Impairment of the transient pupillary light reflex in Rpe65-/- mice and humans with Leber congenital amaurosis
Impairment of the transient pupillary light reflex in Rpe65-/- mice and humans with Leber congenital amaurosis
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DOI：
10.1167/iovs.03-1230
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发表时间：
2004-04-01
影响因子：
4.4
通讯作者：
Cideciyan, AV
中科院分区：
文献类型：
--
作者：
Aleman, TS;Jacobson, SG;Cideciyan, AV
目的。在Leber先天性黑朦（LCA）小鼠模型和Leber先天性黑朦患者中，测定严重视网膜功能障碍和变性对瞬时瞳孔光反射（TPLR）的损害。直接TPLR在麻醉、适应黑暗的Rpe65（-/-）和对照小鼠中被激发，并在增强强度（- 6.6至+ 2.3 log scot-cd）的全场光刺激（0.1秒持续时间）下被激发。米(2))。将9-顺式视网膜给予Rpe65（-/-）小鼠亚组，并在治疗后48小时记录TPLR。在lca患者组中也测量了TPLR。Rpe65（-/-）小鼠和对照小鼠的基线瞳孔直径相似。与对照组相比，Rpe65（-/-）小鼠TPLR阈值提高了5个log单位。Rpe65（-/-）小鼠的TPLR波形与4.8 log-unit调光刺激小鼠的TPLR波形相似。用9-顺式视网膜治疗Rpe65（-/-）小鼠，TPLR阈值降低2.1 log单位。LCA患者的基线瞳孔直径与正常相似，但TPLR异常，阈值升高3至6个log单位以上。当调整到TPLR阈值升高时，大多数患者的瞳孔收缩动力学与正常受试者相似。在LCA小鼠模型和LCA患者中，瞳孔测量法用于量化视力损害，并探测视网膜信号向高级神经中枢的传递。小鼠的结果与在短时间刺激下形成图像的光感受器驱动TPLR早期阶段的主导作用一致。TPLR测量的客观和非侵入性，以及在动物模型中观察到的治疗后向正常的变化，支持了这一概念，即这可能是未来LCA治疗试验中有用的结果测量。
PURPOSE. To determine the impairment of the transient pupillary light reflex (TPLR) due to severe retinal dysfunction and degeneration in a murine model of Leber congenital amaurosis (LCA) and in patients with the disease.METHODS. Direct TPLR was elicited in anesthetized, dark-adapted Rpe65(-/-) and control mice with full-field light stimuli (0.1 second duration) of increasing intensities ( - 6.6 to + 2.3 log scot-cd . m(-2)). 9-cis-Retinal was administered orally to a subset of Rpe65(-/-) mice, and TPLR was recorded 48 hours after the treatment. TPLR was also measured in a group of patients with LCA.RESULTS. Baseline pupillary diameters in Rpe65(-/-) and control mice were similar. TPLR thresholds of Rpe65(-/-) mice were elevated by 5 log units compared with those of control animals. The waveform of the TPLR in Rpe65(-/-) mice was similar to that evoked by 4.8-log-unit dimmer stimuli in control mice. Treatment of Rpe65(-/-) mice with 9-cis-retinal lowered the TPLR threshold by 2.1 log units. Patients with LCA had baseline pupillary diameters similar to normal, but the TPLR was abnormal, with thresholds elevated by 3 to more than 6 log units. When adjusted to the elevation of TPLR threshold, pupillary constriction kinetics in most patients were similar to those in normal subjects.CONCLUSIONS. Pupillometry was used to quantify visual impairment and to probe transmission of retinal signals to higher nervous centers in a murine model of LCA and in patients with LCA. Mouse results were consistent with a dominant role of image-forming photoreceptors driving the early phase of the TPLR when elicited by short-duration stimuli. The objective and noninvasive nature of the TPLR measurement, and the observed post-treatment change toward normal in the animal model supports the notion that this may be a useful outcome measure in future therapeutic trials of LCA.