神经副肿瘤综合征

神经副肿瘤综合征(paraneoplastic neurologic syndromes,PNS)是一组与恶性肿瘤相关,非代谢感染、退行性、转移性或医源性的神经系统疾病受累的疾病。经典的PNS包括了脑脊髓炎、边缘性脑炎(limbic encephalitis,LE)、亚急性小脑变性、感觉神经病、Lambert-Eaton肌无力综合征(Lambert-Eaton myasthenic syndrome,LEMS)、皮肌炎等[1]。目前认为,部分PNS发生与肿瘤神经元抗体相关,其病程特征通常是亚急性起病、进行性进展之后病情趋于稳定。少数PNS病例可在原发性PNS后出现第二个PNS。PNS最常见的原发性肿瘤包括了小细胞肺癌(small-cell lung cancer,SCLC)、卵巢癌、乳腺癌、神经内分泌肿瘤、胸腺瘤和淋巴瘤。PNS的症状通常出现在发现恶性肿瘤之前,因而易导致误诊。诊断PNS对于早期干预原发性疾病,稳定和改善症状尤为关键。     

抗Hu抗体检测在神经系统副肿瘤综合征诊断中的临床意义

目的 探讨抗Hu抗体检测在神经系统副肿瘤综合征诊断中的临床意义.方法 采用间接免疫荧光方法和蛋白免疫印迹法对送检至北京协和医院神经病理实验室的1500余例患者的血清和脑脊液进行抗Hu抗体检测,回顾性分析抗Hu抗体阳性患者的临床资料及诊断.神经系统副肿瘤综合征的诊断标准参照Graus等的诊断标准.结果 共有27例患者抗体阳性,其中血清抗Hu抗体阳性25例,脑脊液抗Hu抗体阳性8例.临床主要表现为感觉神经元神经病、亚急性小脑变性、Lambert-Eaton综合征和抗利尿激素分泌不当综合征引起的脑病等,其中20例(74.1%)患有肿瘤,包括肺癌17例,胃癌2例,不明性质腹部肿瘤1例.7例患者未发现恶性肿瘤,包括多发性肌炎和系统性红斑狼疮(SLE)合并神经肌肉病各1例.根据Graus等神经系统副肿瘤综合征的诊断标准,27例中22例可确诊神经系统副肿瘤综合征或相关的肿瘤,抗Hu抗体的阳性预测值为81.5%.结论 抗Hu抗体阳性对神经系统副肿瘤综合征的诊断具有一定意义;其相关肿瘤以肺癌,特别是小细胞肺癌最常见.其他自身免疫性疾病偶可见抗Hu抗体阳性,需要全面检查和密切随访以排除恶性肿瘤的可能.     

貌似运动神经元病的神经系统副肿瘤综合征1例报告及文献分析

正神经系统副肿瘤综合征(Paraneoplastic neurological syndrome,PNS)是指肿瘤在中枢神经、周围神经、肌肉或神经-肌肉接头处出现远隔效应,导致中枢和周围神经系统损伤的一组疾病综合征,其临床表现具有多样性和复杂性~([1])。由于该疾病早期以中枢或周围神经系统损害症状为主,临床肿瘤症状没有或不明显,因此,早期常常容易误诊。近年来,随着新型PNS相关抗体的检测使得越来越多的患者得以被发现报道~([2])。但以运动神经元病临床表现为首发症状,并表达抗Recoverin及抗Tr(DNER)双抗神经元抗体的PNS未见报道。现将我院近期收治的1例以运动神经元病为临床表现的临床、免疫和肌电图报告如下,并结合相关文献进行分析。     

抗Ma2抗体阳性的淋巴瘤相关副肿瘤综合征1例报告

<正>神经系统副肿瘤综合征(paraneoplastic neurological syndromes,PNS)是指一些恶性肿瘤非直接侵犯或非转移引起的神经和(或)肌肉损害的一组临床症候群,其临床表现复杂多样。随着免疫学技术的发展,研究人员在部分PNS患者的体内发现了一些特异性抗神经元抗体,而不同的抗体可能与某些特定的肿瘤发生关系密切。其中一种抗细胞内抗原抗体——抗Ma2抗体于1999年被发现与睾丸癌联系密切[1]。     

抗amphiphysin抗体、抗Hu抗体双阳性副肿瘤神经综合征(附1例报告及文献复习)

目的提高临床医生对抗amphiphysin抗体、抗Hu抗体双阳性副肿瘤神经综合征的认知。方法回顾分析1例抗amphiphysin抗体、抗Hu抗体双阳性的副肿瘤神经综合征患者的临床表现、检查及诊疗经过等资料,结合文献复习加以讨论。结果患者男性,71岁。主要临床表现为进行性肢体无力加重,脑脊液检查抗amphiphysin抗体、抗Hu抗体双阳性,纵隔肿物病理显示胸腺神经内分泌癌。手术切除后肢体无力症状得到改善,但预后不良。结论副肿瘤神经综合征少见,其神经症状与肿瘤的关联各不相同。特征性副肿瘤抗体,如抗amphiphysin抗体、抗Hu抗体双阳性,对副肿瘤综合征及相关肿瘤的识别与诊断具有重要价值。     

多重抗神经元抗体阳性的神经系统副肿瘤综合征临床分析

目的探讨神经系统副肿瘤综合征患者出现多重抗神经元抗体的临床特征及潜在意义。方法检索2015年7月至2019年12月至宣武医院住院治疗并诊断为"神经系统副肿瘤综合征""癌性副肿瘤综合征""副肿瘤相关性周围神经病""边缘性脑炎"及"自身免疫性脑炎"的患者,筛选出两种或两种以上抗神经元抗体均为阳性的患者。结果在134例符合诊断的患者中,6例存在多重抗神经元抗体,包括抗Amphiphysin抗体合并抗γ-氨基丁酸受体B型(GABA_BR)抗体阳性2例[其中1例抗Hu抗体及抗谷氨酸脱羧酶(GAD65)抗体亦呈阳性],以及抗SOX1抗体合并抗Titin抗体阳性、抗Yo抗体合并抗富亮氨酸胶质瘤失活蛋白1(LGI1)抗体阳性、抗接触蛋白相关蛋白2(CASPR2)抗体合并抗LGI1抗体阳性和抗Hu抗体合并抗Ri抗体阳性各1例。6例患者临床表现均符合副肿瘤综合征,4例为周围神经病或肌肉接头病(其中2例合并边缘性脑炎,1例合并亚急性小脑变性),另2例单纯表现为边缘性脑炎;2例对免疫治疗有效;3例明确诊断癌症,分别为乳腺癌、胆管癌、小细胞肺癌。结论多重抗神经元抗体的存在,可导致患者的临床表现复杂多样,免疫治疗可能有效。存在某种抗神经元抗体的患者即使无相应神经综合征,该抗体亦对恶性肿瘤有提示意义。     

副肿瘤综合征13例临床分析

神经系统副肿瘤综合征(Parasympathetic nervous system,PNS)是由体内恶性肿瘤引起的非转移性神经系统病变,可同时累及神经系统的任何部位,临床表现多种多样,极容易误诊,因此早期确诊对于治疗非常重要.现将笔者诊断的13例PNS患者的临床资料进行分析、总结,报告如下.     

神经系统副肿瘤综合征24例临床分析

目的了解神经系统副肿瘤综合征的临床特点。方法回顾性分析24例神经系统副肿瘤综合征患者的临床资料并进行总结。结果 24例神经系统副肿瘤综合征患者平均年龄68.7岁,男女比例为1∶0.7。神经系统表现为边缘叶脑炎、亚急性小脑变性、脑干脑炎、周围神经病、Lambert-Eaton肌无力综合征和恶病质肌病。肿瘤来源以肺癌为主,占79.1%。75%的病例先于肿瘤表现出PNS的症状。结论 PNS表现多样,早期识别症状对于诊治PNS、发现肿瘤非常重要。     

Y染色体性别决定区相关高迁移率组盒蛋白1联合电压门控钙通道抗体阳性的副肿瘤综合征1例报告并文献复习

目的探讨1例抗Y染色体性别决定区相关高迁移率组盒蛋白1(SOX1)、电压门控钙通道(VGCC)阳性的副肿瘤综合征(PNS)患者的临床特点。方法回顾性分析1例抗SOX1、VGCC阳性的PNS患者的临床资料,并进行文献复习。结果患者为中老年男性,亚急性起病,主要表现为双下肢无力,伴言语含糊。神经系统专科检查示构音障碍,腱反射减弱,左侧病理征阳性,左侧共济运动差。血清及CSF抗SOX1抗体阳性,血清VGCC抗体明显升高。予以糖皮质激素、丙种球蛋白治疗有效,之后予以依托泊苷、顺铂化疗。随访半年患者病情稳定,临床症状改善明显。结论本例PNS表现为Lambert-Eaton肌无力综合征、副肿瘤小脑变性、副肿瘤性周围神经病等叠加综合征,同时存在两种副肿瘤性自身抗体阳性,提示PNS可表现为多系统的神经损害。     

神经系统副肿瘤综合征的临床特征(附1例报告)

目的探讨神经系统副肿瘤综合征(PNS)的临床特征。方法回顾性分析1例临床表现为头痛的神经系统PNS患者的临床资料。结果本例患者表现为反复头痛发作3年。腰穿CSF检查示细胞数正常,蛋白轻度升高;头颅MRI示双侧丘脑异常信号,增强示双侧丘脑低信号。胸部CT示左肺上叶少许胸膜下肺大泡;PET-CT示左肺上叶(主动脉后方)高代谢结节。肿瘤标志物CA19-9、CA242、癌胚抗原水平升高。病理检查确诊为肺腺癌。本研究回顾性总结PNS相关文献报道,其常见临床表现为眩晕、复视、共济失调、斜视性眼阵挛-肌阵挛及脊髓炎。结论 PNS常见表现为眩晕、复视、共济失调、斜视性眼阵挛-肌阵挛及脊髓炎,以反复头痛为临床表现少见,可疑患者应行全身检查排除PNS。     

A single center retrospective study of paraneoplastic neurological syndromes with positive onconeural antibodies

Paraneoplastic neurological syndromes (PNS) are rare immune-mediated disorders, and the detection of onconeural antibodies is helpful for PNS diagnosis. The aim of this study was to investigate the clinical characteristics of patients with PNS with positive onconeural antibodies in a single center in Hubei, China. We retrospectively analyzed the clinical characteristics of 54 patients with positive onconeural antibodies from January 2016 to September 2020. Among 780 patients with suspected PNS, 54 (6.9%) had positive onconeural antibodies. Of those 54 patients, 28 (51.8%) were diagnosed with definite PNS and 13 (24.1%) with possible PNS. Eighteen (33.3%) patients were confirmed with cancer. Ten PNS syndromes were detected among the 28 patients with definite PNS, and they had either classical (12/28, 42.8%) or non-classical syndromes (17/28, 60.7%). Peripheral neuropathy (9/28, 32.1%), subacute cerebellar degeneration (4/28, 14.3%), and limbic encephalitis (4/28, 14.3%) were the most common PNS syndromes. The anti-CV2/CRMP5-antibody was observed most frequently. Lung cancer was the most common tumor type. For patients with possible PNS, peripheral neuropathy was the most common PNS syndrome, and the anti-Tr-antibody was the most frequent onconeural antibody. Immunotherapy was effective in treating PNS. The anti-CV2/CRMP5-antibody was the most subsequently observed antibody. The manifestations of PNS are diverse and include peripheral neuropathy, subacute cerebellar degeneration, and limbic encephalitis. In patients with PNS, lung cancer was the most common tumor.     

Qualitative evidence of Ri specific IgG-synthesis in the cerebrospinal fluid from patients with paraneoplastic neurological syndromes

The presence of Ri-specific oligoclonal IgG bands in the CSF was investigated in five patients with paraneoplastic anti-Ri associated neurological syndromes (PNS) and six controls. In 4/5 CSF samples reactivity of IgG bands with recombinant Ri antigen was found using isoelectrofocusing combined with affinity blotting; in one patient with absence of oligoclonal bands of total IgG in CSF Ri-specific oligoclonal bands were detected with the same sample, indicating a higher sensitivity of Ri-specific affinity blotting as compared to affinity blotting with anti-human IgG antibodies. Our results confirm previous studies demonstrating IgG synthesis against onconeuronal antigens by intrathecal B-cell clones in PNS and extend this observation to patients with anti-Ri syndrome. The pathogenic relevance of these antibodies, however, is further challenged by the finding that specific intrathecal IgG synthesis might not be a prerequisite of CNS involvement, because it was missed in one of our patients.     

PET scan in clinically suspected paraneoplastic neurological syndromes: a 6-year prospective study in a regional neuroscience unit

Background – The role of PET in the diagnosis of paraneoplastic neurological syndromes (PNS) has previously been reported in retrospective studies, from specialized neuro‐oncology units, often selecting patients with positive paraneoplastic antibodies. Objectives – To prospectively assess the usefulness of PET in detecting malignancy in patients clinically suspected of having PNS. Methods – PET was performed in patients suspected of PNS within 4 weeks of the normal CT body scan. All patients were followed up. Results – Eighty patients suspected of having PNS underwent PET. 18/80 (23%) were abnormal and suspicious of malignancy. The total number of definite and probable PNS with abnormal PET was 11/18 (61%). The total number of definite and probable PNS with a normal PET was 3/62 (5%). Only 50% of patients with biopsy‐proven malignancy were positive for paraneoplastic antibodies. The prevalence of abnormal PET in patients presenting with classical PNS was 41% as opposed to 21% in patients with non‐classical PNS. The sensitivity and specificity of PET in diagnosing PNS was 75% and 87% respectively. Conclusions – PET is a valuable tool in clinically suspected PNS. Its use should not be restricted to specialized neuro‐oncology units or in patients with positive paraneoplastic antibodies. Positive yield is the highest amongst patients with classical PNS.     

Onconeural antibodies: improved detection and clinical correlations

Onconeural antibodies are found in many patients with paraneoplastic neurological syndromes (PNS) and define the disease as paraneoplastic. The study describes the presence of onconeural antibodies and PNS in 555 patients with neurological symptoms and confirmed cancer within five years, and compares the diagnostic accuracy of different antibody assays (immunoprecipitation, immunofluorescence and immunoblot). Onconeural antibodies were found in 11.9% of the patients by immunoprecipitation, in 7.0% by immunofluorescence and in 6.3% by immunoblot. PNS were present in 81.8% of the cancer patients that were seropositive by immunoprecipitation. Immunofluorescence and immunoblot failed to detect onconeural antibodies in almost one third of the PNS cases.     

Paraneoplastic neurological disorders

The article provides an overview on the diagnosis and pathogenesis of paraneoplastic neurological disorders (PNDs), and subsequently the current therapeutic strategies in these patients. PNDs are nervous system dysfunctions in cancer patients, which are not due to a local effect of the tumor or its metastases. Most of these clinically defined syndromes in adults are associated with lung cancer, especially small-cell lung cancer, lymphoma and gynecological tumors. In a part of the PND, an overlapping of different clinical syndromes can be observed. Highly specific autoantibodies directed against onconeuronal antigens led to the current hypothesis of an autoimmune pathophysiology. Whereas the most central nervous PNDs are more T-cell-mediated, limbic encephalitis can be caused by pathogenic receptor autoantibodies. The PND of the neuromuscular junction and paraneoplastic autonomic neuropathy are mainly associated with receptor or ion channel autoantibodies. The childhood opsoclonus-myoclonus syndrome and the PNDs associated with receptor/ion channel autoantibodies often respond to immunosuppressive therapies, plasmapheresis and intravenous immunoglobulins. By contrast, most CNS PNDs associated with defined antineuronal antibodies directed against intracellular antigens only stabilize after tumor treatment.     

Management of paraneoplastic neurological syndromes: report of an EFNS Task Force

Paraneoplastic neurological syndromes (PNS) are remote effects of cancer on the nervous system. An overview of the management of classical PNS, i.e. paraneoplastic limbic encephalitis, subacute sensory neuronopathy, paraneoplastic cerebellar degeneration, paraneoplastic opsoclonus-myoclonus, Lambert–Eaton myasthenic syndrome and paraneoplastic peripheral nerve hyperexcitability is given. Myasthenia gravis and paraproteinemic neuropathies are not included in this report. No evidence-based recommendations were possible, but good practice points were agreed by consensus. Urgent investigation is indicated, especially in central nervous system (CNS) syndromes, to allow tumour therapy to be started early and prevent progressive neuronal death and irreversible disability. Onconeural antibodies are of great importance in the investigation of PNS and can be used to focus tumour search. PDG-PET is useful if the initial radiological tumour screen is negative. Early detection and treatment of the tumour is the approach that seems to offer the greatest chance for PNS stabilization. Immune therapy usually has no or modest effect on the CNS syndromes, whereas such therapy is beneficial for PNS affecting the neuromuscular junction. Symptomatic therapy should be offered to all patients with PNS.     

Paraneoplastic epilepsy

Epilepsy can be a manifestation of paraneoplastic syndromes which are the consequence of an immune reaction to neuronal elements driven by an underlying malignancy affecting other organs and tissues. The antibodies commonly found in paraneoplastic encephalitis can be divided into two main groups depending on the target antigen: 1) antibodies against neuronal cell surface antigens, such as against neurotransmitter (N-methyl-d-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), gamma-aminobutyric acid (GABA)) receptors, ion channels (voltage-gated potassium channel (VGKC)), and channel-complex proteins (leucine rich, glioma inactivated-1 glycoprotein (LGI1) and contactin-associated protein-2 (CASPR2)) and 2) antibodies against intracellular neuronal antigens (Hu/antineuronal nuclear antibody-1 (ANNA-1), Ma2/Ta, glutamate decarboxylase 65 (GAD65), less frequently to CV2/collapsin response mediator protein 5 (CRMP5)). In this review, we provide a comprehensive survey of the current literature on paraneoplastic epilepsy indexed by the associated onconeuronal antibodies. While a range of seizure types can be seen with paraneoplastic syndromes, temporal lobe epilepsy is the most common because of the association with limbic encephalitis. Early treatment of the paraneoplastic syndrome with immune modulation/suppression may prevent the more serious potential consequences of paraneoplastic epilepsy.     

Paraneoplastic neurological syndromes: from the diagnosis of exclusion to the use of immunological and molecular markers

For many years paraneoplastic neurological syndromes have been identified through the exclusion of other neurological complications in patients with cancer. The discovery that many paraneoplastic syndromes are associated with immunological reactions allows a specific and comprehensive definition of these disorders, which often can be promptly recognized by the serological detection of antineuronal antibodies. In a significant number of paraneoplastic syndromes the genes coding for the target onconeuronal antigens have been cloned and their functions are being elucidated. This study reviews the pathogenic mechanisms of paraneoplastic neurological syndromes and addresses the most frequently asked questions regarding their diagnosis and treatment.     

Ma2 antibody and multiple mononeuropathies

Anti-Ma2 antibodies belong to a family of onconeuronal antibodies that target proteins expressed in brain, testis and several tumors. Previously observed in patients presenting with limbic encephalitis, they seem to be associated with several other paraneoplastic syndromes. We report the case of a 73-year-old woman presenting sensory and motor neuropathy associated with non-small-cell lung cancer who had Ma2-antibodies.     

Screening for well-characterized paraneoplastic antineuronal antibodies in multiple sclerosis

Some epidemiological surveys have shown an increased incidence of malignancies in patients with multiple Sclerosis (MS). Furthermore, in rare cases central demyelinating disorders like optic neuritis, encephalomyelitis, and myelitis could be of paraneoplastic origin. Antineuronal antibodies are frequently associated with paraneoplastic neurological syndromes (PNS) but are also described in cancer patients without neurological symptoms. In this study, we retrospectively analyzed sera from 247 patients with MS and clinically isolated syndrome (CIS) for the presence of anti-HuD, Yo, Ri, CV2/CRMP5, Ma2, and amphiphysin antibodies using ELISA employing recombinant onconeural antigens. None of the sera revealed high titers of antineuronal antibodies and only two sera from MS patients show weak reactivity, representing in all probability background activity. Furthermore, cancer incidence in our study is low (0.8%). Our analysis does not support an association between MS and well-characterized paraneoplastic antineuronal antibodies, suggestive of a secondary humoral autoimmune response, underlying latent malignancy, or paraneoplastic origin in our cohort. In reverse, negative screening results in samples of MS patients confirm the high specificity of these antibodies for PNS.