第一部分：临床表现
A 73-year-old man was admitted for evaluation of acute ischemic strokes. His medical history was notable for pulmonary sarcoidosis treated with oral prednisone 40 mg daily, type 2 diabetes mellitus, hypertension, and hyperlipidemia. Approximately 1 month prior to admission, he underwent elective right total knee arthroplasty at an outside institution and 1 week postoperatively developed acute delirium and fluctuating fevers. No infectious cause was identified. His mental status continued to decline and head MRI was obtained (figure, A), showing small acute infarcts in multiple vascular territories.
73岁男性，因诊断“急性缺血性脑卒中”入院。既往病史包括：肺结节病，口服泼尼松 40mg /日 治疗，2型糖尿病、高血压病及高脂血症。距此次入院约1月前，患者曾于外院行择期右侧全膝关节置换术，并于术后1周出现了急性谵妄和波动性发热，未发现明确的感染病因。患者的精神状况逐步下降，头颅MRI检查可见多血管供血区的多发急性小梗死灶。
He began having episodes of forced eye deviation and behavioral arrest lasting less than 30 seconds each. He was urgently admitted to our hospital and levetiracetam was started empirically, without recurrence of presumed seizures. He complained only of mild headache and right knee pain. On examination, he was hemodynamically stable and afebrile. He was encephalopathic and had mild right leg weakness, but the rest of the neurologic examination was nonfocal. There was no meningismus. EEG showed mild diffuse slowing but no epileptogenic activity. Complete blood counts, electrolytes, lactate, and sedimentation rate were within normal limits. Chest CT showed stable findings consistent with his diagnosis of pulmonary sarcoidosis, but no acute pathology or evidence of active infection.
患者开始出现发作性眼偏斜和活动障碍，每次持续时间小于30s。立即将患者收治入院，先经验性给予左乙拉西坦治疗，患者再无可疑痫性发作，仅诉轻微头痛和右膝关节疼痛。体查：病人血流动力学稳定，无发热，存在脑病及右下肢轻度乏力，余神经系统体查未见阳性定位体征，脑膜刺激征阴性。脑电图提示轻度的弥漫性慢波、无癫痫样电活动。血常规、电解质、乳酸及红细胞沉降率均在正常范围。胸部CT支持肺结节病，没有活动性病灶，也无证据支持存在急性感染。
：Questions for consideration:
1. What are the potential causes of the infarcts?
2. What additional workup is necessary?
：思考问题：
1.引起患者出现脑梗死的可能病因有哪些？
2.患者还应行哪些检查？
Figure Axial head MRI shows multifocal acute infarcts and magnetic resonance angiogram (MRA) showscerebral vasculature changes before and after treatment with antifungal therapy
图：头颅MRI横断面提示多发急性脑梗死，磁共振血管成像（MRA）示抗真菌治疗前后颅内血管的变化。
(A) Axial diffusion-weighted (top row) head MRI shows restricted diffusion in multiple vascular territories (arrows), including the distribution of bilateral anterior cerebral arteries, right middle cerebral artery, and right posterior cerebral artery. The areas of restricted diffusion show corresponding hypointensity on apparent diffusion coefficient imaging (bottom row), consistent with acute ischemic infarcts. (B) Head MRA shows luminal irregularity of the bilateral posterior cerebral arteries and branches of the right middle cerebral artery (asterisks), consistent with vasculitis. (C) Repeat head MRA after 10 days of antifungal treatment shows interval resolution of the previously visualized irregularities of the intracranial vessels.
（A）头颅MRI轴向弥散加权成像（DWI）示多血管供血区多发弥散受限（箭头处），包括双侧大脑前动脉、右侧大脑中动脉、右侧大脑后动脉。这些弥散受限异常信号在ADC上为低信号，提示为急性缺血性脑梗死。（B）头颅MRA示双侧大脑后动脉和右侧大脑中动脉管腔不规则（星号），提示为血管炎。（C）抗真菌治疗10天后复查头颅MRA提示治疗前明显的颅内血管不规则病变较前好转。
第二部分：鉴别诊断
Acute strokes involving multiple vascular territories can result from numerous etiologies, but are most suggestive of a proximal source of emboli or a diffuse vasculitic process. This distribution of infarcts would not be seen with single artery-to-artery emboli, large vessel stenosis, or chronic small vessel disease. Cardioembolic sources must be ruled out in such cases. Paroxysmal atrial fibrillation could be a contributing factor for emboli, and the presence of a patent foramen ovale could be relevant in a postoperative knee patient at risk for deep vein thrombosis. The presence of fever and encephalopathy is very atypical for most ischemic strokes. Infectious sources such as meningitis must be considered, even in the absence of meningismus. In the setting of immunosuppression, infective endocarditis producing septic emboli is also a possibility. Vasculitis could present with multiple areas of infarct, and the patient was predisposed to autoimmune disease given the history of sarcoidosis. Venous infarcts due to cerebral venous sinus thrombosis warrant consideration, especially in a patient with headache and new-onset seizures.
多种病因可引起累及多血管供血区的急性脑卒中，但最常见于近端来源的栓子或弥漫性血管炎。单纯动脉-动脉栓塞、大血管狭窄或慢性小血管病不会出现这种的梗死分布特点。在这样的病例中，必须排除心源性栓塞。阵发性心房颤动是栓子形成的诱因之一，卵圆孔未闭相关脑梗死可能与膝关节术后病人出现深静脉血栓形成的风险升高有关。在大多数缺血性脑卒中患者中，出现发热和脑病是非常不典型的。感染性病因，如脑膜炎，必须考虑在内，即使临床上无脑膜刺激征。在免疫抑制的状态下，感染性心内膜炎产生脓毒性栓子引起脑梗死也是有可能的。血管炎可引起多发脑梗死，结合患者既往有结节病病史，也支持自身免疫疾病可能。颅内静脉窦血栓形成可引起静脉性脑梗死，本例也应考虑在内，尤其是伴有头痛和新发癫痫发作的患者。
Repeat head MRI on admission showed multiple new small areas of acute infarction, again in multiple vascular territories. Transesophageal echocardiogram was obtained to evaluate for cardioembolic cause of strokes. There was no intracardiac thrombus, valvular vegetations, or right-to-left shunt. Head and neck magnetic resonance angiography (MRA) showed multifocal, asymmetric stenoses involving the bilateral posterior cerebral arteries and branches of the right middle cerebral artery, consistent with vasculitis (figure, B). There was no evidence of venous sinus thrombosis.
入院时复查头颅MRI提示新发多血管供血区的多发小梗死。予行经食管超声心动图检查以了解是否有心源性栓子所致脑卒中可能。结果提示无心内栓子、瓣膜赘生物或右向左分流。头颈MRA提示双侧大脑后动脉和右侧大脑中动脉的多条分支多发不对称狭窄，符合血管炎影像特点（图B），无静脉窦血栓的证据。
：Questions for consideration:
1. What is the differential diagnosis of this patient’s vasculitis?
2. What further tests are indicated to narrow this differential diagnosis?
：思考问题：
1.引起患者血管炎的鉴别诊断有哪些？
2.什么检查可进一步缩小鉴别诊断的范围？
第三部分： 进一步检查
The multifocal infarcts were believed to be due to vasculitis, which is a generic term referring to blood vessel inflammation. The appropriate treatment depends on the underlying cause of vasculitis. CNS vasculitis frequently occurs in the setting of a systemic inflammatory process or connective tissue disease (polyarteritis nodosa, Beh?et disease, systemic lupus erythematosus) but may also be due to various infectious causes, medications, or illicit drug use.
多发脑梗死考虑由血管炎所致，血管炎是血管炎症反应的通用术语。合理的治疗方案的制定取决于引发血管炎的根本病因。中枢神经系统血管炎通常出现在全身炎症反应或结缔组织病（结节性多动脉炎、白塞病、系统性红斑狼疮）中，还可由各种感染性因素、药物、使用非法成瘾物质等所致。
In our patient, serum inflammatory markers were not elevated to suggest a systemic inflammatory process and there was no evidence of other end-organ damage. He was not on any medications known to be associated with vasculitis, and there was no history of illicit drug use. There were no signs of systemic infection and no recent travel history.
患者的血清炎症指标无升高，不支持机体处于全身炎症反应状态，且无其他靶器官损害的证据。目前已知所使用的药物均不会引起血管炎，也不曾使用非法成瘾物质。没有系统性感染的迹象，也没有近期外出旅游史。
The possibility of cerebral involvement of sarcoidosis was entertained. Vascular involvement has been demonstrated in numerous neuropathologic studies of sarcoidosis.1–3 Granulomatous invasion of the vessel walls has been shown to cause vasculitic disruption of the media and internal elastic lamina, leading to infarct in many cases. The granulomatous vasculitis preferentially involves small penetrating arteries, though involvement of larger vessels has also been reported.3 The treatment for vasculitis differs drastically depending on the underlying cause. Sarcoidosis and other inflammatory conditions are treated with immunosuppression, but this could have potentially devastating consequences in the setting of infectious vasculitis.
患者应考虑累及脑部的结节病可能。很多结节病神经系统病变的病理研究已证实存在血管受累。肉芽肿病变侵入血管壁，破坏血管中层和内弹性膜，进而引起脑梗死。肉芽肿性血管炎更倾向于侵犯小的穿支动脉，尽管也有累及大血管的报导。对血管炎的治疗要因其根本病因而异。通常使用免疫抑制剂来治疗结节病和其他炎症性疾病，但这种治疗方案在感染性血管炎中有引起灾难性后果的风险。
To further evaluate the cause of vasculitis in our patient, a lumbar puncture was performed and showed elevated protein of 194 mg/dL, 75 leukocytes/mL (50% neutrophils, 17% lymphocytes, and 33% monocytes/macrophages), and glucose less than 20 mg/dL. CSF Gram stain was negative. PCR testing was negative for herpes simplex, varicella zoster, and Epstein-Barr viruses. Fungal smear, which uses calcofluor white to stain chitin in cell wall of fungi, returned positive. Cryptococcal antigen testing using a lateral flow assay was also positive. Blood and CSF cultures ultimately grew Cryptococcus neoformans var neoformans.
为进一步明确引起该患者血管炎的根本病因，予患者行腰椎穿刺术，结果提示蛋白升高至194 mg/dL, 白细胞75/mL（中性粒细胞50%，淋巴细胞17%，单核/巨噬细胞33%），葡萄糖<20mg>
The patient was started immediately on induction therapy with amphotericin and flucytosine for treatment of cryptococcal meningitis (CM). Head MRA repeated 10 days after starting antifungal therapy showed resolution of the previously visualized vascular irregularity (figure, C). Mental status returned to prior baseline and he was discharged to a rehabilitation facility because of persistent right leg weakness. Fluconazole was started for ongoing treatment of CM.
立即给予患者两性霉素和氟胞嘧啶进行隐球菌性脑膜炎的诱导治疗。抗真菌治疗10天后复查头颅MRA提示颅内血管不规则病变好转（图C）。患者精神状态恢复至起病前的基线水平，予办理出院。患者因右下肢持续乏力转诊康复机构，随后开始予氟康唑作为巩固治疗。
：Question for consideration:
1. What is the unifying diagnosis?
：思考问题：
1.患者的诊断是什么？
第四部分：讨论
It was believed that steroid-related immunosuppression as treatment for pulmonary sarcoidosis made this patient susceptible to CM. The meningitis then caused diffuse vasculitis and presented with multifocal ischemic strokes, encephalopathy, and seizures.
有人认为使用类固醇类免疫抑制剂治疗肺结节病，使得该患者容易感染隐球菌性脑膜炎。这类脑膜炎会引起弥漫性血管炎，表现为多发脑梗死、脑病和癫痫发作。
Cryptococcus neoformans is the most common systemic fungal infection in immunocompromised patients. These patients often present with insidious onset of nonspecific symptoms and sometimes with isolated neurologic complaints. The majority of patients develop fever, headache, and altered mental status over several weeks, though typical meningismus is reported in fewer than 25% of patients. Seizures have been reported in up to 10% of cases.4 Because of the nonspecific symptoms and insidious onset, diagnosis may be delayed.5
新型隐球菌感染是免疫功能低下的患者中最常见的系统性真菌感染。这些患者常表现为隐匿起病的非特异性症状，有时伴有孤立的神经系统症状。大部分患者在几周后会出现发热、头疼及精神状况改变。据报道，少于25%的患者出现典型的脑膜刺激征，在10%的病例中可出现癫痫发作。其症状的非特异性和起病的隐匿性可能会延误诊断。
Cerebral ischemia is a relatively rare but well described complication seen in CM and several mechanisms may be involved. It has been proposed that meningitis can lead to irritation of traversing subarachnoid blood vessels, which in turn causes vasospasm and ischemia.6 This theory is supported by the fact that our patient had evidence of vasospasm in multiple infarcted areas, which resolved with treatment of the underlying meningitis. Inflammation may also lead to endarteritis and small vessel ischemic stroke. Exudates in the setting of chronic meningitis are typically found in the basal cisterns, which may explain why the majority of infarcts in patients with CM are observed in the basal ganglia, internal capsule, or thalamus.7 Although hydrocephalus is a common complication of CM and may contribute to cerebral ischemia by stretching vessels or increasing intracranial pressure,7 this did not seem to be a major factor in the pathology of our patient.
脑缺血是隐球菌性脑膜炎已有报导中相对罕见的并发症，其中可能涉及几种机制。有人提出脑膜炎可刺激蛛网膜下腔的血管，进而引起血管痉挛和缺血。在本例中，有证据支持患者多发脑梗死区存在血管痉挛，且血管痉挛随着脑膜炎的治疗缓解，可支持这一观点。炎症反应可引起动脉内膜炎和小血管性缺血性脑卒中。慢性脑膜炎中常见基底池渗出物，这或许解释了为什么大部分隐球菌性脑膜炎患者的梗死灶多见于基底节、内囊或是丘脑。尽管脑积水是隐球菌性脑膜炎的常见并发症，可能是通过血管牵拉或颅内压升高引发脑缺血，但这似乎并不符合本例患者的主要病理表现。
Infectious causes of stroke are important to consider in all patients, especially those who are immunosuppressed. Identifying the underlying cause is essential to help dictate the appropriate therapy. If diagnosis is made early enough, excellent patient outcomes are possible.
在所有脑卒中中，把感染性因素纳入考虑是非常重要的，尤其是对那些免疫功能低下的患者而言。确定根本病因有助于我们找到合适的治疗方法。如果能尽早明确诊断，患者就有可能获得良好的预后。
编辑：李会琪
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