A 48-year-old woman with recent diagnosis of nonischemic cardiomyopathy and longstanding history of asthma and allergic rhinitis without additional vascular risk factors had intermittent chest pain and dyspnea for 6 weeks, treated with antibiotics and oral steroids without benefit. Subsequently, she developed bilateral leg edema, orthopnea, and chest pain, and was hospitalized twice at another institution. Transthoracic echocardiogram (TTE) demonstrated an ejection fraction (EF) of 30%. Cardiac catheterization was normal. CT of the chest showed a large pericardial effusion (~300 mL) and bilateral pleural effusions. She had urgent pericardiocentesis and right thoracentesis, and was transferred to our institution for further evaluation and care.

患者為48歲女性，因“間歇性胸痛和呼吸困難6周，抗生素及激素治療無效”就診。近期非缺血性心肌病史，并且有長期哮喘和過敏性鼻炎史，無其他血管性危險(xiǎn)因素。之后患者出現(xiàn)雙下肢水腫、端坐呼吸和胸痛，并在外院住院兩次。經(jīng)胸心臟超聲顯示射血分?jǐn)?shù)30%；心導(dǎo)管造影檢查正常；胸部CT提示大量心包積液（300 mL）以及雙側(cè)胸腔積液。患者接受了緊急的心包穿刺和右側(cè)胸腔穿刺并轉(zhuǎn)診至我院行進(jìn)一步評估和診療。

Admission ancillary blood tests showed a C-reactive protein of 12.3 mg/dL and erythrocyte sedimentation rate of 38 mm/h. Leukocyte count was 15.2 K/UL with30% eosinophils (EO%). Subsequent blood count showed a leukocyte count of 13.0–12.3 to 11.5– 13.6 K/UL and EO 33–34 to 29%–31%, respectively.

入院時(shí)血液學(xué)輔助檢查提示CRP 12.3 mg/dL，紅細(xì)胞沉降率38mm/h。白細(xì)胞計(jì)數(shù)15.2 K/UL，嗜酸性粒細(xì)胞30%（EO%）。隨后的血細(xì)胞計(jì)數(shù)顯示白細(xì)胞和嗜酸性粒細(xì)胞分別為13.0–12.3至11.5–13.6 K/UL ，33–34至29%–31%。

On the day of admission, the patient had an episode of blurriness of the right half of her visual field that was further restricted to right upper visual field blurriness. Soon thereafter, she had a migrating right hemibody numbness beginning on her right foot, propagating to the right side of her face. The whole episode lasted 5 minutes, and resolved spontaneously without sequela. Neurologic examination conducted 3 days after index neurologic event was normal.

入院當(dāng)天，患者突然出現(xiàn)右側(cè)視野模糊，隨后視野模糊嚴(yán)格局限于右上象限。緊接著出現(xiàn)由右足發(fā)展至右側(cè)面部的遷移性右側(cè)偏身麻木。整個(gè)發(fā)作過程持續(xù)5分鐘，自發(fā)性完全緩解無任何后遺癥。此次發(fā)作后3天神經(jīng)系統(tǒng)檢查均為正常。

1. Where would you localize the neurologic deficit?

1. 神經(jīng)系統(tǒng)功能缺損定位于哪里？

Our patient most likely experienced a homonymous hemianopia consistent with a contralateral retrochiasmatic lesion. Homonymous hemianopia results from lesions of the occipital lobe (~40%), parietal lobe (~30%), temporal lobe (~25%), or optic tract and lateral geniculate body (~5%).¹

該患者很可能發(fā)生同向性偏盲，提示病灶在對側(cè)視交叉以后的部位。同向性偏盲可定位于枕葉（~40%）、頂葉（~30%）、顳葉（~25%）或視束和外側(cè)膝狀體（~5%）^[1]。

The associated transient right-sided paresthesias further narrow the anatomic localization to the left posterior parieto-occipital cortex.

與之相關(guān)的短暫性右側(cè)感覺異常進(jìn)一步將解剖學(xué)定位縮窄至左后頂枕交界區(qū)皮層。

1. What is your differential diagnosis and what further investigations would you recommend?

1. 您的鑒別診斷和推薦的進(jìn)一步檢查是什么？

Differential diagnosis includes TIAs or ischemic stroke with rapidly improving deficits; seizures; migrainous phenomena; or amyloid spells, the latter characterized by spreading negative (weakness/numbness) and positive (paresthesias) manifestations of brief duration (seconds to minutes) described in some patients with cerebral amyloid angiopathy.²

鑒別診斷包括TIA或癥狀迅速改善的缺血性卒中；癲癇；偏頭痛樣癥狀；或腦淀粉樣蛋白發(fā)作，后者在一些CAA患者中以短暫性（數(shù)秒或數(shù)分鐘）播散性陰性（無力/麻木）或陽性（感覺異常）癥狀為臨床特征^[2]。

Our patient had a history of asthma and evidence of involvement of at least 2 systems, namely nonischemic cardiomyopathy with depressed EF and bilateral pleural and pericardial effusions. The presence of marked blood eosinophilia was a key clinical clue. Diagnostic considerations in patients presenting with multiorgan system dysfunction in the presence of eosinophilia include the following：

1. Eosinophilic granulomatosis with polyangiitis (EGPA)

2. Certain infectious disorders, such as coccidiomycosis or filarial infection by the nematodes Wuchereria bancrofti, Brugiamalayi, or Brugiatimori

3. Loeffler endocarditis, a form of eosinophilic myocarditis associated with endomyocardial fibrosis and recurrent thromboembolic events linked to eosinophilic leukemia, carcinoma, lymphoma, or infections

4. Hypereosinophilic syndrome, characterized by persistent blood and bone marrow eosinophilia with involvement of one or more organ systems (most commonly heart, skin, CNS, gastrointestinal system, or spleen) in the absence of a more definitive diagnosis.

該患者有哮喘病史以及至少2個(gè)系統(tǒng)受累的證據(jù)，即非缺血性心肌病伴EF降低以及雙側(cè)胸腔和心包積液。明顯的嗜酸性粒細(xì)胞增多癥的出現(xiàn)是關(guān)鍵的臨床線索。多器官系統(tǒng)功能障礙伴嗜酸性粒細(xì)胞增多患者的診斷需考慮以下幾種：

1. 嗜酸性肉芽腫性多血管炎（EGPA）

2. 某些感染性疾病，例如球孢子菌病，或由班氏吳策線蟲、馬來絲蟲或帝汶布魯絲蟲引起的血絲蟲感染。

3. Loeffler心內(nèi)膜炎，嗜酸性粒細(xì)胞性心肌炎的一種形式，與心內(nèi)膜纖維化和反復(fù)的血栓栓塞事件相關(guān)，而這些與嗜酸性粒細(xì)胞白血病、惡性腫瘤、淋巴瘤或感染有關(guān)。

4. 嗜酸性粒細(xì)胞增多綜合征，以血液和骨髓中嗜酸性粒細(xì)胞增多為特征，伴一個(gè)或多個(gè)器官系統(tǒng)受累（多為心臟、皮膚、中樞神經(jīng)系統(tǒng)、胃腸道系統(tǒng)或脾臟），而無其他確定診斷證據(jù)。

A thorough history and physical examination, including detailed skin examination, are the most important first steps to further narrow the differential diagnosis. In terms of diagnostic testing, MRI was helpful in determining whether an ischemic or infiltrative CNS disease was present. Transbronchial biopsies from the left upper and right lower lobes demonstrated a dense eosinophilic infiltrate with necrotic debris. Bone marrow biopsy was performed to rule out a primary hematologic process, and showed hypereosinophilia (31%) but otherwise normal cell morphology (figure, D).

一系列詳細(xì)的病史采集和體格檢查，包括細(xì)致的皮膚檢查，是進(jìn)一步縮小鑒別診斷范圍的最重要的第一步。就診斷性檢查而言，MRI有助于判斷是否存在缺血性或浸潤性中樞神經(jīng)系統(tǒng)疾病。左上和右下肺葉的經(jīng)支氣管活檢顯示致密的嗜酸性粒細(xì)胞浸潤伴壞死改變。骨髓活檢可用于排除原發(fā)性血液系統(tǒng)疾病，其結(jié)果顯示嗜酸性粒細(xì)胞增多（31%）和細(xì)胞形態(tài)正常（圖D）。

Immunoglobulin E was 331IU/mL. Other ancillary investigations including antineutrophil cytoplasmic antibodies (ANCA), antinuclear antibody (ANA), rheumatoid factor, and complement C3 C4 were normal. Infectious workup was negative for Aspergillus, Blastomyces, Coccidiodes, Cryptococcus, Histoplasma, Strongyloides, and HIV antibodies, and hepatitis A, B, C panel was unremarkable. Follow up TTE showed mild systolic dysfunction with an EF of 45% and a small pericardial effusion. Cardiac MRI demonstrated patchy fibrosis of the basal and inferior septum suggestive of myocarditis with an EF of 28.9% (figure, A). Brain MRI demonstrated an irregular area of restricted diffusion-weighted image (DWI) in the posterior left temporo-parieto-occipital region indicative of subacute ischemia. There was also a trace amount of subarachnoid blood in this region in the fluid-attenuated inversion recovery sequences. Magnetic resonance angiogram (MRA) of the intracranial vasculature was normal (figure, B and C).

免疫球蛋白E 331 IU/mL。其他的輔助檢查包括抗中性粒細(xì)胞胞漿抗體（ANCA）、抗核抗體（ANA）、類風(fēng)濕因子和補(bǔ)體C3、C4均為正常。曲霉菌、芽生菌、球孢子菌、隱球菌、組織胞漿菌、類圓線蟲相關(guān)感染檢查為陰性，HIV抗體以及甲肝、乙肝、丙肝檢查無特殊發(fā)現(xiàn)。經(jīng)胸心臟超聲顯示輕度收縮功能障礙，射血分?jǐn)?shù)45%，以及少量心包積液。心臟MRI顯示基底膜和下隔膜斑片狀纖維化，提示心肌炎，射血分?jǐn)?shù)28.9%（圖A）。頭顱MRI顯示左后顳頂枕部存在不規(guī)則的彌散受限區(qū)域，提示亞急性缺血性卒中。同時(shí)這個(gè)區(qū)域在FLAIR序列上也顯示了蛛網(wǎng)膜下腔出血的跡象。顱內(nèi)血管MRA正常（圖B和C）。

1. What is your most likely diagnosis?

1. 最可能的診斷是什么？

圖：影像發(fā)現(xiàn)和活檢病理

（A） 心臟MRI顯示基底和中下隔膜斑片狀纖維化，提示心肌炎。左室大小正常，伴嚴(yán)重收縮功能障礙。中量的心包積液，右房收縮期塌陷，右側(cè)大量胸腔積液和左側(cè)中量胸腔積液。（B）頭顱MRI顯示左后顳枕部不規(guī)則彌散受限區(qū)域，提示亞急性腦梗死。同時(shí)這個(gè)區(qū)域在FLAIR序列上也顯示了蛛網(wǎng)膜下腔出血的跡象。（C） 顱內(nèi)血管MRA正常。（D） 經(jīng)支氣管鏡活檢顯示小血管非壞死性嗜酸性粒細(xì)胞性血管炎(×200)。

Tying the seemingly disparate symptoms together led to a final diagnosis of EGPA, known eponymously as Churg-Strauss syndrome, a rare systemic vasculitis affecting small and medium-sized vessels. The American College of Rheumatology established 6 criteria for the diagnosis of EGPA: (1) asthma; (2)＞10% eosinophils on complete blood count; (3) mononeuropathy, mononeuropathy multiplex, or polyneuropathy; (4) migratory or transient pulmonary opacities detected radiographically; (5) paranasal sinus abnormalities; and (6) biopsy containing a blood vessel with extravascular eosinophilic accumulation. The presence of 4 of more of these criteria carries a sensitivity of 85% and a specificity of 99.7% for EGPA.³

將看似無關(guān)的癥狀聯(lián)系在一起，得到了EGPA的最終診斷，也就是Churg-Strauss綜合征，一種罕見的系統(tǒng)性血管炎，累及中小血管。美國風(fēng)濕病學(xué)會設(shè)定的6條EGPA診斷標(biāo)準(zhǔn)包括：（1）哮喘；（2）全血細(xì)胞計(jì)數(shù)中嗜酸性粒細(xì)胞＞10%；（3）單神經(jīng)病、多發(fā)性單神經(jīng)病或多發(fā)性神經(jīng)?。唬?）影像學(xué)可見的遷延性或短暫性肺部陰影；（5）鼻竇異常；（6）活檢發(fā)現(xiàn)伴血管外嗜酸性粒細(xì)胞聚積的血管。符合以上4條或以上標(biāo)準(zhǔn)對于EGPA的敏感度為85%，特異度99.7%[3]。

An older clinically oriented diagnostic scheme referred to as the Lanham criteria listed 3 criteria as diagnostic for EGPA: (1) asthma; (2) peak peripheral eosinophilia .1,500 cells/mL; and (3) systemic vasculitis involving 2 or more extrapulmonary systems.4

先前的基于臨床診斷的Lanham標(biāo)準(zhǔn)提出EGPA的3條診斷標(biāo)準(zhǔn)：（1）哮喘；（2）外周血嗜酸性粒細(xì)胞峰值＞1，500/ μL；（3）累及2個(gè)或更多肺外系統(tǒng)的系統(tǒng)性血管炎[4]。

Under either scheme, our patient can be definitively diagnosed with EGPA given her history of asthma, peripheral blood eosinophilia .10% and .1,500 cells/mL, systemic involvement of the brain and the heart, radiographically transient pulmonary opacities, and transbronchial biopsy showing small vessel non-necrotizing eosinophilic vasculitis.

考慮到哮喘病史、外周血嗜酸性粒細(xì)胞大于10%及大于1，500/ μL、腦和心臟系統(tǒng)性損害、影像學(xué)可見的短暫的肺部陰影、經(jīng)支氣管活檢提示小血管非壞死性嗜酸性粒細(xì)胞性血管炎，不論哪種診斷標(biāo)準(zhǔn)，該患者都可以確診為EGPA。

1. What is the pathophysiology of neurologic involvement and how do you treat this patient?

1. 神經(jīng)系統(tǒng)受累的病理生理機(jī)制是什么，如何治療這個(gè)患者？

Our patient’s condition illustrates many teaching points for the practicing neurologist, with initial consultation often occurring in the context of an unknown multiorgan system process possibly related to a vasculitis. These patients may have already been seen by other specialties without a unifying diagnosis being identified and the clinical question posed to the neurologist is often related to establish possible cause of underlying encephalopathy, polyneuropathy, or stroke. Thorough attention to the consultation question is often rewarded; beware of accidentally blinding yourself to the patient’s true condition by failing to look at the patient’s condition as a whole. Pertinent positives to remember when reviewing a new patient’s history include asthma, renal insufficiency, cardiac involvement, and peripheral eosinophilia. If any of thesea represent and fit well with the diagnostic schemes, treatment should be initiated immediately.

該病例為神經(jīng)內(nèi)科實(shí)習(xí)醫(yī)生提供了很多教學(xué)點(diǎn)，最初的病史詢問通常是在不知與血管炎相關(guān)的多器官系統(tǒng)受累情況下進(jìn)行，。這些患者可能已經(jīng)就診于其他?？漆t(yī)生，沒有獲得一個(gè)統(tǒng)一的確定診斷，而神經(jīng)科醫(yī)生需要解決的臨床問題通常是為潛在的腦病、多神經(jīng)病或卒中尋找可能的病因。對于就診原因的詳細(xì)詢問經(jīng)常會帶來回報(bào)；需警惕不將患者看作一個(gè)整體而看不到患者的真實(shí)情況。當(dāng)對一位新患者進(jìn)行詢問病史時(shí)，需牢記以下相關(guān)的陽性事件：哮喘、腎功能不全、心臟受累、外周嗜酸性粒細(xì)胞增多癥等。任何一項(xiàng)出現(xiàn)并非常符合診斷標(biāo)準(zhǔn)，需要立即開始治療。

Neurologic complications of EGPA are common, with peripheral nervous system involvement in 53%– 78% of patients, and CNS involvement in 6%– 39%.5 Stroke in EGPA has been attributed to the release by the eosinophils of a major basic protein that damages the endothelium causing thrombosis and embolism, and eosinophil cationic protein that creates functioning nonselective pores in the neural membrane and potentiates a hypercoagulable state leading to thrombosis. Subacute progressive dementia and acute encephalopathy have been attributed to the diffuse toxin-mediated neuronal damage and direct infiltration of eosinophils into nervous tissue.6 In cases of CNS involvement, demyelinating processes should be considered in the differential diagnosis because those can mimic small vessel vasculitis in MRI.7

EGPA的神經(jīng)系統(tǒng)并發(fā)癥非常常見，53%-78%的患者有周圍神經(jīng)系統(tǒng)受累，中樞神經(jīng)系統(tǒng)受累占6-39%[5]。EGPA相關(guān)的腦卒中主要是由于嗜酸性粒細(xì)胞釋放一種主要的基質(zhì)蛋白，破壞血管內(nèi)皮進(jìn)而導(dǎo)致血栓形成及栓塞，或者是由于嗜酸性粒細(xì)胞陽離子蛋白導(dǎo)致神經(jīng)元細(xì)胞膜產(chǎn)生功能性非選擇性孔洞引起高凝狀態(tài)導(dǎo)致血栓形成。亞急性進(jìn)展性癡呆和急性腦病的發(fā)生則是由于彌漫性毒素介導(dǎo)的神經(jīng)損傷和嗜酸性粒細(xì)胞對神經(jīng)組織的直接浸潤所致[6]。在中樞神經(jīng)系統(tǒng)受累的病例中，鑒別診斷中需考慮脫髓鞘病變，因?yàn)槊撍枨试诤舜胖锌梢阅７滦⊙苎椎谋憩F(xiàn)[7]。

The 5-factor score, a measure of vasculitic disease activity and prognosis prior to treatment initiation, is based on the presence or absence of 5 clinical factors: (1) age＞65 years; (2) cardiac insufficiency; (3) renal insufficiency; (4) gastrointestinal involvement; and (5) lack of ear, nose, and throat manifestations.8

用于評估血管炎活動(dòng)性和治療前預(yù)后評估的5-因素評分系統(tǒng)，包括以下5種臨床因素：（1）年齡＞65歲；（2）心功能不全；（3）腎功能不全；（4）胃腸道受累；（5）缺乏耳、鼻、和咽喉部表現(xiàn)[8]。

The mainstay of therapy of EGPA, regardless of the 5-factor score, consists of systemic glucocorticoids, usually oral prednisone 1 mg/kg daily. For acute multiorgan disease, consideration may be given to high-dose methylprednisolone (i.e., 1,000 mg daily) for several days prior to oral steroids. The vast majority of patients with EGPA achieve remission with steroid therapy alone. Often a slow 12- to 18-month glucocorticoid taper is required, with the majority of patients ultimately requiring long-term low-dose therapy.⁹

不論5因素評分如何，EGPA治療的基石是系統(tǒng)性糖皮質(zhì)激素治療，通?？诜?qiáng)的松1mg/kg/日。對于急性多器官病變，應(yīng)當(dāng)考慮在口服激素前給予數(shù)日大劑量甲基強(qiáng)的松龍沖擊治療（例如1000mg/日）。大多數(shù)EGPA患者單獨(dú)激素治療后可以獲得緩解。通常糖皮質(zhì)激素需要在12至18個(gè)月內(nèi)緩慢減量，最終大部分患者需小劑量激素長期維持治療。

If the 5-factor score is 1 with mild organ involvement, azathioprine or methotrexate are usually added to the glucocorticoid regimen. If the 5-factor score is ≥1 with severe multiorgan involvement, monthly cyclophosphamide can be added. If the serum ANCA is positive, it is reasonable to add cyclophosphamide even with a 5-factor score of 0, as these patients frequently go on to develop renal insufficiency, peripheral neuropathy, and systemic vasculitis.10

如果5-因素評分為1分且伴輕度臟器受累，激素治療方案中需加入硫唑嘌呤或甲氨蝶呤。如果5因素評分≥1分且伴有嚴(yán)重的多臟器受累，需每月添加環(huán)磷酰胺治療。如果血清ANCA陽性，即使5因素評分為0分添加環(huán)磷酰胺仍是合理的，因?yàn)檫@些患者通常會發(fā)展為腎功能不全、周圍神經(jīng)病和系統(tǒng)性血管炎。

For our patient, a burst of high-dose methylprednisolone, followed by an oral prednisone taper, quickly controlled her symptoms, with the eosinophil percentage dropping to＜1% over a few days. Symptomatically, our patient seemed to require a dose of prednisone of 30 mg daily, with efforts to further taper limited by recurrent asthma attacks, dyspnea on exertion, and chest pain. With a 5-factor score of 2 for cardiac and renal insufficiency, cyclophosphamide induction has been planned in the near future to perhaps spare her continued relatively high-dose glucocorticoids. She had no recurrent ischemic events 1 month after hospital discharge. Her neurologic examination was unremarkable, and she has remained on aspirin 81 mg daily for secondary stroke prevention.

該患者，給予大劑量甲基強(qiáng)的松龍沖擊治療，隨后口服潑尼松，迅速控制了癥狀，表現(xiàn)為數(shù)日內(nèi)嗜酸性粒細(xì)胞百分比降至＜1%。就癥狀控制方面來說，該患者需要30mg/d的強(qiáng)的松，因哮喘復(fù)發(fā)、出現(xiàn)勞累性呼吸困難和胸痛而限制了進(jìn)一步減量。因心臟和腎功能不全，其5-因素評分為2分，，為此該患者近期計(jì)劃進(jìn)行環(huán)磷酰胺誘導(dǎo)治療，可能可以減少其相對較高的糖皮質(zhì)激素的劑量。患者出院后1個(gè)月內(nèi)沒有缺血性卒中事件再發(fā)，神經(jīng)系統(tǒng)檢查無陽性發(fā)現(xiàn)，并且口服阿司匹林（81mg/日）進(jìn)行卒中二級預(yù)防。