人工耳蜗植入前ECAP、EABR和EMLR检测方法的建立及临床应用
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摘要
背景和目的
人工耳蜗是一项运用最成功的生物医学工程技术,挽救了众多的失聪患者。但是术后效果依不同患者差异较大,且装置价格昂贵,因此如何保证术后效果及合理利用有限医疗资源已成为医生和患者家属关心的问题。术前客观听力检查,如畸变产物耳声发射(distortion product otoacoustic emission,DPOAE),听性脑干反应(Auditory brainstem responses,ABR),多频稳态诱发电位(Audio Steady-State Response, ASSR)以及有助测听显示无残余听力的未经过语训的患者,术有听觉言语评估无法感知周围环境声音。此类患者手术风险比较大,一旦出现术后效果欠佳,极易产生医患矛盾。此外,一些双侧极重度聋患者听力损失比较重,有可能是患者听阈过高,常规声刺激不足以诱发出可测出的术前听神经反应,但不能作为患者不适合人工耳蜗植入的证据。电刺激听觉诱发电位如电刺激听神经复合动作电位(Electrically evoked auditory nerve compound action potentials) ECAP),电刺激脑干诱发电位(Electrical Auditory Brainstem Response,EABR),电刺激中潜伏期听觉诱发电位(electrical evoked middle latency response, EMLR)通过电刺激听神经可以获得听神经反应,反映听觉通路的生理状况。如果在人工耳蜗植入前进行电刺激听觉诱发电位测试,则可以直观了解患者真实残余听力,为人工耳蜗植入保驾护航。
本研究致力于建立术前电刺激听觉诱发电位ECAP, EABR, EMLR检测的方法,评估人工耳蜗植入患者听觉通路从耳蜗至听觉皮层的生理功能,指导复杂疑难以及无残余听力患者人工耳蜗植入,并初步预估患者术后听觉言语康复情况。
研究对象
自2009年10月至2012年3月,我们对北京协和医院耳蜗中心进行人工耳蜗手术并开机的约300余例患者,在手术中植入人工耳蜗装置前进行电刺激听觉诱发电位检测。其中,对2010年2月到2011年2月在我院接受cochlear公司Nucleus24R多通道人工耳蜗植入手术的患者进行本课题研究。选择术前客观听力检查(包括DPOAE,ABR,ASSR以及有助测听)显示无残余听力患者共26例做为实验组,男8例,女18例；年龄为11个月-43岁,中位年龄24个月；语前聋20例,语后聋6例；术前影像学检查11名患者耳蜗形态发育正常,4名患者双侧前庭导水管扩大,5名患者双侧耳蜗Mondini畸形,3例内听道狭窄,3例common cavity畸形。同时,根据年龄、性别、耳聋时间、植入耳及耳蜗发育形态配对筛选有残余听力及语言基础的26例患者做为对照组。所有患者术前均行耳蜗水成像MRI检查,可见听神经及耳蜗腔隙存在,其中除1例内听道狭窄患者未行人工耳蜗植入,余均为单侧植入(耳蜗结构正常者植入弯电极CA,共同腔畸形者植入直电极ST)。
第一部分人工耳蜗植入前ECAP检测方法的建立及初步应用
1方法：全麻后常规人工耳蜗手术进路,行标准耳蜗鼓阶开窗(共同腔患者采用前庭开窗),将自制多通道试验电极置入鼓阶,电极连接自制电刺激发生器及Cochlear公司体外言语处理器,后者连接电脑。采用Custom SoundTM EP2.0软件,选取第3号电极,调整优化刺激参数进行神经反应遥测(neural response telemetry,NRT)初步了解听神经功能状态；默认电刺激的波宽为37gm,默认的刺激强度从200CL开始,刺激强度以5Current Level (CL)为阶梯递减或递增至反应阈值给予电刺激脉冲,同时自动记录ECAP波形和阈值。植入正式人工耳蜗后行常规NRT检测,记录ECAP波形和闽值；术后1个月患者开机后采集T、C值,计算试验电极、正式电极ECAP引出率；测算试验电极诱发ECAP波形阈值及N1波潜伏期,并与正式电极ECAP测试比较；两种电极测试所得阈值和开机C值进行相关性研究,进行数据统计分析。
2结果：实验组患者试验电极ECAP引出率65.38%,正式电极ECAP引出率69.23%,经统计学检验没有显著差异(P=0.768>0.05),考虑由于耳蜗畸形患者较多导致ECAP引出率低；可以引出波形的患者ECAP阈值和开机后C值(178.36±22.14)CL有明显相关性(r=0.746),但引出率较低。实验组两种电极ECAP平均阈值分别为(172.11±16.78)CL和(171.05±17.84)CL,经统计学检验没有显著差异(P>0.05)；实验组两种电极测试N1波潜伏期分别为：(0.292±0.063)ms和(0.287±0.060)ms,经统计学检验没有显著差异(t=1.694,p=0.107>0.05)；实验组两种电极ECAP阈值及开机C值数据经单因素方差分析F=0.173,p=0.842,统计学无显著性差异。说明多通道试验电极符合电生理测试需要,但敏感性不强,特异性强。另外,实验组和对照组之间ECAP引出率没有显著差别,说明目前常规应用的客观听力学检查方法,不能发现极重度听力损失患者的残存听力,将他们都诊断为无听力有失偏颇,可能由于患者的残余听神经阈值较高,常规声刺激无法获得听性反应,因此不应将他们全部都排除在人工耳蜗植入适应症之外。但是,两组的ECAP阈值分别为：(172.11±16.78)CL和(158.95±15.42)CL,经统计学检验P<0.05有显著差异,说明实验组患者螺旋神经节空间分布及功能较对照组差,术前检测可以初步评测初级听觉中枢的生理功能。
第二部分：人工耳蜗植入前EABR检测及临床应用
1方法：两组患者置体表记录电极,连接诱发电位仪,耳蜗内自制多通道试验电极连接自制电刺激发生器,同步触发诱发电位仪,选择电刺激脑干听觉诱发电位EABR模式,参考程靖宁方法,记录EABR波形、阂值,计算引出率、V波I/O曲线斜率。术后1个月患者开机后采集T、C值。同一组内对比EABR、 ECAP引出率,对EABR阈值与ECAP闽值,EABR阈值与C值进行相关性分析；两组间比较EABR阈值,V波I/O曲线斜率,比较正常结构耳蜗和畸形耳蜗V波I/O斜率；统计学分析。
2结果：两组52例患者除3例(张xx,扈xx,程xx)实验组的内听道狭窄患者未引出EABR波形外,其余49例均引出有意义EABR波形(以V波为参照)。未引出波形的3例内听道狭窄患者中,有2例植入耳蜗,但开机1年均无听性反应。1例未植入耳蜗。实验组引出率88.46%,对照组引出率100%,高于ECAP引出率,并且与术后开机听性反应一致,说明EABR可以作为筛选耳蜗适应症的工具。实验组EABR阈值(163.82±16.21CL)高于对照组(148.41±15.38CL)；V波I/O曲线斜率耳蜗正常患者好于畸形者,对照组(0.041364±0.013623)好于实验组(0.035227±0.013918),统计学分析两组有显著性差异；同组患者EABR阈值与开机C值相关(r=0.915),可以协助术后预估C值,辅助调机。
第三部分：人工耳蜗植入前EMLR检测方法的建立及初步应用
1方法：正常对照组(声刺激)：选择6例正常听力健康受试者,行短声刺激听觉中潜伏期诱发电位(auditory middle latency response, AMLR)测试,作为EMLR波形和潜伏期的声刺激对照。电刺激实验组和电刺激对照组：术中设备连接与EABR测试相同,选择EABR模式,采用单极刺激,双相Alternation电流方波,脉宽50-100μs,刺激频率11Hz,强度由ECAP阈值上20CL起,以5CL为阶梯递减或递增,听觉诱发电位仪记录EMLR波形。计算引出率、各波波幅、潜伏期、阈值并进行分级。术后1个月患者开机后采集T,C值；开机12月后进行听觉行为分级标准(categories of auditory performance,CAP)评分。同一组内对ECAP阈值、EABR阈值、EMLR阈值和开机T、C值进行相关性研究；对EMLR分级与开机12月CAP评分进行相关性分析。统计学分析两组患者EMLR阈值差异、术后CAP评分差异。
2结果：6例听力正常受试者均可记录到AMLR波形,平均反应阈(12.5±8.6)dB nHL,接近行为测听阈值(10.8±7.3)dBHL。参考AMLR方法首次建立术前EMLR测试,EMLR与AMLR波形相似。两组52例患者除3例实验组内听道狭窄患者未引出EMLR波形外,其余49例均引出有意义EMLR波形(以Pa波为参照),实验组EMLR检出率和EABR检出率一致(88.46%),高于ECAP检出率。实验组患者EMLR平均闽值(151.32±14.31)CL低于ECAP平均阈值(172.11±16.78)CL,差异有统计学意义(P<0.01),EMLR阈值和开机T、C值(相关系数分别r=0.905,r=0.862)有明显相关性,数值上更接近于T值。根据EABR分级对EMLR波形分级,共分为4级,开机12月CAP评分(6.52±0.98)和术中EMLR分级(3.5±0.80)相关性高(spearsman:0.673);实验组EMLR阈值(151.32±14.31)CL高于对照组(140.68±12.84)CL,统计学分析两组有显著性差异；两组之间EMLR分级(U检验：P=0.588)、术后12月CAP评分(U检验：P=0.179)对比统计学上无显著性差异。说明EMLR可以评估史高级别听觉中枢生理功能,与听觉言语发育相关。
结论：
ECAP可以了解电极是否植入成功,电极工作是否正常,螺旋神经节功能是否满足电子耳蜗需要；EABR引出率高,可以反映听神经通路从螺旋神经节到脑干是否通畅；EMLR反映初级听觉皮层听觉中枢的生理功能,可以评估听觉通路完整性。
本研究达成以下几个目标：
1,首次成功建立了术中人工耳蜗植入前,记录3种不同潜伏期电刺激听觉诱发电位(ECAP,EABR,EMLR)的方法,系统评估双侧极重度感音神经性聋患者从毛细胞到听觉皮层整个听觉通路的电生理情况；
2,首次自主制备成功多通道试验电极和电刺激发生器；并首次整合电刺激系统和诱发电位记录系统,缩减记录时间及简化设备。
3,首次在术前建立ECAP检测方法,了解患者螺旋神经节的生理状况,协助无残余听力患者评估听力。
4,在人工耳蜗植入前,采用试验电极通过EABR Ⅴ波I/O曲线斜率等指标判断患者听神经及脑干生理状况；EABR引出率高,可以指导疑难病例人工耳蜗植入。
5,首次在术前建立EMLR检测方法,可以检测初级听觉皮层的生理功能,根据EMLR分级结果初步预估患者术后听觉言语康复能力,为将来的听觉脑干植入做好理论支持工作。
成功建立术中人工耳蜗植入前ECAP、 EABR、 EMLR测试,此项技术可以术前评估听觉通路,初步预测术后患者康复情况,为临床医生和家属提供信心；耳蜗畸形患者ECAP引出率低,但不可由此否认无残余听力,只是术后效果要差于正常耳蜗患者,EABR、 EMLR引出率较高,可以协助术前筛选耳蜗适应症；EMLR和听觉言语相关,可以协助评估术后康复效果。
Background and Purpose:
Cochlear implantation is an effective method of auditory rehabilitation for profoundly hearing-impaired individuals who do not receive adequate benefit from hearing aids, but is expensive. So, it has become the concern of doctors and patients to make the most rational use of limited medical resources. Preoperative objective hearing tests consist of DPOAE, ABR, ASSR and aid-audiometry test showed no residual hearing without language training in patients with preoperative hearing and speech score perceived ambient sound. Such patients'postoperative hearing maybe not good, which can easily generate the doctor-patient conflicts. The patient with "no residual hearing" may be a cochlear malformation or patient with very high hearing threshold, the conventional acoustic stimulation is not sufficient to cause auditory nerve responses leading to the preoperative hearing could not be determined, we can not explain the patient is not suitable for the cochlear implant. Electrical stimulation of the auditory evoked potentials such as ECAP, EABR and EMLR can reflect the auditory pathway physiological conditions. Preoperative electrical stimulation of the auditory evoked potential test in cochlear implant can learn about the patient's real residual hearing, for cochlear implants to escort.
The aim of the current study was to establish the method of preoperative electrical stimulation of the auditory evoked potential including ECAP, EABR and EMLR, to assess the cochlear implant patient's physiological function of auditory pathway from the cochlea to the auditory cortex, in order to guide the complex and difficult cochlear implant, especially patients with no residual hearing, preliminary estimates the patients' postoperative hearing and speech rehabilitation.
Objects:
There were26CI users in the study group (8males and18females), aged from11months to43years, the median age of24months. Cochlear implantation were completed during February2010to February2011in our hospital, the cochlear company Nucleus24R [CA or ST] multi-channel cochlear were implanted, All patients showed no residual hearing by objective hearing tests including DPOAE, ABR, ASSR and aid-audiometry test.2O cases of pre-lingual deafness,6cases of post-lingual deafness. Preoperative imaging studies of11patients with normal cochlear morphogenesis,4patients with bilateral vestibular aqueduct,5patients with bilateral cochlear Mondini malformation, internal auditory tract narrow in3cases,3cases of common cavity deformity. At the same time, we screened26patients with residual hearing and language-based as the control group. Pairing based on age, gender, hearing loss time, implanted ear and cochlear morphology. All patients under MRI examination of cochlear water imaging, visible to the auditory nerve and cochlear cavities exist, and are unilateral implantation except for1case with internal auditory tract narrow.
Part I:Establishment and preliminary application of the method of ECAP before cochlear implantation
Methods:After anesthesia, conventional cochlear implant surgery in cochlear tympani scala fenestration (common cavity in vestibular window), self-made multi-channel test electrode was inserted into the tympani scala, and connected to the homemade electrical stimulation generator and computer pre-installed Custom Sound TM the EP2.0software, The electrode No3were selected, change the stimulation parameters to the neural response telemetry (NRT), the neural response telemetry preliminary understanding of the state of the auditory nerve function; Electrical stimulation pulse was gived above the reaction threshold with stimulus intensity to5CL step decrement or increment, and the ECAP waveform and threshold were automatically recorded. After cochlear implantation, ECAP waveform and threshold were automatically recorded by business electrode. Calculating the positive rate of the test electrodes and the commercial electrode; estimating the test electrode-induced ECAP waveform threshold and the N1wave latency, and comparison with the ECAP waveform induced by commercial electrode; two electrode test income threshold and boot C values of the correlation study the two electrode-induced ECAP threshold and C values, conducted statistical analysis of data.
Results:The positive rate of ECAP leads to65.38%and69.23%from test electrode and commercial electrode in the same group,(considering more cochlear malformation patients in our study lead to the low rate); In study group, the ECAP average thresholds were (172.11±16.78) CL and (171.05±17.84) between two kinds of electrodes, the two surveys are not statistically significant difference (P>0.05); and C values after boot (178.36±22.14CL) significantly correlated(r=0.746), but rate was lower. The latency of N1wave through the two electrodes in the study group was as follows:0.292±0.063ms and0.287±0.060ms, it was not significantly different (t=1.694, p=0.107>0.05); the ECAP thresholds through two electrodes in study group and boot C value were statistically no significant difference (F=0.173, p=0.842), the multi-channel test electrode is suit for electrophysiological testing. In addition, the positive rates of ECAP lead to no significant differences between the study group and the control group, which indicated the objective examination about pre-operative residual hearing was not accurate. However, the ECAP thresholds in two groups were172.11±16.78CL and158.95±15.42CL, it was significantly different (P <0.05), indicating that the spatial ganglion distribution and physiological status in control group were better than study group. The ECAP can preliminary evaluated the physiological functions of the primary auditory center.
Part II:The EABR testing and clinical application before cochlear implantation
Methods: The surface recording electrodes were placed on the two groups under complete aesthesia, connected to the evoked potential device. The self-made multi-channel test electrode was inserted into the tympani scala and connected to the homemade electrical stimulation generator and computer pre-installed Custom Sound TM the EP2.0software, with language processor connected to the triggering port of the auditory evoked potential device. Selecting the EABR mode (reference Cheng Jingning' methods), recording the EABR waveform, threshold, calculating the positive rate and I/O curve slope of V wave. One month after operation, collecting T, C value; Contrasting EABR, ECAP positive rate in the same group; and correlation analysing EABR threshold and ECAP threshold, EABR thresholds and C values. Contrasting EABR threshold, I/O slope of V wave between the two groups, compare the I/O slope of V wave between patients with normal cochlea and deformity cochlear; statistical analysis data.
Results:Two groups of52patients,49cases meaningful EABR waveform were elicited (wave V as a reference),3cases of stenosis of the internal auditory canal cochlear implant was not elicited waveform in study group, and all patients were implanted except one cases of stenosis of the internal auditory canal. The positive rate in study group leads to88.46%, control group leads to100%, higher than that of ECAP. The outcome of EABR was in line with the post-operative boot auditory reaction, indicating that the EABR can be used as a tool for screening cochlear indications. The EABR thresholds (163.82±16.21CL) in study group were higher than that in the control group (148.41±15.38CL); The I/O curve slope of V wave of normal cochlea patients were better than that with deformity cochlear, and the control group (0.041364±0.013623) is better than study group (0.035227±0.013918), there were statistical differences between the two groups (P<0.05). The EABR thresholds and boot C values were significantly correlated (r=0.915) in the same group, can help to estimate the value of C.
Part III:Establishment the method of EMLR in cochlear implantation
Methods:First,6cases of normal hearing healthy subjects were selected to record short-sound evoked auditory middle-latency response (AMLR), as the control of morphology and latency of MLR by electrical stimulation. Before operation, devices were connected according to the EABR test. Selected the EABR mode, changed the stimulation parameters to EMLR mode, with monopolar biphasic electrical stimulation pulses, Alternation stimulation,50～100μs pulse width, stimulation frequency of11Hz, the stimulation intensity decreased or increased from20CL above the strength of the NRT threshold to the reaction threshold with a step of5CL, recording EMLR waveform by auditory evoked potential device. The wave amplitude, latency, threshold, positive rate were calculated and classificated according to the EABR classification.1month after operation, we collected T, C value, assessed patients'hearing and speech rehabilitation through CAP scores tool12month later; Correlation analysed ECAP thresholds, EABR thresholds, EMLR thresholds and T, C value within the same group. Correlation analysed the EMLR classification and the CAP scores; Contrasted EMLR thresholds, postoperative CAP scores between two groups.
Results:The typical AMLR waveforms can be recorded by the composition of five waves in the6cases of normal hearing healthy subjects, with an average response threshold of (12.5±8.6) dB nHL, close to the behavioral audiometric threshold (10.8±7.3) dB HL; According to the AMLR test, we established the method of pre-operative EMLR for the first time, the EMLR waveform were similar to the AMLR. Two groups of52patients,49cases meaningful EMLR waveform were elicited (wave Pa as a reference),3cases of stenosis of the internal auditory canal cochlear implant was not elicited waveform in study group; the positive rate of EMLR in study group was88.46%, same to EABR, higher than ECAP. In study group, the EMLR average threshold (151.32±14.31CL) is lower than the the ECAP average threshold (172.11±16.78CL)(P<0.01), EMLR thresholds and boot T,C values (correlation co-efficient respectively: r=0.905, r=0.862) have a significant correlation values, closer to the T value.12months after booting, the EMLR waveform was divided into4level according to the EABR classfication, and compared with the boot CAP scores, the average boot CAP scores (6.52±0.98) and the intra-operative EMLR levels (3.5±0.80) were significantly correlated (spearsman:0.673). In addition, the EMLR thresholds (151.32±14.31CL) in study group were higher than the control (140.68±12.84CL)(P<0.01); we compared the EMLR levels (U test:P=0.588) and CAP scores (U test:P=0.179) between the two groups, there were no statistically significant difference. Indicating that the EMLR could assess physiological status of higher level auditory center was correlated with hearing and speech development.
Conclusions:
ECAP can evaluate if the implanted electrode is working properly, and if the spiral ganglion meet the need for cochlear implant; the positive rate of EABR leads to high, can reflect the integrity of auditory pathways from the spiral ganglion to the brain stem; EMLR reflect the physiological status of primary auditory cortex, assist in evaluating the integrity of the auditory pathway.
Our studies have achieved the following objectives:
1. Successfully established the methods of intra-operative electrical stimulation auditory evoked potentials (ECAP, EABR, EMLR) in cochlear implantation for the first time.Systematically assess the physiological state of auditory pathway from the hair cells to the auditory cortex in bilateral severe sensori neural deafness patients;
2. Successfully invented a multi-channel test electrodes and electrical stimulus generator for the first time. Successfully integrated the electrical stimulation system and evoked potential recording system, to simplify devices and reduce the recording time.
3. Successfully established the methods of pre-operative ECAP for the first time, to evaluate the physiological status of the spiral ganglion in patients with no residual hearing.
4. Detected the EABR and calculated the Ⅴ-wave I/O curve slope in patients before the cochlear implant through the test electrode, to judge the physiological conditions from auditory nerve to brainstem; the positive rate is high, can guide cochlear implantation in difficult cases.
5. Successfully established the pre-operative EMLR detection method for the first time, can detect the physiological status of the primary auditory cortex; estimate the preliminary post-operative hearing and speech rehabilitation capacity according to the theEMLR classification results; theoretically support the the auditory brainstem implant in the future.
We successfully established the method of intra-operative ECAP, EABR, EMLR monitoring in cochlear implantation. This technique can intra-operative evaluate the auditory pathway, preliminary predict the speech perception outcome after cochlear implantation; provide confidence betwween clinicians and patients. The positive rate of ECAP in patients with cochlear malformation lead to low, but not be deemed to no residual hearing, only the postoperative outcome is worse than patients with normal cochlea; The positive rate of EABR EMLR lead to higher rate, can assist in pre-operative screening the cochlear indications; EMLR correlate with the speech perception outcome after cochlear implantation, can assist in evaluating the postoperative rehabilitation effect.
人工耳蜗是一项运用最成功的生物医学工程技术,挽救了众多的失聪患者。但是术后效果依不同患者差异较大,且装置价格昂贵,因此如何保证术后效果及合理利用有限医疗资源已成为医生和患者家属关心的问题。术前客观听力检查,如畸变产物耳声发射(distortion product otoacoustic emission,DPOAE),听性脑干反应(Auditory brainstem responses,ABR),多频稳态诱发电位(Audio Steady-State Response, ASSR)以及有助测听显示无残余听力的未经过语训的患者,术有听觉言语评估无法感知周围环境声音。此类患者手术风险比较大,一旦出现术后效果欠佳,极易产生医患矛盾。此外,一些双侧极重度聋患者听力损失比较重,有可能是患者听阈过高,常规声刺激不足以诱发出可测出的术前听神经反应,但不能作为患者不适合人工耳蜗植入的证据。电刺激听觉诱发电位如电刺激听神经复合动作电位(Electrically evoked auditory nerve compound action potentials) ECAP),电刺激脑干诱发电位(Electrical Auditory Brainstem Response,EABR),电刺激中潜伏期听觉诱发电位(electrical evoked middle latency response, EMLR)通过电刺激听神经可以获得听神经反应,反映听觉通路的生理状况。如果在人工耳蜗植入前进行电刺激听觉诱发电位测试,则可以直观了解患者真实残余听力,为人工耳蜗植入保驾护航。
本研究致力于建立术前电刺激听觉诱发电位ECAP, EABR, EMLR检测的方法,评估人工耳蜗植入患者听觉通路从耳蜗至听觉皮层的生理功能,指导复杂疑难以及无残余听力患者人工耳蜗植入,并初步预估患者术后听觉言语康复情况。
研究对象
自2009年10月至2012年3月,我们对北京协和医院耳蜗中心进行人工耳蜗手术并开机的约300余例患者,在手术中植入人工耳蜗装置前进行电刺激听觉诱发电位检测。其中,对2010年2月到2011年2月在我院接受cochlear公司Nucleus24R多通道人工耳蜗植入手术的患者进行本课题研究。选择术前客观听力检查(包括DPOAE,ABR,ASSR以及有助测听)显示无残余听力患者共26例做为实验组,男8例,女18例；年龄为11个月-43岁,中位年龄24个月；语前聋20例,语后聋6例；术前影像学检查11名患者耳蜗形态发育正常,4名患者双侧前庭导水管扩大,5名患者双侧耳蜗Mondini畸形,3例内听道狭窄,3例common cavity畸形。同时,根据年龄、性别、耳聋时间、植入耳及耳蜗发育形态配对筛选有残余听力及语言基础的26例患者做为对照组。所有患者术前均行耳蜗水成像MRI检查,可见听神经及耳蜗腔隙存在,其中除1例内听道狭窄患者未行人工耳蜗植入,余均为单侧植入(耳蜗结构正常者植入弯电极CA,共同腔畸形者植入直电极ST)。
第一部分人工耳蜗植入前ECAP检测方法的建立及初步应用
1方法：全麻后常规人工耳蜗手术进路,行标准耳蜗鼓阶开窗(共同腔患者采用前庭开窗),将自制多通道试验电极置入鼓阶,电极连接自制电刺激发生器及Cochlear公司体外言语处理器,后者连接电脑。采用Custom SoundTM EP2.0软件,选取第3号电极,调整优化刺激参数进行神经反应遥测(neural response telemetry,NRT)初步了解听神经功能状态；默认电刺激的波宽为37gm,默认的刺激强度从200CL开始,刺激强度以5Current Level (CL)为阶梯递减或递增至反应阈值给予电刺激脉冲,同时自动记录ECAP波形和阈值。植入正式人工耳蜗后行常规NRT检测,记录ECAP波形和闽值；术后1个月患者开机后采集T、C值,计算试验电极、正式电极ECAP引出率；测算试验电极诱发ECAP波形阈值及N1波潜伏期,并与正式电极ECAP测试比较；两种电极测试所得阈值和开机C值进行相关性研究,进行数据统计分析。
2结果：实验组患者试验电极ECAP引出率65.38%,正式电极ECAP引出率69.23%,经统计学检验没有显著差异(P=0.768>0.05),考虑由于耳蜗畸形患者较多导致ECAP引出率低；可以引出波形的患者ECAP阈值和开机后C值(178.36±22.14)CL有明显相关性(r=0.746),但引出率较低。实验组两种电极ECAP平均阈值分别为(172.11±16.78)CL和(171.05±17.84)CL,经统计学检验没有显著差异(P>0.05)；实验组两种电极测试N1波潜伏期分别为：(0.292±0.063)ms和(0.287±0.060)ms,经统计学检验没有显著差异(t=1.694,p=0.107>0.05)；实验组两种电极ECAP阈值及开机C值数据经单因素方差分析F=0.173,p=0.842,统计学无显著性差异。说明多通道试验电极符合电生理测试需要,但敏感性不强,特异性强。另外,实验组和对照组之间ECAP引出率没有显著差别,说明目前常规应用的客观听力学检查方法,不能发现极重度听力损失患者的残存听力,将他们都诊断为无听力有失偏颇,可能由于患者的残余听神经阈值较高,常规声刺激无法获得听性反应,因此不应将他们全部都排除在人工耳蜗植入适应症之外。但是,两组的ECAP阈值分别为：(172.11±16.78)CL和(158.95±15.42)CL,经统计学检验P<0.05有显著差异,说明实验组患者螺旋神经节空间分布及功能较对照组差,术前检测可以初步评测初级听觉中枢的生理功能。
第二部分：人工耳蜗植入前EABR检测及临床应用
1方法：两组患者置体表记录电极,连接诱发电位仪,耳蜗内自制多通道试验电极连接自制电刺激发生器,同步触发诱发电位仪,选择电刺激脑干听觉诱发电位EABR模式,参考程靖宁方法,记录EABR波形、阂值,计算引出率、V波I/O曲线斜率。术后1个月患者开机后采集T、C值。同一组内对比EABR、 ECAP引出率,对EABR阈值与ECAP闽值,EABR阈值与C值进行相关性分析；两组间比较EABR阈值,V波I/O曲线斜率,比较正常结构耳蜗和畸形耳蜗V波I/O斜率；统计学分析。
2结果：两组52例患者除3例(张xx,扈xx,程xx)实验组的内听道狭窄患者未引出EABR波形外,其余49例均引出有意义EABR波形(以V波为参照)。未引出波形的3例内听道狭窄患者中,有2例植入耳蜗,但开机1年均无听性反应。1例未植入耳蜗。实验组引出率88.46%,对照组引出率100%,高于ECAP引出率,并且与术后开机听性反应一致,说明EABR可以作为筛选耳蜗适应症的工具。实验组EABR阈值(163.82±16.21CL)高于对照组(148.41±15.38CL)；V波I/O曲线斜率耳蜗正常患者好于畸形者,对照组(0.041364±0.013623)好于实验组(0.035227±0.013918),统计学分析两组有显著性差异；同组患者EABR阈值与开机C值相关(r=0.915),可以协助术后预估C值,辅助调机。
第三部分：人工耳蜗植入前EMLR检测方法的建立及初步应用
1方法：正常对照组(声刺激)：选择6例正常听力健康受试者,行短声刺激听觉中潜伏期诱发电位(auditory middle latency response, AMLR)测试,作为EMLR波形和潜伏期的声刺激对照。电刺激实验组和电刺激对照组：术中设备连接与EABR测试相同,选择EABR模式,采用单极刺激,双相Alternation电流方波,脉宽50-100μs,刺激频率11Hz,强度由ECAP阈值上20CL起,以5CL为阶梯递减或递增,听觉诱发电位仪记录EMLR波形。计算引出率、各波波幅、潜伏期、阈值并进行分级。术后1个月患者开机后采集T,C值；开机12月后进行听觉行为分级标准(categories of auditory performance,CAP)评分。同一组内对ECAP阈值、EABR阈值、EMLR阈值和开机T、C值进行相关性研究；对EMLR分级与开机12月CAP评分进行相关性分析。统计学分析两组患者EMLR阈值差异、术后CAP评分差异。
2结果：6例听力正常受试者均可记录到AMLR波形,平均反应阈(12.5±8.6)dB nHL,接近行为测听阈值(10.8±7.3)dBHL。参考AMLR方法首次建立术前EMLR测试,EMLR与AMLR波形相似。两组52例患者除3例实验组内听道狭窄患者未引出EMLR波形外,其余49例均引出有意义EMLR波形(以Pa波为参照),实验组EMLR检出率和EABR检出率一致(88.46%),高于ECAP检出率。实验组患者EMLR平均闽值(151.32±14.31)CL低于ECAP平均阈值(172.11±16.78)CL,差异有统计学意义(P<0.01),EMLR阈值和开机T、C值(相关系数分别r=0.905,r=0.862)有明显相关性,数值上更接近于T值。根据EABR分级对EMLR波形分级,共分为4级,开机12月CAP评分(6.52±0.98)和术中EMLR分级(3.5±0.80)相关性高(spearsman:0.673);实验组EMLR阈值(151.32±14.31)CL高于对照组(140.68±12.84)CL,统计学分析两组有显著性差异；两组之间EMLR分级(U检验：P=0.588)、术后12月CAP评分(U检验：P=0.179)对比统计学上无显著性差异。说明EMLR可以评估史高级别听觉中枢生理功能,与听觉言语发育相关。
结论：
ECAP可以了解电极是否植入成功,电极工作是否正常,螺旋神经节功能是否满足电子耳蜗需要；EABR引出率高,可以反映听神经通路从螺旋神经节到脑干是否通畅；EMLR反映初级听觉皮层听觉中枢的生理功能,可以评估听觉通路完整性。
本研究达成以下几个目标：
1,首次成功建立了术中人工耳蜗植入前,记录3种不同潜伏期电刺激听觉诱发电位(ECAP,EABR,EMLR)的方法,系统评估双侧极重度感音神经性聋患者从毛细胞到听觉皮层整个听觉通路的电生理情况；
2,首次自主制备成功多通道试验电极和电刺激发生器；并首次整合电刺激系统和诱发电位记录系统,缩减记录时间及简化设备。
3,首次在术前建立ECAP检测方法,了解患者螺旋神经节的生理状况,协助无残余听力患者评估听力。
4,在人工耳蜗植入前,采用试验电极通过EABR Ⅴ波I/O曲线斜率等指标判断患者听神经及脑干生理状况；EABR引出率高,可以指导疑难病例人工耳蜗植入。
5,首次在术前建立EMLR检测方法,可以检测初级听觉皮层的生理功能,根据EMLR分级结果初步预估患者术后听觉言语康复能力,为将来的听觉脑干植入做好理论支持工作。
成功建立术中人工耳蜗植入前ECAP、 EABR、 EMLR测试,此项技术可以术前评估听觉通路,初步预测术后患者康复情况,为临床医生和家属提供信心；耳蜗畸形患者ECAP引出率低,但不可由此否认无残余听力,只是术后效果要差于正常耳蜗患者,EABR、 EMLR引出率较高,可以协助术前筛选耳蜗适应症；EMLR和听觉言语相关,可以协助评估术后康复效果。
Background and Purpose:
Cochlear implantation is an effective method of auditory rehabilitation for profoundly hearing-impaired individuals who do not receive adequate benefit from hearing aids, but is expensive. So, it has become the concern of doctors and patients to make the most rational use of limited medical resources. Preoperative objective hearing tests consist of DPOAE, ABR, ASSR and aid-audiometry test showed no residual hearing without language training in patients with preoperative hearing and speech score perceived ambient sound. Such patients'postoperative hearing maybe not good, which can easily generate the doctor-patient conflicts. The patient with "no residual hearing" may be a cochlear malformation or patient with very high hearing threshold, the conventional acoustic stimulation is not sufficient to cause auditory nerve responses leading to the preoperative hearing could not be determined, we can not explain the patient is not suitable for the cochlear implant. Electrical stimulation of the auditory evoked potentials such as ECAP, EABR and EMLR can reflect the auditory pathway physiological conditions. Preoperative electrical stimulation of the auditory evoked potential test in cochlear implant can learn about the patient's real residual hearing, for cochlear implants to escort.
The aim of the current study was to establish the method of preoperative electrical stimulation of the auditory evoked potential including ECAP, EABR and EMLR, to assess the cochlear implant patient's physiological function of auditory pathway from the cochlea to the auditory cortex, in order to guide the complex and difficult cochlear implant, especially patients with no residual hearing, preliminary estimates the patients' postoperative hearing and speech rehabilitation.
Objects:
There were26CI users in the study group (8males and18females), aged from11months to43years, the median age of24months. Cochlear implantation were completed during February2010to February2011in our hospital, the cochlear company Nucleus24R [CA or ST] multi-channel cochlear were implanted, All patients showed no residual hearing by objective hearing tests including DPOAE, ABR, ASSR and aid-audiometry test.2O cases of pre-lingual deafness,6cases of post-lingual deafness. Preoperative imaging studies of11patients with normal cochlear morphogenesis,4patients with bilateral vestibular aqueduct,5patients with bilateral cochlear Mondini malformation, internal auditory tract narrow in3cases,3cases of common cavity deformity. At the same time, we screened26patients with residual hearing and language-based as the control group. Pairing based on age, gender, hearing loss time, implanted ear and cochlear morphology. All patients under MRI examination of cochlear water imaging, visible to the auditory nerve and cochlear cavities exist, and are unilateral implantation except for1case with internal auditory tract narrow.
Part I:Establishment and preliminary application of the method of ECAP before cochlear implantation
Methods:After anesthesia, conventional cochlear implant surgery in cochlear tympani scala fenestration (common cavity in vestibular window), self-made multi-channel test electrode was inserted into the tympani scala, and connected to the homemade electrical stimulation generator and computer pre-installed Custom Sound TM the EP2.0software, The electrode No3were selected, change the stimulation parameters to the neural response telemetry (NRT), the neural response telemetry preliminary understanding of the state of the auditory nerve function; Electrical stimulation pulse was gived above the reaction threshold with stimulus intensity to5CL step decrement or increment, and the ECAP waveform and threshold were automatically recorded. After cochlear implantation, ECAP waveform and threshold were automatically recorded by business electrode. Calculating the positive rate of the test electrodes and the commercial electrode; estimating the test electrode-induced ECAP waveform threshold and the N1wave latency, and comparison with the ECAP waveform induced by commercial electrode; two electrode test income threshold and boot C values of the correlation study the two electrode-induced ECAP threshold and C values, conducted statistical analysis of data.
Results:The positive rate of ECAP leads to65.38%and69.23%from test electrode and commercial electrode in the same group,(considering more cochlear malformation patients in our study lead to the low rate); In study group, the ECAP average thresholds were (172.11±16.78) CL and (171.05±17.84) between two kinds of electrodes, the two surveys are not statistically significant difference (P>0.05); and C values after boot (178.36±22.14CL) significantly correlated(r=0.746), but rate was lower. The latency of N1wave through the two electrodes in the study group was as follows:0.292±0.063ms and0.287±0.060ms, it was not significantly different (t=1.694, p=0.107>0.05); the ECAP thresholds through two electrodes in study group and boot C value were statistically no significant difference (F=0.173, p=0.842), the multi-channel test electrode is suit for electrophysiological testing. In addition, the positive rates of ECAP lead to no significant differences between the study group and the control group, which indicated the objective examination about pre-operative residual hearing was not accurate. However, the ECAP thresholds in two groups were172.11±16.78CL and158.95±15.42CL, it was significantly different (P <0.05), indicating that the spatial ganglion distribution and physiological status in control group were better than study group. The ECAP can preliminary evaluated the physiological functions of the primary auditory center.
Part II:The EABR testing and clinical application before cochlear implantation
Methods: The surface recording electrodes were placed on the two groups under complete aesthesia, connected to the evoked potential device. The self-made multi-channel test electrode was inserted into the tympani scala and connected to the homemade electrical stimulation generator and computer pre-installed Custom Sound TM the EP2.0software, with language processor connected to the triggering port of the auditory evoked potential device. Selecting the EABR mode (reference Cheng Jingning' methods), recording the EABR waveform, threshold, calculating the positive rate and I/O curve slope of V wave. One month after operation, collecting T, C value; Contrasting EABR, ECAP positive rate in the same group; and correlation analysing EABR threshold and ECAP threshold, EABR thresholds and C values. Contrasting EABR threshold, I/O slope of V wave between the two groups, compare the I/O slope of V wave between patients with normal cochlea and deformity cochlear; statistical analysis data.
Results:Two groups of52patients,49cases meaningful EABR waveform were elicited (wave V as a reference),3cases of stenosis of the internal auditory canal cochlear implant was not elicited waveform in study group, and all patients were implanted except one cases of stenosis of the internal auditory canal. The positive rate in study group leads to88.46%, control group leads to100%, higher than that of ECAP. The outcome of EABR was in line with the post-operative boot auditory reaction, indicating that the EABR can be used as a tool for screening cochlear indications. The EABR thresholds (163.82±16.21CL) in study group were higher than that in the control group (148.41±15.38CL); The I/O curve slope of V wave of normal cochlea patients were better than that with deformity cochlear, and the control group (0.041364±0.013623) is better than study group (0.035227±0.013918), there were statistical differences between the two groups (P<0.05). The EABR thresholds and boot C values were significantly correlated (r=0.915) in the same group, can help to estimate the value of C.
Part III:Establishment the method of EMLR in cochlear implantation
Methods:First,6cases of normal hearing healthy subjects were selected to record short-sound evoked auditory middle-latency response (AMLR), as the control of morphology and latency of MLR by electrical stimulation. Before operation, devices were connected according to the EABR test. Selected the EABR mode, changed the stimulation parameters to EMLR mode, with monopolar biphasic electrical stimulation pulses, Alternation stimulation,50～100μs pulse width, stimulation frequency of11Hz, the stimulation intensity decreased or increased from20CL above the strength of the NRT threshold to the reaction threshold with a step of5CL, recording EMLR waveform by auditory evoked potential device. The wave amplitude, latency, threshold, positive rate were calculated and classificated according to the EABR classification.1month after operation, we collected T, C value, assessed patients'hearing and speech rehabilitation through CAP scores tool12month later; Correlation analysed ECAP thresholds, EABR thresholds, EMLR thresholds and T, C value within the same group. Correlation analysed the EMLR classification and the CAP scores; Contrasted EMLR thresholds, postoperative CAP scores between two groups.
Results:The typical AMLR waveforms can be recorded by the composition of five waves in the6cases of normal hearing healthy subjects, with an average response threshold of (12.5±8.6) dB nHL, close to the behavioral audiometric threshold (10.8±7.3) dB HL; According to the AMLR test, we established the method of pre-operative EMLR for the first time, the EMLR waveform were similar to the AMLR. Two groups of52patients,49cases meaningful EMLR waveform were elicited (wave Pa as a reference),3cases of stenosis of the internal auditory canal cochlear implant was not elicited waveform in study group; the positive rate of EMLR in study group was88.46%, same to EABR, higher than ECAP. In study group, the EMLR average threshold (151.32±14.31CL) is lower than the the ECAP average threshold (172.11±16.78CL)(P<0.01), EMLR thresholds and boot T,C values (correlation co-efficient respectively: r=0.905, r=0.862) have a significant correlation values, closer to the T value.12months after booting, the EMLR waveform was divided into4level according to the EABR classfication, and compared with the boot CAP scores, the average boot CAP scores (6.52±0.98) and the intra-operative EMLR levels (3.5±0.80) were significantly correlated (spearsman:0.673). In addition, the EMLR thresholds (151.32±14.31CL) in study group were higher than the control (140.68±12.84CL)(P<0.01); we compared the EMLR levels (U test:P=0.588) and CAP scores (U test:P=0.179) between the two groups, there were no statistically significant difference. Indicating that the EMLR could assess physiological status of higher level auditory center was correlated with hearing and speech development.
Conclusions:
ECAP can evaluate if the implanted electrode is working properly, and if the spiral ganglion meet the need for cochlear implant; the positive rate of EABR leads to high, can reflect the integrity of auditory pathways from the spiral ganglion to the brain stem; EMLR reflect the physiological status of primary auditory cortex, assist in evaluating the integrity of the auditory pathway.
Our studies have achieved the following objectives:
1. Successfully established the methods of intra-operative electrical stimulation auditory evoked potentials (ECAP, EABR, EMLR) in cochlear implantation for the first time.Systematically assess the physiological state of auditory pathway from the hair cells to the auditory cortex in bilateral severe sensori neural deafness patients;
2. Successfully invented a multi-channel test electrodes and electrical stimulus generator for the first time. Successfully integrated the electrical stimulation system and evoked potential recording system, to simplify devices and reduce the recording time.
3. Successfully established the methods of pre-operative ECAP for the first time, to evaluate the physiological status of the spiral ganglion in patients with no residual hearing.
4. Detected the EABR and calculated the Ⅴ-wave I/O curve slope in patients before the cochlear implant through the test electrode, to judge the physiological conditions from auditory nerve to brainstem; the positive rate is high, can guide cochlear implantation in difficult cases.
5. Successfully established the pre-operative EMLR detection method for the first time, can detect the physiological status of the primary auditory cortex; estimate the preliminary post-operative hearing and speech rehabilitation capacity according to the theEMLR classification results; theoretically support the the auditory brainstem implant in the future.
We successfully established the method of intra-operative ECAP, EABR, EMLR monitoring in cochlear implantation. This technique can intra-operative evaluate the auditory pathway, preliminary predict the speech perception outcome after cochlear implantation; provide confidence betwween clinicians and patients. The positive rate of ECAP in patients with cochlear malformation lead to low, but not be deemed to no residual hearing, only the postoperative outcome is worse than patients with normal cochlea; The positive rate of EABR EMLR lead to higher rate, can assist in pre-operative screening the cochlear indications; EMLR correlate with the speech perception outcome after cochlear implantation, can assist in evaluating the postoperative rehabilitation effect.
引文
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1. Ozdamar O, Kraus N . Auditory middle-latency responses in humans. Audiology, 1983,22:34-49.
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