顾建文教授,解放军306医院 颅咽管瘤是发生在颅内鞍上区累及下丘脑的良性肿瘤,手术切除后可达到完全性治愈。但是由于肿瘤多是侵蚀垂体柄、漏斗、灰结节、乳头体和视交叉等下丘脑结构,使手术切除肿瘤困难,术后下丘脑损害合并症如尿崩症、高热和昏迷等,严重影响病人愈后,因之对颅咽管瘤的治疗效果是神经外科水平的标志之一。 颅咽管瘤的发病率北美报告约占人口0.13/10万;占欧洲人颅内肿瘤发病率2.7%~4.9%;国内报道约占颅内肿瘤发病率3.5~5%,其中儿童为5%,成人为3.5%。治疗方法常见的有外放疗、间质内放疗和化疗、手术切除。由于肿瘤呈良性生长,可伴有囊性变和钙化,对放疗和化疗不敏感,不能很好地解除对下丘脑神经结构的压迫,同时也有引起放射性损伤的危险,如早期视力障碍加重、多饮多尿,晚期可有下丘脑功能低下和智力减退等。手术切除由于死亡率高,合并症严重,以往多采取部分切除肿瘤,再结合外放疗来延缓病情的发展。 1990颅咽管瘤是发生在颅内鞍上区累及下丘脑的良性肿瘤,手术切除后可达到完全性治愈。但是由于肿瘤多是侵蚀垂体柄、漏斗、灰结节、乳头体和视交叉等下丘脑结构,使手术切除肿瘤困难,术后下丘脑损害合并症如尿崩症、高热和昏迷等,严重影响病人愈后,因之对颅咽管瘤的治疗效果是神经外科水平的标志之一。 颅咽管瘤的发病率北美报告约年,瑞士Yasargil首先报道肿瘤手术全切除率在90%,术后死亡率16%;1992年,美国Hoffman等人报道肿瘤的手术全切除率在60%,术后死亡率20%;并提示,其疗效与手术方法、肿瘤切除率、术中下丘脑神经结构的保护密切相关。此后人们开始探索积极的肿瘤 全切除术,其理由为:1)全切除可达到完全治愈的效果;2)部分切除肿瘤没有肯定的疗效,并可使手术区解剖结构紊乱和肿瘤与周围结构粘连,使二次手术困难,更难以作到肿瘤全切除;3)目前对大部分肿瘤没有其它好的治疗方法。从文献资料来看,肿瘤全切除的术后死亡率由1990年以前的20%,下降到1995年的10%以下,到2000年报道术后死亡率为5%以下。 下丘脑神经结构和功能的保护是关键;把三脑室前部下丘脑结构分为五个部分;依椐颅咽管瘤的发生部位将其分为下丘脑下型和下丘脑上型。对下丘脑下型的肿瘤,多采取纵裂前入路,对后者手术多采取翼点、额下和经蝶窦入路,利用神经血管间隙切除肿瘤,能从多个方位显露肿瘤,但术中操做使血管神经损伤和血管痉挛的危险性增加。 另外,手术保护下丘脑的显微穿通动脉对维护下丘脑的功能和防止术后并发症如记忆障碍、尿崩症、高热、昏迷和瘫痪十分重要。肿瘤全切除是指,手术显微镜下切除全部肿瘤,术后影像学证实肿瘤消失。目前来看,使肿瘤全切除困难的原因有:1)肿瘤钙化坚硬较大;2)肿瘤与下丘脑结构或穿通动脉粘连;3)肿瘤囊壁薄不能与周围结构分离;4)手术视野限制未能见到残留肿瘤,术后影像检查发现肿瘤未能全切。随访手术后10年内的患者,仍有10%肿瘤复发率。其主要原因:1)全切除仍有肿瘤细胞残留可能;2)手术过程造成肿瘤细胞移位生长;3)肿瘤与第三脑室底无蛛网膜分隔并在下丘脑呈侵润性生长。对于肿瘤复发有占位效应患者,可进行二次手术切除肿瘤。对于远离神经结构的复发实性肿瘤,可采用r-刀或其它立体放射治疗。约50%~80%患者全切除后可发生术后下丘脑和垂体功能障碍并发症。手术早期神经垂体并发症有抗利尿激素(ADH)缺乏引起的尿崩症(DI),患者主要表现为口渴、多饮和多尿;抗利尿激素分泌异常综合征(SIADH),患者除有多饮和多尿外,以低血钠为特征,严重时引起脑水肿,患者出现头痛、恶心、呕吐和抽搐,即脑耗盐综合征(CWS)。还有视上垂体束、视上核和室旁核损伤,患者觅水功能障碍,无口渴感。血钠升高,全身乏力和轻度尿崩症,也称脑盐潴留综合征(CSRS)。腺垂体前叶激素缺乏是颅咽管瘤切除术后需长期治疗的并发症,方法包括发育呆小和迟缓儿童的生长素(GH)的代替治疗;雄性、雌性激素缺乏引起的性发育障碍患者的性腺激素的代替治疗,及其下丘脑功能低下的糖皮质激素代替治疗和甲状腺功能低下的甲状腺素的代替治疗。虽然已有多种人工合成激素代替下丘脑和垂体激素的治疗,但下丘脑和垂体激素的功能并不仅仅是单纯 给予激素代替方法。而是系统的、全面的生理和临床的治疗。从我们术后随访资料来看,青春发育前的患者,下丘脑功能受累不严重,在肿瘤全切除后下丘脑得到良好保护者,患者仍可恢复身体生长和性功能发育。
解放军306医院,顾建文教授 一患者脑袋怕震,怕环境噪声,发现为三叉神经鞘瘤,经过手术切除恢复良好。 三叉神经鞘瘤约占脑瘤的0.2%~1%。可起源于三叉神经的任何节段,但以美克尔(Meckel)囊内为多。属良性肿瘤,生长缓慢。按部位分为颅中窝型、颅后窝型及哑铃型3种。 临床表现主要有三叉神经本身和邻近结构受累的症状和颅内压增高症状。根据肿瘤位置的不同,临床表现如下: 1、颅中窝型:早期多以三叉神经本身受累的症状为主,其表现类似原发性三叉神经痛者约占1/3,为发作性剧痛。三叉神经分布区感觉减退者较多,但有时仅有角膜反射减弱,不可忽略。运动根受累者甚少,或至晚期方始出现。当肿瘤累及邻近结构,特别是肿瘤发展至海绵窦及眶上裂等部位,则出现其它脑神经受累症状,如病侧眼球运动障碍、复视、眼球突出及视力、视野改变等。其中以展神经和动眼神经瘫比较明显,瞳孔常有散大,光反射迟钝。眼球突出约占1/3至1/2,可能系海绵窦受压,影响眼静脉回流,或肿瘤直接经眶上裂突入眶内的结果,眼底静脉常有淤血。若肿瘤向前发展压迫视神经和视交叉时,则有视神经原发性萎缩、视力减退和视野缺损甚至失明。此型颅内压增高症状出现较晚亦较轻。有时肿瘤如鸭蛋大小并无颅内压增高症状。 2、颅后窝型:肿瘤多起源于三叉神经根。运动根受累的症状多较突出,如颞肌及咀嚼肌无力、萎缩等。临床表现为三叉神经痛者极少,但感觉减退可早期出现,且多系第1、2、3支同时受累,也可能仅有角膜感觉减退。肿瘤压迫第7、8对脑神经时,可引起面肌抽搐、周围性面瘫、耳鸣、听力减退,前庭功能亦受累。肿瘤靠近小脑幕者,有第9、10、11对脑神经受损的症状。小脑受压时,多有共济失调。如脑干受压或移位,常出现对侧或同侧锥体束征。一般颅内压增高症状出现较早且较明显。 3、哑铃型:肿瘤跨居中颅窝与后颅窝之间,可由中颅窝向下或由后颅窝向上生长,临床症状兼有上述两型的症状特点。 该例患者术前影像: 该例术后影像
顾建文教授,解放军306医院 Glioblastoma vasculature and vascular mimicry Introduction Glioblastoma (GB) is the most common intracranial malignancy with an annual incidence of approximately 3 – 5 cases per 100,000 individuals. In terms of overall cancer burden GB is uncommon, however, the combination of brain localization, invasiveness, and extremely poor prognosis make it one of the most feared of all cancer diagnosis. Glioblastoma currently has an overall median survival time of 12 – 15 months despite maximally combined therapy of neurosurgery, radiation, and combination thermotherapy. It is interesting to note that the extremely slow development of effective therapy/treatment lies in stark contrast to the rapidly expanding foundation of knowledge regarding the molecular pathogenesis of this disease. The vast majority of research in the field of neuro-oncology has been published in the last 20-30 years, largely driven by a greater understanding of brain tumor genetics. More recent molecular classification has provided the basis for the existence of four distinct types of high-grade primary glioblastoma: classical, mesenchymal, neural, and pro-neural subtypes. These subtypes are differentiated molecularly based upon various proteomic features, signature mutations, methylation features, and currently identified tranional regulators. The comprehensive molecular classification of high-grade gliomas is just now starting to transform current classification, which currently follows the consensus WHO histopathological criteria. Despite sophisticated molecular classification schemes, a relatively high percentage of gliomas remain difficult to reproducibly categorize due to considerable histological overlap. Phenotypically, the tumor displays marked hypercellularity, serpiginous areas of necrosis, and expansive endothelial cell proliferation with tumor vasculature being torturous, disorganized, and highly permeable. Grade IV neoplasms exhibit extremely aggressive proliferation of endothelial cells as compared to Grade II and Grade III tumors. The increased vascular permeability compounds the issue by leading to increased cerebral edema and inflammation. Abnormalities in the endothelial walls, pericyte coverage, and basement membrane also result in loss of structure and function of the critical blood brain barrier. Glioma vasculature formation occurs through at least three distinct processes. 1) Angiogenesis; the process of generating new blood vessels from rerouting and remodeling of pre-existing vessels, 2) Vasculogenesis; classically considered an embryonic process, but has since been identified in tumors as thede novoformation of primitive blood vessels by the differentiation of circulating bone marrow-derived endothelial progenitor cells, and 3) Vascular Mimicry (VM); recently identified to provide a contribution to tumor vasculature by trans-differentiation of glioma cells into tumor-derived endothelial cells (TDECs). Molecular pathways It is said that cancer metastases, regardless of the primary tumor, play by a different set of rules from the primary tumor, and cancer deaths primarily result from invasion and metastases that are resistant to conventional therapies that may otherwise effectively treat the primary tumor. Tumor survival is dependent upon a rich blood supply needed to sustain tumor growth and further metastasis. Malignant gliomas, like other neoplasms, require angiogenesis to establish a source of nutrients/oxygen and to eliminate cellular waste products. The tumor vasculature also creates a localized “niche” microvascular environment within which the tumor-initiating cells may be able to effectively resist therapy. Angiogenesis is a key pathologic event and necessary for the progression of a solitary localized neoplasm to a highly aggressive tumor. This critical tenant subsequently ignited the field of neoplastic angiogenesis research, which has focused on targeting endothelial cells forming the neovasculature of growing tumors and served as the major organizing principle for drug development of various clinical trials. Because GB is one of the most vascular rich tumors and VEGF (vascular endothelial growth factor) is produced by tumor cells, anti-VEGF antibody (bevacizumab/Avastin) has been used in clinical trials. The results of clinical trials are disappointing to say the least, more than half of patients with GB only transiently respond to combination treatment of Avastin andIrinotecan. Mechanisms proposed ot explain resistance to anti-VEGF therapy include 1) Activation of other pro-angiogenic signaling pathways 2) Recruitment of bone marrow (BM)-derived myeloid cells that protect and nurture vascular cells and/or 3) Protection of blood vessels by increased pericyte coverage. In GBs, the antitumor effect of the antiangiogenic therapies is likely due to normalization of vasculature, which also decreases edema. The disappointing results of the angiogenesis inhibitor trials, together with new evidence generated from molecular and animal research on human GB tumor progression, have given insights into the molecular mechanisms underlying the perfusion of tumors, particularly those expressing an aggressiveinvasivephenotypes such as GB. In tumor angiogenesis, bone marrow-derived endothelial cell precursors (ECPs) have historically been known to be the main source of the vascular endothelial cells. However, recently it was shown that BM-derived endothelial precursor cells did not solely contribute to the vascular endothelium, and it is now understood that TDECs in GB transdifferentiated from neuroectoderm and that tumor cells themselves can be involved in tumor angiogenesis. This more recent evidence suggests an alternative mechanism, one whereby tumor microvasculature is derived directly from tumor cells, and this process is called Vascular mimicry (VM). VM describes the functional plasticity of aggressive cancer cells formingde novovascular networks, providing perfusion pathways for expanding tumors, transporting fluid from leaky vessels, and/or connecting to endothelial-lined vasculature. VM evidence suggests that this blood-perfused microvasculature plays a critical role in tumor development and is independent of endothelial cell angiogenesis. Interestingly, VM networks have also been shown to exhibit anticoagulant properties through local expression of anticoagulant molecules with the overall goal to facilitate the flow of blood into and among aggressive tumors. The original study describing VM was based on evidence that showed transport of injected fluorescent dye throughout VM networks. Subsequent experimental evidence has shown real-timein vivophysiologic perfusion of blood between endothelial-lined mouse vasculature and VM networks in human tumor xenografts using Doppler imaging of microbead circulation. This study went on to show that aggressive melanoma cells are capable of de novo three-dimensional vascular structure formation, this finding was subsequently validated by high resolution Electron Microscopy showing the morphological/structural details of the tumor-formed vessels and similarities in ultrastructure between VM and traditional endothelial-lined vasculature. Melanoma studies also showed tumor cells may co-express endothelial, embryonic/stem cell, and tumor cell markers. A really interesting study that describes hypoxia as a catalyst of VM phenotype was demonstrated with the transplanatation of human metastatic melanoma cells into an ischemic mouse limb, which resulted in the formation of a blended vasculature composed of human melanoma and mouse endothelial cells. After blood flow to the limb was sectored, the melanoma cells formed a large tumor, this study demonstrates the amazing influence of the microenvironment on the transendothelial differentiation of melanoma cells, which reverted to a more tumorigenic phenotype as the environmental cues changed. Transdifferentiation of GB stem cells (GSCs) into mural-like (vascular smooth muscle/pericyte-like) tumor cells highlights the plasticity of GSCs. The plasticity of GSCs is further displayed by the multi-potency of neuronal stem cells that are capable of differentiating into several cell lineages (i.e., astrocytes, neurons, and oligodendrocytes); and into a variety of cells such as blood cells, muscle cells, and vascular endothelial cells. Many molecular details underlying VM have been deciphered, but as with any other topic of scientific research, there are still many more questions than answers. However, it is known that critical VM-modulating genes are associated with vascular (VE-cadherin, EphA2, VEGF1) embryonic and /or stem cells (Nodal, Notch4), and hypoxia related (HIF, Twist1) signaling pathways. A few selected common genes and pathways will be discussed briefly in this article. 1)Notch and Nodal signaling pathwaysare tow pathways that have been shown to be critical both for embryonic stem cell regulation and tumor cell behavior; interestingly, crosstalk between these pathways regulates tumor cell behavior, aggressiveness, and VM network formation. Nodal signaling modulates vertebrate embryogenesis functioning in left-right asymmetry determination and stem cell pluripotency; generally absent in adult tissues but is known to become reactivated in aggressive cancer. Noteworthy is the fact that aggressive cancers reactivate Nodal, but not its regulatory protein Lefty, therefore Nodal signaling proceeds unchecked and is able to promote aggressive tumor cell behavior. Notch signaling is important in stem cell differentiation and self-renewal and is expressed in various embryonic and adult tissues. 2) Hypoxia-Inducible-Factor (HIF) complex is a key regulator of oxygen homeostasis in both physiological and pathological environments. HIF can modulate and cross talk with both Notch and Nodal signaling pathways. HIF over-expression in cancer induces the expression of gene products involved in angiogenesis (i.e., VEGF). It is important to note that hypoxia has been shown to induce both Notch and Nodal pathways via HIF1-alpha/2-alpha and HRE signaling. There is significant cross-talk between HIF1-alpha and Notch-signaling, overall working within tumor cells to promote an undifferentiated cellular state. This is how it becomes conceivable that therapeutic usage of antiangiogenic agents may counterintuitively promote tumor plasticity and metastatic/invasive progression. Genetic analysis of individual ECs via microdissection followed by genetic analysis of GB ECs showed that 50-90% of ECs in the GB tumors carry the genetic abnormalities found in the tumor cells themselves, suggesting a common origin. Furthermore, mouse experimentation has revealed that the tumor-derived endothelial cells originated form tumor-initiating cells and did not result from the cell fusion of ECs and tumor cells. Anin vitrodifferentiation assay in the same study suggested that hypoxia was the critically important factor in the differentiation of GB tumor cells to ECs and is independent of VEGF. Tumor derived endothelial cell (TDEC) formation was not only resistant to anti-VEGF receptor inhibitor, but it led to an increase in their frequency. It can be surmised that that TDECs make an important contribution to the resistance of GB to anti-VEGF therapy, and it can therefore also be a potential target for GB therapy. By and large, tumor cell VM nicely illustrates the functional plasticity of the aggressive cancer phenotypes and serves as a selective advantage for rapidly growing tumors in need of perfusion. VM can provide one of several sources for a tumor blood supply that can directly or indirectly interact with other vasculature. The literature is in agreement what the underlying induction of VM seems to be related to hypoxia, which in turn activates a variety of genetic alterations as previously described that then directly promote the transendothelial phenotype of tumor cells capable of VM. Treatment Obstacles As previously mentioned, the detailed and precise deion of the molecular biology of glioblastoma lies in stark contrast to the lack of advances in therapy. With a currently expanding knowledge of molecular biology, more potential targets have been identified and the key will be to develop potent inhibitors and effectively use combinations of them in an appropriate and targeted manner. A major limitation to targeted drug delivery is that migrating primary tumor GB cells blend in with normal tissue, are difficult to identify and target, and do not elicit an angiogenesis response. Additional therapeutic obstacles include 1) No effective agonists/antagonists against identified targets, 2) Therapeutic molecules must pass BBB in order to reach invading cells, including those located at a distance from the central part of tumor. Varying degrees of BBB dysregulation exist within a given GB tumor, by itself, the BBB is known to present a challenge to effective transit of therapeutic molecules to the brain, and continued study of BBB in tumor setting s is needed to lend insight into effective drug delivery in GB, and 3) currently lack ideal animal model for GB treatment studies. Combined antivascular therapy aiming at both mural-like tumor cells and endothelial cells, in addition to cytotoxic drugs targeting tumor cells may hold promise. It seems plausible that the most efficient way to target tumor cell plasticity is to inhibit multiple signaling pathways simultaneously. The molecular pathways that have been experimentally identified as critically involved in VM. The molecular pathways that have been experimentally identified as critically involved in VM, along with failed clinical trial data should serve as a strategic roadmap for drug development with goal being to overcome tumor cell plasticity, drug resistance, neoplastic angiogenesis, invasion and metastasis. The emerging data on embryonic pathways, Notch and Nodal, which are reactivated in aggressive tumor cells, may provide valuable therapeutic targets that exploit the convergence of embryonic and tumorigenic signaling. Suppression of these pathways results in the inhibition of VM, tumorigenicity, and the reversion of the stem cell-like phenotype to that of a differentiated cell type. Simultaneous targeting of the Notch and VEGF pathways may perhaps provide a more viable combination approach to target cancer stem cells with anti-VEGF therapy. Conclusion and Future Work Several centuries of research have shown the high degree of plasticity associated with aggressive neoplasms. With the recent addition of sophisticated molecular tools, the exact mechanisms, etiology, and implications of tumor cell pathobiology have been further elucidated. During this time, research has demonstrated that the presence of a small population of GSCs is closely associated with resistance to radiotherapy and anti-angiogenic therapy. However, clinical treatment using an anti-VEGF therapy alone has routinely failed to significantly affect patient survival and clinical outcomes. It is logical to speculate that as part of its ability to survive in the presence of anti-angiogenic agents and reemerge from dormant primary tumors, GSCs may undergo an alternative vascularization that develops mural-like cell-associated networks and nourishes the bulk of the growing tumor cells. From the literature within the field of neoplastic angiogenesis, it is now appreciated that the tumor vasculature is highly complex and can be derived from a variety of sources, including angiogenic vessels, cooption of preexisting vessels, mosaic vessels lined by both tumor cells and endothelium, and postnatal vasculogenesis. Furthermore, recent studies have shown the tumor origin of endothelial-like cells, vascular mimicry, in specific cancers, further complicating the strategies for targeting a genetically unstable and heterogeneous vasculature. The commitment to genomic characterization of GB has fueled substantial progress in understanding of this cancer, particularly within the past 5-10 years. Extensive genomic characterization has provided a high-resolution image of the various molecular alterations underlying GB, and suggests that indeed this disease represents several histologically similar, yet molecularly heterogeneous diseases. The heterogeneous nature of this neoplasm, both within and across tumors, underscores the difficulty in developing efficacious treatment and provides a challenge both to annotate tumors and to stratify patients for trials and treatment. Despite tremendous progress in understanding of the genetic basis of glioblastoma, targeted therapeutic approaches based on known genomic alterations have yet to be proven efficacious. The morphological heterogeneity that prompted the original deion of high-grade glioma as, “multiforme”, has indeed extended to the molecular level. It is likely that intratumoral heterogeneity and target cooperativity conspire to create a multiple dependency state whereby single-target inhibitors are not sufficient to significantly attenuate tumor growth. There is also an incomplete understanding of the functional consequences of many of the mutated genes in GB. Research is just now beginning to understand how this molecular heterogeneity is manifested and what exactly the functional consequences of these genetic alterations are. It is also not clear if these intermingled cell populations with unique genomic alterations behave as independent tumors or are interdependent with each other. In addition to understanding the molecular basis of GB heterogeneity, it will also be important to consider the contributions and phenotypes of the diverse non-tumor cell types, like stromal and inflammatory cells that also populate the glioma microenvironment. Further work is indeed necessary to fully understand GB biology and will require integrated studies, including genomic, animal models of disease, and as always a careful study of human tissue.
顾建文教授,手术经验,解放军306医院 枕大孔腹侧肿瘤的外科治疗要求对手术入路的暴露、术中椎动脉及神经根的处理很严格。临床多常见与脑膜瘤。表现多以颈项部不适起病,渐出现声嘶、音调低沉、吞咽困难、呛咳
顾建文教授,综述,解放军306医院近年来受激拉曼散射显微成像的技术成为热点。被称为受激拉曼散射显微成像的技术帮助外科医生在手术过程中更好的区分患者脑内的癌组织和正常组织,这可能会提高该类手术的安全性和精确性。近期报道英国首例:成功运用激光探测和智能刀精确切除脑部肿瘤。Reuben Hill,22岁,在读博士,脑部患有肿瘤。他成功接受了一场特殊的脑部肿瘤切除手术:术中采用了两个新技术——激光探测和智能刀。作为实验室成果运用到手术室的成功案例,这场开创性手术是精确外科手术的重大改革。 脑部肿瘤对生命的威胁超过其他任何一种肿瘤,脑部肿瘤切除手术具有很大的难度,因为神经组织交错复杂,肿瘤组织又这些精密结构相连,有时候外科医生通过显微镜都很难看清楚组织结构。同时,切除癌变组织面临着很大风险,因为手术刀必须严格确保在不破坏周围的正常脑组织的前提下,把肿瘤组织切除干净。一旦切到健康组织,会导致严重的副作用,例如丧失说话、听觉等功能。新型激光探针和智能刀大大降低了上述手术风险,且能够向外科医生即时提供组织是否癌变的信息。利用激光探测区分癌变组织和健康组织,且激光能够为外科医生提供肿瘤的映射,达到精确的切除水平。激光探针,利用拉曼光谱分子从组织中反射回来的光进行组织区分,由加拿大温哥华erisante Technology公司研发提供。Vaqas表示,这是第一次将拉曼光谱应用于人脑部手术的成功案例。 那么激光拉曼光谱技术到底还能做什么呢?癌症是威胁人类健康和生命的严重疾病之一,早期诊断与及时治疗是提高癌症患者生存率的最有效途径。激光拉曼光谱技术Ramanspectroscopy;作为一种非侵入性的检测技术,可以无损伤地提供丰富的分子结构特征和物质成分信息,从分子水平上反映癌变组织与正常组织之间的结构差异,从而可用于癌症的早期诊断cancersdiagnosis。综述了激光拉曼光谱技术在皮肤癌、鼻咽癌、肺癌、胃癌、结肠癌、乳腺癌及前列腺癌诊断中的研究进展,并对拉曼光谱技术在癌症诊断中的发展方向和应用前景作了进一步的展望,为癌症的早期检测和诊断技术的应用研究提供参考依据。1928年,印度物理学家Raman在研究中发现了拉曼散射的存在,此后研究人员对这一技术做了深入的研究,但是因为光源的限制使该技术未能得到广泛应用。直到60年代激光问世后,拉曼光谱信号弱的弱点才被彻底攻克,拉曼光谱如虎添翼得到了长足的发展,使其广泛应用于科学研究之中,自此之后激光光源也一直都是拉曼光谱的理想光源。直到1974年,英国科学家Fleischmann在研究吡啶的拉曼光谱时才发现通过某种方式是可以增强待测物的拉曼信号的,但是他们并没有进一步探讨其增强机制。SERS技术的真正发现还要追溯到1977年,这一年,Van Duyne和Jeanmaire等系统地研究了与Fleischmann研究小组相同的体系后,才发现吸附在粗糙Ag表面上的吡啶的拉曼散射信号与溶液相中的同数量的吡啶拉曼散射信号相比,增强了约6个数量级,正是这一发现之后人们才把这一增强现象称为SERS。 随着医学检测和诊断技术的不断提高,癌症的早期临床诊断也取得了迅速发展。但多数情况下仍需采用活组织切片进行诊断,这些方法侵入性强、对患者损伤较大,检测速度慢、并可能引起癌细胞扩散,而且需要检测人员具备一定的病理学知识。为解决上述问题,研究人员一直在不断进行新的检测分析技术的研究和尝试,以实现对癌症进行快速的非侵入性的早期临床诊断。激光拉曼光谱技术作为一种非侵入性的检测技术,可以提供丰富的分子结构特征和物质成分信息,通常被称为物质的分子指纹(molecularfingerprints),可望在分子水平上实现无损检测。与传统的医学诊断方法相比,拉曼光谱检测技术具有非破坏性、非侵入性noninvasivedetection、分辨率高、不用试剂和高度自动化等优点。因此,拉曼光谱技术在医学检测和诊断领域的应用倍受人们的重视。在肿瘤生长和发展过程中,组织细胞内的物质 结构、构象和数量会发生明显变化,拉曼光谱可以对这些信息变化实现高灵敏度、高分辨率的检测,进而在分子水平上揭示癌变组织与正常细胞组织结构之间的差异,通过对比研究癌变组织和正常组织的拉曼光谱,从二者的差异可发现能反映组织病变信息的特征光谱,因此,拉曼光谱检测技术对实现癌症的早期诊断和及时治疗,从而提高癌症患者的生存几率,具有重要意义。本文综述了拉曼光谱技术在多种癌症检测和诊断中的应用及研究进展,并对拉曼光谱技术在此领域的应用前景作了进一步的展望,期望为癌症的早期检测和诊断技术的应用研究工作提供参考信息和指导。 1拉曼光谱技术在癌症检测和诊断中的应用研究 1.1皮肤癌的拉曼光谱检测 皮肤癌主要有三种类型:基底细胞癌(basalcellcarcinoma, BCC)、鳞状细胞癌(squamouscellcarcinoma,SCC)和恶性黑素瘤(melanoma, MM),其中基底细胞癌最为常见。基底细胞癌和鳞状细胞癌若得到及时治疗,几乎所有病例均可治愈,而恶性黑素瘤是最少见但最严重的皮肤癌,若不能及时治疗,则会导致死亡。但是由于这几种癌的症状很相似,所以在诊断过程中存在一定困难,而将病人组织的每一块色素都切除进行活检是不可行的,因此需要寻求一种非侵入性的、无创伤的检测诊断方法。Nijssen等采用近红外激发光源,获得了基底细胞癌组织、真皮组织、上皮组织的拉曼光谱,利用多元统计分析和聚类分析对光谱进行分析,建立了组织分类模型,该模型可以鉴别癌变组织及其周围的非癌变组织,灵敏度达100 %,特异性可达93 %。他们的研究证实拉曼光谱能够准确地确定肿瘤的切除范围,为基底细胞癌的诊断与治疗提供了有力的理论和实验依据。Choi等利用共聚焦拉曼光谱技术对正常组织和基底细胞癌组织进行光谱检测研究,发现二者的光谱存在明显差异,因此,无需对光谱数据进行统计分析,便可以将BCC组织与周围正常组织区分开。Short等研究了节状基底细胞癌肿瘤周边胶原质的变化,发现癌细胞的细胞核中核酸、组蛋白及带有机动蛋白的蛋白质的作用与其在正常表皮细胞中的作用不同。并且获得了真皮组织的拉曼光谱,发现癌细胞周围的真皮组织中, 940 cm-1处拉曼谱线强度增大, 1 210 cm-1和1 270 cm-1处谱线强度明显减小,说明肿瘤周边组织中胶原质不仅含量低,而且结构上也发生了一定的变化。为了利用傅里叶变换拉曼光谱(FT-RS)来区分鳞状细胞癌与正常皮肤, Pereira等采用1 064 nm作为激发光,研究了人体皮肤活检组织的拉曼光谱,发现正常组织中位于860 cm-1和939 cm-1处的拉曼谱线强度明显比癌变组织中的相应光谱强度高,并且在1 555 cm-1~1 560 cm-1波数范围内,归属于核酸的谱线强度也有所不同。Gniadecka等利用近红外傅里叶变换(NIRFT)拉曼光谱研究了黑素瘤与其他皮肤病变的拉曼光谱特征,发现恶性黑素瘤的蛋白质酰胺Ⅰ带强度减小,而脂质特征峰强度增大。并利用神经网络方法进行光谱分析,使得拉曼光谱对恶性黑素瘤诊断的灵敏度和特异性分别达到了85 %和99 %。Huang等利用近红外拉曼光谱(NIR-RS)成功地获得了皮肤黑色素的在体拉曼光谱图,分析光谱发现黑色素的拉曼光谱分别在1 580 cm-1和1 380 cm-1处存在强度较高、频带较宽的拉曼谱带,分别属于芳香环的平面振动和C-C的伸缩振动模式。利用拉曼光谱技术在活体条件下获得了黑色素的光谱信号,表明拉曼光谱可能成为对皮肤进行原位分析与诊断的一种十分有效的临床检测方法。拉曼光谱技术还可用于其他皮肤病的检测中。Cheng等采用显微拉曼光谱技术分析了人类皮肤毛基质(humanskinpilomatrixoma, PMX)中构象与化学成分的变化,发现正常皮肤与软PMX组织和硬PMX组织的拉曼光谱存在明显区别,尤其是1 665cm-1归属于酰胺Ⅰ的特征峰移到1 655 cm-1处,硬PMX组织的拉曼光谱中归属于酰胺Ⅲ的特征峰强度明显减小。这些结果均表明显微拉曼光谱能够有效区分正常皮肤组织、软PMX组织及硬PMX组织。而且拉曼光谱分析技术在识别不同的皮肤病变方面具有很高的精确度,特别是对癌变组织具有很好的识别能力,在恶变肿瘤的原位分析与诊断中具有巨大的潜在应用价值。 1.2鼻咽癌和肺癌拉曼光谱检测 Lau等用拉曼光谱仪检测了鼻咽部的活检标本,每个光谱的采集时间仅为5 s。分析发现在1 290cm-1~1 320 cm-1及1 420 cm-1~1 470 cm-1波数范围内癌变组织的拉曼谱线强度比正常组织中相应谱线强度大,而1 530 cm-1~1 580 cm-1波数范围内,则是正常组织的拉曼谱线强度比癌变组织中相应谱线强度大。他们还利用拉曼光谱分别对喉部的正常组织、癌变组织、鳞状细胞乳头状瘤进行了研究。通过对拉曼光谱的峰值分析表明利用拉曼光谱对正常组织、癌变组织以及鳞状细胞乳头状瘤进行分析检测的灵敏度分别为89 %, 69 %, 88 %;特异性分别为86 %, 94 %, 94 %。Stone等收集了正常组织、不典型增生和癌变组织的拉曼光谱,用多元统计方法分析了光谱差异。可见的光谱区别在850 cm-1~950 cm-1和1 200 cm-1~1 350 cm-1谱段,核酸峰的相对强度随病变发展为恶性而增加。为了探究拉曼光谱对肺癌进行早期光学检测和诊断的可行性, Huang等利用快速弥散型近红外拉曼光谱(NIR-RS)研究了肺癌与正常支气管组织的光谱信息。研究表明,肺癌和正常支气管组织的拉曼光谱有明显区别,发现将拉曼谱线的强度比值酰胺I1 445/酰胺I1 655作为判断标准,能够有效区分肺部正常组织与癌变组织,当酰胺I1 445 /酰胺I1 655 >1时,所检测的组织为正常组织;酰胺I1445/酰胺I1 655<1< span="">时,则为癌变组织。利用此标准区分正常组织与癌变组织的灵敏度和特异性分别可达到94 %和92 %。Yamazaki等构建了一种新型近红外多通道拉曼系统(near-infraredmultichannelRamansystem),该系统用于采集肺部组织拉曼光谱,具有信噪比高、可避免荧光干扰、测量时间短(1 s)等优点。利用该系统收集了210个肺癌组织和正常组织的拉曼光谱,灵敏度达与特异性分别达到91 %和97 %。Min等利用近红外多通道拉曼光谱仪对未经任何处理的肺部组织进行研究,分别采用785nm和1 064 nm作为激发光,结果表明采用785 nm作为激发光时,背景荧光很强检测不到拉曼谱线,而用1 064 nm光源激发时,得到了信噪比很高的拉曼光谱。因此对未经处理的肺部组织进行拉曼光谱分析研究时,通常应采用1 064 nm作为激发光源。Li等研究了在肺癌发展过程中血清的荧光光谱及拉曼光谱的变化,采用488 nm和514.5 nm作为激发光对一组癌症患者的血清每周进行一次检测,研究发现,癌症发展的不同时期荧光光谱没有明显变化,而属于β胡萝卜素的三个拉曼峰(分别位于539 nm、544 nm及556 nm处)强度减小,最后消失。该实验结果表明,在肺癌恶化的过程中,β胡萝卜素的含量逐渐减少,可将此作为诊断肺部是否癌变的依据。 1.3胃癌和结肠癌的检测 凌晓锋等利用傅里叶变换拉曼(FT-Raman)光谱研究了40例胃癌与胃部正常组织,对光谱进行统计处理后发现,酰胺I3 240 /酰胺I2 940,酰胺I1 660 /酰胺I1 450,酰胺I1 080 /酰胺I1 450在胃癌组织中明显升高(3 240 cm-1 , 2 940 cm-1 , 1 660 cm-1,1 450 cm-1 , 1 080 cm-1分别是蛋白质N-H及水的OH伸缩振动、脂类中C-H的伸缩振动、蛋白质酰胺Ⅰ带和水的H-O-H变角振动、CH3或δCH2、核酸中PO的伸缩振动的特征峰位置)。因此可以将这些特征作为判别组织是否癌变的依据之一。唐伟跃等采集了胃窦部正常组织和癌变组织的拉曼光谱,结果表明在癌变组织的拉曼光谱中, 1 089 cm-1线比正常组织的相应谱线明显增强,而且1 459 cm-1线发生分裂。通过这些信息的提取,可望为肿瘤组织的检测分析提供判断依据。为了检测胃肠癌细胞与正常细胞的区别, Yan等利用共聚焦显微拉曼光谱研究了胃肠癌病人单个细胞。结果表明,在癌细胞中, 1 002 cm-1处属于苯丙氨酸的谱线半宽度变窄,白细胞的谱线强度小并且谱线少,而红细胞的谱线强度大而且谱线丰富,并且在1 620 cm-1~1 540 cm-1范围内存在吡咯环CN呼吸伸缩振动的谱线。胃癌细胞的拉曼光谱与正常细胞的拉曼光谱相似,但谱线强度减弱,而且有的谱线消。Huang等利用近红外拉曼光谱仪开展研究,将恶性肿瘤与正常组织及良性肿瘤区分开,通过对105个结肠样本进行拉曼光谱检测,在离体条件下采集到800 cm-1~1 800 cm-1波数范围内高分辨率的拉曼光谱图,分析发现正常组织与癌变组织的光谱差异,并以1 002 cm-1与1 445 cm-1谱线的强度比为横坐标, 1 085 cm-1与1 445 cm-1谱线的强度比为纵坐标建立了诊断算法,此算法识别恶性肿瘤与正常、良性组织的灵敏度达100 %,特异性达96.6 %。Chen等将激光光镊技术与拉曼光谱技术相结合,研究了上皮癌的单个细胞,对收集到的光谱进行主成分分析,再进行对数回归得到能够最有效区分癌细胞与正常细胞的参数方程。此诊断模型总的灵敏度为82.5 %,特异性为92.5 %。此项研究从对上皮癌的诊断到对致癌作用的细胞动力学的研究均有很大的应用价值。Yan等的研究发现,肠癌细胞拉曼谱线强度很弱而且很多谱线消失,并且癌细胞内不同位置的荧光强度不同。这表明拉曼光谱技术能够为肠癌的早期检测和诊断提供一种有效手段。 1.4拉曼光谱在乳腺癌检测中的研究 Haka等用拉曼光谱技术分析了乳腺良恶性病变中微小钙化的化学组成,将之分为Ⅰ型草酸钙和Ⅱ型羟基磷灰石。Ⅰ型诊断为良性,Ⅱ型既有良性也有恶性。通过对拉曼光谱进行主成分分析可区分Ⅱ型微小钙化的良恶性,灵敏度和特异性分别达88 %和93 %。Haka等还利用线性组合模型,将脂肪和胶原质的拟合系数作为参数,对正常的、纤维癌、浸润癌等组织的130个拉曼光谱图进行识别,得到了灵敏度为94 %、特异性为96 %的诊断模型。Bitar等利用傅里叶变换拉曼光谱FT-RS研究正常乳腺组织及包括不同癌症亚型的癌变乳腺组织。比较不同组织的拉曼光谱中特征峰的强度变化,可以将正常组织、纤维囊性组织、原位导管癌、出现坏死组织的原位导管癌、浸润性导管癌、胶原浸润性导管癌、浸润性小叶癌等7种不同组织区分开。赵元黎等利用显微共聚焦拉曼光谱仪检测了40例手术切除乳腺肿瘤周边(肿块边约5 mm)组织的拉曼光谱。研究表明,在不同性质的乳腺肿块周边组织的拉曼光谱中, 1 440 /1 530和1 082 /1 156具有可分性,分别以1.25和1.03作为界线可以对检测目标进行识别分类。闫循领等研究了乳腺癌病人正常乳腺细胞与癌细胞的拉曼光谱。观察谱线得到癌变细胞的拉曼谱线整体变弱,归属于DNA的两个磷酸骨架峰782 cm-1 , 1 084 cm-1和脱氧核糖-磷酸振动峰1 155 cm-1及1 262 cm-1谱线明显减少;表征A型(DNA)构象的特征峰812 cm-1及979 cm-1 ,668 cm-1消失,并有新峰1 175 cm-1出现, 905 cm-1的谱线增强并有6 cm-1的红移,这说明DNA的磷酸骨架有一定的断裂,从而导致癌细胞的分裂繁殖失去有效控制。在癌变组织细胞的拉曼光谱中还发现了很强的一类与钙硬化密切相关的特征峰960 cm-1。这些研究工作为乳腺癌的早期检测和诊断提供了有力的实验依据。 1.5前列腺癌的光谱检测 Crow等利用拉曼光谱技术在离体条件下检测了良性前列腺增生和恶性前列腺癌的活检组织,分析发现前列腺癌组织与良性前列腺增生组织相比,糖原的浓度减小,而核酸的浓度增大。并且利用主成分分析构建了线性判别模型对不同时期的癌变组织的拉曼光谱进行识别,从而实现了对前列腺癌的分级。Crow等又研究了四种不同的前列腺细胞系(LNCap, PCa2b;DUI45, PC3),采用三个主成分PC1、PC2和PC3,建立了PCA/LDA诊断算法。PC1代表核酸(721 cm-1、783 cm-1、1 305 cm-1、1 450cm-1、1 577 cm-1 )、DNA骨架(827 cm-1、1 096 cm-1 )和无序蛋白质(1 250 cm-1、1 658 cm-1 )增加的浓度;PC2代表蛋白质α-螺旋(935 cm-1、1 263 cm-1、1 657cm-1)和磷脂(719 cm-1、1 094 cm-1、1 125 cm-1、1 317cm-1)减小的浓度;PC3代表脂质(1 090 cm-1、1 302cm-1、1 373 cm-1)、糖原(484 cm-1 )和核酸(786 cm-1、1 381 cm-1、1 576 cm-1 )减小的浓度。当PC3的值大而PC2的值小于或等于0时,可将DUI45, PC3两种细胞系识别出来。而当PC2的值大于0, PC3小于或等于0时,可将LNCap, PCa2b两种细胞系识别出来。 2拉曼光谱在肿瘤检测中的应用前景 拉曼光谱技术是一种非破坏性、非侵入性、分辨能力高的检测方法,在癌症诊断中已经初显其优势。但其信号弱、易受背景荧光干扰等缺点限制了拉曼光谱技术的应用。但各种拉曼光谱技术例如时间分辨拉曼光谱技术、傅里叶变换红外拉曼光谱技术等的应用以及研究的不断深入,可有效地克服存在的局限,使其能够在生物医学领域得到更广泛的推广和应用。随着激光光镊技术以及共聚焦显微技术的发展,实现了单细胞水平上对癌变组织的诊断,有望揭示癌变的机理,从而为癌症的诊断建立更为有力的实验基础。光纤技术的引入,能够直接对皮肤等多种组织进行实时、原位测量,既可以减小给患者带来的危害,又可以实现实时、有效的诊断,提高患者的生存几率。总之,随着样本研究的积累,研究方法和设备的改进、统计模型的优化、各种技术与拉曼光谱技术的完美结合,拉曼光谱技术必然会从实验研究转向临床诊断应用,必将在癌症的研究与临床诊断中得到广泛的应用。
作者,顾建文教授,解放军第306医院 一、鞍隔脑膜瘤的影像学诊断意义 目前, 临床及影像学仍将起源于鞍结节、鞍隔、蝶骨平台, 解剖范围直径不超过3 cm以内的脑膜瘤统称为鞍上脑膜瘤。鞍隔脑膜瘤是指自鞍隔脑膜的蛛网膜颗粒生长的脑膜瘤, 较为罕见, 国内仅见25例报道。以往影像学缺乏对鞍隔脑膜瘤的认识, 容易误诊为垂体瘤者, 神经外科多采用经口、鼻、蝶窦入路鞍底行鞍内肿瘤切除术。 由于鞍隔脑膜瘤位于垂体腺上方, 经此入路手术,切除肿瘤难度大, 时常不可避免地损伤垂体腺, 较难全部切除肿瘤, 容易残留肿瘤组织, 术后易复发,术中损伤垂体严重, 可出现或加重视力障碍、失明、内分泌功能失调等并发症。CT、MRI可清楚显示颅内解剖结构, 准确提供病变部位及侵及范围、毗邻关系等资料。既往将鞍隔脑膜瘤笼统地称为鞍上或鞍结节脑膜瘤显然不妥。因此, 影像学应采用鞍隔脑膜瘤诊断名称,对神经外科提高鞍隔脑膜瘤手术治愈率以及其降低手术并发症均具有十分重要的意义。 典型鞍隔脑膜瘤影像 不典型鞍隔脑膜瘤影像 二、鞍隔脑膜瘤CT及MRI诊断 鞍隔脑膜瘤术前CT表现为肿瘤向鞍内生长压迫垂体腺或肿瘤向鞍上、鞍旁生长,CT较难分辨肿瘤与垂体腺等解剖结构,易误诊为垂体瘤等肿瘤。MRI检查鞍隔脑膜瘤向鞍上、鞍内生长压迫垂体腺使之变扁,肿瘤信号酷似垂体瘤等肿瘤,也易误诊为垂体瘤。 有以下表现者应考虑脑膜瘤:CT上表现为鞍上圆形、类圆形均匀或略均匀的稍高密度或等密度影,亦可伴有钙化, 增强明显; MRI在冠状面或矢状面上表现为正常垂体腺之上的圆形或类圆形影,T1WI上呈较均匀等信号,增强明显, 边缘清楚, T2WI上呈略均匀高信号区;临床上结合病人视力障碍及头痛表现,无内分泌紊乱,以及生长激素和泌乳素正常等资料。MRI在冠状面或矢状面上显示正常垂体腺呈均匀类圆形信号,与脑干相仿, 可见垂体柄, 垂体后部呈点状脂肪信号为特征性表现。 由于垂体腺在肿瘤下方, 二者境界较清楚,容易鉴别, 故MRI对诊断鞍隔脑膜瘤有其独道之处。CT 诊断价值不如MRI, 而且CT很难分辨出鞍隔脑膜瘤与垂体腺, 但CT 在显示脑膜瘤伴钙化时比MRI优越。 鞍隔脑膜瘤主要应与垂体腺瘤、颅咽管瘤相鉴别。(1)垂体腺瘤:CT表现为由鞍内向鞍上及鞍旁生长的类圆形、哑铃形肿块,呈均匀或略均匀等密度或稍高密度影,增强明显;MRI T1WI呈等信号或混杂信号, T2WI呈混杂信号或不均匀高信号。由于垂体腺瘤常伴有组织坏死及囊性变, 显示长T1、长T2信号, 结合蝶鞍 X线平片,如蝶鞍扩大、鞍底下陷, 前后床突上翘及骨质变尖细等,临床上病人有内分泌紊乱等表现, 对垂体腺瘤诊断不难。(2)颅咽管瘤 :CT表现为鞍上或突入第 3脑室的圆形、类圆形的囊性低密度区伴囊壁蛋壳样钙化, 诊断不难。但对等密度或高密度颅咽管瘤, 单凭CT较难与鞍隔脑膜瘤鉴别 ,应配合MRI检查。由于颅咽管瘤的瘤内容物含胆固醇角化物、蛋白、正铁血红蛋白、钙化等, 故T1WI上呈混杂信号 (低信号与高信号混杂), 或不均匀低信号; T2WI上呈不均匀高信号或混杂信号;结合病人有内分泌紊乱等表现, 对大多数颅咽管瘤诊断不难。
术者:顾建文教授,解放军306医院 附:一例巨大恶性脑膜瘤切除手术,患者70岁,头痛很久没有在医院检查,直到晚期。手术很顺利,肿瘤侵犯颅骨,顺利切除肿瘤。(手术完成时间2006年8月 ,术者, 顾建文) 恶性脑膜瘤malignant meningioma是指具有某些良性脑膜瘤的特点,逐渐发生恶性变化,呈恶性肿瘤的特点。表现为肿瘤在原部位多次复发,并可发生颅外转移。恶性脑膜瘤生长快,肿瘤多向四周脑内侵入,使周围脑组织胶质增生。随着反复手术切除,肿瘤逐渐呈恶变,最后可转变为脑膜肉瘤。其中良性脑膜瘤中的血管母细胞瘤最常发生恶变。 恶性脑膜瘤可发生颅外转移,主要转移至肺(占35%)、骨骼肌肉系统(17.5%)以及肝和淋巴系统。转移可能与手术操作有关。此外,肿瘤侵犯静脉窦、颅骨、头皮,也可能是造成转移的原因。另外,恶性脑膜瘤也可经脑脊液播散种植。恶性脑膜瘤的平均发病年龄明显低于良性脑膜瘤,肿瘤多位于大脑凸面和矢状窦旁,其他部位,尤其是后颅窝少见,因此恶性脑膜瘤的患者更易出现偏瘫等神经系统损害症状,脑膜瘤的常见症状如癫痫,头痛等在恶性脑膜瘤中常见,但病程较短。恶性脑膜瘤在CT的表现为肿瘤形态不规则,呈分叶状,可出现蘑菇征,边界不清、包膜不完整,信号不均匀。周围水肿明显,没有钙化。增强后肿瘤不均匀强化。肿瘤易侵犯脑组织和颅骨。MRI的T1和T2像显示恶性脑膜瘤都为高信号。有时颈内动脉向肿瘤供血比较明显。根据临床表现,CT及MRI的改变,恶性脑膜瘤的诊断与脑膜瘤诊断一样并不十分困难。恶性脑膜瘤的治疗以手术切除为首选方法,即使复发的恶性脑膜瘤,有条件也可再行手术治疗。术中对侵犯的颅骨、硬脑膜应尽量切除,术后再行硬脑膜修补。对于瘤周的脑组织,可尽量电凝或激光照射,对减少肿瘤残余,防止复发是大有益处。有报道,为了有效延缓复发时间,可进行放疗或同位素肿瘤内放射。对于反复复发的良性脑膜瘤,有人也主张给予放疗,这样对于阻止肿瘤恶变,延长复发时间可能是有帮助的。
作者,顾建文教授,解放军第306医院 脑积水是因颅内疾病引起的脑脊液分泌过多或(和)循环、吸收障碍而致颅内脑脊液存量增加。临床小儿多见头颅增大、囟门扩大、紧张饱满、颅缝开裂愈期不合、落日目、呕吐、抽搐、语言及运动障碍,智力低下;成人多见间断性头痛、头胀、头沉、头晕、耳鸣耳堵、视力下降、四肢无力等。 理论上讲脑积水(hydrocephalus)是脑室和脑池(蛛网膜下腔)内脑脊液总量增多,颅内压力增高,继而引起脑室扩张及脑池、脑沟、脑裂等处的蛛网膜下腔增宽。儿童由于颅缝尚未闭合,脑积水必然会引起头围增加。 (一)分类 脑积水根据发病机制不同分为:①非交通性或梗阻性脑积水,脑室内液体因梗阻不能进入蛛网膜下腔。②交通性脑积水是发生在蛛网膜下腔即脑室外的梗阻或回流障碍,也包括蛛网膜颗粒吸收回流脑脊液障碍。③分泌亢进性脑积水,原因是脑脊液分泌过多,这种类型相当少,是否应看作一种单独的类型,尚有不同的看法。病因是各种各样的:梗阻性脑积水的原因常是先天畸形如导水管狭窄,小脑扁桃体疝(Arnold-Chiari畸形),第四脑室囊肿(Dandy-Woalker综合征)和其它脊椎闭合不全,但也可继发于其它占位性囊肿和肿瘤。胎儿子宫内的感染如弓形体、风疹、巨细胞病毒等感染以及围产期颅内出血也能引起脑积水。交通性脑积水的病因是脑膜炎引起的粘连或外伤性蛛网膜下腔和硬膜下出血。分泌亢进引起的脑积水发生于脉络丛乳头状瘤。 (二)临床症状 头颅异常增大,增长迅速。前囟宽大。额骨前突,前颅凹颅底向下移位。眼球向下倾斜(落日征),患儿精神及体格发育迟缓,肌肉痉挛,偶有抽搐。 (三)CT表现 1.梗阻性脑积水正常第三脑室横径6mm,第四脑室前后径15mm;两侧室最大横径与同一水平颅腔横径之比小于22%~32%(evans指数),脑积水时大于40%,脑室明显扩张,变为圆钝。借助脑室扩张的分布类型确定阻塞部位。单侧或双侧室间孔梗阻导致单侧或双侧侧脑室扩张,而三、四脑室正常。导水管狭窄是先天性脑积水最常见的原因,表现双侧脑室及三脑室扩张,而四脑室正常,偶尔或导水管近端也扩张。四脑室中孔和侧孔(Magendie and Luschka)阻塞,引起所有脑室(包括四脑室)扩张。 2.交通性脑积水CT显示脑室呈球形扩张,程度较轻,第四脑室扩张程度最小。基底池往往扩张,两侧半球也能见到因为脑脊液蓄积引起的脑沟增宽。交通性脑积水有时难以与脑萎缩鉴别。鉴别困难的病例可以在短期后随访复查以除外进行性(亦即活动性)脑积水。 3.活动性(active)脑积水脑室体积进行性增加与所谓静止性(static)或代偿性脑积水不同。活动性脑积水临床症状显著,CT随访检查有进展。较早的CT片上有下列表现:①脑室周围密度减低晕:脑脊液经长期压迫损伤的室管膜进入周围实质,在脑室周围形成带状密度减低区,尤以额角和颞角显著,脑室轮廓由于水肿而变得模糊。②枕角扩张显著,原因是脑白质比较脑神经核团更易受水肿的损害,额角、侧室体部近基底神经节而枕角周围是白质,故枕角扩张显著。另一些作者认为枕部头颅骨生长较快。 4.经治疗的脑积水置入导管可引流侧室脑脊液至右心或腹膜腔。CT可以显示导管尖的位置,但正确的位置并不一定指示正常的功能。如引流好,脑室体积明显减小,数日或数月后脑结构也逐渐恢复正常。这种脑组织体积迅速增加可能是由于引流后原先被压迫伸长的神经纤维重新排列的缘故。引流后往往后遗脑萎缩,脑池、脑沟增宽。CT还可显示由引流引起的合并症:①单侧或双侧硬膜下水瘤:偶尔见于外科引流术后,CT显示贴近颅骨的镰刀状或带状脑脊液密度病变。②硬膜下血肿:如硬膜下水瘤体积过大,导致静脉过度牵引以至撕裂,产生硬膜下血肿。CT显示硬膜下高密度镰刀形血肿影像或血肿下沉在水瘤的底部。③脑内血肿是导管引流术较少引起的伤害血管的合并症。有时能见到沿导管平行分布的出血影像,侧室内也可有出血。④脑室萎缩:常常是由于强有力的引流,引起脑室迅速变小以致脑室壁相互接近,CT上的脑室呈缝隙样。很少的情况下,此种萎缩还可合并脑室炎症、粘连及室管膜下纤维化,由于脑室不扩张,如发生引流障碍则很难诊断。即所谓裂隙脑室综合征(slit-ventricle syndrome),颅内压增加,但脑室狭窄,裂隙状,此时诊断引流不充分主要是根据临床症状而不是CT表现。⑤引流管阻塞,随后CT表现脑室容积增加,脑室周围密度减低,脑室增大不成比例,常常枕角扩张更显著,但若脑室粘连闭塞则例外。⑥脑室限局扩张(Dilatation of isolated sections of a ventricle):导水管狭窄,四室中孔或侧孔闭塞,尽管幕上引流功能正常,但四室仍然扩张,假如其余的脑室相互之间不是自由相通的话,某个部位也可能限局性扩张。在这些情况下就需要同时做几处的引流,治疗脑积水。⑦脑室炎:室管膜和室管膜周围充血,CT显示沿室管壁有明显增强。慢性脑室炎,胶质增生可引起脑室边缘轻度密度增高,即使未用造影剂时也是如此。 (四)MRI特点 除表现脑室扩大外,在梗阻性脑积水,脑脊液可经室管膜渗入脑室周围,脑室周围间质性水肿,在质子密度加权像上表现为脑室周围有一圈高信号,很有特点。 正常压力脑积水,MRI可以显示导水管有流空现象,邻近的第三和第四脑室也可见到流空现象,而没有显著的脑脊液流空被认为是弥漫性脑萎缩的表现(Bradllty,1986,1991),如合并有其它交通性脑积水的MR征象时,有显著的脑脊液信号流空征象则适合作脑室引流手术。 (五)外部性脑积水(external hydrocephalus) 这种患儿也表现头围逐渐缓慢增大,颅缝分离,但不表现脑室扩大,而是基底池、侧裂、纵裂池以及大脑皮质脑沟增宽。有人认为这可能是交通性脑积水的早期阶段,因为有报告这类患者日后发生脑室扩大,需要引流治疗。但也有人认为外部性脑积水是一种良性的、自限的蛛网膜下腔扩大,引流治疗可能会减慢头围的增长,但对临床症状是否有改善也缺乏证据。 值得指出的是1~2岁的婴幼儿、脑发育与颅骨生长的比较,相对缓慢,因而脑沟、裂、池相对较宽。脑表面蛛网膜下腔可以宽达4mm,纵裂池6mm,侧裂池10mm,都属于正常范围。18个月~2岁以后,脑发育加快,脑沟变窄。因此2岁以前不能单凭蛛网膜下腔稍宽,就轻率诊断为脑萎缩或外部性脑积水。必须参照头颅大小以及是否有进行性头围增大两个条件。只有在头围明显增大,头生长加快时才能诊断脑积水(图)。 (六)脑积水和脑萎缩的鉴别 脑实质破坏萎缩也可以引起脑室扩大(中央性萎缩)或脑沟增宽,蛛网膜下腔、脑裂、脑池增大(周围性萎缩),或二者兼而有之(弥漫性萎缩)。在影像上与脑积水相似。 脑积水为颅腔内脑脊液增多,原因是脑脊液动力学异常,引起颅内压力增高。当婴幼儿颅缝尚未闭合时,必然会引起头颅扩大,头围增加。而脑萎缩,脑生长缓慢,其结果是小头畸形(microcephaly),脑萎缩虽然也引起脑沟增宽、脑室扩大,其原因是脑体积减少。因此比较脑与头颅骨的大小有助于诊断脑萎缩。但是如果颅骨也生长缓慢,脑与颅骨没有明显差别,则认识脑萎缩比较困难。所以诊断脑积水必须同时具备脑室扩大,脑沟增宽和头围进行性增大两个条件。而诊断脑萎缩必须确实有脑组织减少的证据,即脑沟、脑室增大伴有头颅外形减小(小头)。不过,也有少数患者脑萎缩与脑积水合并存在,这时单凭影像学,诊断就很困难了。 治疗 1.非手术治疗 适用于早期或病情较轻,发展缓慢者,其方法:①应用利尿剂或脱水剂,如乙酰唑胺、双氢克尿塞、速尿、甘露醇等。②经前囱或腰椎反复穿刺放液。 2.手术疗法 对于重度脑积水,智能低下已失明、瘫痪,且脑实质明显萎缩,大脑皮质厚度小于1cm者,均不适宜手术。手术治疗对进行性脑积水,头颅明显增大,且大脑皮质厚度超过1cm者,可采取手术治疗。 (1)减少脑脊液分泌的手术 脉络丛切除术后灼烧术,现已少用。 (2)解除脑室梗阻病因手术 如大脑导水管形成术或扩张术,正中孔切开术及颅内占位病变摘除术等。 (3)脑脊液分流术 手术目的是建立脑脊液循环通路,解除脑脊液的积蓄,兼用于交通性或非交通性脑积水。常用的分流术有侧脑室-小脑延髓池分流术,第三脑室造瘘术,侧脑室-腹腔、上矢状窦、心房、颈外静脉等分流术等。 3.微创分流术 目前治疗脑积水最普及的疗法是脑室-腹腔分流术,也称微创分流术,并被认为是比较有效的治疗手段之一。微创分流术把微创外科新技术应用到脑室-腹腔分流术中,具有创伤小、对腹腔干扰少,减少腹腔粘连甚至能够松解轻微腹腔粘连,术后瘢痕不明显且隐蔽,疼痛轻、恢复快等诸多优点。术后意识不清、胡言乱语等症状全部消失,生活质量可得到极大改善和提高。
顾建文教授,解放军第306医院 (中国专利:CN2489732,2002-05-08.)垂体腺瘤扫描片均应达到能观察A正侧位蝶窦的大小、壁厚、气化程度,B蝶窦中隔的数量、位置,C蝶鞍的大小、鞍底是否侵蚀、前床突及鞍背的移位程度,D肿瘤与蝶鞍的关系,E鼻中隔是否偏移、前鼻棘清晰、犁状骨规则。 定位方法:眉弓中点、鼻棘-鞍、鼻棘夹角定位法:术前在CT中线矢状位断层扫描片上测量鞍底中点(A)与前鼻棘(B)连线长度和眉弓中点(C)与前鼻棘的夹角,该长度为5~8cm,平均为6.8cm,夹角为56°~64°,平均为60°,术中依据A-B-C夹角及长度剪裁好相应的胶片,即可引导手术入路的角度和深度。 解剖学标志定位法:鼻中隔及犁状骨确定中线结构:术前根据冠状位CT,确定鼻中隔及犁状骨居中情况,严格沿鼻中隔分离鼻粘膜至犁状骨,可保证入路不偏移中线。蝶窦开口与犁状骨体为蝶窦前壁的标志:蝶窦开口一般为蝶窦前壁的上限,犁状骨体部为气化的蝶窦,当手术分离至犁状骨时,上述标志可准确引导切开蝶窦前壁。蝶窦中隔为进一步矫正鞍底中点的重要标志:蝶窦中隔数量及位置不一,提前测量中隔偏移距离,可提示鞍底的中点的准确位置。鞍底的形态提供鞍底中点的标志:鞍底一般在蝶窦腔内呈弓状隆起,其最高点为鞍底的中点。其上往往附着有蝶窦中隔骨质突起,对定位有进一步指导作用。鞍区的骨质破坏提供定位标志:术前仔细研究鞍区受破坏的颅底CT、X线片,将破损区与鞍底的关系测量清楚,术中暴露破损区域时即可找出相应鞍底的位置。 经唇下-鼻中隔-蝶窦入路是经蝶入路鞍区肿瘤切除术的最常用的类型。自1907年始,Cushing采用该术式效果不佳,死亡率高,照明器械不佳及抗生素缺乏,并且对鞍隔上肿瘤暴露不足。故一度停滞发展。后来随着电视X线透视机、显微镜的应用,解决了手术中一些精细操作的问题,使该项手术又呈现了新的生命。但至今为止X线侧位片及电视X光机仍为定位入路所必需的方法,能否直接定位,我们进行了一定的尝试。我们根据Guiot等人对肿瘤对鞍底破坏方式所作的分级,严格选择适应症1-4级及O,A,E级肿瘤122例,行经唇下-鼻中隔-蝶窦入路显微切除术,手术采用我们自行归纳总结的非X线综合定位法,使得手术时间较X线定位法时间明显缩短。应用A-B-C夹角测量鞍底的位置及深度的方法,因A-B,B-C连线长度均为6~8cm,实际测量两线的夹角较为准确,但手术中铺盖无菌单及Cushing氏牵开器的阻挡,妨碍实际的测量,需估测B-C线,有一定的误差。将解剖学标志定位法结合起来,包括手术入路所经途中的一系列标志(鼻中隔定位中线结构、蝶窦开口及犁状骨体提示蝶窦前壁的位置、鞍底的形态及破坏程度和蝶窦中隔的位置可决定鞍底的位置)结合起来综合判断,则能够达到准确判定鞍底位置的目的。总结该方法的经验,要求我们充分利用影像学的资料,仔细分析可能与定位有关的一切信息,在手术过程中加以利用即可得到良好的效果。同时避免选择蝶窦气化不良及蝶窦过大病例。该方法经临床验证,有一定的使用价值。
玄璿,解放军306医院神经内科 绝大多数人在一生中都会有头痛的经历。可你是否知道,有一种头痛是致命的。 56岁的王女士在与丈夫吵了一架后,突然出现剧烈头痛,颈部强直并伴有恶心、呕吐,持续不缓解,后由家人送至解放军306医院。急诊CT检查发现患者为蛛网膜下腔出血(见下图)。神经内科的专家们立即行无创头颈部动脉CTA检查,发现患者前交通动脉动脉瘤,原来,蛛网膜下腔出血的祸根是动脉瘤破裂。全脑血管造影及前交通动脉瘤栓塞手术挽救了王女士的生命。因此脖子硬的头痛是致命的。 颅脑CT检查提示蛛网膜下腔出血 全脑血管造影检查提示前交通动脉动脉瘤(箭头所示) 前交通动脉动脉瘤栓塞术后(箭头所示) 在306医院神经内科蔡艺灵副院长及其团队的积极抢救治疗下,患者被从死亡线上拉了回来,病情得到了控制。住院治疗20天后,患者头痛症状完全消失,未遗留任何神经系统后遗症,顺利出院。 解放军306医院神经内科介入团队在积极进行术前准备 蔡艺灵副院长及其团队在全力救治患者 蛛网膜下腔出血相关知识 蛛网膜下腔出血分为原发性和继发性。原发性蛛网膜下腔出血是指脑底部或脑表面血管破裂后,血液流入蛛网膜下腔引起相应临床症状的一种脑卒中。在脑血管意外中,其仅次于脑血栓和高血压脑出血,位居第三。颅内动脉瘤是导致蛛网膜下腔出血的最常见病因,约占50%~85%。颅内动脉瘤一般病程较为隐匿,但起病突然,一旦发病,致死及致残率极高,因而被称为颅内的“不定时炸弹”,是最危险的脑血管病之一。颅内动脉瘤是威胁人类生命和健康的最常见的重大疾病。 究竟怎样会引起动脉瘤,并导致动脉瘤破裂出血呢? 颅内动脉瘤可能由动脉壁先天性肌层缺陷或后天获得性内弹力层变性或二者的联合作用所致。动脉瘤的发生存在一定程度的遗传倾向和家族聚集性,如在有动脉粥样硬化、动脉瘤家族史及多囊肾患者中,动脉瘤患病率增高。但颅内动脉瘤不完全是先天性遗传,相当一部分是在后天长期生活中发展起来的。随着年龄增长,动脉壁弹性逐渐减弱,薄弱的管壁在血流冲击等因素影响下向外突出形成囊状动脉瘤。病变血管可自发破裂,或因血压突然增高或其他不明显的诱因而导致血管破裂,血液进入蛛网膜下腔,通过围绕在脑和脊髓周围的脑脊液迅速播散,刺激脑膜,引起头痛,颈部强直。长期吸烟、未得到控制的高血压、过量饮酒,都是导致颅内动脉瘤破裂出血的主要危险因素。因此,平时对危险因素加以控制,才有可能在一定程度上降低动脉瘤的发生。也可以通过脑血管造影的影像学手段,来及早发现未破裂动脉瘤的存在,以便能在动脉瘤破裂出血之前给予恰当的治疗。