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Chronic inflammatory demyelinating polyneuropathy
慢性炎性脱髓鞘性 多发性神经病 Chronic inflammatory demyelinating polyneuropathy
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周围神经免疫学 过去认为周围神经属于“特免器官”,不接受免疫监视; 现代“ 特免”的概念受到严重的挑战: 循环血淋巴细胞可进入周围神经
周围神经本身含有大量的免疫相关“ resident” 细胞: resident macrophages mast cells endoneurial capillary endothelial cells.
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周围神经疾病的免疫机制 分子模拟学说:molecular mimicry 超抗原作用:superantigen 免疫网络平衡崩溃
carcinomatous sensory neuronopathy, small-cell lung cancer (SCLC) cells express an antigen that is similar to antigens on neuronal nuclei 超抗原作用:superantigen Superantigens are bacterial or retroviral proteins capable of activating large numbers of T cells through interaction with the VB T cell receptors (TCRs) 免疫网络平衡崩溃 HIV, lymphoma, and interferon therapy
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周围神经免疫损伤机制 一旦血-神经屏障破坏,至少存在4种自身免疫机制造成周围神经损伤: cytotoxic T cell lysis,
antibody-mediated complement dependent attack, membrane damage from cytokines and free radicals released from inflammatory cells, antibody-mediated disruption of nervous system function.
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(a)背根神经节(Hu 抗体) (c ) 雪旺细胞髓鞘 AIDP (d) 神经肌肉接头 (突触前膜钙通道抗体)
癌性感觉神经病 (b)郎飞氏结(GM1抗体) 急性运动轴索神经病 多灶性运动神经病 (c ) 雪旺细胞髓鞘 AIDP (d) 神经肌肉接头 (突触前膜钙通道抗体) Eaton-Lambert syndrome
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慢性炎性脱髓鞘多发神经病 历史回顾 本世纪初开始报道CIDP病例,当时命名为:非家族性肥大性神经炎,特发性神经炎,慢性GBS综合症等;
1958年,Austin报道了2例反复发病的多发性神经病,对类固醇激素反应敏感,具体描述了CIDP特有的临床、电生理和脑脊液表现; 1975年,Dyck等总结了53例“慢性炎性多发神经根神经病”的临床特点,建立了诊断的一般标准; 1989年,Ohio州立大学制定了后来通用的诊断标准(Arch Neurol 1989;46: ); 1991年,Ad Hoc subcommittee of the American Academy of Neurology发表了CIDP的研究诊断标准(Neurology 1991;41: )。
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病理机制 体液免疫 间接证据:临床和实验室检查与GBS相似,血浆交换和静脉注射免疫球蛋白治疗有效; 直接证据不充分:
仅在少数患者血中存在一些抗体(糖蛋白,周围神经的糖脂成分抗体,包括LM1、GM1、MAG、硫酸软骨素C和硫脂等); CIDP腓肠神经活检很难发现免疫球蛋白和补体沉积(二者为体液免疫相关疾病的标志)
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病理机制 细胞免疫机制 尸检发现:脊神经根、神经节、神经干的血管周围和神经内膜单核炎性细胞浸润,提示为细胞介导免疫;
免疫组化研究证实:浸润的单核细胞为巨噬细胞和激活的T淋巴细胞,雪旺细胞表达MHC-Ⅰ和MHC-Ⅱ类抗原; T细胞亚群分析:CD8+细胞毒性/抑制细胞较CD4+细胞更为常见。
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病理学研究 神经活检:腓肠神经或腓神经 脱髓鞘,轴索变性:Barohn 等神经活检结果提示脱髓鞘占48%,轴索病21%,二者混合型13%,正常占18%。 神经内膜和束膜下水肿 神经内膜、外膜血管周围炎性细胞浸润,主要为巨噬细胞和细胞毒性CD8+T淋巴细胞 华勒氏变性 再生神经丛,或雪旺细胞呈洋葱皮样增生
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病理学研究 脊髓和有髓神经纤维 有髓神经纤维密度减少 前角细胞变性、脱失
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The ventral horn of the L4 segment of the spinal cord from a control (A) and from a patient with CIDP (B). Loss of ventral horn cells, especially large neurons, is evident in CIDP.
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The ventral horn of the L4 segment spinal cord from a control (A),and a patient with CIDP (B):Central chromatolysis (arrowheads in B)
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诊断标准 Ad Hoc subcommittee of the American Academy of Neurology发表的CIDP研究诊断标准
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CIDP合并疾病 约5%存在中枢神经系统受累及的证据,表现为痉挛、反射亢进、共济失调,与MS相似,约20%病例CNS在核磁共振或诱发电位出现异常,CNS异常可见于CIDP病程的任何时候; 约10%病例具有相关的系统性疾病:恶性肿瘤,结缔组织病,肝炎,HIV感染,肾小球肾炎,糖尿病,甲状腺毒素; 未明意义的单克隆丙球蛋白病(MGUS); Charcot-Marie-Tooth神经病。
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诊断方法 Useful diagnostic procedures for clarifying the aetiology of peripheral neuropathies STEP 1 History Clinical examination Basic laboratory tests: ESR,CRP, fasting blood glucose,glycosilised haemoglobin, creatinine, urea nitrogen, serum electrolytes including calcium and phosphate,liver enzymes including creatine kinase,cholesterol, triglycerides, complete bloodcell count, serum protein electrophoresis, thyroid function tests (T3, T4, TSH), VDRL and FTA-ABS, HIV, serum levels of folate and vitamin B12, urine analysis
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STEP2 in selected patients depending on the results of the basic investigations Additional laboratory tests: Immunoelectrophoresis and immunofixation, serum levels of vitamin B1, B6, Schilling test, antinuclear antibodies, antineutrocyte-cytoplasm antibodies, circulating immune complexes, rheumatoid factors, antibodies against ganglioside, MAG, Ro, Yi or Hu, screening for occult malignancy, cryoglobulins, porphyrins, phytanic acid, long chain fatty acids, heavy metals, molecular genetic search for mutations in the PMP22, PMP0, connexin-32, EGR2, thyrosinkinase A, transthyretin, gelsoline and apolipoprotein A genes Electroneurography/electromyography Lumbar puncture Biopsy
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周围神经脱髓鞘的电生理判断标准 神经传导速度减慢,小于正常低限的70%(2条神经以上);
远端潜伏期延长,大于正常上限的150%(2条神经以上); 肯定的一过性离散证据,或近端与远端间的波幅差大于20%(1条神经以上); F波消失或延长(至少10次trial)超过正常上限的150%(2条神经以上)。
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轴索性神经病的电生理诊断标准 运动或感觉神经动作电位波幅降低或消失(至少2条神经); 所有神经的传导速度大于正常下限的70%;
远端潜伏期正常或轻微延长,与传导速度成比例; F波正常或轻微延长(小于正常上限的120%); 刺激近端神经无传导阻滞; 肌电图显示:远端肌肉异常自发活动(纤颤电位,阳性尖波,或复杂重复放电),或神经源性运动单位电位伴募集减少。
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鉴别诊断 复发型GBS 多灶性运动神经病 Charcot-Marie-Tooth病1型 遗传性压力易感性神经病
Refsum病,异染性白质营养不良 副蛋白相关性神经病:MGUS,POMES等 副肿瘤综合症 慢性特发性轴索性多发神经病
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治 疗 3种治疗方法经前瞻性、随机对照临床试验证实有效 强的松(prednisone) 血浆交换(plasma exchange)
治 疗 3种治疗方法经前瞻性、随机对照临床试验证实有效 强的松(prednisone) 血浆交换(plasma exchange) 静脉注射免疫球蛋白(intravenous immunoglobulin)
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皮质激素 Typical regimen To begin with high-dose oral therapy at mg/kg/day as a single,morning dose; Severe illness can be treated initially with 1gm of intravenous methylprednisone daily for 4-5 doses,and then with high dose oral prednisone. Once improvement has been documented, the dose is changed to an alternate-day regimen(80mg on one day alternating with 40mg on the opposite day wuth weekly decrements to 80mg and 20mg,80mg and 10mg,80mg and 5mg,finally reaching 80mg and 0mg.) Treatment continued until maximal improvement occurs or the patient has reach a plateau.This occurs in 50% of patients after 6 months of treatment,and in 95% by 12 months.
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免疫球蛋白 Standard regimen:
2.0gm/kg over 4-5 days(I.e.,0.4 or 0.5gm/kg/days, respectively); Maintenance doses: 0.5gm/kg every 3-4 weeks.
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Two exchanges per week for 3 weeks
血浆交换 Two exchanges per week for 3 weeks
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