Abstract 抽象的
Cerebral vasculitis is a rare cause of juvenile stroke. It may occur as primary angiitis of the central nervous system (PACNS) or as CNS manifestation in the setting of systemic vasculitis. Clinical hints for vasculitis are headache, stroke, seizures, encephalopathy and signs of a systemic inflammatory disorder. Diagnostic work-up includes anamnesis, whole body examination, laboratory and cerebral spinal fluid (CSF) studies, magnetic resonance imaging (MRI), angiography and brain biopsy. Due to the rarity of the disease, exclusion of more frequent differential diagnoses is a key element of diagnostic work-up. This review summarizes the steps that lead to the diagnosis of cerebral vasculitis and describes the red flags and pitfalls. Despite considering the dilemma of angiography-negative vasculitis and false-negative brain biopsy in some cases, it is important to protect patients from ‘blind’ immunosuppressive therapy in unrecognized non-inflammatory differential diagnosis.
腦血管炎是青少年中風的罕見原因。它可能作為中樞神經系統原發性血管炎 (PACNS) 或系統性血管炎中的 CNS 表現而發生。血管炎的臨床提示包括頭痛、中風、癲癇發作、腦病變和全身性發炎疾病的徵兆。診斷檢查包括病史、全身檢查、實驗室和腦脊髓液 (CSF) 研究、磁振造影 (MRI)、血管攝影和腦部活檢。由於疾病的罕見性，排除更常見的鑑別診斷是診斷檢查的關鍵要素。這篇綜述總結了腦血管炎診斷的步驟，並描述了危險信號和陷阱。儘管考慮到某些病例中血管造影陰性血管炎和假陰性腦部活檢的困境，但在未識別的非發炎鑑別診斷中保護患者免受「盲目」免疫抑制治療很重要。
Keywords: encephalitis, granulomatosis with polyangiitis, stroke, vasculitis
關鍵字：腦炎，肉芽腫性多血管炎，中風，血管炎
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Introduction 介紹
Cerebral angiitis is a rare cause of stroke, headache, encephalopathy and seizures. Frequently, multi-locular lesions on magnetic resonance imaging (MRI), inflammatory laboratory findings in stroke patients or intracranial stenoses detected in computed tomography angiography (CTA), MRA or angiography raise the suspicion of this diagnosis [1], but none of these findings is reliable enough to allow a definite diagnosis of cerebral vasculitis [1,2]. Traditionally, the terms vasculitis, arteritis and angiitis are used simultaneously, but are interchangeable with each other.
腦血管炎是中風、頭痛、腦病變和癲癇發作的罕見原因。通常，磁振造影(MRI) 上的多房性病變、中風患者的發炎實驗室檢查結果或電腦斷層血管攝影(CTA)、MRA 或血管攝影中檢測到的顱內狹窄會引起對此診斷的懷疑。 1 ]，但這些發現都不夠可靠，不足以明確診斷腦血管炎[ 1 , 2 ]。傳統上，術語血管炎、動脈炎和血管炎同時使用，但可以互換。
What are the steps in order to establish the diagnosis (Fig. 1)?
確定診斷需要採取哪些步驟（圖 1）。 1 ）？
Figure 1. 圖 1.
Flowchart on the diagnostic work-up for cerebral vasculitis.
腦血管炎診斷檢查流程圖。
Reliable clinical suspicion
可靠的臨床懷疑
The first and most important step in the diagnostic work-up is detailed anamnesis and clinical examination, including asking for drug abuse, former medical conditions, characterization of symptoms, especially headaches [3–5], and family medical history. Medical examination should focus on skin or other systemic signs for rheumatic or non-inflammatory diseases (Fig. 2) [6–8].
診斷檢查的第一步也是最重要的一步是詳細的病史和臨床檢查，包括詢問是否濫用藥物、先前醫療狀況、症狀特徵，尤其是頭痛。 3 – 5 ]，以及家族病史。身體檢查應著重於皮膚或其他全身體徵是否有風濕性或非發炎性疾病（圖 1）。 2 ）[ 6 – 8 ]。
Figure 2. 圖 2.
Clinical signs of vasculitis mimics: (a) livedo racemosa in Sneddon's syndrome; (b) juvenile stroke with pulmonary AV-shunts: Morbus Osler; (c) angioceratoma in Fabry's disease.
血管炎的臨床症狀類似於：(a) Sneddon 症候群中的總狀青斑； (b) 患有肺房室分流術的青少年中風：Morbus Osler； (c) 法布瑞氏症的血管角化瘤。
Patients presenting with multi-focal symptoms accompanied by headache, psychiatric symptoms and signs of a systemic inflammatory disorder need a diagnostic work-up in order to exclude or detect cerebral angiitis [9–12]. In particular, younger stroke patients without classical vascular risk factors, patients with clinical signs of a rheumatic disease, i.e. arthritis, Raynaud phenomenon, red eye, lung or kidney affection, and those with inflammatory laboratory findings [high erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), anaemia or cerebrospinal fluid (CSF) pleocytosis] may suffer from an angiitis [13]. The combination of neurological symptoms and signs of a systemic disease need an extensive diagnostic work-up [9,11,14].
出現多灶性症狀並伴隨頭痛、精神症狀和全身性發炎疾病徵象的患者需要進行診斷檢查，以排除或檢測腦血管炎。 9 – 12 ]。特別是，沒有典型血管危險因子的年輕中風患者，有風濕病臨床症狀的患者，即關節炎、雷諾氏現象、紅眼、肺部或腎臟病變，以及有發炎實驗室檢查結果的患者[紅血球沉降速率（ ESR）高， C反應蛋白（CRP）、貧血或腦脊髓液（CSF）細胞增多]可能患有血管炎[ 13 ]。神經系統症狀和全身性疾病徵象的結合需要進行廣泛的診斷檢查。 9 , 11 , 14 ]。
First diagnostic steps in suspected cerebral vasculitis
All patients need a laboratory work-up focusing on inflammation and antibody-mediated diseases [9,15]. Raised acute phase proteins (high ESR, CRP), hypochromic anaemia and low complement are typical findings in the systemic vasculitides. Depending on the underlying condition, anti-neutrophil cytospasmic antibodies (ANCA) or anti-nuclear antibodies (ANA) are detected with high titres [15]. The typical picture in the CSF is a mild lymphocytic pleocytosis combined with an elevated protein level. Oligoclonal banding may occur temporarily [16].
In order to detect a cerebral vasculitis, MRI studies, including diffusion, gradient echo and contrast enhanced T1 sequences, are necessary [9,17,18]. Frequently, both new and older ischaemic lesions are detected; the combination of ischaemic and haemorrhagic lesions is not uncommon. Diffuse white matter lesions suggestive for microangiopathies are frequently observed. Prominent gadolinium-enhancement of the leptomeninges is rare [19,20]. Gadolinium-enhanced intracerebral lesions are observed in about one-third of patients [16].
Special techniques such as ‘Black Blood MRI’ [21], contrast-enhanced vessel MRI or positron emission tomography (PET) imaging may be helpful in order to visualize the inflammation of the vessel wall directly [18,22]. While these techniques have been studied extensively in the variants of giant cell arteritis (GCA) [23,24], data for the other vasculitides are sparse. In the cranial variant of GCA, ultrasound studies with duplex sonography demonstrating the halo sign are highly sensitive and specific [25].
Despite suggestive MRA or CTA, conventional angiography is often mandatory (Fig. 3). Alternating areas of narrowing and dilatation or multi-locular occlusions of intracranial vessels are highly suggestive of vasculitis. However, it should be considered that the ‘typical’ suspicion of vasculitis in angiography is often caused by differential diagnoses such as reversible cerebral vasoconstriction syndrome (RCVS) or other non-inflammatory diseases [4]. Moreover, small-vessel vasculitis is associated typically with negative cerebral angiography [26,27].
Figure 3.
Angiographic findings in vasculitis mimics: (a) Divry–van Bogaert syndrome; (b) bacterial endocarditis (see Berlit [1]); (c) reversible cerebral vasoconstriction syndrome (see Kraemer and Berlit [16]).
In the case of CNS affection in systemic biopsy-proven vasculitis additional brain biopsy is often expendable; however, exclusion of other causes of neurological symptoms such as progressive multi-focal leucencephalopathy or medication side effects is extremely important [28,29].
Diagnosis of definitive vasculitis
Once the tentative diagnosis of cerebral angiitis is established, it must be clarified if the patient suffers from the manifestation of a systemic disease, or whether a primary angiitis of the CNS (PACNS) is the underlying pathology [9,30].
The diagnostic criteria [15] for PACNS include acquired neurological symptoms or findings not explained after a thorough diagnostic assessment, a cerebral angiography demonstrating the features of vasculitis and a CNS biopsy sample demonstrating angiitis [10,16]. Any other disorder including the systemic vasculitides to which the angiographic or pathological features might be secondary must be excluded [30].
PACNS is an uncommon disease in which lesions are limited to the brain and spinal cord. The condition is very rare, with an estimated incidence from 2·4:1 million to fewer than 1:2 million [31]. Since the first histological description in 1922, approximately 500 cases have been published worldwide [31]. Recently, a working group from the Mayo Clinic published a series of 101 patients with PACNS seen over two decades from 1983 to 2003 [10]. We identified 21 patients treated at Alfried Krupp Hospital, Essen, Germany between 2003 and 2008 with a diagnosis of definite PACNS [16]. The most frequent clinical presentations are cerebral ischaemia (75%), headache (60%) and altered cognition (50%) [8,16]. Intracranial haemorrhage is infrequent.
Almost all patients show MRI abnormalities. Ischaemic infarctions with diffusion disturbances are seen in 75%; signs of microangiopathy are present in 65%. Gadolinium-enhanced lesions are detected more frequently with amnestic syndromes at disease onset and with gait disturbances. MR-angiography (MRA) is suggestive of vasculitis in 45% [22]. MRI of PACNS may be suspicious for brain tumour, and PACNS mimicking tumour-like lesions is often diagnosed by biopsy by chance [32]. Conventional cerebral angiography is indicative of vasculitis in up to 75% if performed repeatedly [1,8,11,31].
CSF examinations disclose abnormal findings (cell count >5 cells/μl or total protein concentration >45 mg/dl) in the majority of patients [15]. Oligoclonal banding is found occasionally. Besides possible high CRP, serum screening is unremarkable for complement factors, ANA, ANCA or bacterial or viral antibodies. Although a large-scale ‘laboratory screen’ for autoimmune or infectious diseases is essential to exclude treatable differential diagnoses, one should be prepared for occasional ‘positive’ results.
Brain biopsy represents the gold standard in establishing the diagnosis in PACNS [9,16,26,33–35]. In PACNS, CNS biopsy specimens should be obtained in MRI-or angiographically involved areas [15]. Histopathological examination reveals a definite diagnosis of PACNS in approximately 60% of patients [8]. The ideal diagnostic brain biopsy is a 1-cm3 brain tissue with both grey and white matter as well as leptomeninges, and preferably a cortical vessel. The rate of false-negative brain biopsies is explained by the segmental involvement of vessels and a possible mismatch between radiological abnormalities and histological predominant lesions [8]. The morbidity rate of brain biopsy (0·03–2%) is definitely lower than the risks of unnecessary immunosuppressive treatments [8].
It is apparent that angiography and biopsy do not provide the same information in all patients [8]. Histology showed PACNS in 62% of Salvarini's patients who underwent biopsy [10]. Despite the fact that angiography has become the most frequent method of diagnosing PACNS, brain biopsy remains the gold standard [