Antigen-specific oligoclonal bands in cerebrospinal fluid and serum from patients with anti-amphiphysin- and anti-CV2/CRMP5 associated paraneoplastic neurological syndromes

Using isoelectric focusing and affinity blotting employing paraneoplastic recombinant antigens, we investigated cerebrospinal fluid (CSF) and sera from three patients with positive anti-CV2/CRMP5- and one patient with positive anti-amphiphysin serology. CSF and sera were previously adjusted to total IgG concentrations of 20 mg/l. All patients suffered from paraneoplastic neurological syndromes (PNS) with predominant involvement of the central nervous system (CNS). Using affinity blot preloaded with paraneoplastic antigen, we detected in three of four patients more or stronger specific oligoclonal bands (OCB) in the CSF than in the corresponding serum, providing qualitative evidence of antigen specific intrathecal antibody synthesis. These results are in line with previous studies demonstrating specific OCB predominantly in CSF from patients with anti-Hu-, anti-Yo- and anti-Ri-associated PNS, supporting the hypothesis of autoimmunity in the pathogenesis of PNS. One patient harboured extensive anti-amphiphysin specific OCB, although OCB of total IgG could not be detected, indicating a higher sensitivity for detection of intrathecal antibody synthesis of the affinity blot preloaded with the paraneoplastic antigen, compared with investigation of total IgG OCB. These results could have implications concerning pathophysiological autoimmune aspects in other inflammatory diseases of CNS associated with total IgG OCB, provided that the target antigen is known.     

Paraneoplastic autoantibody panels: sensitivity and specificity,a retrospective cohort

Background: Experts in the autoimmune paraneoplastic field recommend autoantibody testing as “panels” to improve the poor sensitivity of individual autoantibodies in detecting paraneoplastic neurological syndromes (PNS). The sensitivity of those panels was not reported to date in a fashion devoid of incorporation bias. We aimed to assess the collective sensitivity and specificity of one of the commonly used panels in detecting PNS. Methods: A single-centered retrospective cohort of all patients tested for paraneoplastic evaluation panel (PAVAL; test ID: 83380) over one year for the suspicion of PNS. Case adjudication was based on newly proposed diagnostic criteria in line with previously published literature, but modified to exclude serological status to avoid incorporation bias. Measures of diagnostic accuracy were subsequently calculated. Cases that failed to show association with malignancy within the follow-up time studied, reflecting a possibly pure autoimmune process was considered paraneoplastic-like syndromes. Results: Out of 321 patients tested, 51 patients tested positive. Thirty-two patients met diagnostic criteria for paraneoplastic/paraneoplastic-like syndromes. The calculated collective sensitivity was 34% (95% CI: 17–53), specificity was 86% (95% CI: 81–90), Youden's index 0.2 and a positive clinical utility index 0.07 suggesting poor utility for case-detection. Conclusion: This is the first reported diagnostic accuracy measures of paraneoplastic panels without incorporation bias. Despite recommended panel testing to improve detection of PNS, sensitivity remains low with poor utility for case-detection. The high-calculated specificity suggests a possible role in confirming the condition in difficult cases suspicious for PNS, when enough supportive evidence is lacking on ancillary testing.     

神经系统副肿瘤综合征与神经副肿瘤抗体分析

目的探讨神经系统副肿瘤综合征(PNS)临床表现及神经副肿瘤抗体的特征。方法分析2009年1月至2019年9月北京大学第一医院神经内科确诊的110例PNS患者的临床特征及神经副肿瘤抗体类型。结果110例患者出现17种临床综合征,其中43例(39.1%)为经典临床综合征,最常见的为亚急性小脑变性14例(12.7%)和边缘性脑炎11例(10.0%);62例(56.4%)为非经典临床综合征,最常见的为感觉运动周围神经病19例(17.3%)和重症肌无力10例(9.1%)。69例(62.7%)患者发现恶性肿瘤,肺癌20例(18.2%)及血液系统肿瘤12例(10.9%)为最常见的肿瘤。71例(64.5%)患者在血液中检测到特征性副肿瘤抗体,最常见的为抗Amphiphysin抗体26例(23.6%)和抗Yo抗体24例(21.8%)。结论临床表现为非经典副肿瘤综合征的患者,亦应积极进行特征性副肿瘤抗体的检测,并根据抗体结果对特定肿瘤进行重点筛查。     

Enzyme linked immunosorbent assay using recombinant HuD-autoantigen for serodiagnosis of paraneoplastic neurological syndromes

OBJECTIVES: The aim of this study was to evaluate the suitability of an ELISA employing purified recombinant HuD antigen, for detection of specific anti-HuD antibodies in sera and cerebrospinal fluid (CSF) from patients with paraneoplastic neurological syndromes (PNS). MATERIAL AND METHODS: The cutoff for optical density readings was estimated by testing of 145 sera from healthy subjects. Sera from 17 patients with paraneoplastic neurological syndromes (PNS) and evidence of a clear anti-Hu band pattern in an immunoblot employing human cerebellar crude extract as antigen were tested. RESULTS: All 17 sera from patients with PNS revealed a clear positive result in the HuD-ELISA, demonstrating a sensitivity of 100%. Two out of 150 sera from patients with various infectious, autoimmune and neoplastic diseases (excluding PNS) showed a borderline result in the HuD-ELISA. This reveals a specificity of more than 98%. In addition 10 serum/CSF pairs from patients with anti-Hu-syndrome were adjusted to equal IgG concentrations and were tested in parallel in the HuD-ELISA. A specific antibody index (AI=ODCSF/ODserum) over 1.5 indicates intrathecal antibody synthesis. Six of ten patients revealed an AI >1.5, one was borderline (AI=1.5), and three had an AI in the range of 0.9-1.2. There appears to be a correlation between elevated AIs (>1.5) and presence of oligoclonal bands in the CSF. CONCLUSION: Due to its high specificity and sensitivity the recombinant HuD-ELISA is a suitable test for detection of anti-HuD antibodies in patients with putative PNS. In addition, the HuD-ELISA seems to be appropriate for the detection of specific intrathecal HuD-antibody synthesis.     

Paraneoplastic neurological syndromes in patients with carcinoid

Background: Paraneoplastic neurological syndromes (PNS) are mainly associated with small‐cell lung cancer, gynaecological tumours and lymphomas. Few studies report the association of neurological syndromes with a carcinoid, the majority being a serotonin‐related myopathy. We report four patients with a PNS associated with carcinoid. Patients and results: The clinical syndromes were sensory neuropathy, limbic encephalitis, myelopathy and brain stem encephalitis. Two patients had antineuronal autoantibodies (one anti‐Hu, one anti‐Yo), one patient had antinuclear antibodies, and one patient had no autoantibodies. For two of the carcinoids, expression of HuD in the tumour could be demonstrated. Conclusion: This study demonstrates that carcinoids can also be associated with classical antineuronal antibody‐associated PNS.     

An uncontrolled trial of rituximab for antibody associated paraneoplastic neurological syndromes

Abstract Anti-CD20 monoclonal antibody (rituximab) is effectively used in the treatment of B-cell lymphomas. Recent reports in the literature suggest that antibody associated autoimmune disorders may respond to rituximab. We therefore treated nine patients with anti-Hu or anti-Yo associated paraneoplastic neurological syndromes (PNS) with a maximum of four monthly IV infusions of rituximab (375mg/m²). In this uncontrolled, unblinded trial of rituximab, three patients improved ≥1 point on the Rankin Scale (RS). One patient with limbic encephalitis improved dramatically (RS from 5 to 1). Further studies of rituximab in autoantibody associated PNS are warranted.     

Paraneoplastic cerebellar syndromes associated with antibodies against Purkinje cells

The paraneoplastic cerebellar syndrome presents as severe neuroimmunological disease associated with malignancies. Antibodies against antigens expressed by tumor cells cross-react with proteins of cerebellar Purkinje cells leading to neuroinflammation and neuronal loss. These antineuronal antibodies are preferentially investigated by serological analyses while examination of the cerebrospinal fluid is only performed infrequently.

We retrospectively investigated 12 patients with antineuronal antibodies against Purkinje cells with a special focus on cerebrospinal fluid.

Our results confirm a subacute disease with a severe cerebellar syndrome in 10 female patients due to anti-Yo antibodies associated mostly with gynecological malignancies. While standard cerebrospinal fluid parameters infrequently revealed pathological results, all patients presented oligoclonal bands indicating intrathecal IgG synthesis. Analyses of anti-Yo antibodies in cerebrospinal fluid by calculating the antibody specific index revealed intrathecal synthesis of anti-Yo antibodies in these patients. In analogy to anti-Yo syndrome, an intrathecal production of anti-Tr antibodies in one patient who presented with a paraneoplastic cerebellar syndrome was detected. In an additional patient, anti-Purkinje cell antibodies of unknown origin in the cerebrospinal fluid but not in serum were determined suggesting an isolated immune reaction within the central nervous system (CNS) and underlining the importance of investigating the cerebrospinal fluid.

In conclusion, patients with a cerebellar syndrome display a distinct immune reaction within the cerebrospinal fluid including intrathecal synthesis of disease-specific antibodies. We emphasize the importance of a thorough immunological work up including investigations of both serum and cerebrospinal fluid.     

Disturbance in the serum IgG subclass distribution in patients with anti-Hu positive paraneoplastic neurological syndromes

Autoantibodies in patients with paraneoplastic neurological syndromes (PNS) have been reported to be predominantly IgG1 and IgG3 isotypes. However, no data are available about the IgG subclass distribution of the total serum IgG in these patients. Therefore, we investigated the IgG subclass distribution (given as percentage of total IgG) in 15 anti-Hu positive PNS patients, 15 patients with small cell lung cancer (SCLC) without PNS and 23 healthy controls using a commercial enzyme-linked immunosorbant assay test. Although IgG1 (and to a lower extent IgG3) are the predominant subclasses of the anti-Hu antibodies, PNS and SCLC showed a significant decrease in IgG1 and a concomitant increase in IgG2 compared with healthy controls (P < 0.05, respectively). In contrast, only SCLC patients, but not PNS patients, had higher IgG3 and IgG4 values compared with controls (P < 0.05, respectively). There was no correlation between IgG subclass levels and the titre or the predominant isotype of the antineuronal antibodies. PNS patients with autonomic disturbances had lower IgG4 levels than PNS patients without autonomic disturbances (P < 0.05). Our study demonstrates a disturbance in the IgG subclass distribution in PNS patients which is partly different from SCLC patients. The isotype regulation of the anti-Hu antibody seems to be independent from this phenomenon.     

神经系统副肿瘤综合征临床分析

目的 了解神经系统副肿瘤综合征患者的临床特点.方法 收集我院收治的神经系统副肿瘤综合征患者28例,对其临床资料进行回顾性分析.结果 患者多为慢性隐袭或亚急性起病,进行性加重,治疗后无明显缓解,3.8%患者在发现肿瘤后才出现神经症状;96.2%在出现副肿瘤症状后才发现肿瘤,副肿瘤综合征的临床类型有Lambert-Eaton肌无力综合征8例、周围神经病7例、多发性肌炎和皮肌炎4例、脑干脑炎3例、进行性小脑变性2例、边缘系统脑炎2例、运动神经元病1例、进行性多灶性白质脑病1例.结论 神经系统副肿瘤综合征临床表现形式多样,容易误诊,临床早期确诊对于隐匿肿瘤的发现和治疗非常重要.     

SOX1 antibodies in sera from patients with paraneoplastic neurological syndromes

Objectives – SOX1 antibodies have been described in patients with Lambert–Eaton myasthenic syndrome (LEMS) in association with voltage‐gated calcium channel antibodies as serological markers of small cell lung cancer (SCLC). This study was aimed to screen for additional SOX1 autoimmunity in onconeural antibody‐positive sera from patients with paraneoplastic neurological syndromes (PNS) other than LEMS and to identify the clinical–immunological profile and associated tumours of patients with coexisting SOX1 antibodies. Methods– We retrospectively analysed sera from 55 patients with different PNS positive for well‐characterized antineuronal antibodies for the presence of SOX1 antibodies by recombinant ELISA and immunoblot. Results– Eight (14.5%) patients showed additional SOX1 antibodies in the ELISA and the recombinant immunoblot. Five patients had coexisting Hu antibodies, while the other three showed coexisting CV2/CRMP5, amphiphysin, and coexisting CV2/CRMP5 and Hu antibodies, respectively. PNS included (partially overlapping) subacute sensory neuropathy, subacute sensorimotor neuropathy, cerebellar degeneration, brainstem encephalitis, encephalomyelitis and limbic encephalitis. No tumour was detected in two patients, while the others had lung cancer (four SCLC and two non‐SCLC). One patient showed SOX1‐specific intrathecal antibody synthesis. Conclusions– We describe SOX1 reactivity for the first time overlapping with CV2/CRMP5 and amphiphysin antibodies. SOX1 reactivity is predominantly associated with Hu antibodies and SCLC, but can occur also in other types of lung cancer. Neurological manifestations present in patients with coexisting SOX1 antibodies and well‐characterized antineuronal antibodies do not differ from those previously described in patients positive for antineuronal antibodies but no SOX1‐specific anti‐glial antibodies.     

Paraneoplastic antibody during follow-up of a patient with anti-Ri-associated paraneoplastic neurological syndrome

Background – The role of classical antineuronal antibody determinations to confirm the paraneoplastic aetiology of a neurological syndrome is well established. However, the value of antineuronal antibody estimation during follow‐up of paraneoplastic neurological syndromes (PNS) is not known. Aims of the study – Prospective analysis of antibody concentrations in follow‐up serum samples from a patient with anti‐Ri‐associated PNS. Methods – Semiquantitative estimation of antibody concentrations with an ELISA using recombinant Ri antigen. Results – Semiquantitative estimation of circulating anti‐Ri antibodies demonstrated a renewed increase in antibody levels preceding relapse of the cancer, as confirmed using F‐fluorodeoxyglucose positron emission tomography (FDG‐PET). Conclusions – This is the first prospective report on serial anti‐Ri antibody determinations. As a large increase in antineuronal antibody concentrations in follow‐up serum samples preceded relapse of the cancer, paraneoplastic antineuronal antibodies may represent a marker for tumour activity in this case. These results warrant further multicentre studies to investigate the ability of serial quantification of classical antineuronal antibodies in monitoring PNS and in predicting relapse of cancers.     

以球麻痹起病的副肿瘤综合征

目的归纳总结以球麻痹起病的神经系统副肿瘤综合征(PNS)的临床特点及转归,为临床进一步认识PNS提供依据。方法回顾分析作者医院2010-2019年收治的以球麻痹起病的符合PNS诊断标准的患者,按照是否符合重症肌无力(MG)诊断标准,分为MG组及非MG组;比较两组间临床特征、实验室检查指标、治疗、预后的差别。结果收集随访PNS患者20例,其中MG组患者11例,平均发病年龄(39.0±14.0)岁,以女性为主〔8例(72.7%)〕;非MG组共9例,平均发病年龄为(60.0±15.0)岁,以男性为主〔8例(88.9%)〕;非MG组肿瘤标志物阳性率高于非MG组(18.1%比77.8%,P=0.031)。MG组均接受了外科干预治疗;两组中均有部分患者使用激素及(或)丙种球蛋白治疗,痊愈及好转患者比例差异无统计学意义(P>0.05)。MG组无死亡,非MG组死亡2例。结论在以球麻痹首发的PNS患者中,符合MG的患者女性多见,外科手术联合免疫抑制剂能显著改善患者预后,而不符合MG者以老年男性多见,肿瘤标志物阳性率更高,预后及死亡率更差。     

自身抗体对副肿瘤综合征诊断价值的探讨

目的　探讨自身抗体对副肿瘤综合征的诊断价值。方法　利用间接免疫荧光法对 48例疑诊副肿瘤综合征患者进行抗 Yo抗体、抗 Hu抗体、抗 Ri抗体测定和临床随访 ,并与正常人和神经系统其他疾病患者对照。结果　 48例中 ,1例病前有肺癌史 ,2例检查中发现肿瘤 ,4例随访 3～ 1 8个月后发现肿瘤。正常对照组和神经系统其他疾病组自身抗体均为阴性 ,患者组中有 1例呈副肿瘤性脑脊髓炎 ,其抗 Hu抗体阳性 ,相对分子质量为3 80 0 0 ,病理检查证实为小细胞肺癌。结论　自身抗体测定对此病的早期诊断有一定价值 ,但阳性率不高 ,其临床价值尚需进一步随访证实     

IgG1,3 and 4 oligoclonal bands in multiple sclerosis and other neurological diseases

Cerebrospinal fluid (CSF)samples from 10 patients with Multiple Sclerosis (MS) and 7 with other neurological diseases (OND) were studied in order to detect oligoclonal restriction of IgG subclasses 1,3 and 4. Agarose isoelectric focusing (AGA-IEF) followed by Western capillary blotting and immunoperoxidase staining with specific monoclonal antibodies were used. All MS samples showed oligoclonal IgG1 and 6 of them also had IgG3 or IgG4 bands. In the OND group only patients with subacute sclerosing panencephalitis (SSPE) and Guillain-Barré disease (GBD) showed CSF oligoclonal patterns for IgG subclasses. Our results demonstrate that in MS CSF other IgG subclasses beside IgG1 may display an oligoclonal pattern. The finding of more than one subclass in the same band indicates a microheterogeneous composition of these oligoclonal bands.

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Sommario Allo scopo di rilevare un'eventuale restrizione oligoclonale per le sottoclassi IgG1,3 e 4 sono stati studiati campioni di liquido cerebrospinale (LCS) ottenuti da 10 pazienti con Sclerosi Multipla (SM) definita e da 7 pazienti con altre malattie neurologiche (AMN). La metodica utilizzata è stata l'isoelectric focusing in agarosio seguita da Western capillary blotting su nitrocellulosa e colorazione con immunoperossidasi mediante anticorpi monoclonali. Tutti i campioni di SM mostrarono IgG1 oligoclonali e sei di essi presentarono contemporaneamente bande di IgG3 o di IgG4. Tra le AMN solo i pazienti con Panencefalite Sclerosante Subacuta e sindrome di Guillain-Barré mostrarono bande oligoclonali formate da sottoclassi di IgG. I nostri dati dimostrano che nel LCS di SM altre sottoclassi di IgG, oltre alle IgG1, possono essere oligoclonali. La presenza di più di una sottoclasse nella stessa banda depone per una microeterogeneità di queste bande oligoclonali.

     

Paraneoplastic autoimmune encephalitis associated with pleomorphic lung carcinoma: An autopsy case report

A 64‐year‐old man was admitted with acute onset disturbed consciousness. Cerebrospinal fluid analysis revealed pleocytosis and elevated protein, with negative cultures and PCR. Serum antibodies for autoimmune encephalitis were also negative. Brain magnetic resonance imaging (MRI) was unremarkable, but whole‐body CT scan showed a tumor in the left lower lung lobe. Bronchial brush cytology demonstrated clusters of malignant cells, and ¹⁸F‐fluorodeoxyglucose positron emission tomography showed multiple lesions and increased uptake in the lung tumor. Clinically the patient had a stage IV lung carcinoma, graded as T3N3M1b (OSS). Steroid therapy had limited efficacy, but chemotherapy dramatically improved his neurological symptoms. Therefore, he was diagnosed with paraneoplastic autoimmune encephalitis based on the diagnostic criteria for paraneoplastic neurological syndromes. He died due to disease progression 14 months later. Subsequent postmortem examination revealed white ill‐defined nodules in the left lung, with similar nodules in other organs. The brain weighed 1500 g before fixation, and a nodule was observed in the right precentral gyrus. Microscopically, the lung tumor was a pleomorphic carcinoma with an adenocarcinoma component. Multiple areas of micro‐softening (≤500 μm) were identified in the cerebral cortex, gray–white matter junction and basal ganglia, and were distributed diffusely in both the limbic and non‐limbic systems. Mild lymphocytic infiltrates were observed involving few intraparenchymal vessels. Few tumor metastases were observed in the right precentral gyrus. The multiple micro‐softenings may reflect a chronic neuropathologic change of paraneoplastic autoimmune encephalitis. They were too small to be detected by brain MRI. However, these lesions may have the potential to cause the neurological symptoms in the acute phase because they were observed in many anatomical regions. We should pay attention to subtle findings such as micro‐softenings when estimating the neuropathology of autoimmune encephalitis. Further investigations are needed to understand the characteristic neuropathology of this condition.     

Anti-Ma2 Paraneoplastic Encephalitis in Association with Recurrent Cervical Cancer

Background

Paraneoplastic neurological syndromes are rare, and although they are frequently associated with gynecological malignancies, cervical cancer is a rare cause. The symptoms of anti-Ma2 encephalitis are diverse and often present prior to the diagnosis of malignancy.

Case Report

We report a case of a 37-year-old woman with a history of cervical cancer presenting with unexplained weight gain and vertical supranuclear gaze palsy. Magnetic resonance imaging of the brain revealed lesions within the bilateral hypothalami and midbrain. Anti-Ma2 antibodies were eventually found in the serum, prompting a search for malignancy. Recurrent metastatic cervical cancer was found in the retroperitoneal lymph nodes.

Conclusions

This is the first report of cervical cancer in association with anti-Ma2 encephalitis, and highlights the need for a high degree of suspicion in patients with a cancer history presenting with neurological symptoms. The symptoms associated with anti-Ma2 encephalitis are diverse and typically precede the diagnosis of cancer in patients, and should trigger a search for an underlying malignancy.     

免疫抑制治疗对36例神经系统副肿瘤综合征相关抗体定量的动态影响

目的 探讨免疫抑制治疗对神经系统副肿瘤综合征(PNS)相关抗体定量的动态影响。方法 对36例神经系统副肿瘤综合征进行规范化的免疫抑制治疗(包括糖皮质激素或环磷酰胺),在治疗前及治疗开始后1周、4周、治疗后1周,结束后3月分别对患者血清抗-Hu抗体、抗-Yo抗体、 抗-Ri抗体进行定量检测(酶联免疫吸附试验,ELISA),对比治疗前后相关抗体滴度的动态变化情况。结果 血清抗-Hu抗体:治疗开始后1周抗体滴度即开始持续下降(P<0.01),但在治疗后3月,抗体滴度反弹升高,与治疗前比较没有明显差异(P>0.05)。抗-Yo抗体及抗-RI抗体在治疗开始后抗体滴度同样呈持续下降趋势,其中抗-Yo抗体治疗开始后1周下降有明显差异(P<0.01),抗-RI抗体在治疗后4周明显下降(P<0.01),但治疗结束后1周、3月抗体滴度有所上升,但与治疗前比较仍显著下降(P<0.01)。结论 免疫抑制治疗在治疗期间能够一定程度上有效抑制PNS相关抗体的滴度,但对于血清抗-Hu抗体远期抑制效果欠佳。     

寡克隆带和IgG鞘内合成率对多发性硬化的诊断价值

目的探讨寡克隆带(OCBs)和IgG鞘内合成率(IgGSyn)对多发性硬化(MS)诊断的敏感性、特异性,以及定性和定量指标的相关性。方法选取30例MS(MS组)、40例神经系统炎性疾病(NID组)和22例神经系统非炎性疾病(NNID组)患者,应用速率散射比浊法测定血清和脑脊液(CSF)中免疫球蛋白G(IgG)、白蛋白(Alb)水平,等电聚焦结合银染色法检测CSF中OCBs,计算IgGSyn,并对其敏感性、特异性和阳性结果似然比(PRLR)进行分析。结果OCBs阳性率和IgGSyn异常率MS组与NID组比较差异无显著性;MS组、NID组与NNID组比较差异有极显著性(均P<0.01)。MS组和NID组中,OCBs阳性者与阴性者IgGSyn值差异无显著性。对MS诊断的敏感性、特异性和PRLR,OCBs分别为63.3%、77.7%和2.8;IgGSyn为46.7%、75.2%和1.9。结论OCBs和IgGSyn检测结果的不完全一致性提示中枢神经系统内存在不同的体液免疫反应机制,综合分析OCBs和IgGSyn,对MS诊断具有参考价值。     

Autoimmune myastenia gravis with thymoma following the spontaneous remission of stiff-man syndrome

A patient who developed generalized autoimmune myasthenia gravis six years after the spontaneous remission of a stiff-man syndrome is described. He also suffered from chronic active hepatitis and had radiological evidence of a thymoma. He did not have diabetes mellitus. Besides anti-nicotinic acetylcholine receptor antibodies, anti-nuclear, anti-DNA, anti-mitochondrial and anti-skeletal muscle antibodies were found in his serum, while islet-cell antibodies were absent. Immunocytochemistry studies failed to demonstrate autoantibodies to GABA-ergic nerve terminals, although an aspecific neuronal immunostaining was observed. The clinical and immunological features of this case support the hypothesis of a dysimmune pathogenesis of SMS, also in cases not associated with autoimmunity to GABA-ergic nerve terminals. Furthermore, a relationship between thymoma and the neurological syndromes discussed could be considered.

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Sommario Viene descritto il caso di un paziente che sviluppò una forma di Miastenia Gravis generalizzata autoimmune con evidenza radiologica di timoma sei anni dopo la remissione di una sindrome di contrattura muscolare permanente con caratteristiche elettrofisiologiche e di risposta ai farmaci tipiche della “stiff-man syndrome”, sebbene inizialmente associata a transitori segni di sofferenza troncoencefalica. Oltre ad anticorpi contro il recettore nicotico dell'acetilcolina, nel siero del paziente furono riscontrati anticorpi anti-nucleo, anti-DNA, anti-mitocondrio, anti-muscolo scheletrico. Il paziente non era diabetico e non presentava anticorpi contro le isole pancreatiche. Studi di immunoistochimica non hanno dimostrato anticorpi contro i terminali GABA-ergici, sebbene si sia riscontrato un certo grado di immunoreattività neuronale. Le caratteristiche cliniche ed immunologiche di questo caso suggeriscono l'ipotesi di una patogenesi disimmune di alcuni casi di “stiffman syndrome”, anche se non associati ad autoimmunità contro i terminali GABA-ergici ed inducono a considerare la possibilità di un coinvolgimento paraneoplastico-disimmune in queste forme.