CADASIL的临床、影像学特征及其诊断策略(附2例报道)

目的 探讨常染色体显性遗传性脑动脉病伴皮质下梗死和白质脑病(CADASIL)的临床表现及影像学特征和确诊的要素。方法 系统回顾分析经皮肤及肌肉活检或基因检测确诊的2例CADASIL的临床及影像学资料。结果 例1临床表现为进行性记忆障碍,例2临床表现为脑缺血性卒中样发作,2例均无通常的脑血管疾病的危险因素,脑MRI T₂W及FLAIR序列均显示两侧脑室周围及深部脑白质、外囊及前颞区对称性分布的高信号,例1皮肤活检发现在血管壁平滑肌细胞基膜层有嗜锇颗粒(GOM)沉积; 例2基因检测显示Notch3基因外显因子4,c.544C>T位点突变。结论 如若患者具有进行性认知损害、反复缺血性脑卒中样发作等临床表现,且无通常的脑血管病的危险因素,磁共振检查显示两侧脑白质对称性异常信号时,应考虑CADASIL的可能,此时进行皮肤或肌肉活检及/或基因检测有助确诊。     

CADASIL皮肤活检中血管超微结构改变

目的报道12例伴皮层下梗死和白质脑病的常染色体显性遗传性脑动脉病（CADASIL）患者的皮肤血管超微结构改变。方法12例患者分别来自4个不同的CADASIL家族,均以发作性头晕、头痛、缺血性脑卒中和痴呆为主要表现。基因检查证实Notch3基因存在突变。12例患者均做皮肤活检,16例同龄的非CADASIL患者作为对照,观察血管超微结构改变。结果12例患者的皮肤血管超微结构表现：大多数血管壁增厚,颗粒样嗜锇性物质主要沉积在小动脉和小静脉血管平滑肌细胞表面,偶尔位于毛细血管内皮细胞周围。血管平滑肌细胞和内皮细胞变性,它们细胞质中许多充满嗜锇性物质小泡以及线粒体空泡样变性。16例对照中仅1例老年人中偶见血管基底膜增厚。结论退行性变的血管平滑肌细胞和嗜锇颗粒（GOM）是CADASIL特征性病理改变。内皮细胞变性和线粒体改变也在CADASIL致病机理中占有重要作用。这些改变和Notch3基因突变之间的关系还需要扩大样本进一步确定。     

5个CADASIL家族的核磁共振改变特点

目的　分析来自5个CADASIL家族中8名患者的核磁共振(MRI)表现,总结病变不同时期的MRI变化规律及其诊断价值。方法　研究对象为经过超微病理和Notch3基因检查确诊的5个CADASIL家族中的8个患者,均在成年早期发病,主要表现为反复发作的缺血性卒中和进行性痴呆。对先证者1及其母亲、先证者2及其哥哥、姐姐,先证者3、4和5 ,总计8名患者进行了头部MRI检查,其中4名进行了MRI血管成像检查。结果　8名患者的头部MRI均显示多发腔隙性脑梗死,病灶主要分布在基底节、丘脑和脑室旁白质,6例患者出现了外囊梗死,4例出现了胼胝体梗死,3例出现了脑桥梗死。所有8例患者均存在双侧大脑半球多灶性或弥漫性白质疏松,1例患者MRI确诊1年后随访显示多灶性白质病变进展为弥漫性损害,5例患者出现了双侧颞极等T1 长T2 信号。4例患者的头部MRI血管成像检查未见异常。结论　基底节、丘脑和脑室旁白质是CADASIL腔隙性脑梗死的好发部位,外囊和胼胝体梗死以及双侧颞极长T2 信号对本病具有较高的诊断价值。脑干受累可以出现在病程早期,而白质病灶分布形式的变化可以反映病情的进展。     

CADASIL

1 历史背景 伴有皮质下梗死和白质脑病的常染色体显性遗传脑动脉病(cerebral autosomal arteriopathy with subcortical infarctionand leukoencephalopathy,CADASIL)与19号染色体短臂上的Notch 3家族基因相关,80％以上的病人可表现为皮质下腔隙梗死和痴呆。在临床上可类似于高血压性微血管病(Bin-swanger脑病)。1894年Binswanger,1902年Alzheimer先后     

伴脑出血的CADASIL(附1例报道)

目的报道1例以脑出血引发的癫痫为主要临床表现的伴皮质下梗死和白质脑病的长染色显性遗传性脑动脉病(Cerebral autonomic dominant arteriopathy with subcortical infarcts and leucoencephalopa-thy,CADASIL),探讨其可能的发病机制。方法对1例CADASIL患者进行临床表现、影像学及皮肤活检等方面检查。结果患者临床表现为癫痫、偏头痛、记忆力下降及情感障碍,MRI平扫见皮质下多发腔隙性脑梗死及脑白质病变,MRI梯度回波序列见多发微出血灶及右颞顶交界处大出血灶,皮肤活检电镜下见血管内皮下黑色嗜锇样颗粒沉积。结论对于表现为脑出血的患者,也应考虑CADASIL。     

以先兆型偏头痛为主要临床表现的CADASIL(附1例报告)

目的 分析1例以先兆型偏头痛为主要临床表现的伴皮质下梗死和白质脑病的常染色体显性遗传性脑动脉病(cerebral autonomic dominant arteriopathy with subcortical infarcts and leucoencephalopathy,CADASIL),探讨该病早期的临床特点.方法 对1例临床表现为先兆型偏头痛患者,进行临床、影像学分析、Notch3基因外显子测序.结果 该患主要表现为有家族史的先兆型偏头痛,头颅MRI见T2加权像和FLAIR像特征性颞极白质异常高信号,与放射冠、半卵圆中心区腔隙性脑梗死灶并存,Notch3基因外显子测序提示杂合突变c.353C→G(p.Ser118Cys).结论 重视先兆型偏头痛患者的头颅MRI表现,颞极异常信号提示CADASIL可能,进一步行Notch3基因外显子测序可提高CADASIL确诊率.     

CADASIL的临床、神经病理与分子遗传学研究

有关ＣＡＤＡＳＩＬ的研究是近年来证实遗传因素参与ＣＶＤ发病的重要进展之一。家族遗传方式起病，中年发病且逐渐进展的缺血性脑卒中样病程，广泛多发的白质灶，明确的ＭＲＩ白质异常信号以及病理学明确的小动脉病变是本病的基本特征。分子遗传学研究表明：ＮＯＴＣＨ ３基因的多种点突变与本病有关。而基因诊断与外周组织活检相结合有可能是本病最有价值的生前诊断手段。     

CADASIL2个家系报道及文献复习

目的 报道2个CADASIL家系,4例患者的临床表现、影像学特点、基因突变位点。方法 分析总结本科收治的4例CADASIL患者的临床表现、影像学特点、基因突变位点。结果 临床表现为反复发作脑梗死、头痛、认知功能障碍、有家族遗传病史,基因检测定位于19q12的notch3。结论 对于有明确家族史、临床表现反复脑卒中、TIA,可伴头痛、精神行为异常等的患者需进一步完善影像学检查,必要时完善基因检测,做到早期识别并进行提前干预、治疗。     

CADASIL病的临床与基础研究

伴有皮质下梗死和白质脑病的脑常染色体显性遗传性动脉病 ( CADASIL )为家族性疾病。此病首先在 1977年被描述 ,但直至 1993年 Tournier- L asserve等对罹患本病的两大家系进行详细检查和分析 ,认为属独立疾病单元 ,并定名为CADASIL ,同年在巴黎召开首届国际 CADASIL专题讨论会 ,方引起广泛关注。其遗传缺陷被定位于 19q12染色体上 ,临床特征为多次卒中发作和后期痴呆 ,病理上为小的深部多发梗死和白质脑病 ,伴有继发于小动脉中层嗜锇酸颗粒沉积的小血管壁的向心性增厚 ,磁共振 ( MRI)上表现为多灶性皮质下梗死及白质脑病。现对 …     

存在脑血管危险因素CADASIL家系的研究

伴皮质下梗死和白质脑病的常染色体显性遗传性脑病( cerebral autosomal dominant arteriopathywith subcortical infarct-sand eukoencephalopathy,CADASIL)是一种常见的单基因遗传的脑小血管疾病[1] ,由人类19号染色体短臂上的No...     

Peripheral neuropathy in CADASIL

Background Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is a hereditary cerebral microangiopathy associated with mutations in the Notch 3 gene. The clinical phenotype is characterized by cerebral impairment even though typical microvascular changes are diffuse. Objective To assess peripheral neuropathy in patients with CADASIL. Patients and Methods We enrolled eleven CADASIL patients with variable phenotype including clinical signs of peripheral nerve involvement. In all patients electromyography and nerve conduction velocities were performed. Peripheral nerve biopsy was performed in three cases. Results We found sensory motor neuropathy in 7/11 patients. Nerve biopsy revealed axonal and demyelinated findings. Conclusion Our findings suggest that peripheral neuropathy may be part of the CADASIL phenotype.     

Cognitive profile in CADASIL

BACKGROUND: The spectrum of cognitive alterations associated with CADASIL, a model of pure vascular dementia, has not been thoroughly evaluated. OBJECTIVES: The aims of this study were: (i) to describe the cognitive profile in CADASIL patients according to age; (ii) to compare the profile of patients with dementia with that of patients without dementia; and (iii) to determine the association between alterations in performance in different cognitive domains. METHODS: Forty two consecutive individuals with CADASIL (35-73 years old) were investigated. Cognitive skills were analysed in five domains (executive functions, reasoning, attention, memory, visuospatial abilities) according to age and compared between patients with and without dementia. Associations between cognitive performance and stroke were tested. RESULTS: The youngest patients presented with attention (69%), memory (70%), and executive disturbances (100%). Visuospatial abilities and reasoning deteriorated with age, mainly after the age of 60. About one quarter of patients had dementia, and 75% of these were >60 years of age. Age >60 years was associated with a Rankin score >3 and a significant deficit in all cognitive domains. No association was found between dementia and the number of ischaemic attacks. Episodic memory disorder was characterised by difficulties in retrieval rather than impairment of the encoding process. CONCLUSION: Cognitive decline in CADASIL is dominated by early impairment of executive functions. Skills in other cognitive domains deteriorate with age and are found to be diffusely impaired in patients with dementia. The relative preservation of the encoding process in episodic memory impairment, even in individuals with dementia, is noteworthy.     

CADASIL or CADVaSIL?

In the present study, morphological examination of patients from two unrelated Polish families with CADASIL was performed. Using light microscopy, there were evident changes characteristic to the disease. On electron microscopy, deposits of granular osmiophillic material (GOM) were found not only in cerebral arteries and veins but also in cerebral capillaries and vessels of the internal organs. These findings indicate that pathological process in CADASIL is generalized and involves also small vessels devoid of smooth muscle cells. Therefore, we propose to consider a replacement for the name CADASIL that better reflects the morphological picture of the disease like, for example, cerebral autosomal dominant vasculopathy with subcortical infarcts and leukoencephalopathy (CADVaSIL) or, to preserve the commonly known acronym, cerebral autosomal dominant angiopathy with subcortical infarcts and leukoencephalopathy.     

CADASIL患者的中枢前庭功能损害

目的评价常染色体显性遗传性脑动脉病伴皮质下梗死和白质脑病(cerebral autosomald ominant arteriopathy with subcortical infarcts and leukoencephalopathy,CADASIL)的前庭功能状态。方法CADASIL患者和健康志愿者各17名,进行眼震电图检查,包括凝视性眼震试验、自发性眼震试验、水平扫视试验、水平跟踪试验、水平视动性眼震试验和温度试验,比较两组间结果的差异。结果两组受试者均未发现自发性眼震和凝视性眼震。水平扫视试验中,两组间扫视潜伏期和扫视速度无统计学差异。CADASIL组扫视准确度均低于正常对照组,向左扫视时差异有统计学意义(F=5.751,P0.05)。水平跟踪试验中,CADASIL组跟踪增益值(gain,G)(G左:0.79±0.08,G右:0.76±0.12)小于对照组(G左:0.87±0.04,G右:0.86±0.06),差异有统计学意义(t=-3.739、-2.911,均P0.05)。按照跟踪曲线类型将CADASIL组分为跟踪正常亚组和跟踪异常亚组,发现头晕症状与跟踪运动异常有关(P0.05)。水平视动性眼震试验发现CADASIL组视动性眼震增益值(G左:0.79±0.17,G右:0.78±0.18)小于对照组(G左:0.90±0.08,G右:0.89±0.09),差异有统计学意义(t=-2.342、-2.335,均P0.05)。1例患者进行了温度试验,表现为固视抑制失败。结论CADASIL患者存在中枢前庭功能损害,并且与患者的头晕症状有关。     

Dilation of Virchow-Robin spaces in CADASIL

To precise the severity of dilated Virchow-Robin spaces (VRS) in CADASIL patients and to determine their correlation with clinical presentation and other abnormalities on cerebral Magnetic Resonance Imaging (MRI). Dilated VRS were previously associated with aging, hypertension, dementia, epilepsy or migraine. We already reported increased frequency of enlarged VRS in CADASIL patients when compared with family members without the affected haplotype. We analysed clinical and MRI data from 50 CADASIL patients collected prospectively in our center. The presence of dilated VRS was assessed in the subcortical white matter of temporal lobes, the centrum semi-ovale and the basal ganglia. Their severity in each region was evaluated according to the scale proposed by Heier. We compared the clinical data, the severity of white matter abnormalities and the presence of microbleeds in patients with and without dilated VRS. Seventy-eight percent of patients in our series had dilated VRS, mostly located in the lentiform nuclei (94%) and subcortical white matter of the temporal lobes (66%). The severity of these lesions was variable but not correlated neither to the extent of white matter abnormalities nor to the clinical presentation in our patients. Only the age was found to be related to the extent of dilated VRS. Dilated VRS are frequent in CADASIL and mostly located in the temporal white matter and basal ganglia. The dilation of perivascular spaces does not seem to be directly related to the occurrence of ischemic or hemorrhagic lesions in CADASIL. In contrast, the relation with age suggests that either aging, progression of vascular wall alterations during the course of the disease, or both of these processes can favour the extension of VRS in CADASIL.     

Aspirin-associated intracerebral hemorrhage in a patient with CADASIL

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary disease characterized by ischemic stroke, cognitive impairment, migraine and neuropsychological deficit. Although intracerebral hemorrhage (ICH) has been described in patients with CADASIL, the cause of such ICH is still unknown. We present a 39-year-old man with CADASIL who had two years history of untreated hypertension. In this patient, acute ICH developed only two weeks after the initiation of aspirin. Brain images demonstrated a 3cmx3cm hyperacute ICH in the left temporal lobe at the site of previous old hemorrhage. The presence of cerebral microbleed and use of antithrombotics may be associated with development of ICH in patients with CADASIL.