Cerebellar Ataxia and Glutamic Acid Decarboxylase Antibodies Immunologic Profile and Long-term Effect of Immunotherapy
Cerebellar Ataxia and Glutamic Acid Decarboxylase Antibodies Immunologic Profile and Long-term Effect of Immunotherapy
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DOI：
10.1001/jamaneurol.2014.1011
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发表时间：
2014-08-01
期刊：
影响因子：
29
通讯作者：
Graus, Francesc
中科院分区：
文献类型：
--
作者：
Arino, Helena;Gresa-Arribas, Nuria;Graus, Francesc
目前关于谷氨酸脱羧酶65抗体(GAD65-Abs)小脑性共济失调(CA)的临床和免疫学知识是基于病例报告和短期随访数据的小系列。目的报告CA和GAD65-Abs患者的症状、其他抗体、预后因素和长期结果。设计、背景和参与者在自身免疫性神经疾病中心对34例CA和GAD65-Abs患者进行回顾性队列研究和实验室调查，其中25例有长期随访数据(中位数，5.4年；四分位数范围，3.1-10.3年)。主要结果和测量分析临床免疫学特征和免疫治疗反应的预测因素。表达甘氨酸受体GAD65、GAD67、A1亚基的大鼠脑、培养的神经元和人胚胎肾细胞的免疫化学以及一系列已知的细胞表面自身抗原被用来鉴定其他抗体。结果患者年龄中位数58岁(33~80岁)，其中女性28例(82%)。9名患者(26%)在发生CA前几个月报告有脑干和小脑功能障碍或持续性眩晕的发作。13名患者(38%)的临床表现在数周内呈亚急性。9例(26%)患者同时存在僵尸综合征症状。29名患者(85%)出现全身器官特异性自身免疫反应(1型糖尿病和其他)。有长期随访资料的25例患者中有20例接受了免疫治疗(静脉注射免疫球蛋白10例，皮质类固醇和静脉注射免疫球蛋白或其他免疫抑制剂10例)，其中7例(35%)有所改善。临床反应的预测因素包括亚急性发作CA(优势比[OR]，0.50；95%CI，0.25-0.99；P=.047)和及时免疫治疗(OR，0.98；95%CI，0.96-0.99；P=.01)。CA患者(24/34例，71%)和僵尸综合征患者(20/28，71%)的血清GAD67-Abs频率相似。而所有脑脊液标本(CA患者22例，僵人综合征患者17例)均检出GAD67-Abs。4例CA患者仅检出甘氨酸受体抗体，未检出其他细胞表面抗体。甘氨酸受体抗体的存在与CA和GAD65抗体的临床特征无关。结论CA和GAD65抗体阳性、亚急性起病、及时免疫治疗与预后良好相关。持续性眩晕或脑干和小脑发作可能是CA的前兆，应该导致GAD65-Ab检测，特别是在具有全身器官特异性自身免疫的患者中。
IMPORTANCE Current clinical and immunologic knowledge on cerebellar ataxia (CA) with glutamic acid decarboxylase 65 antibodies (GAD65-Abs) is based on case reports and small series with short-term follow-up data.OBJECTIVE To report the symptoms, additional antibodies, prognostic factors, and long-term outcomes in a cohort of patients with CA and GAD65-Abs.DESIGN, SETTING, AND PARTICIPANTS Retrospective cohort study and laboratory investigations at a center for autoimmune neurologic disorders among 34 patients with CA and GAD65-Abs, including 25 with long-term follow-up data (median, 5.4 years; interquartile range, 3.1-10.3 years).MAIN OUTCOMES AND MEASURES Analysis of clinicoimmunologic features and predictors of response to immunotherapy. Immunochemistry on rat brain, cultured neurons, and human embryonic kidney cells expressing GAD65, GAD67, a1-subunit of the glycine receptor, and a repertoire of known cell surface autoantigens were used to identify additional antibodies. Twenty-eight patients with stiff person syndrome and GAD65-Abs served as controls.RESULTS The median age of patients was 58 years (range, 33-80 years); 28 of 34 patients (82%) were women. Nine patients (26%) reported episodes of brainstem and cerebellar dysfunction or persistent vertigo several months before developing CA. The clinical presentation was subacute during a period of weeks in 13 patients (38%). Nine patients (26%) had coexisting stiff person syndrome symptoms. Systemic organ-specific autoimmunities (type 1 diabetes mellitus and others) were present in 29 patients (85%). Twenty of 25 patients with long-term follow-up data received immunotherapy (intravenous immunoglobulin in 10 and corticosteroids and intravenous immunoglobulin or other immunosuppressors in 10), and 7 of them (35%) improved. Predictors of clinical response included subacute onset of CA (odds ratio [OR], 0.50; 95% CI, 0.25-0.99; P =.047) and prompt immunotherapy (OR, 0.98; 95% CI, 0.96-0.99; P =.01). Similar frequencies of serum GAD67-Abs were found in patients with CA (24 of 34 patients [71%]) and in patients with stiff person syndrome (20 of 28 patients [71%]). However, GAD67-Abs were found in all of the cerebrospinal fluid samples examined (22 samples from patients with CA and 17 samples from patients with stiff person syndrome). Glycine receptor antibodies but not other cell surface antibodies were identified in 4 patients with CA. The presence of glycine receptor antibodies did not correlate with any specific clinical feature.CONCLUSIONS AND RELEVANCE In patients with CA and GAD65-Abs, subacute onset of symptoms and prompt immunotherapy are associated with good outcome. Persistent vertigo or brainstem and cerebellar episodes can herald CA and should lead to GAD65-Ab testing, particularly in patients with systemic organ-specific autoimmunities.