with SLE developed either ischemic stroke (8 of 234), cerebral hemorrhage (2 of 234), or SAH (3 of 234).3
SLE增加缺血灶卒中的風險。腦栓塞可能伴發抗磷脂抗體增高或Libman–Sack心內膜炎。而且，也有在SLE中小血管的腔隙性梗死和大血管動脈粥樣硬化性卒中亞型的報導。但是SLE與出血性卒中包括SAH的關係仍不確定。有項研究，SLE患者有5.6%出現缺血性卒中（8/234），腦出血（2/234）或SAH（3/234）。
Although SLE has been associated with vasculitis, the combination of SAH and vasculitis is a rare but often devastating occurrence. Several case reports describe SLE-associated cerebral arteriopathy and arteritis.1,4 Cerebral arteriopathy occurs in ≈6% to 13% of SLE cases. In a postmortem analysis of 88 patients, the predominant pathology was a small-vessel angiopathy with intimal proliferation, mucoid hyperplasia, and hyaline deposition. This can be accompanied by smallvessel obliteration with fibrin thrombus. Rarely, additional perivascular inflammation was found supporting the existence of an accompanying vasculitis. The existence of antiphospholipid antibodies seemed to confer an increased risk of vasculopathy.5
雖然認為SLE與血管炎相關，SAH與血管炎同時存在是個少見的疾病，但卻常常是災難性的。有幾例病例報導描述了SLE相關的腦動脈病和動脈炎。腦動脈病在SLE中的發病率大概是6-13%。一項88例患者的屍檢分析表明，主要的病理改變是小血管動脈病，有內膜的增殖，粘蛋白的增生和透明物質的沉積。也見小血管的閉塞和纖維蛋白性血栓。發現了額外的血管周圍炎症，這很少見，支持同時存在血管炎。抗磷脂抗體的存在似乎引起了血管病的風險增加。
Aneurysmal SAH 動脈瘤性SAHAlthough the incidence of SAH in SLE is lower than that of ischemic stroke,6 1 retrospective analysis found that 3.9% of hospitalized patients with SLE (10 of 258 cases) had SAH.7 In a larger 1077-patient retrospective series, 1% of patients with SLE were diagnosed with SAH.8 Both aneurysmal SAH and nonaneurysmal SAH have been described in the literature involving the anterior and posterior cerebral circulations.9 In a series of 39 previously published SLE-associated SAH cases, 3 patterns of disease were described—distal fusiform aneurysms with either unusual locations or additional vessel abnormalities, multiple saccular aneurysms, or angiographically negative SAH with poor outcome. In the latter category, 5 of the 11 nonaneurysmal SAH SLE patients either died or had significant persistent morbidity.9 Focal transmural angiitis at the location of fusiform aneurysm rupture has been described in a patient with SLE and SAH. These changes accompanied additional vessel irregularities.10
雖然在SLE中SAH的發生率比缺血性卒中要低，一項回顧性研究發現3.9%的SLE住院病人（258例中有10例）患有SAH。一項更大的入組1077例患者的回顧性分析中，有1%的SLE患者診斷為SAH。文獻中描述的既有動脈瘤性SAH也有非動脈瘤性SAH，累及前後循環。在之前發表的包括39例SLE相關SAH的病例系列中，描述了三種類型動脈瘤，位於不常見的部位或者有額外的血管畸形的梭形動脈瘤，多發的囊性動脈瘤，或預後差的血管造影陰性的SAH。在後一種亞型中，11例非動脈瘤性SAH的SLE患者中有5例或者死亡或者遺留明顯的持久的功能殘疾。有一例SLE發生SAH的患者被描述存在梭形動脈瘤破裂處的局部透壁動脈炎。這些病理改變伴有其他的血管不規則改變。
Although steroids and hydroxychloroquine are used as maintenance therapy in patients with lupus, flares associated with vasculitis should be treated promptly and often require a combination of higher dose steroids, intravenous immunoglobulin therapy, or plasmapheresis. SLE-associated cerebral arteritis may necessitate more aggressive management with immunomodulatory therapy like rituximab or belimumab.2
雖然皮質類固醇和羥化氯喹用於狼瘡患者的維持治療，與血管炎相關的病情惡化應馬上治療，常常需要給予更高劑量的激素和靜脈免疫球蛋白聯合應用或與血漿置換合用。SLE相關腦動脈炎可能需要更積極的應用免疫調節治療如利妥昔單抗或貝利單抗。
TAKE-HOME POINTS
• Aneurysmal subarachnoid hemorrhage and central nervous system vasculitis are rare but severe manifestation of SLE often presenting with headaches, neck pain, or encephalopathy.
• Magnetic resonance imaging and angiography may reveal parenchymal hyperintense lesions and varying degrees of beaded and tapered vessel constriction.
• Given the potential for significant morbidity and mortality, aggressive and early treatment with steroids and immunomodulatory agents may be needed to halt the progression of disease.
總 結
l 動脈瘤性蛛網膜下腔出血和中樞神經系統血管炎是SLE很罕見但很嚴重的症狀，表現為頭痛、頸痛或腦病。
l 磁共振和血管成像會表現出腦實質高信號病變和不同程度的串珠樣和逐漸變細的血管收縮樣改變。
l 考慮到其明顯的致殘致死的可能性，需要積極的和早期給予激素和免疫調節藥物來阻斷疾病的進展。