【作者】 冯菁菁；

【导师】 王卫平；

【作者基本信息】 复旦大学 ， 儿科学， 2011， 博士

【摘要】 早产儿即未成熟儿,指出生时胎龄不满37周的新生儿,根据出生体重小于2500克或小于1500克又可分为早产低出生体重(Low Birth Weight, LBW)和早产极低出生体重儿(Very Low Birth Weight, VLBW)。这类儿童由于提前脱离宫内环境,加之生命力较弱和各类围产期并发症的威胁,扰乱了他们的正常发育进程,增加了罹患各类功能障碍的危险性。但是,他们中合并严重脑功能损害者不到8%,更多的是存在隐匿的、持续的大脑结构或功能的损伤,且主要为感觉神经方面的损害。其中,各类视觉功能障碍的发生率达20-46%,是正常同龄儿童的3-5倍,且视觉损伤的发生与视感知觉、视动整合和认知缺陷存在着相关,严重影响了这类儿童的学习能力和学业成绩,给家庭和社会增添许多负担。由于视觉系统具可塑性的特点,若能在生后至2岁的发育关键期内，早发现损害,早进行干预,将大大提高早产儿的生活质量。研究表明，视觉通路的损害是导致视觉损伤的主要原因之一。视觉诱发电位(Visual Evoked Potential, VEP)是一种以闪光或图形变换为刺激物,在枕部皮质区的相应头颅表面记录到的诱发电反应。它能较客观地反映出视网膜感受功能、视路传导功能以及视觉中枢对来自视网膜信息的接受和处理能力。我们将以视觉诱发电位探索早产儿婴幼儿期和学龄前期的视觉系统发育状况及其与认知功能的关系,探究视觉诱发电位在评估早产儿视觉功能方面的应用价值；获得视觉发育关键期内早产儿视觉电生理的发育进程,为进一步制定更有效的干预措施提供依据。本课题主要研究内容如下：1.不同出生体重儿2岁时闪光视觉诱发电位研究通过横向比较三组(正常足月儿、LBW和VLBW)共102例婴幼儿,2岁时的闪光视觉诱发电位反应，结果发现：(1)三组观察对象均引出主波P2,其潜伏期均值和标准差分别为：VLBW组138±18 ms、LBW组122±11ms、对照组120±7ms。随出生体重的增加,P2波潜伏期在VLBW组、LBW组、正常对照组中呈现出缩短的趋势。(2)进一步将P2波潜伏期在三组间做两两比较,结果显示VLBW儿P2波潜伏期较正常足月儿甚至较LBW儿均存在显著落后(P<0.05),而LBW儿与正常足月儿相似。三组婴幼儿P2波振幅比较未显示有统计学差异(P>0.05)。(3)通过比较三组婴幼儿神经运动和视觉认知能力后发现,足月儿的智力、运动发育指数及视觉项目通过率与相同矫正月龄的两组早产儿相比较,都优于早产儿(P<0.01)。两组早产儿之间的智力、运动能力相当(P>0.05),但是在视觉项目通过率的比较中,VLBW儿要差于LBW儿(P<0.05)。(4)以P2波潜伏期值分别与贝莉婴幼儿发育量表(第二版)中的MDI、视觉项目通过率做Spearman’s秩相关分析,得到相关系数rMDI=-0.34;r通过率=-0.42(P<0.01)。校正母亲学历后得到r’MDI=-0.33；r’连过率=-0.41(P<0.01),说明闪光视觉诱发电位主波P2潜伏期与婴幼儿的认知能力和视觉发育状态存在负相关,即潜伏期越短，信息传递速度越快,认知和视觉发育状态越佳。2.学龄前期智能正常早产儿的图形视觉诱发电位研究通过横向比较三组(正常足月儿、LBW和VLBW)共102例智能正常的学龄前期儿童对5种不同空间频率(即从简单到复杂的视觉信息：108’、54’、27’、13’、7’)的图形视觉诱发电位反应。结果发现：(1)所有观察对象在5个空间频率上均记录到图形视觉诱发电位反应,呈现典型的负-正-负(N75-P100-N145)三峰波形。与正常足月儿相比较,所有早产儿的P100潜伏期均显示延长，振幅均降低(P<0.05)。随着格子尺寸的减小即空间频率的增加,P100潜伏期在三组儿童中均呈现延长趋势,振幅呈现下降趋势。(2)将三组儿童在5个空间频率上记录到的P100波潜伏期进行两两比较发现,与正常儿童相比VLBW儿在5个空间频率上的P100潜伏期均明显延长(P<0.01)；而LBW儿童仅在两个格子尺寸最小的图形，即13’和7’的空间频率上显示落后(P<0.05)。(3)将三组儿童在5个空间频率上记录到的P100波振幅进行两两比较发现，在所有空间频率上,与正常对照相比,两组早产儿P100振幅均存在显著下降(P<0.05)；在LBW和VLBW组之间,VLBW组儿童的P100振幅更低(P<0.05)。3.1-18月龄早产儿闪光视觉诱发电位纵向随访通过纵向记录三组(正常足月儿、LBW和VLBW)神经运动发育正常的103例婴幼儿生后1、3、6、9、12、18月龄闪光视觉诱发电位反应,结果显示：(1)从纵向发育的维度看：①闪光视觉诱发电位各波波形分化随着月龄的增长逐渐清晰、稳定，各波波峰之间的距离逐渐缩短；②三组儿童主波P2潜伏期随月龄的变化呈现出曲线相关趋势,它在0-6月龄的缩短速度较快,其中尤以0-3月龄最为迅速,自6月龄至12月龄,下降速度放缓,12至18月龄期间几乎处于平台期。VLBW组P2波潜伏期在0-6月龄内的曲线变化是最为陡直的,下降幅度也是最大的；③以月龄为自变量,P2波潜伏期为应变量，建立三组儿童P2波潜伏期随月龄增长而变化的回归方程为：P2波潜伏期(对照组=184-14.1×实际月龄+1.1×实际月龄2-0.03×实际月龄3(R对照组=-0.71,P＜0.05)P2波潜伏期(LBW=213-21.7×矫正月龄+1.8×矫正月龄2-0.05×矫正月龄3(R LBw=-0.67,P＜0.05)P2波潜伏期(VLBw=245-275×矫正月龄+2.1×矫正月龄2-0.05×矫正月龄3(R VLBW=-0.66.P＜0.05)④三组婴幼儿P2波潜伏期在相邻月龄间的变化程度均随着月龄的增长逐渐缩小：正常足月儿在1-18月龄期间,主波P2潜伏期的发育持续存在,而LBW儿在矫正12个月后,VLBW儿在矫正9个月后,他们的主波P2潜伏期就几乎没有变化了；⑤三组观察对象内均未发现振幅与月龄增长存在相关。(2)从P2波发育在三组间的横向比较看：①VLBW组与正常对照组相比较,在各观察月龄段均存在显著的P2波潜伏期延长(P＜0.05);LBW组与正常对照组相比较,仅在1和3月龄段表现出P2波潜伏期延长(P＜0.05);VLBW组与LBW组相比,在前两个观察月龄(1、3月龄)和最后两个观察月龄(12、18月龄)显示出P2波潜伏期延长(P<0.05)。②相比较对照组,LBW和VLBW组观察对象在矫正1月龄时P2波潜伏期的落后最为严重,两组早产儿与对照组水平相差分别达19%和32%。LBW组在矫正3月龄内将这种差距迅速缩小至6%左右,并在随后的4个观察月龄段内将差距保持在2-5%左右。而VLBW在校正6月龄时才将差距缩小至10%左右,直至18月龄时他们与对照组的差距始终维持在6-10%左右。③三组婴幼儿P2波振幅在1、3月龄存在差异(P<0.05),呈现出对照组最高,LBW次之,VLBW最低的趋势。但在6月龄后,三组之间P2波振幅并未显示出差异。结论无论在婴幼儿期还是学龄前期，早产儿尤其是极低出生体重儿的视觉电生理反应都较同龄正常足月儿落后,特别是在面对复杂信息时,他们视觉系统处理能力的薄弱就更加凸显。早产儿的视觉电生理变化趋势与正常儿童相似，但在视觉电生理发育的过程中，他们虽尽力向正常儿童靠拢,但在其生命早期就已经落下的差距,仍然难以通过自然成长的过程与正常儿童拥有相同的视觉信息处理能力。如果能在早产儿生后矫正6月内进行强化干预,可能会有效促进他们的视觉系统发育。视觉诱发电位能较客观地评估儿童的视觉发育状态,并能较好地反映出儿童某些方面的视觉认知水平,可为临床提供一项简易、无创、无副作用的测评儿童视觉功能的辅助工具。更多还原

【Abstract】 Birth before 37 completed weeks of gestation termed as the preterm newborn or immature infants. Those with the birth weight between 1500 g and 2500 g were classified into low birth weight (LBW) preterm; and those with birth weight between 1000 g and 1500 g were classified into very low birth weight (VLBW) preterm. Premature children are associated with an increased likelihood of neurodevelopmental disorders, because of physical weakness, perinatal complications and premature exposure to the extra-uterine environment. In fact, less than 8% preterm children suffered from serious brain dysfunction, most of them had subtle and permanent brain impairments, especially in sensory nerves. It was reported that the risk of having several sores of visual impairments was 20-46% in preterm, which is 3 to 5 times higher than full-term infants of the same age. Furthermore, several literatures concluded that the prevalence of ophthalmologic impairments is associated with the visual perceptual deficits, visual-motor integration defects and even cognitive defects when they attended primary school. Thus, those children with preterm have school-related problems and require some type of special education services, which may add much pressure to their families and our society. The first 2 years of life are known to be the key plastic period marked by rapid development of the eyes and central visual pathways. Since the earliest detection lead to earliest intervention for optimal development, it will be helpful to promote the quality of life on premature children.It was documented that the defect of visual pathway is one of the main reasons for visual impairments. The visual evoked potential (VEP) is an electrophysiologic signal that can be extracted from the electroencephalographic activity recorded from the human scalp and is generated by neurons in the brain in response to visual stimulation. Analyzing the waveform, latency, and amplitude of VEP may help evaluate the integrity of the retinocortical pathway and detect visual disorders in clinical settings.We planned to investigate visual electrophysiological outcome of preterm infants and preschoolers by VEP in order to explore the correlation between visual cognitive functions and VEP, and to assess the application of VEP in evaluating the visual capability of an infant; We further planed to obtain the evolution of VEP in preterm children from the 1 to 18 corrected months in order to provide evidence for designing the intervention effectively and efficiently.1. Flash visual evoked potentials at 2-year-old infants with different birth weightsExaminations were completed for all of the 102 infants eligible for the study, including 32 VLBW,27 LBW, and 43 full-term healthy infants.(1) Visually evoked response P2 wave was elicited in all of the infants. The mean latency of P2 in VLBW, LBW and full-term group was 138±18 ms,122±11 ms, and 120±7 ms respectively. With increasing birth weight, the P2 latency became shorter.(2) We compared the latency of P2 between any of the two groups. There were no differences in the latency of P2 between the full-term and LBW groups (P>0.05). There were significant differences in P2 latency between full-term and VLBW infants (P＜0.05). The difference in amplitude of N2-P2 between the three groups was not statistically significant (P>0.05).(3) We compared the MDI, PDI and the proportion of visual items passed between any of the two groups. The neuromotor and visual cognitive abilities in the full-term group were significantly better than those of the other two groups (P<0.01). Interestingly, no significant difference in neuromotor development was found between the groups of LBW and VLBW (P>0.05), except for the portion of visual items passed (P<0.05), suggesting that the visual cognitive function in premature infants is poor, especially in the VLBW group.(4) Because P2 latency value showed lower variability, it was used to carry out Spearmen’s rank-order correlation coefficient analysis between the MDI and the percentage of visual items passed. The latency of the main wave P2 was negatively correlated with the MDI and visual cognitive capability (rMDI=-0.34; r visual capability=-0.42, P<0.01). After adjusting for mother’s education, the latency of P2 was still negatively correlated with the MDI and visual capability (r’MDI=-0.33; r’visual capability=-0.41, P＜0.01). It is hypothesized that infants with normal FVEP latency had better neuromotor and visual cognitive development outcomes.2. Pattern visual evoked potential performance in preterm preschoolers with average intelligence quotients Psychometric intelligence measures were completed for all 102 preschoolers eligible for the study, including 20 VLBW,41 LBW, and 41 full-term healthy children. Among them, one LBW child was not able to cooperate with the investigator during PRVEP recording. Thus,101 participants finished the visual electrophysiological test.(1) Pattern reversal visual evoked responses on 108’,54’,27’,13’and 7’ check sizes were elicited in all of the children. A triphasic waveform with negative-positive-negative (N75-P100-N145) components was recorded for all the full-term and preterm children. All latencies in the preterm preschoolers were prolonged compared with controls (P＜0.05). All amplitudes of the preterm children tended to be smaller than those of the controls (P<0.05). In general, P100 latencies in the three groups increased when check size was reduced and spatial frequency was increased; the P100 amplitudes in the three groups decreased with a decrease in the check size and an increase in spatial frequency.(2) Analysis of variance showed that there were significant differences between the preterm and normal children in latencies and amplitudes at all five spatial frequencies (P＜0.05). We further compared the latency of P100 at the five spatial frequencies between any two groups. The P100 wave latencies at all five spatial frequencies were delayed in the VLBW preschoolers compared with the controls (P＜0.01). Between the LBW and control groups, only the latencies for the two smallest check sizes,13’and7’were significantly different (P＜0.05).(3) We compared the amplitudes of P100 at five spatial frequencies between any two groups. At all the frequencies, the P100 amplitudes were lower for both preterm groups than for controls (P＜0.05). When the P100 amplitudes of the LBW and VLBW groups were compared, the VLBW group was significantly lower (P＜0.05).3. A follow-up study on flash visual evoked potential in preterm infants from 1 to 18 monthsFVEP were recorded in 103 infants with average neurodevelopmental outcome, including 20 VLBW,42 LBW, and 41 full-term healthy children, longitudinally at 1, 3,6,9,12 and 18 corrected months. (1) From the longitudinal developmental view:①The morphological differentiation of the waveform in FVEP became clearer and more stable with the increasing of month age. The distance among wave peaks became closer.②The main wave P2 latency had a curve correlation with month age in the three groups. The general development pattern was of fast decrease in the first 6 months of life, especially in the first 3 months, gradual decline from 6 to 12 months of age, and smooth stage between 12 and 18 months. The decrease of P2 latency in VLBW group was the rapidest one among the three groups from lto 6 months.③Because P2 latency value showed lower variability, it was used to carry out regression analysis with month age: P2latency(CONTROL)=184-14.1×CHMA+1.1×CHMA2-0.03×CHMA3 (R=-0.71,P<0.05) P2 latency (LBW)=213-21.7×CMA+1.8×CMA2-0.05×CMA3 (R=-0.67, P＜0.05) P2 latency,(VLBW)=245-27.5×CMA+2.1×CMA2-0.05×CMA3 (R=-0.66, P＜0.05) (Chronological Month Age=CHMA; Corrected Month Age=CMA)④The change of P2 latency between the two neighboring months became smaller with the increase of month age. P2 latency in the control group continued to develop from lto 18 months of age. However, the development of P2 latency in LBW and VLBW group tended to suspend in 12 and 9 corrected months age.⑤There are no association between amplitude and month age in the three groups.(2) From the P2 wave development differences among the three groups:①We compared the latency of P2 at the six recorded months age between any two groups. The P2 wave latencies at all recorded months age were delayed in the VLBW infants compared with the controls (P＜0.05). Between the LBW and control groups, only the latencies for the 1 and 3 months of age were significantly different (P＜0.05). Between the LBW and VLBW groups, the P2 latency was delayed solely for the 1,3 and 12,18 months age (P＜0.05).②Compared with control group, the most serious delay of P2 latency in LBW and VLBW groups was the first month of age, which had 19% and 32% delay from the control infants. LBW group caught up the difference from control infants at 3 months of age on 6% delay. And LBW kept the delay from control group from 2% to 5% during the following four recorded months of age. However, VLBW group caught up the difference from control infants at 6 months of age on 10% delay. And VLBW kept the delay from control group from 6% to 10% during the following recorded months of age.③We compared the amplitudes of P2 at the six recorded months age between any two groups At 1 and 3 months of age, the P2 amplitudes were lower for both preterm groups than for controls (P＜0.05). After 6 months, there are no differences in P2 amplitudes among the three groups (P<0.05).ConclusionsPreterm infants or preschoolers with average overall cognitive abilities still had deficits in visual electrophysiological abilities compared with the healthy full term children, especially when they face more complex information.The visual electrophysiological development pattern of preterm children was the same as healthy full term subjects’. The huge gap which preterm children existed in the early age compared with full term children was not able to catch up by natural developmental pathway, although the preterm children tried to lessen the delay from the full term subjects during the visual evolution period. If the preterm children are able to obtain visual intervention before 6 corrected months of age, their visual development may be promoted more effectively.Additionally, as a noninvasive, convenient and objective measurement, visual evoked potentials are helpful in assessing certain aspects of the visual development and visual function in children.更多还原