Brown Rachel L, Thomas-Black Gilbert, Garcia-Moreno Hector, Chou Michael, Fleszar Zofia, Zandi Michael S, Chapman Miles, Church Andrew J, Hart Melanie, Giunti Paola, Vincent Angela, Lunn Michael P
National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, London, WC1N 3BG, UK.
Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London, WC1N 3BG, UK.
J Neurol. 2025 Feb 22;272(3):222. doi: 10.1007/s00415-025-12926-3.
The interpretation of antibodies to glutamic acid decarboxylase 65 (GAD-Abs) in neurological practice is challenging. GAD-Abs are not considered directly pathogenic and immunotherapy guidelines are lacking.
We undertook a single-center retrospective service evaluation of GAD-Abs, documenting clinical features, immunotherapy responses, and outcomes of 335 patients with positive GAD-Abs measured by indirect ELISA between 2012 and 2020. The serum:CSF ratio of GAD-Ab values was used as a surrogate for intrathecal synthesis.
168 (50%) patients had diagnosed neurological disorders (GAD-ND). Ninety-six had neurological disorders often or sometimes associated with GAD-Abs, i.e., stiff person syndrome spectrum disorders (SPS-SD, n = 26), cerebellar ataxia (n = 21), epilepsy (n = 19), encephalitis (n = 18), or any combination of these ("mixed", n = 12). Seventy-two had other neurological disorders (ONDs) not typically associated with GAD-Abs. We defined a cut-off of 10,000 IU/mL a priori and a posteriori for GAD-Ab associated NDs, but identified values > 10,000 IU/mL in 21% and 11% of patients with ONDs or diabetes respectively, and < 10,000 IU/mL in 39% patients with classical GAD-Ab syndromes, indicating low assay specificity and sensitivity. Low serum: CSF GAD-Ab ratios were consistent with intrathecal synthesis in 12/19 tested; 25/54 patients had oligoclonal bands. 30/50 patients given adequate immunotherapies had partial (n = 17) or good (n = 13) responses, particularly those with SPS-SD or limbic encephalitis. Within the limitations of small subgroups and routine laboratory titrations, patients with GAD-Ab values > 10,000 IU/mL, intrathecal synthesis of GAD-Abs, or oligoclonal bands, were not more likely to improve with immunotherapies than those with GAD-Ab values < 10,000 IU/mL and a non-inflammatory CSF. Rather, treatment response correlated with disease group, principally SPS-SD and encephalitis.
These results suggest caution in over-interpreting GAD-Abs values. Better biomarkers for identifying patients with immunotherapy responsive GAD-Ab disease are needed.
在神经科临床实践中，对谷氨酸脱羧酶65抗体（GAD-Abs）的解读具有挑战性。GAD-Abs不被认为具有直接致病性，且缺乏免疫治疗指南。
我们对GAD-Abs进行了一项单中心回顾性服务评估，记录了2012年至2020年间通过间接ELISA检测GAD-Abs呈阳性的335例患者的临床特征、免疫治疗反应和结局。GAD-Ab值的血清：脑脊液比值用作鞘内合成的替代指标。
168例（50%）患者被诊断患有神经系统疾病（GAD-ND）。96例患有常与GAD-Abs相关或有时与GAD-Abs相关的神经系统疾病，即僵人综合征谱系障碍（SPS-SD，n = 26）、小脑共济失调（n = 21）、癫痫（n = 19）、脑炎（n = 18）或这些疾病的任何组合（“混合”，n = 12）。72例患有通常与GAD-Abs不相关的其他神经系统疾病（ONDs）。我们事先和事后定义GAD-Ab相关神经系统疾病的临界值为10,000 IU/mL，但分别在21%的ONDs患者或糖尿病患者以及39%的典型GAD-Ab综合征患者中发现GAD-Ab值>10,000 IU/mL，表明检测的特异性和敏感性较低。19例接受检测的患者中有12例的低血清：脑脊液GAD-Ab比值与鞘内合成一致；54例患者中有25例有寡克隆带。50例接受充分免疫治疗的患者中有30例有部分（n = 17）或良好（n = 13）反应，尤其是那些患有SPS-SD或边缘性脑炎的患者。在小亚组和常规实验室滴定的局限性内，GAD-Ab值>10,000 IU/mL、GAD-Abs鞘内合成或有寡克隆带的患者与GAD-Ab值<10,000 IU/mL且脑脊液无炎症的患者相比，免疫治疗改善的可能性并不更大。相反，治疗反应与疾病组相关，主要是SPS-SD和脑炎。
这些结果提示在过度解读GAD-Ab值时应谨慎。需要更好的生物标志物来识别对免疫治疗有反应的GAD-Ab疾病患者。
