主题月：遗传代谢性脑病MR(一）

中国妇儿医学影像论坛，旨在为热爱妇产科、儿科的临床医生、影像科医生及相关专业同行搭建学术交流平台，现已增建2群，我们的目标是成为中国最好的妇儿影像交流论坛群！在这里，您可以参与精彩的病例讨论、了解妇儿影像最新进展、获取相关会议信息。感谢您的加入！交流、共享、学习、提高！

  

杨朝湘  06:01

首次“遗传代谢性脑病MR”主题月活动由我来先开个题

杨朝湘  06:01

遗传代谢性脑病虽然罹患人群多为儿童，但远不限于儿童；虽然为少见病，但影像和临床工作中又似乎感觉如影随形，常常要面临对该病的诊断与鉴别诊断，如很多脑炎MRI看上去很像遗传代谢性脑病，而有时一些遗传代谢性脑病看上去又像脑炎。加上遗传代谢性脑病种类繁多， “异病同影”和临床表现重叠严重，因此让我们对它的感觉是既熟悉，又陌生。是综合医院和专科医院相关科室都需要面对的诊断难题。

杨朝湘  06:01

作为儿科影像经典的Caffey在书中辟出专章“Inherited metabolic brain disorders”对遗传代谢性脑病做了较为详细的分类讲解，包括其遗传学、临床表现和以MRI为主的影像学。当然，由于该病种类数以百计，专章虽然洋洋数万言，仍难以一一涵盖。我们不过籍此专章为基础，在主题月期间，学习其中的病例影像和相关知识，以达到提高、扩大和丰富对遗传代谢性脑病MRI的认识的目的。

杨朝湘  06:01

本次主题月的开题即借用Caffey书中的图片病例，以期抛砖引玉。希望群中同道积极参与，群中大咖能拔冗指点一二。感兴趣的、有见解的、抑或有困惑的、欲提高的同道都可以在主题月期间谈谈您对的遗传代谢性脑病MRI的看法、经验、认识，抑或困惑。围绕这个主题列举证实病例或可疑病例，或者相关课件或文献。共同分享、共同提高！

杨朝湘  06:02

先上3例（来自Caffey），如果您已看过Caffey这一章节，请略过。

杨朝湘  06:02

Case 1

杨朝湘  06:02

杨朝湘  06:02

2岁男孩。A图为T2 FLAIR，B图为TE=35ms MRS，C图为TE=288ms MRS

杨朝湘  06:02

Case 2

杨朝湘  06:03

杨朝湘  06:03

7岁男孩。A图为T2WI，B图为T2 FLAIR，C图为短TE MRS，D图为长TE MRS

杨朝湘  06:03

Case 3

杨朝湘  06:03

杨朝湘  06:03

4岁女孩。A图为T2WI，B图为T2 FLAIR，C图为ADC图，D图为TE=35ms MRS，E图为TE=144ms MRS

杨朝湘  06:04

3个图片病例的答案在以下6个选项中，请选择：
A、Krabbe病
B、枫糖尿病
C、甲基丙二酸血症
D、粘多糖病
E、佩-梅病
F、异染性脑白质营养不良

杨朝湘  18:50

杨朝湘  18:50

是Krabbe病

杨朝湘  18:51

也就是“球形细胞脑白质营养不良”

杨朝湘  18:51

书中图注：Abnormal hyperintense T2 and FLAIR signals are noted within the centrum semiovale with sparing of the subcortical U fibers and posterior limbs of the internal capsules. Relatively increased diffusion is seen in the periatrial and parietal white matter. The spectra demonstrate significant elevations of lactate, choline, and myo-inositol, with diminished N-acetylaspartate reflecting neuroaxonal loss, demyelination, and glial activation
译：双侧半卵圆中心异常高信号，皮层下U形纤维及内囊后肢未受累。ADC图示脑室旁及顶叶白质病变区弥散相对增高。MRS示乳酸峰、胆碱峰和肌醇峰明显升高及NAA峰下降，提示神经轴索损伤、脱髓鞘，及神经胶质增生活跃。

杨朝湘  18:52

这是Caffey对该例的描述

杨朝湘  18:53

另外，书中对该病的讲解如下：

杨朝湘  18:53

Globoid cell leukodystrophy (Krabbe disease) arises from a deficiency in the enzyme β-galactocerebrosidase, leading to the accumulation of cerebroside and galactosylsphingosine, which induces apoptosis in the oligodendrocyte cell lines.
Krabbe病病因为β-半乳糖苷酶缺陷，致脑苷酯和半乳糖苷鞘氨醇的异常贮积，引发少突胶质细胞凋亡。

杨朝湘  18:53

Globoid cell leukodystrophy, an autosomal-recessive disorder, has a frequency of 2 in 100,000 in a series reported from Sweden. It is seen predominantly in young children; however, the infantile form is the most common. Onset of symptoms usually begins between 3 and 5 months after birth with irritability.
Krabbe病为常染色体隐性遗传病，发生率为2/100000。多发于小儿，婴儿型最为常见。症状通常出现于生后3到5个月，表现为易激惹。

杨朝湘  18:53

The disease continues to progress, with development of symptoms mimicking encephalitis with motor deterioration and atypical seizures. At the end stage of the disease, the child is in a vegetative state with decerebrate posturing. Elevated CSF protein has been reported, to a larger extent in adult phenotypes than in phenotypes affecting younger people. Positional ocular flutter has been reported in one patient with infantile Krabbe disease. In nerve conduction studies, the severity of abnormalities appears to correlate with the severity of clinical symptoms.
病变继续进展，临床症状可类似脑炎，表现为运动功能退化和不典型的癫痫发作。病变晚期，患儿可呈去大脑强直的植物状态。有报道发现CSF中蛋白升高，这主要见于成人型。还有个例报道发现Krabbe病患儿出现眼球震颤。神经传导研究表明，病变的严重程度与临床症状的严重程度相关。

杨朝湘  18:53

The disease involves predominantly the white matter of the cerebral hemispheres, cerebellum, and spinal cord. Pathologic changes include a marked toxic reduction in the number of oligodendrocytes. Multinucleated cells that appear to be globoid, as well as reactive macrophages, are scattered throughout the white matter region. Hypomyelination may be extensive and eventually leads to gliosis and scarring in the white matter region. Gray matter involvement in the basal ganglia region also can be found with punctate calcification.
病变主要累及大脑、小脑和脊髓的白质。病理改变包括少突细胞明显减少，多核细胞呈球形，以及反应性巨噬细胞散在分布于脑白质内。髓鞘形成减少较为广泛，并最终导致神经胶质增生及瘢痕形成。基底节灰质可受累，可表现为点状钙化。

杨朝湘  18:53

Delayed myelination may be the first finding noted on MRI in infants with this disorder. In infantile Krabbe disease, MRI findings may be normal, but as the disease progresses, classic Krabbe features emerge; this phenomenon is probably related to the immature myelination. The appearance of Krabbe disease on MRI is featured as one of either two patterns. A patchy hyperintense periventricular signal on T2-weighted images, consistent with hypomyelination, eventually may evolve into a more diffuse pattern in the white matter. In this form, involvement of the thalami with a hyperintense T2 signal often is present as well. A second pattern is a patchy low signal on T2-weighted images in a similar distribution to the hyperdense regions seen on CT, which is suspected to represent a paramagnetic effect from calcium deposition in the region.
MRI最早可表现为髓鞘化延迟，也可能表现正常。随着疾病的进展，逐渐出现典型的Krabbe病MRI表现。一种表现为T2WI上于脑室旁白质内出现斑片状异常高信号，并持续进展为弥漫状。丘脑亦可受累而呈T2高信号。另一种表现为T2WI上出现斑片状异常低信号，对应于脑CT上的高密度区，这可能是钙盐沉积所导致的顺磁性效应所致。

杨朝湘  18:54

Additional early changes include increased density in the distribution of the thalami, cerebellum, caudate heads, and brainstem that may precede the abnormally low attenuation of white matter in the centrum semiovale. Symmetric enlargement of the optic nerves also has been described in persons with Krabbe disease. The distal optic nerves are primarily involved; however, a case has been described with proximal prechiasmatic enlargement of the nerves. At times, changes within the cerebellar white matter also have been reported, with hyperintensity on T2-weighted images. The findings within the spinal cord are visualized as atrophic changes.
其他表现还包括丘脑、小脑、尾状核头及脑干可先于半卵圆中心出现异常信号；视神经对称性增粗，主要累及视神经远端，也有病例报道发现视交叉前部近端增粗；有时小脑白质亦可出现T2异常高信号；脊髓可发生萎缩。

杨朝湘  18:54

Proton MRS demonstrates the reduced NAA expected with neuroaxonal loss but also has revealed disturbances in glial cell metabolism associated with hypomyelination. In addition to a reduced NAA level, elevated levels of choline and mI also have been reported in this condition, which is consistent with the general neurodegenerative pattern as seen on proton spectroscopy. DWI also has been applied in a limited number of patients with Krabbe disease.
MRS可见NAA峰下降，及胆碱峰和肌醇峰升高。

杨朝湘  18:58

杨朝湘  18:59

这是病例二，答案是：异染性脑白质营养不良

杨朝湘  18:59

图注：An abnormal hyperintense signal in the periventricular white matter throughout the cerebrum, sparing the subcortical U fibers. The signal has a “tigroid” appearance on T2-weighted images. The spectra demonstrate significant elevations of choline and myo-inositol with diminished N-acetylaspartate reflecting neuroaxonal loss, demyelination, and glial activation
译：双侧脑室旁白质对称性异常高信号，不累及皮层下U形纤维。T2WI上病变区出现“虎斑”征。MRS示胆碱峰和肌醇峰明显升高及NAA峰下降，提示神经轴索损伤、脱髓鞘，及神经胶质增生活跃。

杨朝湘  18:59

这是文中图例说明。

杨朝湘  19:00

关于此病，缩写为MLD，文中有如下讲解：

杨朝湘  19:00

In persons with MLD, the primary metabolic defect is a deficiency in the enzyme arylsulfatase A, resulting in the accumulation of cerebroside sulfate within the lysosome. MLD has four subtypes: congenital, late infantile, juvenile, and adult.
MLD为原发性代谢缺陷性疾病，是由于芳香基硫酸酯酶A缺陷导致硫酸脑苷脂在溶酶体内贮积。MLD有四个亚型，即先天型、晚期婴儿型、少年型和成人型。

杨朝湘  19:00

The late infantile subtype is the most common and presents from around 14 months to 4 years of age. The early presentations are an unsteady gait that progresses to severe ataxia and flaccid paralysis, dysarthria（构音障碍）, mental retardation, and decerebrate posturing. Gallbladder involvement has been reported, possibly appearing before the onset of neurologic symptoms. Intestinal involvement also has been reported, specifically polypoid masses in one patient.
晚期婴儿型最常见。发病年龄在14个月到4岁。其临床表现早期为步态不稳，后进展至严重共济失调和弛缓型瘫痪、构音障碍、肌张力降低、智力低下，及至去大脑强直。有报道称MLD可出现胆囊症状，可能出现在神经系统症状之前。也有报道发现MLD合并肠道异常，特别是有一例合并了多发肠息肉状肿物。呈进行性发展，一般在5岁前死亡。

杨朝湘  19:00

Histologic analysis of the abnormal nervous tissue demonstrates a complete loss of myelin (demyelination) followed by axonal degeneration. Metachromatic granules are reported within engorged lysosomes in white matter and neurons and on peripheral nerve biopsies. Oligodendrocytes are reduced in number, and areas of demyelination predominate throughout the deep white matter region. Early sparing of the subcortical arcuate white matter fibers (“U” fibers) occurs until late in the disease process.
组织学可见病变区髓鞘完全脱失，随之轴突变性。有研究发现于脑白质和神经元中可见肿胀的溶酶体，其内充满异染颗粒。少突胶质细胞减少，深部脑白质区明显脱髓鞘。弓形纤维在病变早期不受累，只在病变进展至晚期才被累及。

杨朝湘  19:00

An inflammatory response typically is absent, which accounts for a lack of enhancement in this disorder, but eventually, even myelinated white matter is replaced by astrogliosis and scarring. The corpus callosum is involved before significant progression; atrophy is a late sign.
病变区缺乏炎性反应，这也解释了为什么影像上在增强后病变无强化。最终病变区白质会被星形胶质细胞增生和瘢痕所代替。胼胝体在早期即可受累。晚期会出现脑萎缩。

杨朝湘  19:00

Demyelination also can be seen in the posterior limbs of the internal capsule, descending pyramidal tracts, and the cerebellar white matter. Thalamic changes may be common in primary MLD, and isolated cerebellar atrophy may be seen in some atypical later-onset variants.
内囊后肢、下行的锥体束及小脑白质也可发生脱髓鞘。丘脑异常也较为多见。在一些不典型的晚发型MLD中，也可出现孤立性的小脑萎缩。

杨朝湘  19:01

On T2-weighted images, there is marked hyperintensity of the white matter fiber tracts involving the cerebral hemispheres that may extend to the cerebellum, brainstem, and spinal cord. The findings further demonstrate diffuse deep white matter involvement with relative sparing of subcortical white matter. The findings initially are focal and patchy, but later, a diffuse, hyperintense T2 signal of the centrum semiovale develops. Two distinct white matter appearances have been noted that mimic what was previously considered to be pathognomonic of Pelizaeus-Merzbacher disease (PMD). Punctate areas of hypointensity (“leopard skin” appearance) and radiating patterns of linear tubular structures of T2 hypointensity (“tigroid” appearance/虎斑征) are seen, with areas of relatively normal-appearing white matter within the areas of demyelination.
在T2WI上，受累的双侧半卵圆中心脑白质呈明显异常高信号，并可扩展至小脑、脑干和脊髓。通常不累及弓状纤维。在病变初期半卵圆中心白质异常信号可能是局灶性的、斑片状的，到后期则呈弥漫性的。以往曾认为异常白质区内出现“豹纹”或“虎斑”征（即T2WI上，脱髓鞘高信号病变区内出现条纹状或斑点状正常组织低信号），是佩梅病较为特征性的表现。但现在认为MLD亦可出现。

杨朝湘  19:01

Proton MRS studies have demonstrated reduced NAA, which is expected with neuroaxonal loss, but they also have revealed disturbances in glial cell metabolism associated with elevated mI and choline. The levels of NAA in white matter have been found to correlate with motor function in children with MLD
MRS可见NAA峰下降，这是神经轴索损伤的表现。而肌醇峰和胆碱峰升高，这是神经胶质细胞代谢紊乱的表现。研究发现，脑白质NAA水平与患儿的运动功能相关。

杨朝湘  19:03

杨朝湘  19:04

病例1：粘多糖病（II型）

杨朝湘  19:04

图注：Prominent perivascular spaces are demonstrated with a diffuse, abnormal, hyperintense signal throughout the periventricular and subcortical white matter. The spectra demonstrate diminished N-acetylaspartate levels with elevated lactate, which may reflect histiocytic cell infiltration of the perivascular spaces and brain parenchyma
译：脑室旁及皮层下白质见弥漫性异常高信号伴多发较宽的血管旁间隙。MRS示NAA峰下降、乳酸峰升高，提示血管旁间隙和脑实质内组织细胞浸润。

杨朝湘  19:04

The mucopolysaccharidoses are the best known of the lysosomal abnormalities affecting predominately gray matter. The primary metabolic defect in this group of disorders is a failure to break down sulfates (dermatan, heparan, and keratan); thus mucopolysaccharides fill up and overburden the lysosomes within histiocytes of the brain, bone, skin, and other organs.
粘多糖病（粘多糖贮积病）是最为熟知的主要累及脑灰质的溶酶体病。粘多糖病是一组硫酸盐（如皮肤素、乙酰肝素和角质素）分解代谢障碍所致的原发性代谢缺陷性疾病。患者脑、骨、皮肤和其他器官的组织细胞溶酶体内粘多糖贮积和过载。
Eight subtypes have been defined; however, six distinct forms are now recognized within this classification scheme, based on which metabolite is involved. The six are referred to as Hurler (IH), Hunter (II), Sanfilippo (III), Morquio (IV), Maroteaux-Lamy (VI), and Sly (VII),
粘多糖病有8个亚型。其中的6个较为明确，分别为：Hurler (IH型)、Hunter (II型)、Sanfilippo (III型)、Morquio (IV型)、Maroteaux-Lamy (VI型)，和Sly (VII型)综合征。
All of these diseases are autosomal recessive except type II, Hunter, which is an X-linked recessive condition. Hydrocephalus is common, probably as a result of plugging of the pacchionian granulation.
在这6个亚型中，只有II型Hunter综合征不是常染色体隐性遗传，而是X性联隐性遗传。常见脑积水，这可能是的蛛网膜颗粒堵塞导致脑脊液吸收障碍的结果。

光光同学'jiao  19:07

杨老师 那这病例跟肾上腺脑白质营养不良在影像上有区别嘛？

杨朝湘  19:10

肾上腺脑白质营养不良MRI是比较有特征性的，第一典型的会出现“蝶翼”征，即病变主要累及双侧枕叶白质并累及胼胝体压部，第二增强后病变周边出现环形强化，这在其他脑白质营养不良疾病中较少出现。

杨朝湘  19:12

杨朝湘  19:12

这个就是肾上腺脑白质营养不良

mhj  19:19

@杨朝湘  广东省妇幼保健院放射科 杨老师 豹纹征能不能明示一下

杨朝湘  19:20

杨朝湘  19:21

是的，红箭指的，，但主要是在轴位上观察

杨朝湘  19:20

白色病变区中出现低信号条纹，，

杨朝湘  19:25

今天这三例有一个共性，，就是它们都是溶酶体贮积病

杨朝湘  19:26

书中对溶酶体贮积病，是这样讲的；

杨朝湘  19:26

The lysosomes are intracellular organelles responsible for degrading lipids, proteins, and complex carbohydrates. In most lysosomal disorders, the genetic mutation resulting in the absence or partial deficiency of an enzyme or protein is known and functionally understood. For most of the lysosomal diseases, the substrate for the defective enzyme builds up, leading to intralysosomal storage. Although the diseases are complex, mechanical disruption of the cell as a result of the storage of nondegradable material leads to cellular dysfunction.
溶酶体为细胞内细胞器，作用在于降解脂类、蛋白和碳水化合物。大多数溶酶体疾病都源自基因突变所致的酶或蛋白缺乏或缺陷。正是由于相关酶的缺陷导致相应底物不能降解而在溶酶体中异常贮积。其结果便是细胞的破坏及相应细胞功能障碍。

杨朝湘  19:26

In general, the pathology primarily involves neuronal dysfunction rather than loss, with the exception of differential loss of Purkinje cells that characterize several storage diseases, including Niemann-Pick disease type C and the massive cell loss that occurs in the neuronal ceroid lipofuscinoses (NCLs).
一般而言，溶酶体病主要是导致神经元功能障碍而非丧失。蒲肯野细胞是个例外，溶酶体病可致该细胞丧失，这会导致如Niemann-Pick病C型等。而神经元蜡样脂褐质贮积病(NCLs)则会出现大量该细胞的丧失。

杨朝湘  19:26

Lysosomal disorders typically are inherited as autosomal-recessive traits; they usually afflict infants and young children. However, adult-onset forms exist. The collective frequency of lysosomal storage diseases is estimated to be approximately 1 in 8000 live births,.
溶酶体贮积病为常染色体隐性遗传病。主要发生于婴幼儿。也可见于成人。其发病率约1/8000。
Lysosomal disorders primarily affecting gray matter include the gangliosidoses（神经节苷脂贮积病）, mucopolysaccharidoses（MPS）, and NCLs. Two of the more common lysosomal disorders, metachromatic leukodystrophy (MLD) and Krabbe disease, demonstrate abnormalities in white matter. However, broader involvement of gray and white matter often occurs in later stages of lysosomal disease progression
溶酶体贮积病中，主要累及脑灰质的有神经节苷脂贮积病、粘多糖病（MPS）和神经元蜡样脂褐质贮积病(NCLs)。主要累及脑白质的有异染性脑白质营养不良（MLD）和Krabbe病，这两种病要较前几种病更常见些。但当溶酶体病进展到后期，则灰白质都常会被累及。

杨朝湘  20:00

是的。少见。日常工作中，很多时候是做为排他性诊断的，就是在排除了常见的炎性（如病脑）血管性（如梗死）和脱髓鞘病变（如ADEM）后才考虑。能考虑到是这个病以提示临床做相关检查，即使不具体到是何病种（比较有特征性的除外），我想也应该算是差不多了，具体看个人功夫了。